PROFESSIONALHOSPITALNEWS IRELAND Ireland’s Dedicated Hospital Professional Publication HPN May HOSPITALPROFESSIONALNEWS.IEIssue202296 This Publication is for Healthcare Professionals Only When it comes to your patient’s psoriasis treatment goals What means everything to the patient? The potential for nothing left on their skin.1,2 * Nothing on the skin: Defined as 75% achievement of PASI90 at Week 16 and ≥50% achievement of PASI 100 at Week 52 in UltIMMa-1 and UltIMMa-2.1 High skin clearance matters to patients: Patients who achieve and maintain high levels of skin clearance (PASI 90-99 or PASI 100) have significantly better HRQoL than those with lower levels of skin clearance (PASI 75-89).2 Sustaining high skin clearance or complete skin clearance is associated with incremental and durable benefits in HRQoL and mental health of psoriasis patients.2 PRESCRIBING INFORMATION (PI). SKYRIZI®▼ (risankizumab) 75 mg solution for injection in prefilled syringe; Skyrizi 150 mg solution for injection in pre-filled pen and Skyrizi 150 mg solution for injection in prefilled syringe. Refer to Summary of Product Characteristics (SmPC) for full information before prescribing. PRESENTATION: Skyrizi 150 mg solution for injection in pre-filled pen/syringe: each prefilled pen/syringe contains 150 mg risankizumab in 1 mL solution. Skyrizi 75 mg solution for injection in pre-filled syringe: each pre-filled syringe contains 75 mg risankizumab in 0.83 ml mL solution. INDICATION: Plaque Psoriasis: For treatment of moderate to severe plaque psoriasis in adults who are candidates for systemic therapy. Psoriatic Arthritis: alone or in combination with methotrexate (MTX), is indicated for the treatment of active psoriatic arthritis in adults who have had an inadequate response or who have been intolerant to one or more disease-modifying antirheumatic drugs (DMARDs). DOSAGE AND ADMINISTRATION: Intended for use under guidance and supervision of a physician experienced in diagnosis and treatment of psoriasis. Dosage: The recommended dose of Skyrizi is 150 mg by subcutaneous injection at weeks 0, 4, and every 12 weeks thereafter (either as two 75 mg pre-filled syringe injections or one 150 mg pre-filled pen or pre-filled syringe injection). Two 75mg pre-filled syringes should be injected for the full 150 mg dose. Consider discontinuation of treatment in patients showing no response after 16 weeks of treatment. Some patients with initial partial response may subsequently improve with continued treatment beyond 16 weeks. Special Populations: Elderly: No dose adjustment required. Renal or hepatic impairment: No dose adjustment required. Paediatric Population: No data available. Overweight patients: No dose adjustment required. CONTRAINDICATIONS: Hypersensitivity to any of the active substances or excipients. Clinically important active infections (e.g. active tuberculosis). SPECIAL WARNINGS AND PRECAUTIONS: See SmPC for full details. In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded. Skyrizi may increase the risk of infections. In patients with a chronic infection or history of recurrent infections, or known risk factors for infection, Skyrizi should be used with caution. Treatment with Skyrizi should not be initiated in patients with any clinically important active infection until the infection resolves or is adequately treated. Patients should be evaluated for tuberculosis infection prior to initiating treatment. Anti-TB therapy should be considered prior to initiating Skyrizi in patients with a past history of latent or active TB in whom an adequate course of treatment cannot be confirmed. Completion of all appropriate immunisations should be considered prior to initiating therapy. If a patient has received live vaccination (viral or bacterial), it is recommended to wait at least 4 weeks prior to starting treatment with Skyrizi. Patients treated with Skyrizi should not receive live vaccines during treatment and for at least 21 weeks after treatment. If a serious hypersensivity reaction occurs, administration of Skyrizi should be discontinued immediately and appropriate therapy initiated. Excipients with known effect (75 mg solution for injection only): Skyrizi contains 68.0 mg sorbitol and less than 1 mmol sodium (23 mg) per 150 mg dose. INTERACTIONS: The safety and efficacy of Skyrizi in combination with immunosuppressants, including biologics or phototherapy have not been evaluated. PREGNANCY AND LACTATION: Women of Childbearing potential: An effective method of contraception during treatment and for at least 21 weeks after treatment should be used. Pregnancy: Limited data available. It is preferable to avoid the use of Skyrizi during pregnancy as a precautionary measure. Lactation: It is not known whether Skyrizi is excreted in breast milk. Human IgGs are known to be excreted in breast milk during the first few days after birth, which decreases to low concentrations soon afterwards; consequently, a risk to the breast-fed infant cannot be excluded during this short period. A decision should be made whether to discontinue/abstain from Skyrizi therapy, taking into account the benefit of breastfeeding to the child and the benefit of Skyrizi therapy to the woman. Fertility: The effect of Skyrizi on human fertility has not been evaluated. ADVERSE REACTIONS: See SmPC for full details on adverse reactions. Very common adverse reactions (≥1/10): Upper respiratory infections. Common adverse reactions (≥1/100 to <1/10): Tinea infections, headache, pruritus, fatigue and injection site reactions. ▼ This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions via HPRA Pharmacovigilance; Website: www.hpra.ie. Suspected adverse events should also be reported to AbbVie Limited on 01-4287900. LEGAL CLASSIFICATION: POM (S1A). MARKETING AUTHORISATION NUMBERS/PRESENTATIONS: Skyrizi 75 mg solution for injection in pre-filled syringe (Pack of 2 pre-filled syringes): EU/1/19/1361/001; Skyrizi 150 mg solution for injection in pre-filled pen: EU/1/19/1361/002; Skyrizi 150 mg solution for injection in prefilled syringe: EU/1/19/1361/003. Not all presentations may be marketed. Further information is available from: AbbVie Ltd., 14 Riverwalk, Citywest Business Campus, Dublin 24, D24XN32. DATE OF REVISION: November 2021 PI/1361/004 HRQoL, Health-Related Quality of Life; PASI, Psoriasis Area Severity Index. REFERENCES: 1. Gordon KB, et al. Lancet 2018; 392: 650-661. 2. Ryan C et al. Poster presented at the 27th European Academy of Dermatology & Venerology (EADV) Congress 2018; September 12–16; Paris, France. Skyrizi® Summary of Product Characteristics, available on www.medicines.ie. Date of preparation: April 2022 | IE-RISN-220005 IN THIS SpondyloarthropathyandPrecisionCautionNEWS:ISSUE:NeededtoProtectHospitalsPage7REPORT:FocusingonMedicinePage12CONFERENCE:ESCAcuteCardiovascularCare2022Page14FEATURE:FamilialSyndromicNon-SyndromicAortopathyPage24CPD:SARS-CoV-2Infection/Cocid-19OutcomesPage31RHEUMATOLOGYFOCUS:WomenwithAxialPage35RHEUMATOLOGYFOCUS:EstablishingaFractureLiaisonServicePage54
Joining Excellence and Innovation
Hospitals have faced an especially challenging year. They have risen to the occasion with aplomb. That’s why we want this year’s Awards to be the biggest yet – not only in recognition of excellence, but as applause to the teams around Ireland who helped keep the country going during the pandemic pressures.
The Awards will represent a celebration of all hospital healthcare teams who were working tirelessly on the frontline, for their incredible efforts during the Covid-19 pandemic.
The HPAs are the most influential and respected networking event, lauding excellence, innovation and service development; judged by key influencers including renowned respected experts.
Entry forms will be available shortly. We look forward to welcoming you all to The O’Reilly Hall at University College Dublin on Saturday 8th September 2022 for what promises to be an unmissable night.
Hospital Professional Awards 2022 For further information contact Aoife Jackson at: aoife@ipn.ie or Kelly Jo Eastwood at: kelly-jo@ipn.ie 2022 Award Categories: GSK Excellence in Respiratory Initiative of the Year Award Grunenthal Advancing the Standard of Care in Pain Management Award Accord Innovation in Aseptic Compounding Award GSK ViiV Infectious Diseases Project of the Year Medisource Hospital Pharmacy Technician of the Year Novartis Neurology- Neurological Innovation Award Sanofi Hospital Specialist Award Galapagos Multidisciplinary Team Award MSD Excellence in Oncology Award Pharmasource Hospital Pharmacist of the Year Award Hospital Pharmacy Team of the Year Consultant-Led Team of the Year Young Hospital Pharmacist of the Year Excellence in Haematology Award Date: Saturday 8th October, 2022 Venue: The O’Reilly Hall, University College Dublin If it’s out there... we can source it for you For more information please contact: Free Phone 1800 440 440 I PharmaSource@uniphar.ie www.uniphar.ie 500m+ TREATED WORLDWIDE1 recommended for therapeutic and prophylactic dosage ranges. Low body weight increased risk of bleeding at prophylactic and treatment dose ranges. Obese higher risk for thromboembolism however there is no consensus for dose patients should be observed carefully. Heparins can suppress adrenal aldosterone leading to hyperkalaemia, particularly in patients such as those with chronic renal failure, pre-existing metabolic acidosis, taking medicinal to increase potassium; plasma potassium should be monitored regularly patients at risk. Fertility, Pregnancy and Lactation: Enoxaparin sodium should pregnancy only if the physician has established a clear need. Enoxaparin sodium during breastfeeding. Interactions: Not Recommended: Systemic salicylates, acid at anti-inflammatory doses, and NSAIDs including ketorolac. Other (e.g.
Further details to be confirmed in the next issue alteplase, reteplase, streptokinase, tenecteplase, urokinase) and Caution: Platelet aggregation inhibitors including acetylsalicylic acid used at dose (cardioprotection), clopidogrel, ticlopidine, and glycoprotein IIb/IIIa indicated in acute coronary syndrome due to the risk of bleeding. Dextran 40. glucocorticoids. Medicinal products increasing potassium levels. Adverse Reactions: Hepatic enzyme increases (mainly transaminases > 3 times the upper limit of haemorrhage,
The foundation for these Awards lies in our collaboration with leading pharmaceutical companies; without their investment and support, the event would not be possible.
thrombocytosis (platelet increase >400 G/L). Common: Haemorrhagic thrombocytopenia, allergic reaction, headache, urticaria, pruritus, erythema, injection pain / other reaction (such as oedema, haemorrhage, hypersensitivity, mass, pain, or reaction). Uncommon: Hepatocellular liver injury, bullous irritation, skin necrosis at injection site, intracranial haemorrhage, haemorrhage. Rare: Eosinophilia, cases of immuno-allergic thrombocytopenia (in some cases thrombosis was complicated by organ infarction or limb anaphylactic/anaphylactoid reactions including shock, spinal/neuraxial haematoma degrees of neurologic injuries including long-term or permanent paralysis, injury, alopecia, cutaneous vasculitis, skin necrosis, injection site nodules, following therapy > 3 months, hyperkalaemia. Please refer to the SPCs for full Pharmaceutical Precautions: Do not mix with other products. Do not store above freeze. Legal Category: POM. Marketing Authorisation (MA) Numbers: PA540/97/4; Clexane 4,000IU: PA540/97/5; Clexane 6,000 IU: PA540/97/6; PA540/97/7; Clexane 10,000 IU: PA540/97/1; Clexane Forte 12,000 IU: Clexane Forte 15,000 IU: PA540/97/2 MA Holder and further information is request from: Sanofi Ireland Ltd., 18 Riverwalk, Citywest Business Campus, contact IEmedinfo@sanofi.com Tel: 01 403 5600. Date of Preparation: June events should be reported. Reporting forms and information can be found at: www.hpra.ie; E-mail: medsafety@hpra.ie. events can also be reported to Sanofi Ireland Ltd. Tel: 01 403 5600. Alternatively, send via Email to IEPharmacovigilance@sanofi.com Sanofi Data on File for Clexane use. SAIE.ENO.18.05.0153c2018(10,000 IU (100mg)/1ml) and June 2018 (15,000 IU (150mg)/1ml) preparation: August 2018 10/08/2018 10:39 MEDISOURCE LOGO Navy Blue Colour (Text in logo) Pantone 5265c CMYK C77% M70% Y0% K40% Aqua Marine Colour (Symbol) Pantone 3115c
To mark what has been an incredibly tumultuous year, IPN Communications are thrilled to announce that the Hospital Professional Awards will once again take to the stage in 2022.
17 5014 PROFESSIONALHOSPITALNEWS IRELAND Ireland’s Dedicated Hospital Professional Publication HOSPITALPROFESSIONALNEWS.IE HospitalProfessionalNews@HospitalProNews
|
Contents EditorForeword
Hospital Professional News is a publication for Hospital Professionals and Professional educational bodies only.
| Ruth
|
| Dr
| Dr
CPD: SARS-CoV-2 Infection/ Cocid-19 Outcomes
I hope you enjoy the issue.
Joan reflected that, “The conclusion of the SIG’s work is very timely for EAHP’s advocacy activities linked to hazardous medicinal products. I hope that the findings of the SIG will help improve the handling of these products in Europe and will feed into the work of the European Commission focused on the development of a definition, the establishment of an indicative list of hazardous medicinal products and the creation of guidance material for the safe management of hazardous drugs products.”
| Leah
Rheumatology Focus: Systemic Lupus Erythematous P61
8
IPN Communications Ireland Ltd Clifton House, Lower Fitzwilliam Street, Dublin 2 (01) 669 0562
Maryanne Murphy-Lyons Rooney
ESC Acute CardioVascular Care 2022 P14
MANAGER/CPDACCOUNTLEAD
Dr Daire O’Leary Orla Killeen
5 HOSPITALPROFESSIONALNEWS.IE | HPN • MAY 2022 May Issue Issue 96
The Chair of the IMO NCHD Committee, Dr John Cannon, has written to all NCHDs urging participating at the forthcoming meeting where the IMO will outline the startling extent of unsafe working hours and the increasing disputes over agreed contract terms. The meeting was held virtually.
| Phil
All rights reserved by Hospital Professional News. All material published in Hospital Professional News is copyright and no part of this magazine may be reproduced, stored in a retrieval system of transmitted in any form without written permission. IPN Communications Ltd have taken every care in compiling the magazine to ensure that it is correct at the time of going to press, however the publishers assume no responsibility for any effects from omissions or errors.
| Professor
Professor Brendan Kelly Sinead Maguire
Dr Robert O’Connor Yvonne O’Meara
DIGITAL MARKETING & EDITORIAL EXECUTIVE Danielle danielle@hospitalprofessionalnews.ieNorton
Cannabis and Mental Illness P28
editorial@hospitalprofessionalnews.ie ACCOUNTS
Turn to page 12 for the full story.
Sector stability and patient access to medicines P15
| Dr
Dr Ahmed Al Badi Brian Healey Ursula Fearon Órla Tynan
Mr Saleem Jahangeer Niall Khan
New Director of Compliance Appointed at HPRA P8
The Congress had served as the backdrop for the launch of the results from the first SIG focusing on Hazardous Medicinal Products. The SIG was tasked with examining national strategies and requirements across Europe for the management of hazardous medicines, identifying best practices, promoting better sharing and implementation of these practices between countries and stimulating heightened awareness by governments and EU regulators of the critical impacts that hazardous medicinal products may have in relation to healthcare workers’ and individuals’ health and safety, and the accompanying need for urgent action on the topic.
Our Special Focus for May is on Rheumatology and we have some excellent articles featured by renowned authors in this field including Professor Ursula Fearon and colleague Órla Tynan of Trinity Biomedical Sciences Institute discussing Serum MicroRNA Signatures as Diagnostic Tools that Distinguish Rheumatoid and Psoriatic Arthritis and Dr Daire O’Leary, Dr Orla Killeen of the National Centre for Paediatric Rheumatology, Children’s Health Ireland at Crumlin. Their article looks at Chronic Nonbacterial Osteomyelitis: Challenges of a Rare Rheumatic Disease.
Finbar O’Shea Daniel Cagney
Mude - swan@ipn.ie CONTRIBUTORS
| Dr
Design
Rheumatology Focus: Chronic Nonbacterial LungRheumatoidRheumatologyOsteomyelitisFocus:ArthritisandInterstitialDisease P50
PUBLISHER
Achilleas Floudas Madigan
|
Clinical R&D: P82
Management of Asthma in Children P18
REGULARS
World Pharmacists Day 2022 P17
Theresa Lowry-Lehnen Morrow
Mr Aaron Glynn Frances Doherty
In other news, on page 20 the Irish Medical Organisation (IMO) details how they have called an emergency meeting of NCHDs across the country. The meeting was set to address the deteriorating working conditions and flagrant contractual breaches faced by NCHDs on a daily basis.
DIRECTOR Ian
| Dr
EDITORIAL Rachel cs.ipn@btconnect.comWilson
Sibongile
Dr Laura Durcan Kenny Franks
| Tracy
In this May issue we take a closer look at the recent European Association of Hospital Pharmacists Congress which took place recently in Vienna. Ireland’s own hospital chief pharmacist Joan Peppard presented at the event within her remit as Chair of the EAHP Special Interest Group (SIG).
EDITOR Kelly Jo Eastwood
BUSINESS
Professor John Carey David O’Sullivan
|
| Mr
| Dr
Feature: Familial Syndromic and Non-Syndromic Aortopathy
Bird Professor
DESIGN Stoddart
Dr Fiona Wilson Gallagher
Dr John Stack Ronan Cahill
Anne-Barbara Mongey Megan Hanlon
Eliminating the Burden of Cervical Cancer P74
GROUP DIRECTOR Natalie n-maginnis@btconnect.comMaginnis
Healthcare and assess the standard and quality of care in services as Ireland enters the next phase of the COVID-19 pandemic.
“The inspections will focus on leadership, governance and management of services, and how services ensure the rights of
It is estimated that 1 out of every 100 Irish people will experience an episode of psychosis in their Exampleslifetime.of
detection and intervention for psychosis endure for at least 20 years. The authors found that, while associations between delayed treatment and worse longterm outcome can vary depending on what outcome is measured, they are sustained across decades in a way that could not be explained by other factors.
• abnormal sensory experiences
HIQA will carry out inspections across healthcare services to monitor against the National Standards for Safer Better
patients using them are properly respected. We will also focus on service safety, assessing the key areas of infection prevention and control, medication safety, transitions of care, and care for patients with deteriorating conditions, such as sepsis. During these inspections, we will also review the conditions in which care is provided in emergency departments, as well as in other key clinical areas.”
The researchers found that people with longer delays in treatment had worse outcomes 20 years later in terms of their symptoms (such as hallucinations and social withdrawal), functioning (such as employment status), and quality of life (such as having satisfying interpersonal relationships).
6 MAY 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE
New Irish research has found that delay in treating psychosis can worsen symptoms, functioning, and quality of life and remain evident for at least 20 years after a patient first experiences the illness.
New Programme of Healthcare Inspections
Dr Donal O'Keeffe, research psychologist at DETECT
studied again at 6 months and 4, 8, 12 and 20 years later, with participants' psychotic symptoms, functioning and quality of life assessed at each time point.
News
This longitudinal study suggests that the advantages of early
symptoms are:
The Health Information and Quality Authority (HIQA) has announced it is to commence a new inspection and monitoring programme of public acute hospitals and rehabilitation and community inpatient healthcare services.
This research concludes that the longer someone experiences untreated psychosis, the poorer
Director of Healthcare Regulation, Sean Egan, said, “Healthcare services have faced numerous challenges in the past few years, most notably COVID-19, the cyberattack and capacity issues. These have all had a lasting impact on the health service, and major
• impairment in emotionality, motivation and sociability that can disrupt numerous day-today activities and relationships
Irish Study on Psychosis Reveals Alarming Results
While the importance of early detection and treatment for physical health conditions, such as cancer and heart disease, is now seen as "conventional wisdom", this study indicates that this is also the case for the mental health condition of psychosis.
The research was conducted in the DETECT Early Intervention in Psychosis Service in collaboration with RCSI University of Medicine and Health Sciences, and was supported by the St John of God Research Foundation through funding from the Health Research Board and the Stanley Medical Research Institute, USA.
efforts are still required to enable services to fully recover. HIQA’s new monitoring programme aims to monitor and publicly report on the quality and safety of healthcare services, as they continue this recovery process and adapt to new realities.
The study, led by researchers at the DETECT Early Intervention in Psychosis Service and RCSI University of Medicine and Health Sciences, has garnered international attention and is published today in The American Journal of Psychiatry.
Dr Donal O'Keeffe, research psychologist at DETECT and lead author, commented: “We found that a longer delay between when a person first experiences psychosis and is treated influences the extent of their recovery in the short, medium, and long term. While psychosis typically occurs in early adulthood, it can also occur at any stage in a person's life. Therefore, everyone needs to be aware of how to identify it.”
• irrational beliefs and impairment in thought processes
is their outcome for at least 20 years after the initial diagnosis. It also emphasises the importance of seeking help from mental health services, often via one's GP, as soon as possible after people first experience the signs and symptoms of psychosis.
The study, one of the longestrunning studies of its kind to be undertaken globally, involves 171 persons who first presented with psychosis to Cluain Mhuire Mental Health Service or St John of God Hospital in Dublin between 1995 and 1999. They were then
“Anyone in hospital who tests positive for Covid-19 has to be treated on a Covid ward, which restricts what care can be given to other medical or surgical patients.
“In order to fill these record number of vacant Consultant posts, the Government must reverse the flawed decision to cut the pay of Consultants appointed after 2012 and end the pay disparity immediately.
Advances in Precision Medicine
The Irish Hospital Consultants Association (IHCA) has urged the public to use a higher degree of caution over the coming weeks given the widespread community transmission of the coronavirus and the resulting increase in Thehospitalisations.Associationsaid
Gary McAuslan, CEO, aCGT Vector, said, “When identifying partners to work with, aCGT Vector places a great emphasis on finding companies with an aligned vision and an eagerness to drive further innovation in precision medicine development.”
it would encourage the 700,000 people yet to receive a third booster vaccine dose to consider doing so in order not only to protect themselves and their families against serious illness, but also to protect those who are at highest risk of harm from Covid-19 and the most vulnerable in society.
of approved Consultant posts that are vacant or filled on a temporary, locum or agency basis has reached an all-time high of 837 posts.
An increased awareness among the public of the impact of this latest wave of the pandemic could also help protect the health service from buckling under the strain of record emergency presentations and increased Covid activity in our hospitals.
“In addition, having 5,000 health staff out due to Covid has a devastating impact on the delivery of timely care to patients.
“The vacancies and the shortage of Consultants have resulted in excessive workloads being carried by understaffed medical and surgical teams to the detriment of patients. Unfortunately, there has been no let-up in the workload pressures being faced by this exhausted cohort of staff.
“These workforce pressures are not helped by the fact that the number
Empiric Logic has developed an artificial intelligence (AI) data analysis and high-potentialDublin,headquarteredGarethEmpiricmosttreatmentproceduralrapidlycell(Chimerictherapy,aCGTusingtheorchestrationbioinformaticsplatformtosimplifyexplorationofhumanhealth,genomicsandotherdata.Vector’sfocusiscellularincludingCAR-TAntigenReceptor-T)immunotherapy,whichisevolvingasatherapeuticapproachfortheofrarediseases,andcriticallycancer.Logic,foundedbyO’Sullivanin2018,isatNovaUCD,inandisanEnterpriseIrelandstart-up(HPSU).
“There is continuous commentary about the health service being under pressure but other than short-term, unsustainable solutions, like cancelling scheduled essential care, not enough is being done to actually increase our public hospital capacity and put in place sustainable solutions to ensure the provision of timely care to patients as needed. Cancelling essential
7 HOSPITALPROFESSIONALNEWS.IE | HPN • MAY 2022 News
surgeries will only increase record waiting lists even further.
Empiric Logic, a bioinformatics SaaS start-up,(software-as-a-service)hasannouncedthat it has signed a partnership agreement with aCGT Vector, a point-of-care cellular therapy company.
aCGT Vector, based at the Mill Enterprise Hub in Co. Louth, is also a member of the HEALED Consortium, which last year secured Disruptive Technologies Innovation Fund (DTIF) funding of ¤6.8 million as part of a 3-year, ¤10.5 million programme, to develop next generation cell therapies for cancer.
“We recognise the need, after two years of the pandemic, to manage living alongside Covid-19, but at this point we should be in a much better position in terms of having the required hospital capacity to meet the current demand for care. However, in the absence of Government action to increase our public hospital capacity, the public may once again have to play its part in getting this latest surge under control.
Under the agreement Empiric Logic will apply its secure machine learning data analytics capabilities to support aCGT Vector in bringing its precision medicine therapies quicker and more efficiently to market, in Ireland and further afield, to help improve patient outcomes.
“It also must appoint a new Independent Chair, agreed with the representative organisations, to oversee the new Consultant contract negotiations, which have stalled by the State with no engagement since last December.”
“Empiric Logic has that vision and not only are they going to be able to help us with access to their software platform capability, they will also help us architect and further refine our data curation, collection, analysis and management process. This will
“We’re delighted to be able to partner with aCGT Vector and participate in their journey to disrupt the CAR-T-cell therapeutic development space and help them to bring these proven lifesaving precision medicines more efficiently and quickly to patients in Ireland and around the world,” said Gareth O’Sullivan, CEO, Empiric Logic.
He added, “Partnerships such as this enable Empiric Logic to further improve our ability to address varied use cases for our technology while also helping blend genomics analysis with analysis of other clinical and phenotype data. Access to well curated and quality data sources is a key driver in allowing us to help companies such as aCGT Vector improve patient outcomes.”
Extra Caution Needed to Protect Hospitals
Commenting on the impact of the current wave of the pandemic, IHCA President Professor Alan Irvine, said, “Once again, the massive capacity deficits in our public hospitals means that they cannot cope with the high number of people currently presenting at our emergency departments and the surge in Covid activity in hospitals, without having to cancel essential scheduled surgeries, diagnostic investigations, and outpatient appointments. This cannot be the go-to solution to our hospital capacity deficits.
enable us to make better use of the data we collect to support better patient care and outcomes in a secure and privacy preserving manner.”
Gareth O’Sullivan, CEO, Empiric Logic
ARVO Annual Meeting
Grainne Power - Director of Compliance - Health Products Regulatory Authority
As Hospital Professional News was going to press, The ARVO Annual Meeting was taking place in Colorado.
A key focus for Ms Power is to support Ireland’s position as a key global location for pharmaceutical and manufacturebiopharmaceuticalandexport through delivering an expert, robust and agile inspectorate. She will also play a lead role in further expanding the HPRA’s national, European and international influence with respect to the activities within the Compliance department’s remit. Of note, she will oversee its participation and contribution to relevant committees and working groups at the European Medicines Agency (EMA), European Commission, Pharmaceutical Inspection Cooperation Scheme (PIC/S), Heads of Medicines Agencies (Working Group of Enforcement Officers), World Health Organisation (WHO) Member
Prior to taking up this new role, Ms Power was Director of the HPRA’s Human Products Authorisation and Registration department. With over 25 years’ experience in leadership positions across the Irish pharma/ biopharma manufacturing sectors, she has extensive relevant experience of quality operations, systems and compliance.
8 MAY 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE
This took place at The Bon Secours Hospital in Galway.
First in Ireland for Professor Kearns
“We are delighted with Grainne’s appointment as Director of Compliance where she will bring to bear a wealth of regulatory, technical and sectoral experience. Working with the Compliance team, Grainne will provide leadership across a number of crucial functions that serve to protect public and animal health including oversight of the national inspections programme, suspected quality defects and product recalls as well as riskbased sampling and analysis,” says Dr Nolan.
The Health Products Regulatory Authority (HPRA) has announced the appointment of Grainne Power as Director of Compliance. Ms Power will provide strategic and operational leadership to the Compliance department and will work closely with the management team to oversee the inspection, licensing, market compliance and enforcement activities of the HPRA.
Mr Kearns is Consultant Orthopaedic Surgeon with a keen interest in Foot & Ankle surgery. His interest was first developed during his fellowship in the NHS in Birmingham. He was exposed to numerous techniques and operations which he has gone on to develop in his own practice. Since his appointment in Galway he has gone on to pioneer new methods and techniques in Foot and Ankle surgery and has published a number of papers on his modifications to well known procedures.
Congratulations to Professor Stephen Kearns on being the first surgeon in Ireland and the UK to implant the Quantum Total Ankle Replacement from In2Bones.
Commenting on the appointment, Dr Lorraine Nolan, Chief Executive of the HPRA, stressed the importance of the position in ensuring compliance with relevant standards and legislation, and delivering on the organisations commitment to regulating medicines for the benefit of people and animals.
ARVO is the premiere gathering for eye and vision scientists at all career stages, students, and those in affiliated fields to share the latest research findings and collaborate on innovative solutions. For 2022, the Meeting was hosted May 1 - 4 in Denver, Colo., and virtually May 11 – 12. The June issue of HPN will carry full details from this congress.
State Mechanism on Substandard and Falsified Medical Products, Permanent Forum on International Pharmaceutical Crime (PFIPC) and Official Medicines Control Laboratories (OMCL) Network.
NewNewsDirector of Compliance Appointed at HPRA
Side-effects: The overall safety profile of bevacizumab is based on data from over 5,700 patients with various malignancies, predominantly treated with bevacizumab in combination with chemotherapy in clinical trials. The most serious adverse reactions were: gastrointestinal perforations; haemorrhage, including pulmonary haemorrhage/haemoptysis, which is more common in non-small cell lung cancer patients: arterial thromboembolism. The most frequently observed adverse reactions across clinical trials in patients receiving bevacizumab were hypertension, fatigue or asthenia, diarrhoea and abdominal pain. Very common (> 1/10) side effects were: febrile neutropenia, leucopenia, neutropenia, thrombocytopenia, anorexia, hypomagnesaemia, hyponatraemia, peripheral sensory neuropathy, dysarthria, headache, dysgeusia, eye disorder, lacrimation increased, hypertension, thrombo-embolism (venous), dyspnoea, rhinitis, epistaxis, cough, rectal haemorrhage, stomatitis, constipation, diarrhoea, nausea, vomiting, abdominal pain, wound healing complications, exfoliative dermatitis, dry skin, skin discoloration, arthralgia, myalgia, proteinuria, ovarian failure, asthenia, fatigue, pyrexia, pain, mucosal inflammation, weight decreased.
BUILDING ONTO THE CLINICAL EXPERIENCE OF BEVACIZUMAB WITH PFIZER1 ▼This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. Refer to section 4.8 of the SPC for how to report adverse reactions. ZIRABEV® is a biosimilar of bevacizumab2 ZIRABEV®▼ (bevacizumab) 25 mg/ml concentrate for solution for infusion PRESCRIBING INFORMATION - IE Please refer to the full Summary of Product Characteristics (SmPC) before prescribing Zirabev. Presentation: Each 4 ml and 16 ml vial containing 100 mg or 400 mg respectively of bevacizumab concentrate for solution for infusion (bevacizumab is a recombinant humanised monoclonal antibody produced by DNA technology in Chinese Hamster Ovary cells). Administration: Intravenous (IV) infusion only under the supervision of a physician experienced in the use of antineoplastic medicinal products. If first (over 90 mins) and second (over 60 mins) infusions are well tolerated, all subsequent infusions may be administered over 30 mins. Dose reductions not recommended. If indicated, therapy should be stopped or temporarily suspended. Indications and dosage: 1) Zirabev (5 or 10 mg/kg every 2 weeks or 7.5 or 15 mg/kg every 3 weeks) in combination with fluoropyrimidine-based chemotherapy is indicated for treatment of adult patients with metastatic carcinoma of the colon or rectum. 2) Zirabev (10mg/kg every 2 weeks or 15mg/kg every 3 weeks) in combination with paclitaxel is indicated for first-line treatment of adult patients with metastatic breast cancer. 3) Zirabev in combination with capecitabine is indicated for first-line treatment of adult patients with metastatic breast cancer in whom treatment with other chemotherapy options including taxanes or anthracyclines is not considered appropriate. Patients who have received taxane and anthracycline-containing regimens in the adjuvant setting within the last 12 months should be excluded from treatment with Zirabev in combination with capecitabine. 4) Zirabev (7.5 or 15 mg/kg every 3 weeks), in addition to platinumbased chemotherapy (for up to 6 cycles, then Zirabev monotherapy), is indicated for first-line treatment of adult patients with unresectable advanced, metastatic or recurrent non-small cell lung cancer other than predominantly squamous cell histology. 5) Zirabev (15 mg/kg every 3 weeks) in combination with erlotinib is indicated for first-line treatment of adult patients with unresectable advanced, metastatic or recurrent non-squamous non-small cell lung cancer with Epidermal Growth Factor Receptor (EGFR) activating mutations. 6) Zirabev (10 mg/kg every 2 weeks) in combination with interferon alfa-2a is indicated for first line treatment of adult patients with advanced and/or metastatic renal cell cancer. 7) Zirabev (15 mg/kg every 3 weeks), in combination with carboplatin and paclitaxel (for up to 6 cycles followed by Zirabev monotherapy until disease progression, a maximum of 15 months or until unacceptable toxicity, whichever occurs earlier) is indicated for the front-line treatment of adult patients with advanced (International Federation of Gynecology and Obstetrics (FIGO) stages III B, III C and IV) epithelial ovarian, fallopian tube, or primary peritoneal cancer. 8) Zirabev (15 mg/kg every 3 weeks), in combination with carboplatin and gemcitabine (6 to 10 cycles, followed by Zirabev monotherapy) or in combination with carboplatin and paclitaxel (6 to 8 cycles, followed by Zirabev monotherapy), is indicated for treatment of adult patients with first recurrence of platinum-sensitive epithelial ovarian, fallopian tube or primary peritoneal cancer who have not received prior therapy with bevacizumab or other VEGF inhibitors or VEGF receptor–targeted agents. 9) Zirabev (10 mg/kg every 2 weeks) in combination with paclitaxel, topotecan (given weekly), or pegylated liposomal doxorubicin is indicated for the treatment of adult patients with platinum-resistant recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who received no more than two prior chemotherapy regimens and who have not received prior therapy with bevacizumab or other VEGF inhibitors or VEGF receptor–targeted agents. If topotecan is administered every 3 weeks, the Zirabev dose is 15 mg/kg every 3 weeks. 10) Zirabev (15 mg/kg every 3 weeks), in combination with paclitaxel and cisplatin or, alternatively, paclitaxel and topotecan in patients who cannot receive platinum therapy, is indicated for the treatment of adult patients with persistent, recurrent, or metastatic carcinoma of the cervix. Elderly patients (≥ 65 years of age): Dosage adjustments are not required in elderly patients. Hepatic impairment & renal impairment: The safety and efficacy have not been studied in patients with hepatic or renal impairment. Paediatric patients (< 18 years): Not indicated. Contra-indications: Hypersensitivity to the active substance or to any of the excipients. Hypersensitivity to Chinese Hamster Ovary (CHO) cell products or other recombinant human or humanised antibodies. Pregnancy. Pregnancy and lactation: Women of childbearing potential have to use effective contraception during (and up to 6 months after) treatment. Bevacizumab is contraindicated in pregnancy. Women must discontinue breast-feeding during therapy and not breast-feed for at least six months following the last dose of bevacizumab. Warnings and precautions: Traceability: Zirabev is a biological medicine; clearly record the name and batch number. There is an increased risk of developing the following serious conditions (see
SmPC for full guidance on patient risk factors and when to discontinue or withhold Zirabev): Gastrointestinal (GI) perforations and fistulae, GI-vaginal fistulae, Non-GI fistulae, wound healing complications, hypertension, aneurysms and artery dissections, posterior reversible encephalopathy syndrome (PRES), proteinuria, arterial thromboembolism, venous thromboembolism, haemorrhage, pulmonary haemorrhage/haemoptysis, congestive heart failure, neutropenia and infections, hypersensitivity reactions/infusion reactions, osteonecrosis of the jaw. Zirabev is not formulated for intravitreal use. Unapproved intravitreal use has led to serious ocular adverse reactions including permanent blindness as well as systemic adverse effects including non-ocular haemorrhages and arterial thromboembolic reactions. As bevacizumab may cause ovarian failure, discuss fertility preservation strategies with women of child-bearing potential prior to starting treatment. Consideration should be given to patients who are on a controlled sodium diet. Sodium content: 3 mg sodium per 4 ml vial and 12.1 mg sodium per 16 ml vial.
jaw, non-mandibular osteonecrosis, ovarian failure, foetal abnormalities. See SmPC for full details on all other side effects. Driving and operating machinery: If patients are experiencing symptoms that affect their vision or concentration, or their ability to react, they should be advised not to drive and use machines until symptoms abate. Legal category: POM, S1A Marketing Authorisation Number: EU/1/18/1344/001, EU/1/18/1344/002 Marketing Authorisation Holder: Pfizer Europe MA EEIG, Boulevard de la Plaine 17, 1050 Bruxelles, Belgium. Last revised: 05/2021 Ref: bZR 6_0 For further information on this medicine please contact: Pfizer Medical Information on 1800 633 363 or at medical.information@pfizer.com. For queries regarding product availability please contact: Pfizer Healthcare Ireland, Pfizer Building 9, Riverwalk, National Digital Park, Citywest Business Campus, Dublin 24 + 353 1 4676500. References: 1. ZIRABEV® (bevacizumab) Summary of Product Characteristics. 2. European Medicines Agency. ZIRABEV® EPAR summary for the public. https://www.ema.europa.eu/en/medicines/human/EPAR/zirabev . Accessed August 2021. PP-BVC-IRL-0046 | Date of Preparation: August 2021 Scan QR Code to morelearnaboutZIRABEV®
Common (≥1/100 to <1/10) reported side-effects were: sepsis, abscess, cellulitis, infection, urinary tract infection, anaemia, lymphopenia, hypersensitivity, infusion reactions, dehydration, cerebrovascular accident, syncope, somnolence, congestive heart failure, supraventricular tachycardia, thrombo-embolism (arterial), haemorrhage, deep vein thrombosis, pulmonary haemorrhage/haemoptysis, pulmonary embolism, hypoxia, dysphonia, gastrointestinal perforation, intestinal perforation, ileus, intestinal obstruction, recto-vaginal fistulae, gastrointestinal disorder, proctalgia, palmar-plantar erythro-dysaesthesia syndrome, fistula, muscular weakness, back pain, pelvic pain and lethargy. The following severe side effects (frequency not known) have also been reported: necrotising fasciitis, hypersensitivity, infusion reactions, posterior reversible encephalopathy syndrome, hypertensive encephalopathy, aneurysms and artery dissections, renal thrombotic microangiopathy, pulmonary hypertension, nasal septum perforation, GI ulcer and perforation, rectal haemorrhage, gallbladder perforation, osteonecrosis of the
Director of Healthcare Technology at MDI Medical. “The combined partnership between MDI Medical and TUH has allowed for the design and implementation of mobile WOWs tailored to the hospital’s workflow and will create a leading healthcare device strategy for the integration of clinical systems to support patients and caregivers.”
With the implementation of the EWS-enabled WOWs, TUH intends to explore opportunities integrating their Electronic Patient Record and Early Warning Score system, allowing them to talk together for a streamlined experience.
Tallaght University Hospital has made a key step in their fiveyear strategic plan for improving access to services by joining up with MDI Medical to announce the roll-out of a hospital-wide electronic patient record (EPR) – named Project Synergy. The design, development and implementation of over 100 Workstations on Wheels (WOWs) in partnership with MDI Medical will revolutionise the way clinicians can access patient data and how patient care is delivered across the hospital’s multiple locations and aligning the “Anytime, Anywhere, Any Device” strategy. Powered by software developed by Northern Ireland and Galway-based companies and with the design and delivery of the WOWs from MDI Medical in Meath, the project reflects the exceptional work of healthcare technology companies coming together on the Island of Ireland. Phase 1 to overhaul the clinical experience and enhance patient care falls in line with priorities laid out by Tallaght University Hospital’s 2019-2024 strategy to replace legacy systems and implement digital enabled care. Through the implementation of TUH’s Synergy EPR and facilitating digital information sharing through mobile-enabled solutions, departments and clinical wards within the Hospital have been joined up giving clinicians access to a wealth of centralised information which facilitates faster and more accurate treatment.
RevolutionisingNews Patient Care at Tallaght Hospital
“Our partnership with Tallaght University Hospital has introduced the latest Healthcare IT solutions and will improve how hospital staff can electronically document across the continuum of care,” commented Gareth Dempsey,
10 MAY 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE
A member of the Tallaght University Hospital team assesses a patient using one of the over 100 Workstations on Wheels (WOWs) implemented in partnership with MDI Medical to revolutionise the way clinicians can access patient data and how patient care is delivered through the Hospital’s ‘Project Synergy,’ which is implementing a hospital-wide electronic patient record (EPR)
A major development in the continuum of care is the introduction of the Vital Signs Automation project/Early Warning Score – EWS. Early Warning Scores are validated tools designed to facilitate the early detection of potential deterioration in a patient’s condition based on changes in routinely measure physiological parameters over time. Rapid recognition of these changes followed by appropriate escalation and response is associated with improved patient outcomes.
The mobile WOWs are also reducing the amount of travel through the hospital required from patient care teams, therefore cutting down on time inefficiencies, lessening the risk of infection spread, and helping to ease the burden for busy healthcare workers who spend a significant amount of time travelling between bedsides and reporting stations and communicating with other departments within the hospital.
The implementation of the Workstations on Wheels means these can be brought to the patient’s bedside for immediate access to information including patient history, laboratory results and care notes as well as offering a localised entry point for data including reporting during ward rounds and updating patient vitals, offering a stable, practical, and portable solution for caregivers.
“The introduction of the EWSenabled WOWs has enabled electronic recording of all physiologic parameters integral to the EWS score thereby reducing the time taken to capture these measurements as well as ensuring accurate calculation of the total score,” said Srininvas Kamila, IT Senior Project Manager, Tallaght University Hospital. “The effectiveness of the response limb of the EWS is critically dependent on accurate scoring. In our experience, the EWS-enabled WOWs are user friendly with easy to interpret displays.
printer, and key vital signs monitors which put all key information at the clinician’s fingertips, allowing for urgent care and reporting to take place simultaneously. Manual capture and documentation of EWS parameters is time consuming with the potential for errors in calculation of final scores that may result in delayed identification of patients at risk of clinical deterioration.
Specially designed to allow for patient monitoring support and intervention, EWS-enabled carts are fitted with additional equipment including a PC, barcode scanner,
“Notable features include an automatic on-screen countdown prompt for nursing staff to perform the next set of patient observations as well as a central viewing screen that allows clinical staff to have full sight of EWS scores for all patients in an area thereby quickly identifying any patients requiring rapid review. We anticipate that additional functionality in development will include automatic escalation to for example the clinical team, critical care outreach or anaesthetic team based on the EWS score and the escalation pathway in place locally; thereby reducing time taken to respond to potentially deteriorating patients under our care.”
Commenting on the collaborative project between the hospital and MDI Medical, David Wall, Chief Information Officer at Tallaght University Hospital said: “Our collaboration with MDI Medical to introduce over 100 WOWs across TUH has improved the patient and clinician experience by joining up multiple locations and departments within TUH, enhancing collaborative healthcare and providing staff with increased access to patient information to better inform treatment plans. By taking a strategic approach to rolling out the WOWs across our Hospital and working closely with MDI Medical every step of the way, we have been able to introduce staff to the new technology in a way that enhances and improves their way of working rather than disrupting their workflow.”
Presentation: Toujeo SoloStar and DoubleStar pre-filled pens. Each ml contains 300 units of insulin glargine. SoloStar pen contains 1.5ml (450 units) of solution for injection. DoubleStar pen contains 3ml (900 units) of solution for injection.
Legal Category: POM. Marketing Authorisation Number: SoloStar 3 Pen pack: EU/1/00/133/034, DoubleStar EU/1/00/133/038. Marketing Authorisation Holder: Sanofi Aventis Deutschland GmbH, D-65926 Frankfurt am Main, Germany. Further information is available from: Medical Information, Sanofi 18 Riverwalk, Citywest Business Campus, Dublin 24 or contact IEmedinfo@sanofi. com. Date of preparation: July 2020.
Shared features with Toujeo SoloStar
Please refer to Summary of Product Characteristics (SmPC) before prescribing.
Paediatric: When switching basal insulin to Toujeo, dose reduction of basal and bolus insulin needs to be considered on an individual basis, in order to minimise the risk of hypoglycaemia. The safety and efficacy of Toujeo in children and adolescents below 6 years of age have not been established. Contraindications: Hypersensitivity to insulin glargine or any excipients. Precautions and Warnings: Traceability: In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded. Toujeo is not the insulin of choice for treatment of diabetic ketoacidosis. Patients must be instructed to perform continuous rotation of the injection site to reduce the risk of developing lipodystrophy and cutaneous amyloidosis. There is a potential risk of delayed insulin absorption and worsened glycaemic control following insulin injections at sites
®
Toujeo ® DoubleStar™ holds more units per pen than any other basal insulin pen on the market1-4
Adverse events should be reported. Reporting forms and information can be found at www.hpra.ie; email: medsafety@hpra.ie Adverse events should also be reported to Sanofi Ireland Ltd. Tel: 01 403 5600. Alternatively, send via email to IEPharmacovigilance@sanofi.com
®
Indication: Treatment of diabetes mellitus in adults, adolescents and children from the age of 6 years. Dosage and Administration: Toujeo is administered subcutaneously, by injection into the abdominal wall, the deltoid or the thigh, once daily, at any time of the day, preferably at the same time every day. Injection sites must be rotated within a given injection area from one injection to the next in order to reduce the risk of lipodystrophy and cutaneous amyloidosis. The dose regimen (dose and timing) should be adjusted according to individual response. Do not administer intravenously. In type 1 diabetes mellitus, Toujeo must be combined with short-/ rapid-acting insulin to cover mealtime insulin requirements. In patients with type 2 diabetes mellitus, recommended daily starting dose is 0.2 units/kg followed by individual dose adjustments. Toujeo can also be given together with other anti-hyperglycaemic medicinal products. Switch between insulin glargine 100 units/ml and Toujeo: Insulin glargine 100 units/ml and Toujeo are not bioequivalent and are not directly interchangeable. When switching from insulin glargine 100 units/ml to Toujeo, this can be done on a unit to unit basis, but a higher Toujeo dose (approximately 10-18%) may be needed to achieve target ranges for plasma glucose levels. When switching from Toujeo to insulin glargine 100 units/ml, the dose should be reduced (approximately by 20%). Switching from other basal insulins to Toujeo: A change of dose and/or timing of the basal insulin and concomitant anti hyperglycaemic treatment may be required. Dose adjustments may also be required if the patient’s weight or lifestyle changes, the timing of insulin dose is changed or other circumstances arise that increase susceptibility to hypo- or hyperglycaemia. Toujeo must not be mixed or diluted with any other insulin or other medicinal products. Close metabolic monitoring is recommended during a switch and in the initial weeks thereafter. SoloStar 1-80 units per single injection in steps of 1 unit and DoubleStar 2-160 units in steps of 2 units. When changing from Toujeo SoloStar to Toujeo DoubleStar, if the patient’s previous dose was an odd number then the dose must be increased or decreased by 1 unit. Toujeo DoubleStar prefilled pen is recommended for patients requiring at least 20 units per day. Special Populations: Insulin requirements may be diminished in the elderly or patients with renal or hepatic impairment.
Date of preparation: August 2020 | MAT-IE-2000823 (v1.0)
Toujeo ® is available in two pre-filled insulin devices
• Pen size • 5-second hold time5,6 • 42-day shelf life after first use1 • Same technical platform
Prescribing Information:
with these reactions. A sudden change in the injection site to an unaffected area has been reported to result in hypoglycaemia. Blood glucose monitoring is recommended after the change in the injection site, and dose adjustment of antidiabetic medications may be considered. Hypoglycaemia: In case of insufficient glucose control or a tendency to hyper/hypoglycaemic episodes, the patient’s adherence to the prescribed treatment regimen, injection sites and proper injection technique and all other relevant factors must be reviewed before dose adjustment is considered. Particular caution should be exercised, and intensified blood glucose monitoring is advisable for patients in whom hypoglycaemic episodes might be of clinical relevance and in those where dose adjustments may be required. Warning signs of hypoglycaemia may be changed, less pronounced or absent in certain risk groups, potentially resulting in severe hypoglycaemia and loss of consciousness. Risk groups include patients in whom glycaemic control is markedly improved, hypoglycaemia develops gradually, an autonomic neuropathy is present, or who are elderly. The prolonged effect of subcutaneous insulin glargine may delay recovery from hypoglycaemia. Intercurrent illness: Requires intensified metabolic monitoring and often it is necessary to adjust the insulin dose. Insulin antibodies: administration may cause insulin antibodies to form. Use with pioglitazone: Cases of cardiac failure have been reported when pioglitazone was used in combination with insulin, especially in patients with risk factors for development of cardiac heart failure. If the combination is used, patients should be observed for signs and symptoms of heart failure, weight gain and oedema. Pioglitazone should be discontinued if any deterioration in cardiac symptoms occurs. Medication errors: Insulin labels must always be checked before each injection to avoid errors between Toujeo and other insulins. Patients must be instructed to never use a syringe to remove Toujeo from the SoloStar or DoubleStar pre-filled pen, A new sterile needle must be attached before each injection. Needles must not be re-used. Pregnancy and lactation: There is no data from exposed pregnancies in controlled clinical trials. However, there is a large amount of data on use of insulin glargine 100 units/ ml in pregnant women indicating no specific adverse effects on pregnancy and no specific malformative nor feto/neonatal toxicity. The use of Toujeo may be considered during pregnancy, if clinically needed. Careful monitoring of glucose control is essential. It is unknown if insulin glargine is excreted in breast milk. Interactions: Substances that affect glucose metabolism may require adjustment of insulin glargine. Adverse Reactions: Very common: Hypoglycaemia. Prolonged or severe hypoglycaemia may be life-threatening. Common: Lipohypertrophy, injection site reactions, including redness, pain, itching, hives, swelling, or inflammation.
References: 1. Toujeo® Summary of Product Characteristics.
Toujeo (insulin glargine 300 units/ml)
allowing you to choose the most suitable device for your patients *Toujeo ® DoubleStar™ is recommended for patients requiring at least 20 units of basal insulin per day1 1.References: Toujeo® Summary of Product Characteristics. 2. Lantus® Summary of Product Characteristics. 3. Tresiba® Summary of Product Characteristics. 4. Levemir® Summary of Product Characteristics. 5. Toujeo® DoubleStarTM Package leaflet: information for the user. 6. Toujeo® SoloStar® Package leaflet: information for the user.
celebrated innovation and excellence with several other awards focused on Statement implementation, students and
Hospital Pharmacists – Changing Roles in a Changing World
Between February 2021 and February 2022, the SIG focusing on Hazardous Medicinal Products collected information on the classification of hazardous medicinal products and their handling in Europe through desk research, horizon scanning activities as well as surveys of hospital pharmacists’ views at individual and national levels. This work was complemented by the knowledge and experience of the SIG members and led to the creation of a European definition for the term ‘hazardous medicinal product’ and recommendations to improve their classification and Hospitalhandling.pharmacists and members of the multidisciplinary team – such as nurses, pharmacy technicians and others – are dealing with hazardous medicinal products in their daily work. Their safe handling is of uttermost importance for the safety of healthcare workers and patients
For the first time, EAHP's President András Süle presented the "EAHP Board of Directors Professional Excellence Award" which recognises an individual who has made outstanding contributions to EAHP and the hospital pharmacy profession. This award went to Leonidas Tzimis, a Greek hospital pharmacist that has worked for many years on harnessing the benefits of digitalisation for hospital pharmacies.
Between the 23rd and the 25th of March more than 1,932 hospital pharmacists from over 50 different countries came together for the 26th edition of EAHP's congress. The programme was packed with seminars, workshops and interactive sessions focused on the changing roles of hospital pharmacists in a changing world.
Hazardous Medicinal Products
Chair of the SIG Joan Peppard
Attendees of this session learned more about the classification landscape for hazardous medicinal products and the need for a European definition.
The keynotes touched on value-based healthcare, shared decision making and cell and gene therapies. As usual the exhibition area was a big draw for participants that wanted to learn more about the latest technologies and Also,network.EAHP's
The 26th Congress of the European Association of Hospital Pharmacists (EAHP) also served as the backdrop for the launch of the results from the Association’s first Special Interest Group (SIG) focusing on Hazardous Medicinal Products. The SIG was tasked with examining national strategies and requirements across Europe for the management of hazardous medicines, identifying best practices, promoting better sharing and implementation of these practices between countries and stimulating heightened awareness by governments and EU regulators of the critical impacts that hazardous medicinal products may have in relation to healthcare workers’ and individuals’ health and safety, and the accompanying need for urgent action on the topic.
After two challenging years during which hospital pharmacists and their frontline healthcare colleagues have worked tirelessly for their patients, the European Association of Hospital Pharmacists (EAHP) held its first educational in-person event.
Poster Walk
EAHP's poster walk, a unique Congress feature, brought together participants and poster authors to discuss the latest research developments. The Scientific Committee awarded the 1st prize for poster submissions to Benedict Morath for the abstract and poster titled 'Implementation of an interprofessional pre-operative medication management program in cardiac surgery – a pre post quality improvement study'. The 2022 Good Practice Initiative (GIP) award and the Statement Implementation Award went to Beatriz Ardizone for her work on the 'Web Dialogue: One more step in EAHP'stelepharmacy'.26thCongress
Since EAHP turned 50 on the 6th of March, a special history walk was set up for congress participants which allowed them to discover EAHP's achievements over the last 5 decades. The first Special Interest Group of EAHP focused on Hazardous Medicinal Products released the finding of its work on Wednesday afternoon.
team welcomed numerous individuals at the EAHP booth to talk about the European Statements of Hospital Pharmacy, the self-assessment tool and the Association's advocacy work. Students had the opportunity to learn more about ethical challenges during the programme specially designed for them. In addition, they got to meet with representatives of the European Pharmaceutical Students' Association (EPSA).
EAHP President András Süle
12 MAY 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE EAHP 2022
also
contributions to EAHP. The Board of Directors awarded the Statement Implementation Award to the GPI winner Beatriz Ardizone. This award acknowledges contributions with a specific emphasis on implementing the European Statements of Hospital Pharmacy. The 2022 EAHP-EPSA Student Science Award went to Aiva Birne for her abstract 'Evaluation of harmful and potentially harmful excipients for newborns found in medications used in children's clinical university hospital (department of neonatology) in 2019'.
“Value is no longer produced simply by delivering medical technology and medicines, in a value-based healthcare paradigm, instead, value emerges when the perspectives of the healthcare system and patients fuse resulting in optimal patient experience as well as strong clinical outcomes. Factors such as new technology, availability of information and communication between patients and healthcare professionals (HCPs) enable the fusion.
Hospital pharmacists that attended the launch, learned that there is no European definition for hazardous medicinal products and no clear European-wide guidance on their management. They exchanged with Joan Peppard and Falko Schüllner, who presented the SIG results, on the high awareness across EAHP’s member countries about hazardous medicinal products and the significant efforts that were made at an institutional level into the management of hazardous medicinal products thanks to the work of pharmacists over the years. However, despite these efforts, both speakers stressed at the launch that there remains an exposure risk to healthcare workers and caregivers that needs to be addressed.
He said, “The view on healthcare systems in Europe is moving from a productivity paradigm, which focuses on the amount of healthcare services provided, to a value-based healthcare paradigm, which focuses on patient health outcomes. In this paradigm shift, the healthcare system is rejecting a systemic “one-size-fits-all” approach, in order to apply a more patient-centered approach.
EAHP President András Süle welcomed the publication of the report by thanking the SIG and stressing that, “The SIGs valuable contributions and the engagement of its members throughout the past year have undoubtedly triggered the discussion around closing gaps by identifying classification
13 HOSPITALPROFESSIONALNEWS.IE | HPN • MAY 2022
“To measure value-based healthcare, tools such as Quality Adjusted Life Years (QALY) and Patient Reported Outcome (PRO), may be implemented in the healthcare systems to support value-based practice within limited healthcare budgets.
My thanks are not only addressed to the members of this SIG but also extend towards all the chief pharmacists across Europe and EAHP’s member associations that contributed to the survey activity in autumn 2021.”
The Congress was opened with a keynote lecture by Dr Steven Simeons, Professor of Health Economics, KU Leuven, Department of Pharmaceutical and Pharmacological Sciences, who talked about value based healthcare.
“Traditionally, patient treatments were based on guidelines and other evidence-based treatment tools. In value-based healthcare, patient preferences in medical treatment are now fundamental to the way value is defined.
Leonidas Tzimis, Hospital Pharmacist, Crete with EAHP President András Süle
Dr Steven Simeons opened the EAHP 2022 Congress in Vienna with a keynote lecture on value-based healthcare
treated with these medicines. Their classification plays an essential role in determining suitable handling procedures. However, unlike the United States, Europe does not have one single body similar to the National Institute for Occupational Safety and Health (NIOSH) that addresses all questions linked to the classification of hazardous medicinal products.
“This transition from productivity to value-based healthcare requires hospital pharmacies to reconsider their strategic thinking to remain a key player within healthcare.”
Reflecting on the work of the SIG, the Chair of the SIG Joan Peppard highlighted that, “The conclusion of the SIG’s work is very timely for EAHP’s advocacy activities linked to hazardous medicinal products. I hope that the findings of the SIG will help improve the handling of these products in Europe and will feed into the work of the European Commission focused on the development of a definition, the establishment of an indicative list of hazardous medicinal products and the creation of guidance material for the safe management of hazardous drugs products.”
To better understand the classification landscape for hazardous medicinal products in Europe, the SIG on Hazardous Medicinal Products (financially supported by Amgen) carried out an investigation, examining national strategies and requirements across Europe for the management of hazardous medicines, identifying best practices, promoting better sharing and implementation of these practices between countries and stimulating heightened awareness by governments and EU regulators of the critical impacts that hazardous medicinal products may have in relation to healthcare workers' and individuals' health and safety, and the accompanying need for urgent action on the topic.
The first European Association of Hospital Pharmacists Board of Directors Professional Excellence Award was given at the congress to Leonidas Tzimis of Greece. Leonidas is a Hospital Pharmacist at Chania General Hospital, Crete.
systems around Europe, creating a European model and a definition of the term ‘hazardous medicinal products’ applicable to the European treatment landscape.
• Sex differences in treatment and mortality of patients with cardiogenic shock.
Among them:
and to heart health,” noted Dr Krychtiuk. “Leaders in this rapidly advancing field will give up-tothe-minute information on how the environment affects the heart and what to expect in the future as this problem becomes more and more relevant.”
14 MAY 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE ESCardio 22
• Elevated troponin and longterm outcome of patients with COVID-19.
Pregnant women have also been excluded from studies and a session is devoted to cardiovascular emergencies around pregnancy. “These are complex situations since two lives at stake,” said Dr Krychtiuk. “We see heart attacks in older pregnant women, for example. We do however also see other forms of heart attacks, caused by dissection and it is debatable whether we should follow the standard practice of placing a stent to restore blood flow and then giving blood thinners for several months to prevent clots. Leaders in the field will provide guidance on what is safe to do in such scenarios.”
“These results provide reassuring data that may encourage patients with a history of myocarditis to get vaccinated against SARS-CoV-2,” said study author Dr Iyad Abou Saleh of Hospices Civils de Lyon, France. “It should be noted that the majority of patients in our study received the BNT162b2 mRNA vaccine and therefore the findings may not apply to other vaccines.”
• Novel predictor of neurological outcome after cardiac arrest.
ESC Acute CardioVascular Care 2022: At the Forefront of Cardiac Emergencies
New scientific findings were showcased in the abstracts.
• Artificial intelligence (AI) to diagnose and treat acute coronary syndrome.
Not to miss: how to move the needle in outcome of out-ofhospital cardiac arrest. “Cardiac arrest is lethal within minutes if untreated and fewer than one in five patients survive,” said Dr Krychtiuk. “Here we also have high-tech therapies but the actions that really make a difference are bystanders with(CPR)cardiopulmonaryperformingresuscitationandshockingthepatientanautomatedexternal
Cutting edge management of urgent heart problems was revealed during ESC Acute CardioVascular Care 2022, a scientific congress of the European Society of Cardiology (ESC).
Myocarditis is an inflammation of the heart muscle. Signs and
The meeting brings together cardiologists, illprofessionalsparamedicscardiacanaesthesiologists,intensivists,internists,surgeons,nurses,andotheralliedwhocareforacutelycardiacpatients.
cardiogenic shock and how that might be influenced with novel therapies.”
Also of interest: the impact of climate on acute cardiovascular conditions. “Climate change is a real threat to the planet
Dr Konstantin Krychtiuk, scientific chair of the congress said, “Treatment of cardiac emergencies caused by cancer and anti-cancer therapies is an emerging field. Increasingly in clinical practice we are consulted by oncologists about acute coronary syndrome, acute heart failure and other critical heart conditions. Clinical trials of these diseases have often excluded those with cancer and during this session we will hear how experts manage cardiac emergencies in these patients.”
Digital health has the potential to transform other aspects of acute cardiac care too: hear how AI could warn cardiac intensivists of impending life-threatening situations. Dr Krychtiuk explained: “Each patient in the intensive care unit generates thousands of data points on bodily functions every minute. Clinicians have developed their own approaches for recognising worrying patterns, but AI may be able to identify serious problems one or two hours earlier.”
COVID-19 vaccination is safe in patients with previous myocarditis
A small study has shown that SARS-CoV-2 vaccination in patients who had an inflamed heart muscle in the past is not associated with a recurrence of the condition or other serious side effects. The research was presented at ESC Acute CardioVascular Care 2022, a scientific congress of the European Society of Cardiology (ESC).
defibrillator (AED) before the ambulance arrives. This session will focus on teaching CPR to laypeople and schoolchildren, the most effective locations and signage for AEDs, and innovative citizen responder programmes which use apps to alert bystanders when a victim is nearby.”
Acute cardiovascular care focuses on patients with life-threatening conditions such as heart attack, cardiac arrest, acute heart failure and cardiogenic shock. The annual congress of the Association for Acute CardioVascular Care (ACVC), a branch of the ESC, took place 18 to 19 March online.
• Do heart attack symptoms predict the likelihood of survival?
Dr Konstantin Krychtiuk, Scientific Chair, ESC Acute CardioVascular Care 2022
Also on the agenda: state-ofthe-art in cardiogenic shock, a life-threatening condition in which the heart suddenly fails to pump sufficient blood to the organs. Dr Krychtiuk pointed out: “Cardiogenic shock is usually caused by a very large heart attack where 50% or more of the heart’s function is lost within seconds. Even with fast treatment using high-tech machines to help or replace the circulation, only around half of patients survive. In the meeting we will explore what happens in the body during
Rosuvastatin + Ezetimibe
MAT-IE-2101261 (v1.0) – August 2021 Reference: 1. Suvezen Summary of Product Characteristics * LDL-C: Low-density lipoprotein Cholesterol ** Suvezen is available in 3 doses in Ireland. Suvezen 10mg/10mg, 20mg/10mg and 40mg/10mg: Each film-coated tablet contains 10mg; 20mg or 40mg of
excessive quantities of alcohol and/or have a history of liver disease. Renal effects: Proteinuria has been observed in patients treated with higher doses of rosuvastatin and was transient or intermittent in most cases. Proteinuria has not been shown to be predictive of acute or progressive renal disease. An assessment of renal function should be considered during routine follow-up of patients treated with a dose of 40mg. Diabetes mellitus: Some evidence suggests that statins raise blood glucose and in some patients, at high risk of future diabetes, may produce a level of hyperglycaemia where formal diabetes care is appropriate. This risk, however, is outweighed by the reduction in vascular risk with statins and therefore should not be a reason for stopping statin treatment. Patients at risk (fasting glucose 5.6 – 6.9mmol/l, BMI >30kg/m2, raised triglycerides, hypertension) should be monitored both clinically and biochemically according to national guidelines. Interstitial lung disease: Exceptional cases have been reported with some statins, especially with long term therapy. Presenting features can include dyspnoea, non-productive cough and deterioration in general health (fatigue, weight loss and fever). If it is suspected, statin therapy should be discontinued. Protease inhibitors: Increased systemic exposure to rosuvastatin has been observed in subjects receiving rosuvastatin concomitantly with various protease inhibitors in combination with ritonavir. Consideration should be given both to the benefit of lipid lowering by use of Suvezen in HIV patients receiving protease inhibitors and the potential for increased rosuvastatin plasma concentrations when initiating and up titrating rosuvastatin doses in patients treated with protease inhibitors. The concomitant use with certain protease inhibitors is not recommended unless the dose of rosuvastatin is adjusted. Fibrates: The safety and efficacy of ezetimibe administered with fibrates have not been established. If cholelithiasis is suspected in a patient receiving Suvezen and fenofibrate, gallbladder investigations are indicated and therapy should be discontinued. Anticoagulants: If Suvezen is added to warfarin, another coumarin anticoagulant, or fluindione, the International Normalised Ratio (INR) should be appropriately monitored. Fusidic acid: Suvezen must not be co-administered with systemic formulations of fusidic acid or within 7 days of stopping fusidic acid treatment. In patients where the use of systemic fusidic acid is considered essential, statin treatment should be discontinued throughout the duration of fusidic acid treatment. There have been reports of rhabdomyolysis (including some fatalities) in patients receiving fusidic acid and statins in combination. The patient should be advised to seek medical advice immediately if they experience any symptoms of muscle weakness, pain or tenderness. Statin therapy may be re-introduced seven days after the last dose of fusidic acid. In exceptional circumstances, where prolonged systemic fusidic acid is needed, e.g., for the treatment of severe infections, the need for co-administration of Suvezen and fusidic acid should only be considered on a case by case basis and under close medical supervision. Suvezen contains lactose monohydrate and sodium: Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine. This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium-free’. Interactions: Contraindicated combinations: Ciclosporin. Not-recommended combinations: Fibrates and other lipid-lowering products, protease inhibitors, transporter protein inhibitors and fusidic acid. Other possible interactions: Cytochrome P450 enzymes, antacids, colestyramine, anticoagulants, Vitamin K antagonists, erythromycin, oral contraceptive/hormone replacement therapy. When co-administering rosuvastatin with other medicinal products known to increase exposure to rosuvastatin, doses should be adjusted (see SmPC for full details). The maximum daily dose should be adjusted so that the expected rosuvastatin exposure would not likely exceed that of a 40mg daily dose of rosuvastatin taken without interacting medicinal products. Fertility, Pregnancy and Breastfeeding: No clinical data are available on the use of ezetimibe during pregnancy. Potential risk from inhibition of HMG-CoA reductase outweighs the advantage of treatment during pregnancy. If a patient becomes pregnant during use of Suvezen, treatment should be discontinued immediately. Animal studies have shown excretion of medicinal product through breast milk. However, there are no data in humans. No clinical trial data on the effects of fertility in humans. Adverse Reactions: Adverse drug reactions previously reported with one of the individual components (ezetimibe or rosuvastatin) may be potential undesirable effects with Suvezen. Common (≥1/100 to <1/10): diabetes mellitus, headache, dizziness, constipation, nausea, abdominal pain, diarrhoea, flatulence, myalgia, ALT and/or AST increased, asthenia and fatigue. Uncommon (≥1/1,000 to <1/100): decreased appetite, paraesthesia, hot flush, hypertension, cough, dyspepsia, gastroesophageal reflux disease, nausea, dry mouth, gastritis, pruritus, rash, urticaria, arthralgia, muscle spasms, neck pain, back pain, muscular weakness, pain in extremity, ALT and/or AST increased, blood CPK increased, gamma-glutamyltransferase increased, liver function test abnormal, chest pain, pain, asthenia, oedema peripheral. Rare (≥1/10,000 to <1/1,000): thrombocytopenia, hypersensitivity reactions including angioedema, pancreatitis, increased hepatic transaminases, myopathy (including myositis), rhabdomyolysis, lupus-like syndrome and muscle rupture. Very rare (<1/10,000): polyneuropathy, memory loss, jaundice, hepatitis, arthralgia, haematuria, gynaecomastia. Not known: thrombocytopenia, hypersensitivity (including rash, urticaria, anaphylaxis and angioedema), depression, peripheral neuropathy, sleep disturbances (including insomnia and nightmares), dizziness, paraesthesia, cough, dyspnoea,
diarrhoea, pancreatitis, constipation, hepatitis, cholelithiasis, cholecystitis, Stevens Johnson syndrome, erythema multiforme, immune-mediated necrotising myopathy, tendon disorders (sometimes complicated by rupture), myalgia, myopathy/rhabdomyolysis, oedema, asthenia. See SmPC for full details on adverse reactions. Legal Category: POM. Marketing Authorisation Numbers: 10mg/10mg: PA0540/193/001; 20mg/10mg: PA0540/193/002; 40mg/10mg: PA0540/193/003. Marketing Authorisation Holder: Sanofi-Aventis Ireland Ltd. T/A SANOFI, Citywest Business Campus, Dublin 24, Ireland. Further information is available from: Sanofi, 18 Riverwalk, Citywest Business Campus, Dublin 24 or contact IEmedinfo@sanofi.com Date of Preparation: December 2020. Adverse events should be reported. Reporting forms and information can be found at www.hpra.ie; email: medsafety@hpra.ie Adverse events should also be reported to Sanofi Ireland Ltd. Tel: 01 403 5600. Alternatively, send via email to IEPharmacovigilance@sanofi.comSingle-pillcombinationandrosuvastatinofezetimibeavailablein3doses** COMBININGPOWER AND CONFIDENCE AGAINST LDL-C* IN THE TREATMENT OF HYPERCHOLESTEROLAEMIA
20 mg /10 mg Rosuvastatin + Ezetimibe 10 mg /10 mg Rosuvastatin + Ezetimibe 40 mg /10 mg
Prescribing Information: Suvezen (rosuvastatin/ ezetimibe) film-coated tablets refer to the Summary Characteristics (SmPC) for full prescribing details. Presentations: Suvezen 10mg/10mg, 20mg/10mg and 40mg/10mg: Each film-coated tablet contains 10mg; 20mg or 40mg of rosuvastatin (as rosuvastatin calcium) respectively, and 10mg ezetimibe. Indication: Suvezen is indicated for substitution therapy in adult patients who are adequately controlled with rosuvastatin and ezetimibe given concurrently at the same dose level as in the fixed combination, but as separate products, as adjunct to diet for treatment of primary hypercholesterolaemia (heterozygous familial and non-familial) or homozygous familial hypercholesterolaemia. Dosage and Administration: The patient should be on and continue, an appropriate lipid-lowering diet, during treatment with Suvezen. Suvezen is not suitable for initial therapy. Treatment initiation or dose adjustment, if necessary, should only be done with the monocomponents and after setting the appropriate doses the switch to the fixed dose combination of the appropriate strength is possible. Patient should use the strength corresponding to their previous treatment. The recommended dose is one Suvezen tablet daily. To be administered at any time of the day, with or without food. The tablet should be swallowed whole with a drink of water. If co-administered with bile acid sequestrant (BAS), administration of Suvezen should occur either ≥2 hours before or ≥4 hours after administration of a BAS. Special populations: Paediatric (<18 years): Safety and efficacy has not been established. Elderly (>70 years): Starting dose of 5 mg rosuvastatin is recommended. The combination is not suitable for initial therapy. Hepatic impairment: Mild: No dosage adjustment is required. Moderate/Severe: Treatment with Suvezen is not recommended. Renal impairment: Mild: No dose adjustment is necessary. Moderate (creatinine clearance <60 ml/min): The recommended start dose is rosuvastatin 5mg. Race: The recommended start dose is rosuvastatin 5 mg for patients of Asian ancestry due to increased systemic exposure. The fixed dose combination is not suitable for initial therapy. Monocomponent preparations should be used to start the treatment or to modify the dose. Suvezen 40 mg/10 mg tablets are contraindicated in these patients. Genetic polymorphisms: In patients who are known to have specific types of genetic polymorphisms that can lead to increased rosuvastatin exposure, a lower daily dose of Suvezen is recommended. Dosage in patients with pre-disposing factors to myopathy: The recommended start dose is rosuvastatin 5mg in patients with pre-disposing factors to myopathy. Suvezen 40 mg/10 mg tablets are contraindicated in some of these patients. Concomitant therapy: The risk of myopathy (including rhabdomyolysis) is increased when Suvezen is administered concomitantly with certain medicinal products that may increase the plasma concentration of rosuvastatin (e.g. ciclosporin and certain protease inhibitors including combinations of ritonavir with atazanavir, lopinavir, and/or tipranavir). Whenever possible, alternative medications should be considered, and, if necessary, consider temporarily discontinuing Suvezen therapy. In situations where coadministration of these medicinal products with Suvezen is unavoidable, the benefit and the risk of concurrent treatment and rosuvastatin dosing adjustments should be carefully considered. Contraindications: Hypersensitivity to the active substances or excipients. Pregnancy, breast-feeding and in women of childbearing potential not using appropriate contraceptive measures. Active liver disease or any serum transaminase elevations which are unexplained, persistent or exceeding 3x the upper limit of normal (ULN). Severe renal impairment (creatinine clearance <30ml/min); myopathy or receiving concomitant ciclosporin. 40mg/10mg dose contraindicated in patients with pre-disposing factors for myopathy/rhabdomyolysis; such factors include: Moderate renal impairment (creatinine clearance <60ml/min), hypothyroidism, personal or family history of hereditary muscular disorders, previous history of muscular toxicity with another HMG-CoA reductase inhibitor or fibrate, alcohol abuse, situations where an increase in plasma levels of rosuvastatin may occur, Asian patients, concomitant use of fibrates.
calcium) respectively, and 10mg
Precautions and Warnings: Skeletal muscle effects: have been reported in rosuvastatin-treated patients with all doses and in particular with doses >20mg. As with other HMG-CoA reductase inhibitors, reporting rate for rhabdomyolysis is associated with use at doses >40mg. Post-marketing experience with ezetimibe, cases of myopathy and rhabdomyolysis have been reported. If myopathy is suspected based on muscle symptoms or is confirmed by a creatine phosphokinase (CPK) level, Suvezen and any of these other agents that the patient is taking concomitantly should be immediately discontinued. All patients starting therapy with Suvezen should be advised of the risk of myopathy and told to report promptly any unexplained muscle pain, tenderness or weakness, particularly if associated with malaise or fever. Creatine kinase (CK) measurement: CK should not be measured following strenuous exercise or in the presence of a plausible alternative cause of CK increase. If CK levels are significantly elevated at baseline (>5x ULN) a confirmatory test should be carried out within 5 – 7 days. If the repeat test confirms a baseline CK >5x ULN, treatment should not be started. Patients with pre-disposing factors for myopathy/ rhabdomyolysis: Caution should be exercised in these patients. Risk: benefit of treatment should be considered and clinical monitoring is recommended. CK levels should be measured in these patients. Therapy should be discontinued if CK levels are markedly elevated (>5x ULN) or if muscular symptoms are severe and cause daily discomfort. If symptoms resolve and CK levels return to normal, then consideration should be given to reintroducing treatment at the lowest dose. Immune-mediated necrotising myopathy (IMNM): Clinically characterised by proximal muscle weakness and elevated serum CK, has been reported very rarely during or after treatment with statins, including rosuvastatin, despite discontinuation of statin treatment. In clinical trials an increase in the incidence of myositis and myopathy has been seen in patients receiving other HMG-CoA reductase inhibitors together with fibric acid derivatives. Suvezen should not be used in any patient with an acute, serious condition suggestive of myopathy or predisposing to the development of renal failure secondary to rhabdomyolysis (e.g. sepsis, hypotension, major surgery, trauma, severe metabolic, endocrine and electrolyte disorders; or uncontrolled seizures). Liver effects: In controlled co-administration trials in patients receiving ezetimibe with statin, consecutive transaminase elevations ≥3x ULN have been observed. It is recommended that liver function tests be carried out prior to, and 3 months following, the initiation of treatment. Rosuvastatin should be discontinued or the dose reduced if the level of serum transaminases is >3x ULN. The reporting rate for serious events is higher at the 40mg dose. In patients with secondary hypercholesterolaemia caused by hypothyroidism or nephrotic syndrome, the underlying disease should be treated prior to initiating therapy with rosuvastatin. Liver disease and alcohol: As with other HMG-CoA reductase inhibitors, rosuvastatin should be used with caution in patients who consume
Suvezen is indicated for substitution therapy in adult patients who are adequately controlled with rosuvastatin and ezetimibe given concurrently at the same dose level as in the fixed combination, but as separate products, as adjunct to diet for treatment of primary hypercholesterolaemia (heterozygous familial and nonfamilial) or homozygous familial hypercholesterolaemia1 rosuvastatin (as rosuvastatin ezetimibe.
Please
of Product
Among the vaccinated patients, 12 had one dose and 43 had two doses. Patients were mainly vaccinated with BNT162b2 mRNA (53 patients, 96.4%). One patient had the mRNA-1273 vaccine and one had the Ad26.COV2-S [recombinant] vaccine.
Cardiogenic shock is a lifethreatening condition in which the heart suddenly fails to pump enough blood to supply the body’s organs with sufficient oxygen. It is usually caused by a large heart attack. It is estimated that up to 10% of patients with heart attacks affecting a large area of the heart also develop cardiogenic shock. Only half of patients who experience cardiogenic shock will survive.
The researchers included all patients hospitalised in Hospices Civils de Lyon during the last five years (from January 2016 to June 2021) with a diagnosis of acute myocarditis. Patients were contacted by telephone and asked if they had been vaccinated, with which vaccine, how many times, and whether they had any side effects. Patients were also asked if they currently had COVID-19 or had contracted it in the past.
A total of 142 patients with a prior history of confirmed acute myocarditis were enrolled in the study. The average age was 31 years and 20.3% were women. Among them, vaccination status was known for 71 patients (50%):
16 MAY 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE ESCardio 22
Women more likely to die after heart emergency than men
Women are less likely to receive lifesaving treatment for cardiogenic shock than men, according to research presented at ESC Acute CardioVascular Care 2022, a scientific congress of the European Society of Cardiology (ESC).
The researchers performed multivariate analysis to examine whether sex was independently associated with each therapy and with mortality. The analysis was adjusted for age and outof-hospital cardiac arrest at presentation as both factors affect outcome in heart attack patients with cardiogenic shock and are known to differ between women and men with the condition. The analysis revealed that female sex was independently associated with lower use of mechanical circulatory support and with worse short- and long-term survival.
Dr Holle said, “There is increasing evidence that women with acute heart problems are more likely than men to have non-specific symptoms such as shortness of breath, nausea, vomiting, coughing, fatigue, and pain in the back, jaw or neck. This might be one reason why more women than men in our study were initially admitted to a local, rather than specialist, hospital. Increased recognition that women may have symptoms other than chest pain could minimise delays in diagnosis and treatment and potentially improve prognosis.”
55 patients were vaccinated and 16 were not vaccinated. The main reason given for not getting the vaccine was the fear of myocarditis recurrence (12 patients, 75% of non-vaccinated patients). Vaccination status was unknown for 66 patients and five patients had died before the COVID-19 outbreak.
symptoms include fatigue, chest pain, shortness of breath, and rapid heartbeats. The inflammation can reduce the heart's ability to pump and can also cause arrhythmias (irregular heartbeats). Prevalence is estimated at 10 to 106 cases per 100,000 individuals worldwide. The leading cause of myocarditis is viral infection.
A total of 1,716 heart attack patients with cardiogenic shock were enrolled in the study, of which 438 (26%) were women. The average age of women was 71 years compared with 66 years for men. Patient characteristics were similar between sexes except for hypertension and chronic
The aim of this study was to investigate differences in treatment and survival between women and men with a heart attack and cardiogenic shock.
“The women and men in our study had similar clinical characteristics when they developed cardiogenic shock after a heart attack,” said study author Dr Sarah Holle of
Dr Abou Saleh pointed out, “Our experience shows that in some situations patients have avoided vaccination because they, or their GP, were afraid it could cause another bout of myocarditis. We hypothesised that SARS-CoV-2 vaccination would not increase the risk of myocarditis recurrence in patients who had the condition in the past.”
Copenhagen University Hospital, Rigshospitalet, Denmark. “This was a retrospective study so it is difficult to know why clinicians made certain treatment decisions. But the findings indicate that greater awareness among health professionals that women have heart attacks and may develop cardiogenic shock could be a step towards equitable management and outcomes.”
The study included all consecutive adults admitted between 2010 and 2017 to two highly specialised centres providing cardiogenic shock care for twothirds of the Danish population. Data on patient characteristics, treatment and 30-day mortality were extracted from medical records. Long-term mortality data were obtained from the Danish National Patient Registry.
obstructive pulmonary disease which were more common among women. Women were significantly more likely than men to be initially admitted to a local hospital (41% women versus 30% men), while significantly more men presented with out-of-hospital cardiac arrest (25% women versus 48% men).
When shock occurred, women and men had comparable clinical parameters such as blood pressure, heart rate, plasma lactate (a marker of oxygen levels in the organs) and left ventricular ejection fraction (heart pump function).
Regarding treatments, significantly lower proportions of women received mechanical circulatory support (19% women versus 26% men), minimally invasive or surgical procedures to restore blood flow to blocked arteries (83% women versus 88% men), and mechanical ventilation (67% women versus 82% men). Women were significantly less likely than men to survive in the short- and long-term. At 30 days after the heart event, just 38% of women were alive compared with 50% of men. At 8.5 years, 27% of women were alive compared with 39% of men.
Dr Abou Saleh said: “We showed that SARS-CoV-2 vaccination in patients with a history of acute myocarditis is not associated with a risk of recurrent myocarditis or other serious side effects. Our results should be interpreted with caution due to the small number of patients and the predominant use of one type of vaccine.”
Dr Holle concluded, “Treatment guidelines are based on studies which primarily enrolled men. Further research is needed to determine whether women and men with cardiogenic shock might benefit from different interventions.”
Rare cases of myocarditis following SARS-CoV-2 vaccination have been reported in the scientific literature with a prevalence of 2.1 cases for 100,000 inhabitants. However, there are a lack of data regarding the risk of myocarditis recurrence after SARS-CoV-2 vaccination in patients with a history of the condition.
The researchers also obtained information about side effects following vaccination from medical records. These included serious events such as death, arrhythmias, and recurrent myocarditis. There were no serious adverse events after SARS-CoV-2 vaccination.
photonic chip which enables ultra-high spatial resolution at video rates in optical microscopy, far beyond the diffraction limit of visible light.
This patented technology could aid early diagnostics and precision medicine, and help deliver improved drug treatments for patients facing a range of lifethreatening diseases.
“On behalf of myself and the wider PEARlabs team at UCD I am very pleased to receive this important Innovation Award. We are highly motivated to develop the best imaging methodology which will enable improved diagnostics and hence tailored therapies for highly relevant diseases to people,” said Professor Zerulla.
“I would like to thank the NovaUCD team for all their continuing support over the last number of years.”
Since he joined UCD in 2014 Professor Zerulla has disclosed 11
“Pharmacy united in action for a healthier world” is the theme of World Pharmacists Day on 25 September 2022.
inventions to NovaUCD, 5 of which have been patented.
The NovaUCD Innovation Award recognises excellence in innovation and of successes achieved in the commercialisation of UCD research or other intellectual activity over several years.
A total of eight awards were presented by Professor Barbara Dooley, Acting UCD Registrar and Deputy President during a ceremony held in the UCD University Club.
“The NovaUCD Innovation Awards which have become a key annual event at UCD, were established to recognise and highlight the successes being made by members of our research, innovation and entrepreneurial communities across the University,” said Professor Barbara Dooley.
Among the other 2022 awardees were the founders of BioSimulytics, NovoGrid, TestReach and Wayflyer.
His company PEARlabs, a spin-out from the UCD School of Physics, has been awarded over ¤700k in funding through the SFI Future Innovator Prize programme to further develop this technology.
A researcher whose work has the potential to transform the understanding of processes such as cell signalling and cell proliferation in cancer has also won this year’s NovaUCD Innovation Awards.
Patented Technology
17 HOSPITALPROFESSIONALNEWS.IE | HPN • MAY 2022 News
“I would like to take this opportunity to congratulate all those who have received Awards today and I wish them ongoing successes in the years ahead as they continue to deliver impact for the economy and society through their commercialisation, consultancy, entrepreneurial and innovation activities.”
This year’s theme aims to showcase pharmacy’s positive impact on health around the world and to further strengthen solidarity among the profession.
Innovation Awards Announced
“The United Nations Sustainable Development Goal number 3 sets out a number of health targets, including for non-communicable diseases (such as cardiovascular disease, cancer, diabetes, chronic respiratory disease and mental health) and communicable diseases (for example, HIV, tuberculosis and neglected
Professor Ronan Cahill, Professor of Surgery at UCD School of Medicine/MaterUniversityMisericordiaeHospital
tropical diseases). We have seen improvements in many of these areas and our profession should be proud of and make known its contributions. However, the COVID-19 pandemic has hindered progress and it is imperative that we rally to build back better,” said FIP president Mr Dominique
TheJordan.World Pharmacists Day campaign is led by FIP every year and provides an opportunity to promote the pharmacy profession. The theme is chosen by the FIP Bureau. We kindly request that organisations and individuals use FIP’s official campaign materials or that FIP is acknowledged in any alternative World Pharmacists Day materials or events developed. Please direct any queries to Ms Lin-Nam Wang (linnam@fip.org).
Professor Ronan Cahill has been awarded the 2022 NovaUCD Innovation Champion of the Year Award. Professor Cahill is Professor of Surgery at UCD School of Medicine and at the Mater Misericordiae University Hospital where he is championing digital innovation and innovative solutions in surgery.
The International Pharmaceutical Federation is inviting colleagues from all sectors of the pharmacy profession to take part in the campaign and show the world how pharmacists are united for health, regardless of and overcoming conflict, different politics and cultures, and economic disparity.
Professor Cahill has a major academic interest in surgical innovation and new technologies and is active in forging research partnerships, both nationally and internationally, focused on clinical and medical device development via phase 1, 2 and 3 trials.
At the Mater Hospital, he has led the establishment of a Clinical Anatomy Centre with Professor James Jones, UCD School of Medicine, the only in-hospital Advanced Surgery Training, Research and Development unit in the country which has provided over 1,000 training days for undergraduates and postgraduates through consultant level masterclasses.
Professor Dominic Zerulla received the 2022 award in recognition for the development of a novel
World Pharmacists Day 2022
ManagementAsthmaofAsthma in Children
18 MAY 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE Childhood
The cough is isolated with no other respiratory symptoms
The differential diagnosis for asthma includes inhaled foreign body, cystic fibrosis, primary ciliary dyskinesia, bronchopulmonary
There is chronic production of sputum
Symptoms are triggered by viral infections, exercise, allergen exposure, changes in weather, laughter, irritants such as car exhaust fumes, smoke, or strong smells
Symptoms are exerciseinduced dyspnoea with noisy inspiration (stridor)
Asthma is one of the most common chronic diseases worldwide affecting an estimated 300 million. Prevalence is increasing in many countries, especially in children. Asthma is a major cause of school and work absence (Manning et al., 2005). The Asthma Society of Ireland estimate that that 1 in 5 children experience asthma at some stage in their life. Poorly controlled asthma is expensive in terms of hospitalisations, visits to out of hour services, days missed from school and the negative impact on quality of life for children and their families. The Asthma Insights and Reality in Europe study revealed that a child with asthma will lose 10 days from school per year (Manning et al., 2005, Manning et al., 2007)
The Global Initiative for the diagnosis and Management of Asthma (GINA) provide professionals with a guide for symptom patterns in children which is useful in determining the probability of an asthma diagnosis (Figure 1). In children over 5, it is useful to carry out a peak flow diary for 2 weeks with the child recording their peak flow twice daily. Reversibility testing to Salbutamol can also be carried out for these children with an increase in PEFR of 12% indicating a positive diagnosis for asthma. Spirometry with bronchodilator reversibility may also be performed in children over 5.
There is a decreased probability that symptoms are due to asthma if:
Asthma is a heterogeneous disease, usually characterized by chronic airway inflammation which is defined by the history of respiratory symptoms such as wheeze, shortness of breath, chest tightness and cough that vary over time and in intensity, together with variable expiratory airflow limitation (GINA, 2021)
Assessment and identification of trigger factors can be challenging and very often, parents may not be aware of the potential trigger factors. Asking the parent to observe for potential trigger factors and use a symptom tracker over a period of time can be useful. Trigger factors can be inhaled (house dust mite, pollen, strong odours, smoke, animal dander), swallowed (foods, food additives and preservatives, medications such as Ibuprofen and betablockers) and non-allergic such as exercise, laughing or crying.
There is an increased probability that symptoms are due to asthma if:
There is shortness of breath associated with dizziness, lightheadedness or peripheral tingling
In children, asthma can be difficult to diagnose due to various differential diagnoses and the inability to perform peak flow readings in children under 5 years of age. A comprehensive and accurate history taking is essential and should include family history, medical and surgical history of the child, birth history, medications and trigger factors. Children born prematurely are at higher risk of developing asthma. Symptom history includes duration, type, onset, and pattern of symptoms. Symptom history can be difficult to obtain with some parents being vague about symptoms and the use of symptom diary is useful in these situations.
Physical assessment includes height and weight measurement. Chest examination to include chest expansion, percussion and auscultation. Chest x-ray is not indicated for the diagnosis of asthma unless the child fails to respond to inhaled treatment. Allergy testing may be useful in helping to identify possible trigger factors. Forced Exhaled Nitrous Oxide (FEN0) testing can be helpful to confirm the diagnosis of asthma and to assess eosinophilic inflammation.
ASSESSMENT AND DIAGNOSIS OF ASTHMA
Symptoms often worse at night or in the early morning
Written by Ruth Morrow, Respiratory Nurse Specialist, Asthma Society of FigureIreland1:
There is more than one type of symptom (wheeze, shortness of breath, cough, chest tightness)
Symptoms vary over time and in intensity
Symptom pattern in children (GINA, 2021)
Pulse rate <100 beats/min >200 beats/min (0 3 years) >180 beats/min (4 5 years)
All children who experience an acute exacerbation of asthma should be reviewed 6 hours after their event if they are not referred to secondary care. Criteria for immediate transfer to secondary care include:
Parent/carer unable to manage child at home
Oncebeforetoinhalercontrolledcorticosteroids.shouldSalbutamolisthecorticosteroidchangemanagementapproachGINAasthmacontroltest.com/).https://www.(2021)providesastep-wiseforthepharmacologicalofasthma.Inarecenttotheguidelines,aninhaledshouldbeusedatsametimewhenSalbutamolused.ChildrenwhoareusingmorethantwiceaweekbecommencedoninhaledIfthechildisnotontheappropriatestep,techniqueandadherencemedicationshouldbereviewedmovinguptothenextstep.optimalcontrolhasbeen
19 HOSPITALPROFESSIONALNEWS.IE | HPN • MAY 2022
Paediatrician with Asthma & Allergy and Lisa Egan Respiratory Paediatric ANP from the Midlands Hospital, Portlaoise.
Table 1: Assessment of acute exacerbation of asthma (GINA, 2021)
in March 2020.
Assessment of asthma control involves assessing symptoms over the previous 4 weeks and assessing risk factors for poor outcomes. Treatment issues should also be addressed at every visit and should include:
Checking inhaler technique and adherence
References available on request
Symptoms Mild Severe
Child is unable to speak or drink Cyanosis
4. Additional treatments can include - For moderate/severe exacerbations, give 2 puffs of ipratropium bromide 80mcg (or 250mcg by nebulizer) every 20 minutes for one hour only
1. Features of severe exacerbation at initial or subsequent assessment
3. Unable to be managed at home
Persisting tachypnoea despite 3 administrations of inhaled SABA, even if the child shows other clinical signs of improvement
Silent chest on auscultation
Asthma and COVID19 in children with asthma
Central cyanosis Absent Likely to be present
Wheeze intensity Variable Chest may be quiet
1. Oxygen therapy - 24% delivered by face mask (usually 1L/min) to maintain oxygen saturation 94-98%.
3. Oral corticosteroids - Give initial dose of oral prednisolone (12mg/kg up to maximum of 20mg for children <2 years; 30 mg for 2-5 years).
2. Risk reduction: to minimize future risk of exacerbations, fixed airflow limitation and medication side-effects
Assessment and Management of Acute asthma
1. Oxygen therapy - 24% delivered by face mask (usually 1L/min) to maintain oxygen saturation 94 98%
3. Oral corticosteroids - Give initial dose of oral prednisolone (1 2mg/kg up to maximum of 20mg for children <2 years; 30 mg for 2 5 years)
Symptom control: to achieve good control of symptoms and maintain normal activity levels
The goals of 1.managementasthmaare:
Subcostal retraction
Risk factors for poor outcomes
Accurate and timely assessment of acute asthma exacerbations should be carried out to ensure a successful outcome. Table 1 differentiates between a mild and severe acute exacerbation.
Table 1: Assessment of acute exacerbation of asthma (GINA, 2021)
Oximetry on presentation (SaO2) >95% <92%
Management of Stable Asthma
Reviewing the child’s written asthma action plan?
Social environment that impairs delivery of acute treatment
MDI with spacer is the first choice for the delivery of medication in stable asthma for children under 5 and up to the age of 7/8. After this, a dry powder device or breath actuated device may be an option for the delivery of treatment. Nebulizers should be reserved for the management of severe acute exacerbations of asthma. Side effects of inhaled corticosteroid medication include dysphonia and oral candidiasis and parents should be educated in the avoidance of these side effects ie rinsing the mouth out
Asking about side-effects
and brushing the teeth. Where face masks are used, it is vital to ensure that mask is the correct size and fits correctly to form a seal around the mouth and nose so as to avoid deposition of the drug into the eyes. The face should be washed following administration of inhaled corticosteroids.
2. Inhaled bronchodilatorshort-acting-2–6 puffs of Salbutamol by spacer, or 2.5mg by nebulizer, every 20 min for first hour, then reassess severity. If symptoms persist or recur, give an additional 2-3 puffs per hour. Admit to hospital if >10 puffs required in 3-4 hours.
Lack of response to 6 puffs of inhaled SABA (2 separate puffs, repeated
3 times) over 1-2 hours
The management of acute asthma includes:
Accurate and timely assessment of acute asthma exacerbations should be carried out to ensure a successful outcome. Table 1
Asthma Awareness Week runs from 1-7 May 2022. The Asthma Society of Ireland are running a webinar for health care professionals and parents/ guardians on Thursday 5th May 2022 with Dr Tariq Consultant
Speech Sentences Words
Exploring the parent’s attitudes and goals for their asthma?
Children who experience uncontrolled asthma symptoms, had one or more exacerbation in the previous year, the start of the child’s usual ‘flare-up’ season (especially if autumn), has major psychological or socio-economic problems for child or family, poor adherence with controller medication, or children with incorrect inhaler technique are at risk of an exacerbation in the coming months.
The Asthma Control Test (ACT) for children is a useful tool to assess the child’s level of control and the impact asthma may be having on their day-to-day life (available on
Assessment and Management of Acute asthma
The management of acute asthma includes:
dysplasia and immune deficiency. Failure to respond to treatment warrants further investigation to out rule any of these conditions.
This article has explored asthma in children which can be difficult and challenging to diagnose and treat. Asthma is the most common chronic condition affecting over 10% of children. The burden of childhood asthma is significant in terms of healthcare costs and the impact on the child’s and family’s quality of life. With good asthma control, children can expect to live a normal and fulfilled childhood.
A study by Shi et al (2021) explored data from primary care, community prescribing, hospital admissions, and deaths. It provides a detailed insight into the risk of severe SARS-CoV-2 in children aged 5–17 years with asthma in Scotland. The findings from Shi and colleagues’ study suggest that compared with children without asthma, the risk of admission to hospital with COVID-19 is increased in children with a diagnosis of asthma particularly when they have previously been admitted to hospital with asthma or have required two or more courses of oral corticosteroids in the 24 months before the study start date in March 2020.
achieved for at least 3 months, then medication can be titrated down.
2. Lack of response to initial bronchodilator treatment
4. Additional treatments can include - For ipratropiumexacerbations,moderate/severegive2puffsofbromide80mcg(or 250mcg by nebulizer) every 20 minutes for one hour only.
Oxygen saturation <92% when breathing room air
2. Inhaled short acting bronchodilator - 2–6 puffs of Salbutamol by spacer, or 2.5mg by nebulizer, every 20 min for first hour, then reassess severity. If symptoms persist or recur, give an additional 2 3 puffs per hour. Admit to hospital if >10 puffs required in 3 4 hours.
Altered consciousness No Agitated, confused or drowsy
differentiates between a mild and severe acute exacerbation.
• Increasing levels of emigration due to toxic working environment
Professor Subrata Ghosh, a global leader in research into Crohn's disease and ulcerative colitis
Dr Cannon said that the NCHD Committee would consider various steps to have the situation addressed including the possibility of industrial action. He said, “No doctor ever wants to go take industrial action let alone go on strike so the fact that this is even part of the conversation shows how unsustainable the present situation is.”
The Chair of the IMO NCHD Committee, Dr John Cannon, has written to all NCHDs urging participating at the forthcoming meeting where the IMO will
• NCHDs not being paid for all hours worked
working in the Irish health services playing critical roles on the front line of patient care and progressing to work as Consultants or General Practitioners.
As Hospital Professional News was going to press, the Irish Medical Organisation (IMO) called an emergency meeting of NCHDs across the country for Monday 11th April. The meeting was set to address the deteriorating working conditions and flagrant contractual breaches faced by NCHDs on a daily Therebasis.areover 7,500 NCHDs
• NCHDs routinely being required to work single shifts in excess of 24 hours and over 48 hours a week
• Rising mental health issues amongst NCHDs
“The NCHD cohort is critical to the successful operation of the health services and is the lifeblood of the next generation of Consultants
• Inability to take full annual leave or study leave entitlements
World-leading expert in gut inflammation joins UCC
¤5.6 million in funding has been awarded to Professor Subrata Ghosh, a global leader in research into Crohn's disease and ulcerative colitis, to establish a worldleading research lab at University College Cork (UCC), through a prestigious Science Foundation Ireland Research Professorship Programme award.
Microbiome Ireland SFI Research Centre, to investigate precision medicine in relation to gut inflammation and the microbiome.
20 MAY 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE
This will contribute to furthering research in IBD, Crohn's Disease and Ulcerative Colitis, which affect 40,000 people in Ireland and ten million people globally every year.
The grant will resource a science research lab, and equipment, as well as 13 personnel, to investigate
the nascent area of the microbiome in relation to gut inflammation and how it can be influenced by precision medicine to address critical health challenges.
Professor Ghosh is a Fellow of the Academy of Medical Sciences, UK and Fellow of the Canadian Academy of Health Sciences, the highest honours bestowed for leadership in life sciences and health research in those
and GPs. But the HSE and the Government continue to take this group for granted and force them to work illegal hours, often without correct pay and with little regard to their physical or mental health.”
outline the startling extent of unsafe working hours and the increasing disputes over agreed contract terms. The meeting was held Accordingvirtually.to
“There is a reason why doctors leave Ireland, and we hope that Government and the HSE will pay attention and do something to address the systemic problems in our healthcare system. However, we will be recommending to our members that if we do not get reasonable and serious engagement there may be no alternative but to consider industrial action because allowing the current situation to persist is just not acceptable. It is bad for doctors and bad for patients.”
IMONewswarns of Industrial Action
countries. Attracted to UCC from the University of Birmingham (UK) because of the world-class research in microbes and food carried out at APC Microbiome Ireland and Teagasc, Prof Ghosh says that many of the important clues to what causes Crohn's Disease and Ulcerative Colitis, both currently incurable, are emerging from their research.
Professor Ghosh will lead the new AUGMENT project at UCC’s APC
Dr Cannon, key issues include:
• NCHDs continuing to be required to work far in excess of legal and safe working hours often in breach of the European Working Time Directive
“Chronic inflammatory diseases and cancer are major causes of disability and death in Ireland and in the world. Current treatments are limited by their efficacy ceiling and adverse effects” commented Prof Ghosh. “Increasing the efficacy of currently used targeted therapies and minimising adverse events through modulation of the gut microbiome may have a major impact on the life of the sufferers and address the economic burden of expensive therapies that prove to be ineffective. This SFI Research Professorship award aims to work with those affected by chronic inflammatory diseases and cancer to find novel solutions that enhance the efficacy of current drugs and minimise harmful side effects by understanding the role of the gut microbiome in mediating the action of drugs.”
Crescent Building, Northwood Business Park, Santry, Dublin 9, D09 X8W3, Ireland. Tel: 01 8629 700, Fax: 01 8629 725, Lo call: 1 850 665665. infoireland@novonordisk.com www.novonordisk.ie Saxenda® and the Apis bull logo are registered trademarks owned by Novo Nordisk A/S. Date of preparation: January 2022. IE22SX00004. liraglutide
Novo
to GI side effects and take precautions to avoid fluid depletion. Signs and symptoms of dehydration, including renal impairment and acute renal failure have been reported. Patients with type 2 diabetes mellitus receiving Saxenda® in combination with insulin and/or sulfonylurea may have an increased risk of hypoglycaemia. Dizziness can be experienced mainly during the first 3 months of treatment, therefore use caution when driving or using machines if dizziness occurs. Episodes of clinically significant hypoglycaemia have been reported in adolescents (≥12 years) treated with liraglutide; patients should be informed about characteristic symptoms of hypoglycaemia and appropriate actions. Fertility, pregnancy and lactation: Saxenda® should not be used during pregnancy or breastfeeding. If a patient wishes to become pregnant, or pregnancy occurs, treatment with Saxenda® should be discontinued. Undesirable effects: Very common (≥1/10): headache, nausea, vomiting, diarrhoea, constipation. Common (≥1/100 to <1/10): hypoglycaemia, insomnia, dizziness, dysgeusia, dry mouth, dyspepsia, gastritis, gastro-oesophageal reflux disease, abdominal pain upper, flatulence, eructation, abdominal distension, cholelithiasis, injection site reactions, asthenia, fatigue, increased lipase, increased amylase. Uncommon (≥1/1,000 to <1/100): dehydration, tachycardia, pancreatitis, delayed gastric emptying, cholecystitis, urticaria, malaise. Rare (≥1/10,000 to <1/1,000): anaphylactic reaction, acute renal failure, renal impairment. The SmPC should be consulted for a full list of side effects. Legal category: POM MA number: 5 x 3 ml pre-filled pens EU/1/15/992/003 For complete prescribing information, please refer to the SmPC which is available on www.medicines.ie or by email from infoireland@novonordisk.com or from the Clinical, Medical and Regulatory Department, Novo Nordisk Limited, 1st Floor, Block A, The Crescent Building, Northwood Business Park, Santry, Dublin 9, Ireland. Date last revised: November 2021.
Your patients with obesity have the will. You can offer them the way.
I haVe the will to work out eVery day. But I still need help to lose weight and keep it off.
of concomitantly administered insulin or insulin secretagogues (such as sulfonylureas) to reduce risk of hypoglycaemia. Blood glucose self-monitoring is necessary to adjust the dose of insulin or insulin-secretagogues. The safety and efficacy of Saxenda in children below 12 years of age has not been established. Contraindications: Hypersensitivity to the active substance or to any of the excipients. Special warnings and precautions for use: Saxenda® must not be used as a substitute for insulin in patients with diabetes mellitus. Diabetic ketoacidosis has been reported after rapid discontinuation or dose reduction of insulin. There is no clinical experience in patients with congestive heart failure New York Heart Association (NYHA) class IV and therefore Saxenda® is not recommended for use in these patients. Saxenda® is not recommended in patients: aged 75 years or more, treated with other products for weight management, with obesity secondary to endocrinological or eating disorders or to treatment with medicinal products that may cause weight gain, with severe renal impairment including end-stage renal disease, with severe hepatic impairment. Saxenda® must be used with caution in patients with mild or moderate hepatic impairment. Saxenda® is not recommended in patients with inflammatory bowel disease and diabetic gastroparesis. Acute pancreatitis has been observed with the use of GLP-1 receptor agonists, patients should be informed of the characteristic symptoms. If pancreatitis is suspected, Saxenda® should be discontinued; if acute pancreatitis is confirmed, Saxenda® should not be restarted. In clinical trials for weight management, a higher rate of cholelithiasis and cholecystitis was observed in patients on Saxenda® than those on placebo, therefore inform patients of characteristic symptoms. Use with caution in patients with thyroid disease. An increase in heart rate was observed with liraglutide in clinical trials. Heart rate should be monitored at regular intervals and patients informed of the symptoms of increased heart rate. For patients who experience a clinically relevant sustained increase in resting heart rate, treatment with Saxenda® should be discontinued. Patients treated with Saxenda® should be advised of the potential risk of dehydration in relation
Saxenda® Liraglutide injection 3 mg. Please refer to the full Summary of Product Characteristics (SmPC) before prescribing. Saxenda® 6 mg/ml solution for injection in a prefilled pen. One pre-filled pen contains 18 mg liraglutide in 3 ml. Indication: Adults: Saxenda® is indicated as an adjunct to a reduced-calorie diet and increased physical activity for weight management in adult patients with an initial Body Mass Index (BMI) of ≥ 30 kg/m² (obesity) or ≥ 27 kg/m² to < 30 kg/ m² (overweight) in the presence of at least one weight-related comorbidity. Treatment with Saxenda® should be discontinued after 12 weeks on the 3.0 mg/day dose if patients have not lost at least 5% of their initial body weight. Adolescents (≥12 years): Saxenda® can be used as an adjunct to a healthy nutrition and increased physical activity for weight management in adolescent patients from the age of 12 years and above with obesity (BMI corresponding to ≥30 kg/m2 for adults by international cut-off points)* and body weight above 60 kg. Treatment with Saxenda should be discontinued and re-evaluated if patients have not lost at least 4% of their BMI or BMI z score after 12 weeks on the 3.0 mg/day or maximum tolerated dose. *See table 1 in SmPC. Posology and administration: Adults: The starting dose is 0.6 mg once daily. Dose should be increased to 3.0 mg once daily in increments of 0.6 mg with at least one-week intervals to improve gastro-intestinal (GI) tolerability. If escalation to the next dose step is not tolerated for two consecutive weeks, consider discontinuing treatment. Adolescents (≥12 years): A similar dose escalation schedule as for adults should be applied. The dose should be increased until 3.0 mg (maintenance dose) or maximum tolerated dose has been reached (see SmPC). Adults and Adolescents: Daily doses higher than 3.0 mg are not recommended. Saxenda® is administered once daily at any time, independent of meals, subcutaneously injected in the abdomen, thigh or upper arm, preferably around the same time of the day. Saxenda® must not be administered intravenously or intramuscularly. Saxenda® should not be used in combination with another GLP-1 receptor agonist. When initiating treatment in patients with type 2 diabetes mellitus, consider reducing the dose
ROBERTO, civil servant; Age: 48 BMI: 39 Patient portrayal.
Abbreviated Prescribing Information Nordisk The
Limited, First Floor, Block A,
Adverse events should be reported to the Health Products Regulatory Authority. Information about adverse event reporting is available at www hpra.ie. Adverse events should also be reported to Novo Nordisk on Tel: 1850 665 665 or complaintireland@novonordisk.com
ONPATTRO® is a trademark of Alnylam Pharmaceuticals, Inc. © 2020 Alnylam Pharmaceuticals, Inc. All rights reserved. September 2021 | TTR02-CEMEA-00005
identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions.RegardlesshereditaryONPATTROmanifestationsstage
ONPATTRO® (patisiran)in
infusions of Onpattro without experiencing IRRs before each reduction in corticosteroid premedication. Therapy should be initiated under the supervision of a physician knowledgeable in the management of amyloidosis.Consult the summary of product characteristics for further details about the method of administration. Contraindications: Severe hypersensitivity (e.g., anaphylaxis) to the active substance or any of the excipients. Special warnings and precautions for use: IRRs have been observed in patients treated with Onpattro. In patients experiencing an IRR, the majority experienced the first IRR within the first 2 infusions. Across clinical studies, the most common symptoms (reported in ≥ 2% of patients) of IRRs were flushing, back pain, nausea, abdominal pain, dyspnoea, and headache. IRRs may also include but are not limited to hypotension, syncope and pruritus. To reduce the risk of IRRs, patients should receive premedications on the day of Onpattro infusion, at least 60 minutes prior to the start of infusion. If an IRR occurs, slowing or interrupting the infusion and institution of medical management (e.g., corticosteroids or other symptomatic treatment) should be considered, as clinically indicated. If the infusion is interrupted, resumption of the infusion at a slower infusion rate may be considered after symptoms have resolved. The Onpattro infusion should be discontinued in the case of a serious or life-threatening IRR. Some patients who experience IRRs may benefit from a slower infusion rate or additional or higher doses of one or more of the premedications with subsequent infusions to reduce the risk of IRRs. By reducing serum TTR protein, Onpattro treatment leads to a decrease in serum vitamin A (retinol) levels. Serum vitamin A levels below the lower limit of normal should be corrected and any
monitoring.
Onpattro® (patisiran) Abbreviated Prescribing Information
medicinal product
Now reimbursed in Republic of Ireland.
Please refer to the Summary of Product Characteristics for further information. Name of the Medicinal Product: Onpattro (patisiran) 2 mg/mL concentrate for solution for infusion. Qualitative and quantitative composition: Each mL contains patisiran sodium equivalent to 2 mg patisiran. Each vial contains patisiran sodium equivalent to 10 mg patisiran formulated as lipid nanoparticles. Therapeutic Indication: Onpattro is indicated for the treatment of hereditary transthyretin-mediated amyloidosis (hATTR amyloidosis) in adult patients with stage 1 or stage 2 polyneuropathy. Posology and method of administration: The recommended dose of Onpattro is 300 micrograms per kg body weight administered via intravenous (IV) infusion once every 3 weeks. Dosing is based on actual body weight. For patients weighing ≥ 100 kg, the maximum recommended dose is 30 mg. Vitamin A supplementation at approximately 2500 IU vitamin A per day is advised for patients treated with Onpattro. All patients should receive premedication prior to Onpattro administration to reduce the risk of infusion- related reactions (IRRs). Each of the following medicinal products should be given on the day of Onpattro infusion at least 60 minutes prior to the start of infusion: • Intravenous corticosteroid (dexamethasone 10 mg, or equivalent), • Oral paracetamol (500 mg), • Intravenous H1 blocker (diphenhydramine 50 mg, or equivalent), • Intravenous H2 blocker (ranitidine 50 mg, or equivalent) For premedications not available or not tolerated intravenously, equivalents may be administered orally. If clinically indicated, the corticosteroid may be tapered in decrements no greater than 2.5 mg to a minimum dose of 5 mg of dexamethasone (intravenous, IV), or equivalent. The patient should receive at least 3 consecutive IV
This is subject to additional This will allow quick
has demonstrated benefits vs placebo across the
manifestations typically seen in patients with hereditary
amyloidosis with stage 1 or 2 polyneuropathy1,3,4 1.ReferencesONPATTRO®. EU Summary of Product Characteristics. 2. Coelho T, et al. Curr Med Res Opin. 2013;29(1): 63–76. 3. Adams D, et al. N Engl J Med. 2018;379(1):11–21. 4. Solomon SD, et al. Circulation. 2019;139(4):431–443. ATTR, TTR amyloidosis; hATTR, hereditary ATTR amyloidosis; TTR, transthyretin. Developed and produced by Alnylam Pharmaceuticals ONPATTRO®: Your opportunity to reset treatment expectations in hereditary ATTR amyloidosis with polyneuropathy (patisiran) is indicated for the treatment of hATTR amyloidosis in adult patients with stage 1 or stage 2 polyneuropathy1 Adverse events should be reported. Reporting forms and information can be found at HPRA Pharmacovigilance, Website: https://www.hpra.ie/homepage/about-us/report-an-issue/ human-adverse-reaction-form. Adverse events should also be reported to Alnylam Netherlands B.V. at 1800 924260 (+353 7 667 05596) or medinfo@alnylam.com
woman. Undesirable effects: The most frequently occurring adverse reactions reported in Onpattrotreated patients were peripheral oedema (29.7%) and infusion-related reactions (18.9%). The only adverse reaction resulting in the discontinuation of Onpattro was an infusion-related reaction (0.7%). The adverse reactions are presented below as MedDRA preferred terms under the MedDRA System Organ Class (SOC) by frequency. Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. The frequency of the adverse reactions is expressed according to the following categories: Very common (≥ 1/10) Infusion-related reaction, Peripheral oedema. Common (≥ 1/100 to < 1/10) Bronchitis, Sinusitis, Rhinitis, Vertigo, Dyspnoea, Dyspepsia, Erythema, Arthralgia, Muscle spasms, Uncommon (≥ 1/1,000 to < 1/100) Extravasation. Prescribers should consult the Summary of Product Characteristics for further details of the above and for details of other adverse reactions. Marketing Authorisation Number EU/1/18/1320/001. Additional information is available from the Marketing Authorisation Holder: Alnylam Netherlands B.V. Antonio Vivaldistraat 150 1083 HP Amsterdam, Netherlands. Legal Classification: Medicinal product subject to restricted medical prescription. Pack size and Price: €8520.84 per vial (10mg/5ml) of Onpattro (patisiran) concentrate for solution for infusion. Date of last revision: 02/2021.
Regardless of the mutation or predominant symptomatology, all patients with hereditary ATTR amyloidosis develop mixed symptoms2
ocular symptoms or signs due to vitamin A deficiency should be evaluated prior to initiation of treatment with Onpattro. Patients receiving Onpattro should take oral supplementation of approximately 2500 IU vitamin A per day to reduce the potential risk of ocular toxicity due to vitamin A deficiency. Referral for ophthalmological assessment is recommended if patients develop ocular symptoms suggestive of vitamin A deficiency, including reduced night vision or night blindness, persistent dry eyes, eye inflammation, corneal inflammation or ulceration, corneal thickening or corneal perforation. Serum vitamin A levels should not be used to guide vitamin A supplementation during treatment with Onpattro. Fertility, pregnancy and lactation: There are no data on the effects of Onpattro on human fertility. No impact on male or female fertility was detected in animal studies. There are no data on the use of Onpattro in pregnant women. Animal studies are insufficient with respect to reproductive toxicity. Due to the potential teratogenic risk arising from unbalanced vitamin A levels, Onpattro should not be used during pregnancy, unless the clinical condition of the woman requires treatment. As a precautionary measure, vitamin A and thyroid stimulating hormone (TSH) levels should be obtained early in pregnancy. Close monitoring of the foetus should be carried out in the event of an unplanned pregnancy, especially during the first trimester. Women of childbearing potential have to use effective contraception during treatment with Onpattro. It is unknown whether Onpattro is excreted in human milk. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from Onpattro, taking into account the benefit of breast feeding for the child and the benefit of therapy for the
ONPATTRO® multi-system ATTR
Familial Syndromic and Non-Syndromic Aortopathy
First described in 1896 by French paediatrician Antoine BernardJean Marfan, this syndrome represents the commonest form of syndromic aortopathy. It is an autosomal dominant disorder caused by mutations in the FBN-1 gene encoding fibrillin-1. Fibrillin-1 is a large, extracellular matrix glycoprotein that serves as a structural component of microfibrils. These forcebearing support structures are widely distributed in elastic and nonelastic tissues.
Current guidelines for prophylactic aortic surgery include an ascending aortic or root diameter ≥50mm (ESC(1) and ACCF/ AHA(2)), ≥45mm in the presence of additional risk factors (ESC and ACCF/AHA) or ≥40mm if considering pregnancy (ACCF/ AHA). Unfortunately, present data indicate that as many as 15% of individuals experience acute aortic syndromes while outside of these thresholds. The identification of individuals at increased risk, despite a lower aortic diameter, represents an important priority for future investigation.
Individuals affected by MFS are subject to an increased rate of aortic dilatation compared to the general population, as well
Loeys-Dietz syndrome
Approximately 25% of aortic dissections have an identifiable genetic basis. Individuals with familial aortopathy may present with a syndromic (associated with a phenotypic presentation) or nonsyndromic (pure vascular type) variant. In syndromic aortopathies, aortic disease is an overwhelming contributor to morbidity and mortality. For example, over 90% of Marfan syndrome (MFS) deaths relate to aortic complications. Familial aortopathies account for the majority of aortic dissections in younger age groups (<40s). Current management includes surveillance, lifestyle adjustment, pharmacological therapies, and prophylactic or emergent aortic surgery. Genetic counselling plays an additional role.
Mr Niall Khan
Loeys-Dietz syndrome (LDS) is a connective tissue disorder first described by Bart Loeys and Harry C Dietz in 2005. This autosomal dominant condition is characterized by aortic aneurysms, generalized arterial tortuosity, hypertelorism, bifid uvula or cleft palate. Five genes are implicated, all affecting the signalling of transforming growth factor β (TGFβ). The 5 subtypes of LDS (LDS 1-5) are respectively named according to the gene involved; TGFBR1, TGFBR2, SMAD3, TGFB2 and TGFB3. The disorder is rare, with an estimated prevalence of <1 in 100,000. LDS 1 and 2 appear to be the commonest and are associated with significant cardiovascular involvement.
24 MAY 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE
as an increased risk of acute aortic events at any given aortic diameter. Aortic dissection most commonly occurs in the third decade and a significant proportion of remaining individuals will have undergone prophylactic aortic surgery by this age.
MFS affects 0.5-1 in 10,000 live births with a uniform sex distribution. Diagnosis is via the Ghent nosology (Table 1), within which the typical clinical features are well described (Table 2). Clinical diagnosis with the Ghent nosology appears to correlate well with the presence of FBN-1 gene mutations. Central to the diagnosis are the findings of a positive family history, aortic root dilatation (Figure 1), or ectopia lentis.
Introduction
Mr Saleem Jahangeer
Marfan Syndrome
Written by Mr Niall Khan, Specialist Registrar in Cardiothoracic Surgery, St James’s Hospital & Mr Saleem Jahangeer, Consultant Cardiothoracic and Aortic Surgeon- aorta@stjames.ie
Aortopathy is a term which encompasses all disorders of the aortic wall, not solely aneurysm, acknowledging that size is not the sole contributor to aortic complications. The commonest, and potentially preventable, cause of death in aortopathy is acute aortic dissection. This arises when regional wall stress leads to intimal disruption, separation of the intima and media, and development of a false lumen. Subsequent complications such as aortic rupture or acute aortic valve insufficiency contribute to the considerable mortality rate associated with this condition.
Table 1
In presence of family history • Ectopia lentis AND Family History of Marfan syndrome • A systemic score ≥ 7 points AND Family History of Marfan syndrome • Aortic Root Dilatation Z score ≥ 2 above 20 yrs. old, ≥ 3 below 20 yrs. old + Family History of Marfan syndrome In absence of family history • Aortic Root Dilatation Z score ≥ 2 AND Ectopia Lentis • Aortic Root Dilatation Z score ≥ 2 AND FBN1 • Aortic Root Dilatation Z score ≥ 2 AND Systemic Score ≥ 7pts • Ectopia lentis AND a FBN1 mutation associated with Aortic Root Dilatation
The aortopathy in LDS leads to rapidly progressive aneurysmal disease. Congenital heart disease is a further association, including conditions such as bicuspid aortic valve, atrial septal defect, and persistent ductus arteriosus. The presence of such conditions further contributes to the progression of aortopathy. Aortic dissection is frequent and has been reported in individuals as young as three months of age.
In general, prophylactic aortic surgery is indicated at established size thresholds when the perceived risk of spontaneous complications is estimated to outweigh that of the elective repair. Outcomes for elective surgery are superior to those of emergency repair. A proportion of those experiencing acute aortic complications may also succumb before reaching the operating Unfortunately,table.current guidelines for prophylactic aortic surgery are imperfect. Acute aortic syndromes continue to occur in those below guideline’s thresholds. This phenomenon is particularly pronounced in those with familial aortopathy, in whom further contributors to aortic wall weakness exist, independent of size alone. Due to the relative rarity of these conditions, reliable thresholds for intervention have been difficult to determine, and a personalized approach must often be Thisemployed.articlewill review the most well described familial aortopathies and provide an overview of their management.
Given the relative rarity of these disorders, data to support specific indications for prophylactic surgery are lacking. The ESC does not make any specific recommendation in the case of LDS, but highlight a need for
Syndromic Aortopathies
Aortic Disease
The health information contained in this ad is provided for educational purposes only. Date of Preparation: February 2021 GCMA code: PP-RDP-IRL-0105 heart failure with preserved ejection fraction in patients typically over 60 years old5-7 Life-threatening, underrecognized, and underdiagnosed, ATTR-CM is a rare condition found in mostly older patients in which misfolded transthyretin proteins deposit in the heart.1-7 It is vital to recognize the diagnostic clues so you can identify this disease. to standard heart failure therapies (ACEi, ARBs, and beta blockers)8-10 between QRS voltage and left ventricular (LV) wall thickness11-13 of carpal tunnel syndrome or lumbar spinal stenosis3,8,14-20 showing increased LV wall thickness6,13,16,21,22 —autonomic nervous system gastrointestinaldysfunction-includingcomplaints or unexplained weight loss6,16,23,24 1.References Sipe JD, Benson MD, Buxbaum JN, et al. Amyloid fibril proteins and amyloidosis: chemical identification and clinical classification International Society of Amyloidosis 2016 Nomenclature Guidelines. Amyloid. 2016;23(4):209-213. 2. Maurer MS, Elliott P, Comenzo R, Semigran M, Rapezzi C. Addressing common questions encountered in the diagnosis and management of cardiac amyloidosis. Circulation. 2017;135(14):1357-1377. 3. Connors LH, Sam F, Skinner M, et al. Heart failure due to age-related cardiac amyloid disease associated with wild-type transthyretin: a prospective, observational cohort study. Circulation. 2016;133(3):282-290. 4. Pinney JH, Whelan CJ, Petrie A, et al. Senile systemic amyloidosis: clinical features at presentation and outcome. J Am Heart Assoc. 2013;2(2):e000098. 5. Mohammed SF, Mirzoyev SA, Edwards WD, et al. Left ventricular amyloid deposition in patients with heart failure and preserved ejection fraction. JACC Heart Fail. 2014;2(2):113-122. 6. Maurer MS, Hanna M, Grogan M, et al. Genotype and phenotype of transthyretin cardiac amyloidosis: THAOS (Transthyretin Amyloid Outcome Survey). J Am Coll Cardiol. 2016;68(2):161-172. 7. González-López E, Gallego-Delgado M, Guzzo-Merello G, et al. Wild-type transthyretin amyloidosis as a cause of heart failure with preserved ejection fraction. Eur Heart J. 2015;36(38):2585-2594. 8. Narotsky DL, Castano A, Weinsaft JW, Bokhari S, Maurer MS. Wild-type transthyretin cardiac amyloidosis: novel insights from advanced imaging. Can J Cardiol. 2016;32(9):1166.e1-1166.e10. 9. Brunjes DL, Castano A, Clemons A, Rubin J, Maurer MS. Transthyretin cardiac amyloidosis in older Americans. J Card Fail. 2016;22(12):996-1003. 10. Castaño A, Drach BM, Judge D, Maurer MS. Natural history and therapy of TTR-cardiac amyloidosis: emerging disease-modifying therapies from organ transplantation to stabilizer and silencer drugs. Heart Fail Rev. 2015;20(2):163-178. 11. Carroll JD, Gaasch WH, McAdam KP. Amyloid cardiomyopathy: characterization by a distinctive voltage/mass relation. Am J Cardiol. 1982;49:9-13. 12. Cyrille NB, Goldsmith J, Alvarez J, Maurer MS. Prevalence and prognostic significance of low QRS voltage among the three main types of cardiac amyloidosis. Am J Cardiol. 2014;114(7):1089-1093. 13. Quarta CC, Solomon D, Uraizee I, et al. Left ventricular structure and function in transthyretin-related versus light-chain cardiac amyloidosis. Circulation. 2014;129(18):1840-1849. 14. Connors LH, Prokaeva T, Lim A, et al. Cardiac amyloidosis in African Americans: Comparison of clinical and laboratory features of transthyretin V122I amyloidosis and immunoglobulin light chain amyloidosis. Am Heart J. 2009;158(4):607-614. 15. Nakagawa M, Sekijima Y, Yazaki M, et al. Carpal tunnel syndrome: a common initial symptom of systemic wild-type ATTR (ATTRwt) amyloidosis. Amyloid. 2016;23(1):58-63. 16. Rapezzi C, Merlini G, Quarta CC, et al. Systemic cardiac amyloidoses: disease profiles and clinical courses of the 3 main types. Circulation. 2009;120(13):1203-1212. 17. Sperry BW, Reyes BA, Ikram A, et al. Tenosynovial and cardiac amyloidosis in patients undergoing carpal tunnel release. J Am Coll Cardiol. 2018;72(17): 2040-2050. 18. Westermark P, Westermark GT, Suhr OB, Berg S. Transthyretin-derived amyloidosis: probably a common cause of lumbar spinal stenosis. Ups J Med Sci. 2014;119(3):223-228. 19. Yanagisawa A, Ueda M, Sueyoshi T, et al. Amyloid deposits derived from transthyretin in the ligamentum flavum as related to lumbar spinal canal stenosis. Mod Pathol. 2015;28(2):201-207. 20. Sueyoshi T, Ueda M, Jono H, et al. Wild-type transthyretin-derived amyloidosis in various ligaments and tendons. Hum Pathol. 2011;42(9):1259-1264. 21. Phelan D, Collier P, Thavendiranathan P, et al. Relative apical sparing of longitudinal strain using two-dimensional speckle-tracking echocardiography is both sensitive and specific for the diagnosis of cardiac amyloidosis. Heart. 2012;98(19):1442-1448. 22. Ternacle J, Bodez D, Guellich A, et al. Causes and consequences of longitudinal LV dysfunction assessed by 2D strain echocardiography in cardiac amyloidosis. JACC Cardiovasc Imaging 2016;9(2):126-138. 23. Coelho T, Maurer MS, Suhr OB. THAOS - The Transthyretin Amyloidosis Outcomes Survey: initial report on clinical manifestations in patients with hereditary and wild-type transthyretin amyloidosis. Curr Med Res Opin. 2013;29(1):63-76. 24. Swiecicki PL, Zhen DB, Mauermann ML, et al. Hereditary ATTR amyloidosis: a single-institution experience with 266 patients. Amyloid. 2015;22(2):123-131. LEARN HOW TO RECOGNIZE THE CLUES OF ATTR-CM AT: S U S P E C T A N D D E T E C T . I E CONSIDER THE FOLLOWING CLINICAL CLUES, ESPECIALLY IN COMBINATION, TO RAISE SUSPICION FOR ATTR-CM AND THE NEED FOR FURTHER TESTING SUSPECT A(TRANSTHYRETINATTR-CMAMYLOIDCARDIOMYOPATHY)LIFE-THREATENING DISEASE THAT CAN GO UNDETECTED H FpEF I NEDDNTOLERANCEISCORDANCEIAGNOSISCHOERVOUSSYSTEM
Aortic Disease
Aortic dissection in TS appears to occur at lower aortic diameters than in other aortopathies. Given the typical short stature of these individuals, there is a need to use thresholds indexed for body size. Aortic size index (ASI) has emerged as the leading method for guiding intervention, and describes the ratio of aortic diameter to body surface area. However, ASI presents its own limitations. It is unreliable in females below the age of sixteen. Furthermore, the use of TS-specific Z scores has been proposed, given limitations associated with comparing this group to the general population. The ESC and ACCF/AHA do not make specific recommendations for TS in their respective guidelines. However, for individuals with short stature in general, the ESC recommends intervention at an ASI ≥27.5mm/ m2 for the ascending aorta or root. The ACCF/AHA recommend intervention when the crosssectional aortic area divided by height exceeds 10cm2/m. The International Turner Syndrome Consensus group published broad guidance in 2017. They recommend intervention in individuals ≥16 years of age with an ascending ASI ≥2.5cm/m2 and associated risk factors for aortic dissection, including bicuspid aortic valve, elongation of the transverse aorta, coarctation of the aorta and/or hypertension.
in vascular EDS is the least well established. In addition to a lack of clear data, the friability of the tissues and associated potential for haemorrhage mean that surgery, even in the elective setting, is fraught with risk. Consequently, the ESC and ACCF/AHA do not make specific recommendations to support the role of prophylactic aortic surgery in this group.
Cardiac MR images showing the characteristic pear shaped aorta seen in Marfan syndrome. Image used with permission from Treasure T, Takkenberg JJ, Pepper J. Surgical management of aortic root disease in Marfan syndrome and other congenital disorders associated with aortic root aneurysms. Heart. 2014;100(20):1571 6.
Table 2
Pectus Carinatum Pectus Excavatum or Chest Asymmetry Deformity (+2) (+1)
Protucio Acetabulae (+2) Scoliosis or Thoracolumbar Kyphosis (+1)
Reduced Elbow Extension (+1) 3 of 5 Facial Features (+1)
Figure 1
Cardiovascular manifestations are common in TS, and include bicuspid aortic valve (30%), coarctation of the aorta (12%), thoracic aortic aneurysm (30%) and aortic dissection. The incidence of aortic dissection is up to 100 times more frequent in TS compared to the general population, occurring most commonly in the third decade. Hypertension is frequent, with multiple driving factors, and contributes to increased aortic
Turner Syndrome
Implicating the SMAD3 gene. Syndromic features include craniofacial dysmorphism,
individualized decision making. The ACCF/AHA recommend intervention at an aortic diameter of ≥42mm on echocardiogram;transoesophagealor≥44-46mmon CT/MRI, acknowledging the limited quality of available evidence.
Wrist AND Thumb Sign (+3) Wrist OR Thumb Sign (+1)
SyndromeAneurysms-Osteoarthritis
26 MAY 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE
connective tissue disorders. Mutations in genes affecting collagen are prominent, with aortopathy primarily seen in vascular EDS (previously known as type 4 EDS). This group have mutations of the COL3A1 gene, which encodes type 3 collagen. Affected individuals may have short stature, thin scalp hair, characteristic facial features (such as large eyes, small chin, and thin nose and lips).
Children with rapidly progressive aneurysms in the >99th percentile are repaired at a root diameter of 20-22mm, so that an adult sized graft may be accommodated. Root aneurysms in children that are slowly progressive are repaired at 40mm. In adults, root aneurysms are also repaired at 40mm, or if the growth rate exceeds 5mm per year. In adults, the descending aorta is repaired when diameter exceeds 45-50mm, or if growth rate exceeds 10mm per year.
Figure 1: Cardiac MR images showing the characteristic pearshaped aorta seen in Marfan syndrome. Image used with permission from Treasure T, Takkenberg JJ, Pepper J. Surgical management of aortic root disease in Marfan syndrome and other congenital disorders associated with aortic root aneurysms. Heart. 2014;100(20):1571-6.
Notably, MacCarrick and colleagues at John’s Hopkins University, describe their approach to the management of LDS (3).
short stature, primary ovarian failure, lymphoedema, and congenital heart disease (affecting over 50%). The TIMP1 and TIMP3 genes have recently been implicated in the aortopathy associated with TS. These genes encode proteins which inhibit matrix metalloproteinases, a group of compounds involved in the breakdown of extracellular matrix.
The aortic wall is composed of type 1 and 3 collagen, which have a high resistance to biomechanical forces and contribute significantly to the force-bearing capability of the aortic wall. The aortic wall in those with vascular EDS is therefore fragile and prone to dilatation, rupture and dissection. Indeed, aortic dissection occurs at an increased rate in vascular EDS, even in the absence of pre-existing aortic dilatation. The median survival of these individuals is 48 years, with arterial rupture representing the primary cause of Themortality.roleofprophylactic surgery
PneumothoraxSpontaneous (+2) Dural Ectasia(+2)
Hindfoot Deformity (+2) Plain Flat Foot (+1)
Ehlers-Danlos Syndrome
ofdisordersyndromeAneurysms-osteoarthritis(AOS)isanautosomalwhichrepresents2%syndromicaortopathies.
Ehlers-Danlos syndrome (EDS) refers to a broad group of fourteen
Turner syndrome (TS) results from complete or partial absence of the second X chromosome, occurring in 1 in 2500 live-born females. Mosaicism may also occur. It is one of the commonest human chromosomal abnormalities. Characteristic features include
Skin Striae (+1) Severe Myopia (+1)
wall stress. As with MFS and LDS, cardiovascular disease is the leading cause of mortality in individuals affected by TS.
Systemic Score
Mitral Valve Prolapse Reduced Upper Segment/Lower (+1) Segment & Increased Arm span/Height (+1)
Relating to extracellular FBN1* matrix COL3A1* LOX
Lifestyle Intervention
Relating to TGFβ signalling
Conclusion
another important area. Aortic wall stress is significantly elevated in pregnancy, with increased cardiac output being a key driver. The risk of aortic dissection is therefore raised, occurring most commonly in the third trimester. Those planning pregnancy may require prophylactic aortic surgery at lower thresholds.
Beta blockers are used to reduce aortic wall stress. More recently, angiotensin receptor blockers are being used in MFS to reduce the rate of progression of aneurysmal disease. This practice is occasionally employed in other disorders such as LDS, inferring from the positive experience in MFS populations. It has recently emerged that certain medications may have an adverse effect on the natural history of aortopathy. Calcium channel blockers may increase wall stress through a reduction in cardiac afterload. Fluoroquinolones have been positively associated with aortopathy, potentially through their adverse effect on extracellular matrix, and should be avoided.
27 HOSPITALPROFESSIONALNEWS.IE | HPN • MAY 2022
SMAD*TGFB2*TGFBR2*TGFBR1*
Phenotypic features include craniofacial dysmorphism (elongated face, beaked nose, micrognathia, high arched palate), hyper-extensible skin, and skeletal features (arachnodactyly, chest wall deformities).
Counselling
The role of endovascular strategies is debated and there have been concerns regarding long-term outcome. These relate to the landing of stent grafts into segments of aorta in which the wall may be inherently abnormal, or be subject to progressive dilatation.
Individuals should be counselled on monitoring for the signs and symptoms of acute aortic syndromes. In those with aneurysmal disease, avoidance of high intensity isometric exercise is essential to avoid sudden increases in wall stress. Strict adherence to prescribed anti-hypertensive medication must be maintained. Sudden
Unlocking the genetic make-up of familial aortopathy will allow us in the future to offer a completely personalised management for those patients, especially regarding personalised thresholds for interventions.
Surveillance represents a cornerstone of management for individuals with aortopathy. Regular surveillance is critical
Non-Syndromic Aortopathies
Arterial involvement is characterised by tortuosity, aneurysms and dissections which may involve any segment of the arterial tree. Optimal management has yet to be established given the relative novelty of this condition. Therefore, many clinicians choose strategies based on those used in MFS and LDS.
References available on request
Close surveillance is critical even after aortic repair, to monitor for disease progression in the remaining native aorta.
An MDT approach is indispensable in the management of those with syndromic aortopathy. These multisystem disorders require organised, comprehensive care; potentially delivered through specialised clinics, encompassing all relevant caregivers at a single visit.
Recent advances in our understanding of aortic disease have revealed an increasingly prominent role of genetics in the development of aortopathy. The natural history of familial aortopathy is less predictable than in non-genetic forms.
The vascular component is characterised by elongated, tortuous arteries which are prone to both stenosis and aneurysm. Large and medium sized vessels are typically affected, especially the aorta and pulmonary artery. Given the rarity of this condition, incidence rates of complications such as aortic dissection are not well understood. Management protocols have yet to be borne out in the literature and at present, are individualised.
Arterial Tortuosity Syndrome
Emerging recognition of these genes is anticipated to change future practice. For example, the ACTA2 gene (one of the commonest to be detected) and the MYLK genes are associated with aortic dissection at diameters <5cm, suggesting a possible need for earlier prophylactic surgery in this cohort. Whole exome sequencing is being utilized in some international centres with a special interest in this area (4). This allows detection of culprit genes in the proband, followed potentially by assessment of relatives with more specific gene sequencing panels targeted to the culprit gene. Crucially, this practice continues to enable the detection of novel culprit Clinicalgenes.guidelines have yet to provide specific recommendations for intervention in individuals with non-syndromic familial aortopathy. However, as understanding of the gene-disease association for familial aortopathy improves, a more personalized approach may become available to these families.
for monitoring the progression of aortic dilatation and the development of associated complications such as aortic incompetence. In the absence of widely accessible, reliable biomarkers; imaging remains the sole means of guiding intervention.
hypertension in the setting of missed medications is a potential precipitating event for acute complications.
Imaging is carried out at regular intervals based on the individual risk profile, typically 6 to 12 monthly. Factors contributing to this risk profile include those relating to the underlying genetic disorder, family history of aortic dissection or rupture, increased rate of progression (>3mm per year for example), or increased baseline diameter.
Medical Intervention
Regardless of the mode of intervention, these patients require life-long surveillance as other segments of the aorta tend to dilate over time.
Genes implicated in non-syndromic familial aortopathy
Management of Familial SurveillanceAortopathies
cutaneous anomalies, and mild skeletal features. Osteoarthritis and other joint disorders such as osteochondritis dissecans occur at an early age.
aortopathies account for a further 20% based on currently known culprit genes. Given the lack of phenotypic features, these individuals often come to attention later in life, potentially in the setting of a presentation with an acute aortic syndrome. At least 30 genes have been identified, generally encoding proteins involved in extracellular matrix, vascular smooth muscle cell function, or TGFβ signaling (Table 3). Many of these genes are also associated with syndromic aortopathies, but presenting in the absence of typical phenotypic features.
Individuals with a high suspicion of a familial aortopathy should be referred to a clinical geneticist (ESC) for family testing and molecular investigation. As age of onset is variable, even healthy ‘at-risk’ relatives require regular screening at five-year intervals until a diagnosis is ruled out or established Pre-pregnancy(ESC).counselling is
Arterial tortuosity syndrome is a very rare syndromic aortopathy, displaying an autosomal recessive pattern of inheritance. The SLC2A10 gene is implicated.
PRKG1MYLKMYH11
Non-syndromic familial aortopathies represent a heterogeneous group wherein there is familial clustering of aortic disease, typically presenting at a young age, in the absence of syndromic features. While syndromic aortopathies account for around 5% of thoracic aortic disease, non-syndromic familial
Surgical Intervention
Relating to smooth muscle ACTA2 cell function
Table 3
Surveillance may include transthoracic echocardiogram to assess the aortic valve, root, and proximal ascending aorta. CT and MRI provide accurate imaging of the entire aorta and its branches. MRI is often favoured in a younger cohort. Ideally, surveillance is carried out at a dedicated centre where expertise in aortic imaging is available. This uniformity enables reliability in serial measurements and minimizes inter-observer error.
Surgical options are varied and depend on the morphology of the aorta. Replacement of the diseased aortic segment provides definitive treatment for the diseased segment. Given the younger age of this cohort of patients, valve-preserving procedures are preferred.
*Genes also associated with syndromic aortopathies may be detected in the absence of the phenotypic features associated with that syndrome.
28 MAY 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE Mental CannabisHealthand Mental Illness
I can confirm all of this from clinical practice: cannabis presents a systematic risk to mental health. The situation improves if the person stops smoking cannabis, but sometimes symptoms return.
depression worse. It can also bring on depression.”
If this happens, is their ongoing illness due to cannabis alone or would it have happened anyway, with cannabis acting as a trigger? Was schizophrenia precipitated or caused by cannabis? These are difficult questions in individual cases, but the overall research is clear: cannabis is strongly associated with psychosis and other mental illnesses. Cannabis is bad for mental health.
The second question about cannabis is a little different: Given that cannabis is bad for mental health, what should we do in order to reduce the harm caused by cannabis in society? Should cannabis be illegal, decriminalised or legalised? This is a topic of continual public debate and there are many issues to be balanced: medical evidence, the need to protect the vulnerable, and the value of civil liberties.
Early use is especially troubling, because “the younger a person begins using cannabis, the more at risk they are of developing a major depressive disorder. Cannabis use disorder has been associated with a greater risk of developing bipolar affective disorder and having more frequent relapses. Cannabis can make anxiety disorders worse. Adolescent cannabis users are at higher risk of developing anxiety disorders, particularly those people who use high-potency cannabis.”
In the end, we should do whatever reduces cannabis use and minimises the harm from cannabis that I see every week in my clinical work. The first priority must be public education. Regardless of whether it is legal or illegal, cannabis is bad for mental health. If you smoke cannabis, please seek assistance stopping. Your mental health will thank you.
Brendan Kelly is Professor of Psychiatry at Trinity College Dublin and author of “In Search of Madness: A Psychiatrist’s Travels Through the History of Mental Illness” (Gill Books, 2022).
Written by Professor Brendan Kelly, Professor of Psychiatry, Trinity College Dublin
Cannabis is the most common illegal drug that I come across in clinical practice, but public discussion about cannabis is often very confused. The problem is that two questions about the drug get mixed up together. First, is cannabis bad for mental health? Second, if cannabis is bad for mental health, what should we do about it? These two questions are linked, but are also separate in several important respects.
Looking at the effects of cannabis more broadly, the College of Psychiatrists of Ireland summarised the evidence in 2021 in a (freely available) paper titled “Cannabis and Your Mental Health.” The College points out that “cannabis can make existing mental illness get worse. Cannabis use can trigger new mental illness, that is, sometimes people become mentally ill for the first time very soon after using cannabis. The number of people admitted to psychiatric hospitals in Ireland with a cannabis related diagnosis has trebled since 2002.”
The College adds that “cannabis is linked with psychosis. Cannabis users are three to four times more likely to develop psychosis than those who never use it”. In addition, “cannabis can make
With regard to the first question, overwhelming evidence now confirms that cannabis is bad for mental health. In 2017, the US National Academies of Sciences, Engineering and Medicine reviewed all of the evidence (positive and negative) pertaining to likely links between cannabis and psychosis, and concluded that the higher the cannabis use, the greater the risk of schizophrenia and other psychoses.
Finally, “cannabis use is also associated with self-harm and suicidal behaviour” because “young people who smoke cannabis regularly are three times more likely to attempt suicide than people who never use cannabis. Long-term cannabis users are more likely to report thoughts of suicide than non-users. In 2018, cannabis was the most common street drug used among men aged 15-24 who had self-harmed in Ireland.”
Ability to Drive and Use Machines: Alert patients on the risk of hypoglycaemia when dapagliflozin is used in combination with a sulphonylurea or insulin.
GFR
Dosage and Administration: Adults: Type 2 diabetes mellitus: The recommended dose is 10mg once daily. Consider a lower dose of insulin or insulin secretagogue such as a sulphonylurea when used in combination with dapagliflozin to reduce the risk of hypoglycaemia. Children and adolescents: No dose adjustment in children aged 10 years and above. No safety and efficacy data available for children below 10 years of age. Heart Failure: The recommended dose is 10mg once daily. Chronic kidney disease: The recommended dose is 10 mg once daily. Children and adolescents: <18 years: Safety and efficacy not yet established. Elderly: ≥65 years: No dose adjustment is recommended based on age. Renal impairment: No dose adjustment is required based on renal function. Due to limited experience, it is not recommended to initiate treatment with dapagliflozin in patients with GFR < 25 mL/min. If GFR falls below 45 mL/min, additional glucose lowering treatment should be considered in patients with diabetes mellitus if further glycaemic control is needed. Mild or moderate hepatic impairment: No dose adjustment. Severe hepatic impairment: Starting dose of 5mg is recommended, if well tolerated, dose may be increased to 10mg. Method of administration: Forxiga can be taken orally at any time of day with or without food. Tablets should be swallowed whole.
Date of API preparation: 11/2021 Veeva ID: IE-3322
CKD = chronic kidney disease; CV = cardiovascular; DAPACKD = Dapagliflozin And Prevention of Adverse outcomes in Chronic Kidney Disease; ESKD = end-stage kidney disease; hHF = hospitalisation for heart failure; HR = hazard ratio.
Undesirable Events: Consult SmPC for full list of side effects. Very common (≥1/10): Hypoglycaemia (when used with SU or insulin). Common (≥1/100 to <1/10): Vulvovaginitis, balanitis and related genital infections, urinary tract infection, dizziness, rash, back pain, dysuria, polyuria, haematocrit increased, creatinine renal clearance decreased during initial treatment, dyslipidaemia. Uncommon (≥1/1,000 to < 1/100): Fungal infection, volume depletion, thirst, constipation, dry mouth, nocturia, vulvovaginal pruritus, pruritus genital, blood creatinine increased during initial treatment, blood urea increased, weight decreased. Rare (≥ 1/10,000 to < 1/1,000): Diabetic ketoacidosis (when used in type 2 diabetes mellitus). Very Rare (< 1/10,000): Angioedema, necrotising fasciitis of the perineum (Fournier’s gangrene).
Further product information available on request from: AstraZeneca Pharmaceuticals (Ireland) DAC, Block B, Liffey Valley Office Campus, Dublin 22. Tel: +353 1 609 71 00. FORXIGA is a trademark of the AstraZeneca group of companies.
Legal Category: Product subject to prescription which may be renewed (B).
Marketing Authorisation Holder: AstraZeneca AB, SE-151 85 Södertälje, Sweden.
Marketing Authorisation Number: EU/1/12/795/002; EU/1/12/795/007.
Veeva ID: IE-3514 Date of Prep: February 2022
Drug Interactions: Diuretics: Dapagliflozin may add to the diuretic effect of thiazide and loop diuretics and may increase the risk of dehydration and hypotension. Insulin and insulin secretagogues: Consider a lower dose of insulin or insulin secretagogue when used in combination with dapagliflozin to reduce the risk of hypoglycaemia. Interference with 1,5 AG assay: Monitoring glycaemic control with 1,5-AG assay is not recommended as measurements of 1,5 AG are unreliable in assessing glycaemic control in patients taking SGLT2 inhibitors. Alternative methods should be used.
1. Heerspink HJL et al. N Engl J Med. 2020;383(15):1436–1446.
Adverse events should be reported directly to: HPRA Pharmacovigilance, Website: www.hpra.ie Adverse events should also be reported to AstraZeneca Patient Safety on Freephone 1800 800 899
FORXIGA is now approved for adult patients with CKD.2
2. FORXIGA 10 mg film-coated tablets. Summary of product characteristics. November 2021.
DAPA-CKD was stopped early due to efficacy benefit, because of the unplanned early stop, this secondary endpoint is considered nominally significant; Secondary endpoints showed that FORXIGA in conjunction with other CKD therapies reduced the relative risk of the composite of CV death or hHF by 29% (1.8% ARR: nominal p=0.009) and also reduced the relative risk of all-cause mortality by 31% (2.1% ARR; nominal p=0.004) vs placebo with other CKD therapies. There were comparable rates of the individual component of CV death, FORXIGA vs placebo (3.0% vs 3.7%; HR 0.81; 95% CI, 0.58, 1.12)1 ©AstraZeneca 2022. All Rights Reserved.
FORXIGA 10 mg Once daily No requiredtitration
References:
Pregnancy and Lactation: Not recommended during the second and third trimesters of pregnancy. Treatment should be discontinued when pregnancy is detected. Do not use whilst breast-feeding.
ABRIDGED PRESCRIBING INFORMATION
FORXIGA® (dapagliflozin) 5MG & 10MG FILM-COATED TABLETS.
treatment
ANDOFBYTOPROTECTIONBRINGLIFEREDUCINGTHERISKOFTHECOMPOSITEDECLININGKIDNEYFUNCTION,ESKD,RENALORCVDEATH*1
Consult Summary of Product Characteristics (SmPC) before Indications:prescribing. Adults and children aged 10 years and above: Type 2 diabetes mellitus: For the treatment of insufficiently controlled type 2 diabetes mellitus as an adjunct to diet and exercise, as monotherapy when metformin is considered inappropriate due to intolerance, or in addition to other medicinal products for the treatment of type 2 diabetes. Adults: Heart Failure: Indicated in adults for the treatment of symptomatic chronic heart failure with reduced ejection fraction. Chronic kidney disease: Indicated in adults for the treatment of chronic kidney disease.
Contraindications: Hypersensitivity to dapagliflozin, or excipients.
*In DAPA-CKD, the primary endpoint showed that FORXIGA in conjunction with other CKD therapies reduced the relative risk of the composite endpoint of ≥50% sustained decline in eGFR, reaching ESKD, and renal or CV death by 39% (5.3% ARR) vs placebo with other CKD therapies in 4304 adult patients with CKD with an eGFR of 75 to 25 mL/ min/1.73m2 (median follow-up of 2.4 years; p<0.001).1
of dapagliflozin is recommended until volume depletion is corrected. Diabetic ketoacidosis (DKA): Rare cases of DKA, including life-threatening and fatal cases, have been reported in patients treated with SGLT2 inhibitors, including dapagliflozin. In a number of cases, the presentation of the condition was atypical with only moderately increased blood glucose values, below 14mmol/L (250mg/dL). The risk of DKA must be considered in the event of non-specific symptoms such as nausea, vomiting, anorexia, abdominal pain, excessive thirst, difficulty breathing, confusion, unusual fatigue or sleepiness. Patients should be assessed for ketoacidosis immediately if these symptoms occur, regardless of blood glucose level. In patients where DKA is suspected or diagnosed, dapagliflozin treatment should be stopped immediately. Treatment should be interrupted in patients who are hospitalised for major surgical procedures or acute serious medical illnesses. Monitoring of ketones is recommended in these patients. Measurement of blood ketone levels is preferred to urine. Treatment with dapagliflozin may be restarted when the ketone values are normal and the patient’s condition has stabilised. Before initiating dapagliflozin, factors in patient history that may predispose to ketoacidosis should be considered. Patients who may be at higher risk of DKA include patients with a low beta cell function reserve (e.g. patients with low C peptide or latent autoimmune diabetes in adults (LADA) or patients with a history of pancreatitis), patients with conditions that lead to restricted food intake or severe dehydration, patients for whom insulin doses are reduced and patients with increased insulin requirements due to acute medical illness, surgery or alcohol abuse. SGLT2 inhibitors should be used with caution in these patients. Restarting SGLT2 inhibitor treatment in patients experiencing a DKA while on SGLT2 inhibitor treatment is not recommended, unless another clear precipitating factor is identified and resolved. Dapagliflozin should not be used for treatment of patients with type 1 diabetes. Necrotising fasciitis of the perineum (Fournier’s gangrene): Postmarketing cases have been reported in female and male patients taking SGLT2 inhibitors. Urgent surgical intervention and antibiotic treatment is required. Advise patients to seek medical attention if they experience a combination of pain, tenderness, erythema, or swelling in the genital or perineal area, with fever or malaise. Either uro-genital infection or perineal abscess may precede necrotising fasciitis. If suspected, discontinue Forxiga and institute prompt treatment (including antibiotics and surgical debridement). Urinary tract infections: Temporary interruption of dapagliflozin should be considered when treating pyelonephritis or urosepsis. Elderly (≥65 years): Elderly patients are more likely to have impaired renal function, be treated with medicines such as anti-hypertensives or diuretics, and be at a greater risk of volume depletion. Cardiac failure: Experience with dapagliflozin in NYHA class IV is limited. Chronic kidney disease: There is no experience with dapagliflozin for the treatment of chronic kidney disease in patients without diabetes who do not have albuminuria. Patients with albuminuria may benefit more from treatment with dapagliflozin. Lower limb amputations: Counsel patients with diabetes on routine preventative foot care as an increase in cases of lower limb amputation (primarily of the toe) has been observed in long term, clinical studies in type 2 diabetes mellitus with SGLT2 inhibitors. Urine laboratory assessments: Patients will test positive for glucose in the urine due to mechanism of action. Lactose: Patients with rare hereditary problems of galactose intolerance, total lactase deficiency, or glucose-galactose malabsorption should not take Forxiga.
Warnings and Precautions: Renal impairment: Due to limited experience, it is not recommended to initiate treatment with dapagliflozin in patients with GFR < 25 mL/min. The glucose lowering efficacy of dapagliflozin is dependent on renal function, and is reduced in patients with GFR < 45 mL/min and is likely absent in patients with severe renal impairment. Hepatic impairment: Exposure is increased in patients with severe hepatic impairment. Use in patients at risk of volume depletion and/or hypotension: Dapagliflozin increases diuresis which may lead to a modest decrease in blood pressure, it may be more pronounced in patients with very high blood glucose concentrations. Exercise caution in patients for whom a dapagliflozin induced drop in blood pressure could pose a risk, such as patients on anti hypertensive therapy with a history of hypotension or elderly patients. Careful monitoring of volume status and electrolytes is recommended in conditions leading to volume depletion, such as acute gastrointestinal illness. In volume depleted patients temporary interruption
Presentation: Film-coated tablets. 5mg or 10mg of dapagliflozin (as propanediol monohydrate). Each 5mg tablet contains 25mg of lactose. Each 10mg tablet contains 50mg of lactose.
tolerated.
Amgen Inc., its subsidiaries, or af liates. Date of PI preparation: April 2021 (Ref: IE-KYP-0321-00001) Adverse events should be reported directly to Health Products Regulatory Authority (HPRA) using the available methods via www.hpra.ie. Adverse reactions/events should also be reported to Amgen Limited on +44 (0)1223 436441 or Freephone 1800 535 160 1.References Stewart AK, et al. N Engl J Med 2015;372:142-52. 2. Amgen data on le. CSR 20130395. 24 September 2017; Table 7-3. 3. Siegal DS, et al. J Clin Oncol 2018;36:728-34. 4. KYPROLIS® SPC available at www.medicines.ie. © 2022 Amgen Inc. All rights reserved. IE-KYP-0322-00011. March 2022 Amgen Ireland Limited 21 Northwood Court, Santry, Dublin 9 Results
of the
haemolytic uraemic syndrome (TTP/HUS) have been reported, some events have been fatal. Monitor for signs and symptoms of TTP/HUS and stop treatment if suspected. Once excluded, Kyprolis can be restarted. The safety of reinitiating Kyprolis in patients previously experiencing TTP/HUS is unknown. Posterior reversible encephalopathy syndrome (PRES): Cases of PRES have been reported. Kyprolis should be discontinued if PRES is suspected. The safety of reinitiating Kyprolis therapy in patients previously experiencing PRES is not known. Hepatitis B Virus (HBV) reactivation: Cases of HBV reactivation have been reported. Patients should be screened for HBV before initiation of treatment. For patients with positive HBV serology, consider prophylaxis with antivirals. Monitor for clinical and laboratory signs of HBV reactivation during and after the end of treatment. The safety of resuming car lzomib after HBV is adequately controlled is not known. Resumption of therapy should be discussed with experts in managing HBV. Progressive Multifocal Leukoencephalopathy (PML): Cases of PML have been reported in patients receiving car lzomib who have had prior or concurrent immunosuppressive therapy. Patients should be monitored for any new of worsening neurological, cognitive or behavioural signs and symptoms that may be suggestive of PML. If PML is suspected, further administration must be suspended until PML has been excluded by a specialist with appropriate diagnostic testing. If PML is con rmed, car lzomib must be discontinued. Contraception: Female patients of child bearing potential (and/or their partners) must use effective contraception measures during and for one month following treatment. Kyprolis may decrease the ef cacy or oral contraceptives. Patients using oral contraceptives or hormonal contraception associated with a risk of thrombosis should switch to an alternative method. Male patients must use effective contraception measures during and for 3 months following treatment if their partner is pregnant or of childbearing potential not using effective contraception. Sodium content: Each 10mg, 30mg and 60mg vial contains 37, 109 and 216 mg sodium, respectively. Cyclodextrin content: Each 10mg, 30mg and 60mg contains 500, 1500 and 3000 mg of cyclodextrin (betadex sulfobutyl ether sodium), respectively. Interactions: Caution should be observed when car lzomib is combined with medicinal products that are substrates of CYP1A2, 2C8, 2C9, 2C19 and 2B6 (e.g. oral contraceptives), or with substrates of P-gp (e.g. digoxin, colchicine). Fertility, pregnancy and lactation: No available data on use of Kyprolis in pregnant women; should not be used during pregnancy unless the potential bene t outweighs the potential risk to the foetus. Breast-feeding is contra-indicated during and for at least 2 days after treatment with Kyprolis. No fertility studies have been performed. Undesirable Effects: Adverse reactions in patients receiving Kyprolis: very common (≥ 1/10) pneumonia, respiratory tract infection, thrombocytopenia, neutropenia, anaemia, lymphopenia, leukopenia, hypokalaemia, decreased appetite, insomnia, dizziness, peripheral neuropathy, headache, hypertension, dyspnoea, cough, vomiting, diarrhoea, constipation, abdominal pain, nausea, back pain, arthralgia, pain in extremity, muscle spasms, increased blood creatinine, pyrexia, peripheral oedema, asthenia, fatigue, chills; common (≥ 1/100 to < 1/10) sepsis, lung infection, in uenza, herpes zoster, urinary tract infection, bronchitis, gastroenteritis, viral infection, nasopharyngitis, rhinitis, febrile neutropenia, dehydration, hyperkalaemia, hypomagnesaemia, hyponatraemia, hypercalcaemia, hypocalcaemia, hypophosphataemia, hyperuricaemia, hypoalbuminaemia, hyperglycaemia, anxiety, confusional state, paraesthesia, hypoaesthesia, cataract, blurred vision, tinnitus, cardiac failure, myocardial infarction, atrial brillation, tachycardia, ejection fraction decreased, palpitations, deep vein thrombosis, hypotension, ushing, pulmonary embolism, pulmonary oedema, epistaxis, oropharyngeal pain, dysphonia, wheezing, pulmonary hypertension, gastrointestinal haemorrhage, dyspepsia, toothache, increased alanine aminotransferase, increased aspartate aminotransferase, increased gammaglutamyltransferase, hyperbilirubinaemia, rash, pruritus, erythema, hyperhidrosis, musculoskeletal pain, musculoskeletal chest pain, bone pain, myalgia, muscular weakness, acute kidney injury, renal failure, renal impairment, decreased creatinine renal clearance, chest pain, pain, infusion site reactions, in uenza-like illness, malaise, increased c-reactive protein, increased blood uric acid, infusion related reaction; uncommon (≥ 1/1,000 to < 1/100) clostridium dif cile colitis, cytomegalovirus infection, hepatitis B virus reactivation, drug hypersensitivity, HUS, TTP, tumour lysis syndrome, intracranial haemorrhage, cerebrovascular accident, PRES, cardiac arrest, cardiomyopathy, myocardial ischaemia, pericarditis, pericardial effusion, ventricular tachycardia, hypertensive crisis, haemorrhage, ARDS, acute respiratory failure, pulmonary haemorrhage, interstitial lung disease, pneumonitis, gastrointestinal perforation, acute pancreatitis, hepatic failure, cholestasis, multiorgan dysfunction syndrome. In a phase III study comparing KdD with Kd, secondary primary malignancies were reported (1.9% in KdD; 1.3% in Kd arm). Please consult the Summary of Product Characteristics for a full description of adverse reactions.
KYPROLIS® in combination with lenalidomide and dexamethasone (KRd) is indicated for the treatment of adult patients with multiple myeloma who have received at least one prior therapy.4
KRd
le,
Consider patients with a high tumour burden at greater risk. Ensure patients are well hydrated before Kyprolis administration in cycle 1 and subsequent cycles as needed. Consider uric acid lowering medicinal products in patients at high risk for TLS. Monitor for evidence of TLS during treatment. Stop Kyprolis until TLS is resolved. Infusion reactions: Infusion reactions, including life-threatening reactions, have been reported in patients who received Kyprolis. Reactions can occur immediately following or up to 24 hours after administration of Kyprolis. Dexamethasone should be administered prior to Kyprolis to reduce the incidence and severity of reactions. Haemorrhage and thrombocytopenia: Haemorrhage, often associated with thrombocytopenia has been reported; some events have been fatal. Venous thromboembolic events: Events, including deep vein thrombosis and pulmonary embolism with fatal outcomes, have been reported. Closely monitor patients with known risk factors for thromboembolism, minimise all modi able risk factors (e.g. smoking, hypertension and hyperlipidaemia), and administer other agents that may increase the risk of thrombosis with caution (e.g. erythropoietic agents or hormone replacement therapy). Hepatic toxicity: Cases of hepatic failure, including fatal cases, have been reported. Thrombotic microangiopathy: Cases of thrombotic microangiopathy, including thrombotic thrombocytopenic purpura and
trademark owned or licensed
(1-3
For a DEEP & DURABLE response when multiple myeloma relapses choose KYPROLIS ® DURABLEMedianRESPONSEPFS1 (Primary Endpoint n=792) months26.3vs Rd 17.6 months (HR 0.69,95% CI:0.57-0.83; 1-sided p<0.0001) Median follow-up 32 months DEEP ORRRESPONSE1,2 (Secondary Endpoint) 87.1%vsRd66.7% (OR 3.47, 95% CI: 2.41-5.00; 1 sided p<0.0001) Median follow-up 32 months ExtendedOSSurvival3 (Secondary endpoint) months48.3vs Rd 40.4 months (HR 0.79, 95% CI: 0.67-0.95; 1 sided p<0.0045) Median follow-up 67 months In the phase 3 ASPIRE trial, Kyprolis (carfilzomib), lenalidomide and dexamethasone (KRd) delivered: 32% of KRd patients achieved a CR or better vs 9% in the Rd arm 3,4 Kyprolis® (car lzomib) Brief Prescribing Information Please refer to the Summary of Product Characteristics (SmPC) before prescribing Kyprolis. Pharmaceutical Form: Powder for solution for infusion presented as a single use vial. Indication: Kyprolis in combination with daratumumab and dexamethasone, with lenalidomide and dexamethasone or with dexamethasone alone is indicated for the treatment of adult patients with multiple myeloma who have received at least one prior therapy. Dosage and Administration: Intravenous (iv) infusion on two consecutive days each week for 3 weeks (days 1, 2, 8, 9, 15 and 16), followed by a 12 day rest period. Each 28-day period is considered one treatment cycle. Kyprolis in combination with lenalidomide and dexamethasone (KRd): Infuse over 10 minutes at a starting dose of 20mg/m2 (max dose 44mg) on days 1 & 2 of cycle 1. If tolerated, increase dose to 27mg/m2 (max dose 60mg) on day 8 of cycle 1. From cycle 13, omit doses on day 8 & 9 of each cycle. In combination with Kyprolis, lenalidomide is administered as 25 mg orally on days 1–21 and dexamethasone is administered as 40 mg orally or iv on days 1, 8, 15, and 22 of the 28 day cycles. Continue treatment until disease progression or until unacceptable toxicity occurs; treatment beyond 18 cycles should be based on an individual bene t:risk assessment as data are limited. Consider appropriate dose reduction for lenalidomide according to the current lenalidomide SmPC. Kyprolis in combination with dexamethasone (Kd): Infuse over 30 minutes at a starting dose of 20 mg/m2 (max dose 44 mg) on days 1 and 2 of cycle 1. If tolerated, increase dose to 56 mg/m2 (max dose 123 mg) on day 8 of cycle 1. Dexamethasone is administered as 20 mg orally or iv on days 1, 2, 8, 9, 15, 16, 22, and 23 of the 28 day cycles. Continue treatment until disease progression or until unacceptable toxicity occurs. Kyprolis in combination with daratumumab and dexamethasone (KdD): Infuse over 30 minutes at a starting dose of 20mg/m2 (max dose 44mg) on days 1 & 2 of cycle 1. If tolerated, increase dose to 56mg/m2 (max dose 123mg) on day 8 of cycle 1. In combination with Kyprolis, daratumumab is administered at 8mg/kg on days 1 & 2 of cycle 1, then 16mg/kg on day 8 and weekly thereafter. Administer preinfusion medication to reduce risk of infusion-related reactions with daratumumab. Dexamethasone is administered as 20 mg orally or iv on days 1, 2, 8, 9, 15, & 16, then 40mg on day 22 of each cycle. For patients > 75 years of age, dexamethasone is administered as 20 mg orally or intravenously weekly after the rst week. Order of administration on days when more than one medicine is administered: dexamethasone, preinfusion medication for daratumumab, car lzomib, daratumumab, post infusion medication for daratumumab. Continue treatment until disease progression or until unacceptable toxicity occurs. Refer to the current daratumumab SmPC for additional detail regarding concomitant medication and appropriate dose reduction for daratumumab. All regimens: Modify dosing based on haematologic, renal and other non-haematologic toxicity as de ned in the SmPC. Consider antiviral prophylaxis in patients treated with Kyprolis to decrease the risk of herpes zoster reactivation. Monitor platelet counts frequently. Thromboprophylaxis is recommended based on an individual bene t:risk assessment. Adequate hydration is required before Kyprolis administration in cycle 1, especially in patients at high risk of tumour lysis syndrome or renal toxicity, give additional uids after Kyprolis administration in cycle 1 as needed. Monitor all patients for evidence of volume overload and tailor uid requirements to individual patient needs. Oral and/or intravenous hydration is not required on days when intravenous daratumumab is dosed in the KdD regimen. Monitor serum potassium monthly or more frequently as clinically indicated. Assess renal function at treatment initiation and monitor at least monthly, particularly in patients with lower baseline creatinine clearance (CrCL < 30 mL/min) for whom there are limited ef cacy and safety data. Assess liver enzymes and bilirubin at treatment initiation and monitor monthly during treatment, regardless of baseline values; pay special attention to patients with moderate and severe hepatic impairment for whom there are very limited ef cacy and safety data. Contraindications: Hypersensitivity to the active substance or to any of the excipients; women who are breast-feeding. Refer to relevant SmPC for contraindications, special warnings and precautions for products used in combination with Kyprolis. Special Warnings and Precautions: For patients who experience grade 3 or 4 cardiac events or dyspnoea, or pulmonary toxicities/hypertension or hypertensive crisis, stop Kyprolis until recovery and consider whether to restart Kyprolis at 1 dose level reduction based on a bene t/risk assessment. Cardiac disorders: New or worsening cardiac failure, myocardial ischaemia and infarction have occurred, including fatal outcomes. The risk of cardiac failure is increased in elderly (≥ 75 years) and Asian patients. A thorough assessment for cardiovascular risk factors prior to starting treatment is recommended. Patients with signs or symptoms of NYHA Class III or IV cardiac failure, recent history of myocardial infarction (in the last 4 months), and in patients with uncontrolled angina or arrhythmias should have a comprehensive cardiological assessment prior to starting treatment. Electrocardiographic changes: Cases of QT interval prolongation and of ventricular tachycardia have been reported. Pulmonary toxicity: Acute respiratory distress syndrome (ARDS), acute respiratory failure, and acute diffuse in ltrative pulmonary disease such as pneumonitis and interstitial lung disease have occurred, some events have been fatal.
Pharmaceutical Precautions: Do not mix or administer as an infusion with other medicinal products. Store at 2°C to 8°C (in a refrigerator). Do not freeze. Store in original carton to protect from light. Reconstitute with sterile water for injections. Reconstituted solutions in the vial, syringe, or intravenous bag may be stored at 2°C – 8°C for up to 24 hours or at 25°C for up to 4 hours. Inspect visually before administration; do not administer if any discoloration or particulate matter is observed. Legal Category: POM. Presentation, Basic Costs and Marketing Authorisation Number: Kyprolis 60 mg, pack of 1: EU/1/15/1060/001. Kyprolis 30 mg, pack of 1: EU/1/15/1060/003. Kyprolis 10 mg, pack of 1: EU/1/15/1060/002. Price in Republic of Ireland is available on request. Marketing Authorisation Holder: Amgen Europe B.V., Minervum 7061, NL-4817 ZK Breda, The Netherlands. Further information is available from Amgen Ireland Limited, 21 Northwood Court, Santry, Dublin D09 TX31. Kyprolis is a registered by are from ITT population prior lines of treatment). was generally well For full details Kyprolis safety pro please refer to the Summary of Product Characteristics (SPC) available online www.medicines.ie/medicines/kyprolis-32623/spc.at
Pulmonary hypertension: Pulmonary hypertension has been reported, some events have been fatal. Dyspnoea: Evaluate dyspnoea to exclude cardiopulmonary conditions including cardiac failure and pulmonary syndromes. Hypertension: Hypertension, including hypertensive crisis and hypertensive emergency, has been observed, some events have been fatal. Control hypertension prior to starting and during treatment. Evaluate all patients for hypertension during treatment. If hypertension cannot be controlled, reduce dose. Acute renal failure: Cases of acute renal failure have been reported, some of these events have been fatal. Tumour lysis syndrome (TLS): Cases of TLS, including with fatal outcome, have been reported.
KRd
In CLL, CD5 + B cells undergo malignant transformation. They are activated by the acquisition of mutations leading to monoclonal B cell lymphocytosis (MBL). MBL is defined as an asymptomatic condition where the absolute monoclonal B cell count is <5 x 10 9/L. It occurs in 4-5% of healthy adults and is a proposed precursor of CLL. Most cases of CLL are preceded by MBL while only 1-2% with MBL can develop CLL every year (Jain & Rai, 2012). In CLL, further accumulation of genetic abnormalities and subsequent oncogenic transformation of monoclonal B cells occurs (Burger, 2020). The diagnosis of CLL requires the presence of ≥5000 B-lymphocytes/μL in the peripheral blood for duration of at least 3 months. The clonality of the circulating B cells needs is confirmed by flow cytometry. Furthermore, there may be evidence of lymphadenopathy or organomegaly by physical or CT exam (Hallek, 2019).
This CPD article will particularly focus on and examine the evidence on the treatment of CLL with Bruton's tyrosine kinase inhibitors (BTKi’s) particularly in the newly diagnosed CLL setting.
Background and Overview
Chronic Lymphocytic Leukemia (CLL): An overview of its management and treatment with Bruton's tyrosine kinase Inhibitors
Orlaith Cormican RGN, Bsc, MHsc, Post Graduate Certificate in Cancer Care and Haematology: Orlaith is a Clinical Nurse Specialist in Haematology at the Midlands Regional Hospital. Orlaith has worked in cancer care and haematology since 2013. She is currently completing a PhD via the HRB SPHeRE programme. Her areas of interest include chronic haematological malignancies and quality of life in this area. Orlaith works with CLL patients on a daily basis.
The majority of CLL cases are diagnosed through blood counts, differential counts, a blood smear and immunophenotyping.
CLL and small lymphocytic lymphoma (SLL) are different clinical presentations of the same pathological disease and commonly referred to as CLL(Patel & Pagel, 2021). The term CLL is used when the disease manifests primarily in the
What is it?
CLLthreatening.remainsan
CLL is the most common leukaemia in the western world (AlSawaf et al., 2020). CLL is more common in males and is generally associated with those over the age of 70 (NCRI, 2022). All leukaemia’s in Ireland account for 2.4% of all malignant disorders and there are over 500 new diagnoses of CLL made in Ireland every year. The cause of CLL is unknown.
Risk factors include family history of haematological malignancy, increasing age and working in farming or hairdressing (Slager et al., CLL2014).ischaracterised by the clonal proliferation and accumulation of neoplastic B-lymphocytes in the blood, bone marrow lymph nodes and spleen (Al-Sawaf et al., 2020).
The course of the disease generally follows a period of “watch and wait”, followed by treatment with periods of relapse and remission. It remains an incurable disease however there are a number of novel treatments that have become available which have changed the course of the disease, improving patient’s response to treatments and overall quality of life.
blood, whereas SLL is used when involvement is primarily nodal (Rai KR, Stilgenbauer, 2021). Patients with CLL commonly develop complications associated with an intrinsic immune dysfunction resulting in immunodeficiency and autoimmune disorders. Ten per cent of patients will present with autoimmune haemolytic anaemia (Christi, M, 2020). Infection, anaemia and thrombocytopenia are the most common disease related complications. The increased risk of severe infections in CLL patients is primarily related to the disease and treatment related immunodeficiency, mainly bacterial and herpes virus family. Tumour lysis syndrome (TLS) and secondary cancers are less common but also potentially life
CPD 87: ONCOLOGY CLL 1. REFLECT Before reading this module, consider the following: Will this clinical area be relevant to my practice? 2. IDENTIFY If the answer is no, I may still be interested in the area but the article may not contribute towards my continuing professional development (CPD). If the answer is yes, I should identify any knowledge gaps in the clinical area. 3. PLAN If I have identified a knowledge gap - will this article satisfy those needs - or will more reading be required? 4. EVALUATE Did this article meet my learning needs - and how has my practise changed as a result?Have I identified further learning needs? 5. WHAT NEXT At this time you may like to record your learning for future use or assessment. Follow the CPD ContinuingDevelopmentProfessional CPD 4 previous steps, log and record your Publishedfindings.by HPN. Copies can be downloaded copyright,Disclaimer:www.irishpharmacytraining.iefromAllmaterialpublishedisnopartofthiscanbeused in any other publication without permission of the publishers and author. Abbvie has no editorial oversight of the CPD programmes included in these modules
Mary Kelly Orlaith Cormican
60 Second Summary
MaryAUTHORS:Kelly, FFNMRCSI, RANP, RNP, Msc, BSc Cancer Nursing, BSc Adult Nursing: Mary is an Advanced Nurse Practitioner in Haematology at the Midlands Regional Hospital, Tullamore. Mary has worked in Haematology Nursing for the past 24 years. She has worked in all Haematology nursing care settings both in the UK and Ireland at St Marys and St Bartholomew’s Hospitals, London, Blackrock Clinic and Midland Regional Hospitals. Mary manages CLL patients as part of her clinical caseload.
B cell receptor signalling leading to activation of various intracellular signalling pathways plays an important role in the survival of CLL cells (Stevenson & CaligarisCappio, 2004). These pathways are now being successfully exploited as therapeutic targets (Jain & Rai, 2012).
not been identified.
COVID19 has had a significant impact on CLL patients, many of them being immunodeficient due to the nature of the disease or the multiple lines of treatment received. As such treatments for this high risk group are welcomed.
incurable disease but there continues to be progress made in therapeutics, with the emergence of newer therapies improving overall survival (OS) and being well tolerated by patients enabling them to maintain a good quality of life for many years (Sharma & Rai, 2019). For those patients who are relatively asymptomatic, they may follow the “watch and wait” protocol followed up by clinical observation without receiving any therapies (Milne et
Chronic LeukuemiaLymphocyticalsoknown as CLL is a cancer that affects the blood and bone marrow. CLL affects the white blood cells called lymphocytes. It accounts for 2.4% of cancer diagnose in Ireland every year, affects men more than women and is more common in those over the age of CLL70.comprises over 40% of all leukaemias, affects older patients and may be asymptomatic for much of its course. It is often detected only through routine blood counts and only picked up if the individual presents to clinical services. Approximately 10% of individuals with CLL report a family history of the condition or a forbutlymphoproliferativerelateddisorder,thegeneswhichaccountincreasedsusceptibilityhave
31
The IGHV mutation status is also a useful prognostic and treatment indicator; mutated IGHV tends to be less aggressive and especially when combined with additional prognostic factors such as favourable cytogenetics (Puiggros et al., 2014).
Table 1 Stage
Enlarged Lymph nodes, liver or spleen. 2 Characteristics (StageRisk0)
Abnormal increase in the number of lymphocytes in the circulating blood and the marrow
Diagnosis, Staging and Prognosis
al., 2020). Treatment is usually commenced at disease progression or when the patient starts to develop symptoms associated with CLL (Milne et al., 2020). The majority of patients with a diagnosis of CLL will have more than one comorbidity at diagnosis, which may influence treatment selection (Kabel C, 2021). In addition, treatment can be patient- dependent, considering compliance, convenience, financial toxicity and duration of therapy (Murphy, 2021).
Abnormal increase in the number of lymphocytes in the circulating blood and the marrow
Abnormal increase in the number of lymphocytes in the circulating blood and the marrow
Abnormal increase in the number of lymphocytes in the circulating blood and the marrow
Thrombocytopenia (platelet counts <100,000/uL)
There is no single standard front line therapy regime for all patients with symptomatic or advanced CLL (Rai III-IV, Binet C) or patients with progressive cytopenias. Several initial
Abnormal increase in the number of lymphocytes in the circulating blood and the marrow
High (StagesRiskIII & IV)
Table 1 TableScore2 Risk Category 5 year cumulative risk to start treatment 0 Low 8.4% 1 Intermediate 28.4% 2-3 High 61.2% Table
Enlarged spleen and/or liver
OR
The red blood cell or platelets counts are normal or only slightly low.
Abnormal increase in the number of lymphocytes in the blood and marrow
Enlarged lymph nodes
Anemia (hemoglobin <11g/dL)
Anemia (hemoglobin <11g/dL)
OR
Abnormal increase in the number of lymphocytes in the circulating blood and the marrow
OR
Prognostic indicators
Indications for treatment outlined by the International working group CLL (IWCLL) criteria include progressive lymphadenopathy, organomeagly, deteriorating blood counts and constitutional symptoms (Hallek et al, 2018). In addition the presence of progressive lymphocytosis, a doubling time of < 6 months, Hb less than 100g/L or a platelet count of < 100 x 109/L or treatment resistant autoimmune cytopenias are indications to commence treatment (Milne et al, 2020).
The red blood cell or platelets counts are normal or only slightly low.
Cytogenetics may detect abnormalities on the chromosomes, which are associated with CLL. Samples are from the blood or bone marrow. FISH analysis may identify abnormalities associated with chromosomes 11, 12 13 and 17: deletion 13q, deletion 11q, trisomy 12, and deletion 17p. Deletion 13q remains the most favourable prognostic group, with deletion 17p being the least favourable (Puiggros et al., 2014). Furthermore, genomic abnormalities associated with TP53 mutation tend to be characterised as high risk and associated with adverse outcomes
Low (StageRisk0)
Treatment selection
Abnormal increase in the number of lymphocytes in the blood and marrow
High (StagesRiskIII & IV)
Abnormal increase in the number of lymphocytes in the circulating blood and the marrow
Stage Characteristics
Enlarged spleen and/or liver
The clinical course of CLL is extremely varied. Clinical trials in early stage CLL have failed to show survival benefit and therefore by international guidelines treatment is not recommended in this cohort. Ongoing randomised trials are evaluating the use of modern therapies in early stage disease and prognostic markers associated with poor clinical outcomes. However, until treatment benefit proves more as beneficial, treating in this setting is reserved for patients enrolled in these clinical trials (Rai KR, Stilgenbauer, 2021).
No enlargement of the lymph nodes, spleen, or liver and with near normal red blood cell and platelet counts.
A patient’s prognosis is dependent on disease stage; in addition to the presence or absence of high-risk markers (See Table 1 and 2). The Rai staging system classifies CLL into three separate risk groups. The Binet staging system classifies CLL into three stages (Table 1).
Table 1
Intermediate Risk (Stages I & II)
Condoluci et al., (2020) developed an International Prognostic score for early stage CLL (IPS-E). The IPS –E aims to predict time to first treatment (TTFT) in patients with early asymptomatic CLL at the time of diagnosis. The CLL-IPI-E combines genetic, biochemical and clinical parameters to categorise patients into risk groups (Table 2). The following three covariates were consistently and independently correlated with TTFT, Unmutated IGHV, absolute lymphocyte count >10x 109/L and presence of palpable lymph nodes. Each covariate is assigned 1 point each and scoring is used to classify risk. Importantly, del (17p) and TP53 mutations were not prognostic for TTFT but are important in predicting treatment response and guiding treatment choice once indicated (Rai KR, Stilgenbauer, 2021).
Low
Treatment and Management
Intermediate Risk (Stages I & II)
Enlarged lymph nodes
No enlargement of the lymph nodes, spleen, or liver and with near normal red blood cell and platelet counts.
Lymphocytosis itself, even if extreme, is not a strict indication for treatment if patients have no symptoms and adequate bone marrow function. However, extreme lymphocytosis (>200,000/ micro/L) is associated with an increased risk of hyperviscosity and may serve as an indication for treatment in an otherwise asymptomatic CLL patient (Rai KR, Stilgenbauer, 2021).
Enlarged Lymph nodes, liver or spleen.
32 CPD 87: ONCOLOGY CLL
Abnormal increase in the number of lymphocytes in the circulating blood and the marrow
OR
Thrombocytopenia (platelet counts <100,000/uL)
CLL has a widely variable disease course, influencing prognosis. Some patients die rapidly, within 2-3 years of diagnosis, due to CLL complications. Most patients live 5-10 years, with an initial course that is relatively benign, followed by a terminal, progressive and resistant phase lasting 1-2 years (Christi, M, 2020). Significant morbidity from both the disease and complication of therapy may exist in the later phase (Rai & Barrientos, 2014).
At least 90% of patients have one or more co-morbidities, therefore an MDT approach involving patients and outlining the potential benefits and risks of a particular treatment is important when considering treatment (Thurmes et al., 2008). Optimising health related quality of life (HRQoL) and managing adverse events are also important considerations in the decision to treat and choice of therapy (Patel & Pagel, 2021).
CyclophosphamideBedamustine
Tumour
Frey et al., (2016) reports disease severity as a predictor of poor HRQoL. In addition, toxicities associated with long-term targeted treatments have been shown to affect adherence, thus the emergence of limited duration therapies where appropriate is welcome.
FatigueThrombocytopeniainfectionsRespiratoryNauseaDiarrhoeaLowSyndromeLysisbloodcounts Table 3
Table: 3 Chemo Drugs MonclonalAntibodies inhibitorsKinase InhibitorsPI3K
The BCR pathway is implicated in the pathogenesis of several B-cell malignancies, including MCL, diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, and CLL. BTK's pivotal role in signalling through the B-cell surface receptors and results in activation of pathways necessary for B-cell trafficking, chemotaxis and adhesion. These BTKi work by forming a covalent bond with a cysteine residue (Cys-481) in the BTK active site, leading to sustained inhibition of BTK enzymatic activity.
Bruton Tyrosine Kinase (BTK) InhibitorsIbrutinib, Acalabrutinib
Ibrutinib
Ibrutinib was the first available oral small molecule inhibitor that binds to BTK preventing its kinase activity. This affects multiple signalling pathways and disrupts the interaction between CLL cells and the microenvironment leading to further apoptosis (Milne et al, 2020). Ibrutinib is indicated for the treatment of CLL and SLL with or without del (17p) (SPC, 2021).
Adverse events of clinical interest over time for patients on Ibrutinib included hypertension, atrial fibrillation and less commonly major haemorrhage (Ghia, P, Owen, C et al., 2021).
Bendamustine and rituximab and Obinutuzumab plus chlorambucil are also regimes that are active in CLL. These regimes are also options for older patients with cardiovascular comorbidities where BTK inhibitor therapy could increase the risk of cardiovascular events. CIT may be considered in patients where a time-limited treatment is preferable. Newer treatment options with fixed duration combinations for example Ibrutinib and ventoclax will further challenge the role of chemoimmunotherapy in the near future.
Fludarabine Rituximab Ibrutinib Idelalisib Venetoclax Chlorambucil Obinutuzumab Acalabrutinib
Potent, small-molecule inhibitors of BTK developed to treat CLL include, Ibrutinib and Acalabrutinib.
Clinical trials demonstrated the clinical benefit of Ibrutinib in a variety of clinical settings (Ghia et al., 2021). The Resonate trial showed improved PFS, OS and ORR for Ibrutinib versus ofatumumab in previously treated patients (Byrd et al., 2014). Resonate 2 showed ibrutinib superiority in PFS, OS and ORR in treatment naïve patients when compared to Chlorambucil. Further Resonate-2 analysis revealed 61% of patients were alive and progression free at 6.5 years and 6.5 year OS was 78%.
Although FCR is not an effective option for patients with TP53 and del (17q) mutations, for patients with mutated IGHV trials showed that time limited FCR can provide functional cure and therefore despite its diminishing role FCR may still be considered in this patient group.
treatments options exist, with varying rates of complete response, time to progression and associated toxicities (See Table 3). Patient’s treatment is individualised based on the patient, tumour characteristics and goals of therapy
Chemo immunotherapy (CIT)
Common
When planning treatment it is also important to consider the current pandemic. Nevertheless, in those patients with active CLL, treatment should not be withheld, because data suggests that the outcome of patients with COVID-19 is better if their cancer is under control. In patients requiring intervention, BTKi’s may represent the preferred therapeutic option (Roschewski et al., 2020).
Similar to management in most malignancies, the most suitable treatment for a patient is selected based on genetic features of the disease itself (Milne et al, 2020). Molecular assessment prior to every line of treatment is essential to avoid ineffective treatments.
33
The iLLUMINATE trial compared Ibrutinib plus obinutuzumab versus chlorambucil and obinutuzumab. The results showed significantly
For many years Fludarabine, cyclophosphamide and Rituximab (FCR) were the gold standard treatment for CLL. FCR yielded high overall response rates of up to 95% with some patients remaining in remission for over a decade.
inhibitors(BCL-2)lymphoma-2B-cell
Targeted Treatments
Treatment options for CLL include CIT, targeted therapies, radiation therapy and supportive care.
Over the past two decades, a dramatic increase in our understanding of the pathogenesis of CLL has led to the development of small molecule inhibitors for CLL targeting the B cell
Side Effects Hair LowvomitingNauseaLossMouthlosssoresofappetiteandbloodcounts Chest pain Heart faintlightheaded,FeelingbreathingTroubleCoughtonguefaceSwellingracingoftheanddizzy,or FibrillationAtrialcountsLowRashbodyfeetSwellingbreathshortnessFatigue,ConstipationNauseaDiarrhoeaofoftheandhands,aches,blood PneumonitiscountsLowPneumoniaCoughNauseaFatigueFeverDiarrhoeablood
receptor pathway and the apoptotic regulator BCL2 (Milne et al, 2020). These targeted therapies, enable patients to be treated with a chemotherapy free regime.
Acalabrutinib proves to be an effective treatment for patients with relapsed/refractory (R/R) disease. The study demonstrated a statistically significant and clinically meaningful PFS with Acalabrutinib compared with Idelalisib plus Rituximab (I-R) or Bendamustine plus Rituximab (B-R). The benefit of Acalabrutinib was seen across all patient subgroups including those with del (17p) or TP53. In addition, a tolerable safety profile was demonstrated. Acalabrutinib is licenced to treat adults with mantle cell lymphoma (MCL) who have received at least one prior treatment for their cancer, or adults with CLL or SLL.
• 17p deletion or TP53 mutation, or
immunoglobulins may benefit this population. The dose is generally calculated at 0.4/kg and given intravenously every 4 weeks.
In 2020, the emergence of COVID brought new difficulties for those diagnosed with CLL. CLL generally associated with the older age group is also be linked with immunodeficiency (Montserrat, 2020). This categorises those with a CLL diagnosis as being at risk of severe disease (Montserrat, 2020).
Patients with CLL require strong psychosocial support due to oftenvarying treatments dependent on their disease. Most medications come with a side effect profile and it is vital that patients are educated about this as well as the symptoms associated with disease. It is well documented that adherence to medications is critical to treatment success (Gast & Mathes, 2019). As we move to more oral based regimes it is imperative we impress on our patients the need for adherence with medications and ensure we ask about adherence at every consultation (Usherwood, 2017). The specialist nurse plays
Prior to commencing BTK treatment a detailed history of past medical history, drug allergies and current medications is obtained. The prescriber assesses the patient’s ability to self-administer and will involve family members /carers in education sessions where appropriate. It is important to check for food and drug interactions when prescribing Ibrutinib and Acalabrutinib.
Patient Management/Education
ELEVATE-TN Trial
Elevate trial
CLL and COVID
• Previously treated CLL patients Administration
patient benefits including limited treatment duration with a shorter period for side effects, outpatient based therapy and reduced financial burden on patients and carers (DePace, 2021).
The Elevate trial was the first trial of Acalabrutinib versus Ibrutinib in previously treated CLL. Patients were randomised to Acalabrutinib 100mg orally twice daily or Ibrutinib 420mg orally once daily and continued until disease progression or unacceptable toxicity. The primary endpoint was non-inferiority and secondary endpoints included incidence of Atrial fibrillation, grade >/ three infections, Richter’s transformation (RT) and (OS). At a median follow up of 40.9 months, Acalabrutinib was non-inferior to Ibrutinib, with a medium PFS of 38.4 months in both arms. Acalabrutinib demonstrated lower frequencies of adverse events (AE). Cardiovascular events were less common with Acalabrutinib, 9.4% vs 16% for atrial fibrillation (AF) and 9.4% vs 23.2% for hypertension.
References available on request
improved PFS (Moreno et al., 2019). Ibrutinib is taken orally at the same time each day. Ibrutinib is generally well tolerated; though there are some common side effects (Table 3).
BTK inhibitors and Fixed duration treatment
a role in educating the patient and their family about the common side effects seen often in many treatments as well as the risks of developing an oncological emergency such as tumour lysis syndrome or neutropenic sepsis. Some specific targeted therapies have rare side effects such as tumour lysis syndrome associated with venetoclax. Nurses need to empower patients with the correct resources to identify these potential complications rapidly and to escalate if necessary.
• No 17p deletion or TP53 mutation, (FCR), or (B-R) is unsuitable.
Acalabrutinib is a highly selective, potent BTK inhibitor (Ghia et al, 2020). In the phase II study that evaluated. Acalabrutinib in relapsed/refractory CLL, Acalabrutinib resulted in an overall response rate (ORR) of 93% in patients with Del (17p) and 90% of those with complex karyotype.
With this immunodeficiency it is likely that even with the COVID19 vaccine patients with a diagnosis of CLL will have an impaired or inadequate response with limited antibodies produced (Roeker et al., 2021). However it does appear that response rates and antibody titres do improve with subsequent doses of the vaccine (Herishanu et al., 2022). Due to the limited response in CLL patients, a primary dose followed by a fourth dose 3 months later is recommended (HSE, Patients2022).are
In this randomised, controlled, phase 3 trial the efficacy of Acalabrutinib with or without obinutuzumab versus chlorambucil and obinutuzumab for treatmentnaïve CLL patients was compared. At a median follow up of 28.3 months median PFS was longer with Acalabrutinib – obinutuzumab (A-O) and monotherapyAcalabrutinibcompared with obinutuzumab-chlorambucil (O-C). Estimated PFS at 24 months was 93% with A-0, 87% for patients on Acalabrutinib monotherapy and 47% in the O-C arm. Patients on A-O and Acalabrutinib tolerated treatment well and had a manageable safety profile, with 79% of patients remaining on therapy after a median follow up of 28.3 months. Sharman et al., (2020) concluded that Acalabrutinib with or without obinutuzumab is efficacious and a well tolerated treatment for patients with treatment – naïve CLL.
Drug combinations with fixed duration regimens such as Ibrutinib in combination with venetoclax are producing promising progression free survival data and improved
Supportive Care in CLL CLL is generally associated with a gradual decrease in antibody-mediated immunity and the development Hypogammaglobulinemiahypogammaglobulinaemia.ofis a condition caused by low serum immunoglobulin or antibody levels. Immunoglobulins have the ability to recognize antigens to trigger a biological response and eradicate infectious sources (Huq M, Bhatnagar NK, Hypogammaglobulinemia2021). is the most common primary immunodeficiency and encompasses a majority of immune-compromised Furthermore,replacementtherapyearlyvaccination,strategiesItHamblin,associatedandtreatmentsbediseaseandseverecorrelateLowersubclassesandupHypogammaglobulinemiapatients.affectsto85%ofallpatientswithCLLmayaffectallimmunoglobulin(IgG,IgA,andIgM).immunoglobulinlevelswithincreasedriskforandrecurrentinfectionsseverityincreaseswithprogresson.Thiscanexacerbatedbythedifferentapatientreceivesthelymphocytopeniawithsame(Hamblin&2008).isimportanttoimplementtoreducerisk;includingantibioticprophylaxis,pre-emptiveantimicrobialandimmunoglobulintherapies.intravenous
The Future of CLL
ASCEND trial
encouraged to inform their healthcare provide should they test positive for COVID19. The proceeding patient care is assessed based on individualised risk, severity of treatment and current treatments available. The use of treatments e.g. sotrivimab, redensivir and paxlovid will be considered based on each individual patient.
Grapefruit and Seville oranges are contraindicated in patients on Ibrutinib and with Acalabrutinib concomitant use of CYP3A inhibitors or inducers should be avoided. Patients on gastric reducing agents require specific advice due to the potential for drug interaction.
Acalabrutinib
Based on the above studies and committee appraisal, in April of last year NICE, (2021) recommended the use of Acalabrutinib as a monotherapy for adult patients with:
Small molecule inhibitors have revolutionised CLL treatment. It is anticipated that they will be used in the majority of patients, early after diagnosis and with curative intent. They are generally well tolerated and enable patients to maintain a good quality of life. Given the success of newer agents such as venetoclax in the clinical setting thus far, it is likely that BCL-2 inhibition will take on an increasingly important role in the treatment of CLL going forward.
34 CPD 87: ONCOLOGY CLL
Acalabrutinib is a self-administered oral capsule taken twice daily, 12 hourly. Patients are advised to swallow the capsule whole with a glass of water, with or without food.
Worse Scores but Similar Patterns of Disease Activity: Interpreting Outcomes in women with axial spondyloarthropathy
As women with axSpA are more likely to have non-radiographic disease,8 the formal recognition of nr-axSpA allowed these women not only to have a diagnosis of their condition but also to be
Data were extracted from the ASRI and cleaned for analysis. A series of descriptive comparison analyses was carried out on all participants captured in the ASRI, stratified on the basis of sex. Participants
The Ankylosing Spondylitis Registry of Ireland (ASRI) is a large, observational, national registry of patients with axSpA in Ireland. Currently, the ASRI contains data on 887 patients recruited from 12 rheumatology centres nationally, representing all
35
There has been a considerable shift in the sex distribution of axSpA over time. Historically described as strongly malepredominant disease with male to female sex ratios reported as high as 10:1,4 more recent studies have reported ratios closer to 2–3:1.5 One of the major factors contributing to this dramatic shift is the Assessment of SpondyloArthritis international Society (ASAS) classification criteria for axSpA, which recognized not only r-axSpA, also called ankylosing spondylitis (AS), but also nr-axSpA.6 While initially believed to represent an early stage of disease, longitudinal studies have demonstrated that only 10–40% of nr-axSpA will advance to r-axSpA over time.7
Enrolment consisted of a single clinical visit involving a structured interview, a series of questionnaires
eligible for treatment previously reserved for r-axSpA only.
Previous research into women with axSpA has demonstrated significantly worse quality of life, functional ability, and disease activity, as well as a poorer response to treatment compared to men.9 Detailed analysis and characterization of axSpA in women is the first step in optimizing management and outcomes in this significant proportion of the population.
StudyMETHODpopulation
HOSPITALPROFESSIONALNEWS.IE | HPN • MAY 2022
The aim of this study is to carry out a focused analysis of disease activity, reporting of disease, and impact of disease in women compared to men with axSpA. This sex-based analysis goes beyond summary comparisons, to capture how axSpA affects women, examine the relationship between functional ability and spinal mobility, and highlight directions for future research.
geographic regions of Ireland. This study includes data on all axSpA patients captured within the ASRI since enrolment began in 2013. To be considered for enrolment in the ASRI, participants must have been diagnosed with axSpA by a rheumatologist and must meet the 2009 ASAS classification criteria for axSpA. This enabled capture of both radiographic and nonradiographic disease. Additional eligibility criteria included: age over 18 years, fluency in English, and presence of full capacity to consent to participation.
to capture patient-reported outcomes (PROs), a focused clinical examination, and chart review. This captured information on baseline demographics (age, sex, ethnicity), details of disease history (age at symptom onset, delay to diagnosis, disease duration), pattern of disease (articular and manifestations),extra-articularandtreatments [non-steroidal anti-inflammatory drugs (NSAIDs), disease-modifying anti-rheumatic drugs (DMARDs), and biological agents]. Information on imaging radiographs,(conventionalMRI)andserology (inflammatory markers, HLA-B27) was also captured via a medical records review.
Statistical analysis
RHEUMATOLOGY FOCUS: AXSPA
Outcomes and assessment
Written by Sinead Maguire, Department of Rheumatology, St James’s Hospital Dublin/School of Medicine, Trinity College Dublin; Dr Fiona Wilson, Associate Professor, Physiotherapy, Trinity College Dublin; Phil Gallagher, Department of Rheumatology, St Vincent’s University Hospital & Finbar D O’Shea, Consultant Rheumatologist, St James’s Hospital Dublin/School of Medicine, Trinity College Dublin
Once identified, eligible patients were invited to participate in the ASRI. To limit the possibility of selection bias, investigators recruited as many patients as possible from each centre, including participants across the spectrum of disease severity, socioeconomic status, and geographic regions in the country. Prior to enrolment, trained investigators discussed what participation in the ASRI would involve, the purpose of the ASRI, and how the collected information would be used and protected. Participants were encouraged to ask questions of the investigator prior to signing a written consent form. Ethical approval for the ASRI was obtained from local hospital ethics committees from all participating centres, including the Joint Research Ethics Committee for St James’ and Tallaght University Hospital. Trained investigators at each centre were responsible for local oversight of data collection. All data were collected and stored in compliance with national data protection legislation.
Despite the evolution of classification and epidemiology of axSpA, much of what is known about axSpA is based on research into men with AS.9 As a result, there remains a considerable underrepresentation of axSpA in women in published research. Combined with the underrecognition of the disease in women,10 there is a significant need for increased awareness and focused research on the sex-specific impact and disease manifestations of axSpA.11
Multiple PROs were recorded for each participant. These outcome measures are validated for use in axSpA and capture information on numerous aspects of participants’ daily living.12 PROs captured via self-administered questionnaires were the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI),13 Bath Ankylosing Spondylitis Function Index (BASFI),14 Health Assessment Questionnaire (HAQ),15 and Ankylosing Spondylitis Quality of Life questionnaire (ASQoL).16 Focused clinical examination to assess spinal mobility allowed for calculation of the Bath Ankylosing Spondylitis Metrology Index (BASMI).17 Responses were recorded along a numerical rating system of a visual analogue score. For all outcome measures, higher scores indicated a greater level of impairment or severity.
Axial spondyloarthropathy (axSpA) is an autoinflammatory arthritis predominantly involving the axial spine.1 The defining feature is inflammatory sacroiliitis, which can be detected on X-ray in radiographic axial spondyloarthropathy (r-axSpA), or on magnetic resonance imaging (MRI) in non-radiographic axial spondyloarthropathy (nr-axSpA).2 This causes symptoms of inflammatory back pain such as nocturnal pain and prolonged early morning stiffness (EMS). Several articular and extra-articular manifestations (psoriasis, inflammatory colitis, and uveitis) are recognized, which can aid in clinical identification of axSpA. Onset is typically in the third decade, with a higher incidence in Caucasians and an association with human leucocyte antigen (HLA)-B27.3
Figure 1. Mean Bath Ankylosing Disease Activity Index (BASDAI) scores plotted by sex. EMS, stiffness. < 0.01
EMS, early morning stiffness. *Indicates statistically significant difference between sexes (p < 0.05)
who did not have sex recorded were excluded from the analysis. A Shapiro–Wilk test was used to assess normality of distribution for all included variables. Differences between continuous variables in the two groups were tested for significance using an independent two-tailed t-test or a Mann–Whitney U-test. A chi-squared test for independence was used to assess statistical significance in differences in categorical variables between sexes.
Females with axSpA recorded significantly higher ASQoL (7.51 vs 6.12; 95% CI 0.56, 2.22; p < 0.01) and BASDAI (4.57 vs 3.83; 95% CI 0.37, 1.10; p < 0.01) scores compared to males. They also recorded trends towards worse mean HAQ (0.59 vs 0.51; 95% CI 0.002, 0.16; p = 0.05) and BASFI scores (3.85 vs 3.63; 95% CI 0.22, 0.66; p = 0.32), but these differences were not significant. Spinal mobility, as captured in the BASMI, was significantly less impaired in females than in males (3.58 vs 4.16; 95% CI 0.94, 0.22; p < 0.01).
Overall, women with axSpA reported worse disease activity and greater impairment quality of life compared to men, captured average BASDAI and ASQoL scores. There non-significant trends towards worse HAQ representing greater impairment of function. women recorded significantly better spinal captured via the BASMI, with a lower = 0.619
10.008.006.004.002.00.00 .00 2.00 4.00 6.00 8.00 10.00 10.008.006.004.002.00.00 .00 2.00 4.00 6.00 8.00 10.00BASMIBASMI SABFI SASABFIBFIab r
a high prevalence of HLA-B27 positivity (88.7%).
For the correlation analysis, data from patients with both BASFI and BASMI scores were included. Variables were assessed with a Shapiro–Wilk test for normal distribution, in addition to visual inspection of a scatterplot to determine the presence of a monotonic relationship between the two variables. Once established, a Spearman’s rankorder correlation was run between the two PROs. Records were then split by sex and a Spearman’s rank-order correlation was undertaken to assess the strength of correlation of scores within each sex. An alpha level of p < 0.05 was deemed significant. SPSS version
Results
3 – Other pain 3.82 3.19 0.01 4 – Discomfort 4.05 3.29 < 0.01 5 – EMS 4.55 3.94 0.01 6 – EMS duration 3.54 3.12 0.07 Ranking by severity 1 – most severe Fatigue Spinal pain 2 Spinal pain Fatigue 3 EMS EMS 4 Discomfort Discomfort 5 Other pain Other pain 6 – least severe EMS duration EMS duration
Figure 1. Mean Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) component scores plotted by sex. EMS, early morning stiffness
2 – Spinal pain 5.51 4.63
26 (IBM Corp., Armonk, NY, USA) was used to carry out all statistical analyses in this study.
In terms of articular manifestations, females had a significantly higher prevalence of dactylitis (9.9% vs 5%, p = 0.01) and a trend towards an increased prevalence of peripheral arthritis (36.2% vs 28.3%, p = 0.08). For extraarticular manifestations (EAMs), females reported a significantly higher prevalence of both uveitis (40.5% vs 35.7%, p = 0.01) and colitis (17.2% vs 7.9, p < 0.01) compared to males.
MAY 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE 36 RHEUMATOLOGY FOCUS: AXSPA
each sex, with average component scores plotted in a spider chart for visualization of results.
There was a statistically significant, strong positive correlation between BASMI and BASFI scores in axSpA patients [rs(678) = 0.568, p < 0.01], based on calculations by a Spearman’s rank-order correlation.
Discussion
This analysis of real-world data from a large axSpA patients captured in the ASRI outlines nificant burden of disease in women with is reflected by worse PROs, with a higher prevalence articular and extra-articular manifestations women compared to men with axSpA. The contained within this study provides valuable into the impact of axSpA and how this varies men and women.
www.scandjrheumatol.se
No significant differences between sexes were noted in delay to diagnosis (females vs males: 7.42 vs 8.18; 95% CI 2.03, 0.52; p = 0.24) or age at symptom onset (25.9 vs 26.6; 95% CI 2.49, 1.02; p = 0.41). r-axSpA was more commonly encountered in males than females (78.1% vs 70.7%, p = 0.02), while nr-axSpA was significantly more prevalent in females (21.9% vs 29.3%, p = 0.02).
Focused analysis of the BASDAI involved comparison of mean total score and mean component scores between sexes. In addition to statistical testing for significance of differences, components were ranked by average scores within
At the time of data extraction, 886 participants were enrolled in the ASRI. The patient population comprised 232 females (26.2%) and 644 males (72.6%), with a mean ± sd age of 45.9 ± 12.6 years (range 18–85 years), mean disease duration of 19.4 ± 12.3 years, and mean delay to diagnosis of 8 ± 8.5 years. Mean scores for the ASRI population were: ASQoL 6.47 [95% confidence interval (CI) 6.07, 6.95], HAQ 0.53 (95% CI 0.55, 0.6), BASDAI 4.02 (95% CI 3.81, 4.19), BASFI 3.67 (95% CI 3.47, 3.89), and BASMI 4 (3.85, 4.17). The majority of the population was Caucasian (90.2%), with
r = 0.572ss
The question of why women record worse PROs, including the BASDAI, still remains. The findings of our analysis demonstrated that women with axSpA had a significantly higher burden of a number of both articular and extra-articular manifestations. This could explain the higher average scores across a number of items within the BASDAI, with a greater burden of inflammatory symptoms potentially contributing to the increased severity of fatigue observed in women with axSpA. Of interest, a previous study examined the topography of pain reporting in axSpA and reporting
classified as r-axSpA than males with axSpA, although the majority of the ASRI population had radiographic led to the recommendation of sex-specific when considering the results of the BASDAI. SpinalFemalesPain
Discussion
Women with axSpA recorded significantly worse total BASDAI scores compared to men, consistent with results from other large axSpA cohorts.8, 19, 20 Further focused analysis of the individual components of the BASDAI demonstrated that this was due
This analysis of real-world data from a large cohort of axSpA patients captured in the ASRI outlines the significant burden of disease in women with axSpA. This is reflected by worse PROs, with a higher prevalence of articular and extra-articular manifestations noted in women compared to men with axSpA. The analysis contained within this
by the Shapiro–Wilk test (p < 0.01). The relationship between the two measures was monotonic (as the BASFI score increases, so too does the BASMI score), as determined by visual inspection of the Therescatterplot.wasastatistically
Data on both BASMI and BASFI scores were available for 680 patients, and were included in the analysis. Variables were not normally distributed, as assessed
HOSPITALPROFESSIONALNEWS.IE | HPN • MAY 2022 37
Males
Figure 2. Correlation between Bath Spondylitis Functional Index (BASFI) Ankylosing Spondylitis Metrology (BASMI) in (A) females and (B)
Figure 2. Correlation between Bath Ankylosing Spondylitis Functional Index (BASFI) and Bath Ankylosing Spondylitis Metrology Index (BASMI) in (A) females and (B) males
Women with axial spondyloarthropathyWomen with axial spondyloarthropathy
Other Pain Discomfort EMS EMS Duration Fatigue0123456
Overall, women with axSpA reported significantly worse disease activity and greater impairment of their quality of life compared to men, captured via worse average BASDAI and ASQoL scores. There were also non-significant trends towards worse HAQ and BASFI, representing greater impairment of function. However, women recorded significantly better spinal mobility, captured via the BASMI, with a lower proportion classified as r-axSpA than males with axSpA, although the majority of the ASRI population had radiographic disease. These findings are supported by studies in other large international axSpA cohorts, which reported similar differences between sexes.8, 18–21
Spinal mobility and function
Females with axSpA reported worse mean total BASDAI (4.6 vs 3.83; 95% CI 0.37, 1.10; p < 0.01), compared to males. Within the BASDAI, females scored significantly worse than males across all components (Fatigue: 5.56 vs 4.51, p < 0.01; Spinal pain: 5.51 vs 4.63, p < 0.01; Other pain: 3.82 vs 3.19, p = 0.01; Discomfort: 4.05 vs 3.29, p < 0.01; EMS: 4.55 vs 3.94, p = 0.01), with the exception of duration of EMS, which demonstrated a nonsignificant trend towards higher average scores in females (3.54 vs 3.12, p = 0.07) (Table 2). Ranking of the BASDAI components by mean scores in order of overall severity revealed identical ranking in both sexes for four of the six components of the BASDAI, with the only variation observed in the component ranked as the most severe. For males this was spinal pain, while for females it was fatigue. Plotting of average component scores for each sex revealed a similar pattern in disease activity (Figure 1).
BASDAI analysis
to worse scores across all six components of the BASDAI in women, and not driven by higher scores in any single component. Ranking of mean component scores in order of severity between sexes revealed identical ranking of four of the six BASDAI components. The main difference observed in this ranking was the symptom ranked as the most severe within each sex, which was spinal pain in men and fatigue in women. However, when examining the mean scores for these two components within each sex, minimal difference was noted. This suggests that despite differences in total scores, the overall pattern of disease activity, as captured by the BASDAI, is strikingly similar in men and women.
study provides valuable insight into the impact of axSpA and how this varies between men and women.
significant, strong positive correlation between BASMI and BASFI scores in axSpA patients [rs(678) = 0.568, p < 0.01], based on calculations by a Spearman’s rank-order correlation. A Spearman’s rank-order correlation analysis following splitting of records by sex showed that the correlation became stronger when assessed within each sex [females rs(144) = 0.619, p < 0.01; males rs(509) = 0.572, p < 0.01] and had a slightly stronger association with in females (Figure 2).
immediately apparent; however, research and advances in motion capture technology may offer further Previousinsights.27studies have proposed that the higher prevalence of centralized sensitization20 and fibromyalgia28 in women could be significant contributors to the differences detected in patient outcomes, as both can lead to chronic widespread pain (CWP).29, 30 Although these issues are more common in women in the general population, they are clinical diagnoses of exclusion.31, 32
The most obvious but least understood cause for variations between men and women is hormonal differences.43
MAY 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE 38 RHEUMATOLOGY FOCUS: AXSPA
Conclusion
The elegance of the BASDAI is in the simplicity of the design, allowing both ease of use for patients and ease of interpretation for clinicians. It is one of the most commonly used outcome measures in clinical practice for monitoring disease activity in axSpA. For this reason, it is essential to ensure that the wealth of information captured by this tool is interpreted in a way that adequately reflects the clinical picture in both men and women with axSpA.
Men with axSpA have previously been shown to have a higher prevalence of radiographic disease and a worse severity of radiographic disease over time.21, 25, 26 It would be expected that this would result in greater impact on functional ability; however, males in the ASRI demonstrated a non-significant trend towards better BASFI scores compared to females. The stronger correlation noted in women with axSpA in our study indicates that as the level of spinal mobility worsens, a larger change is observed in deterioration of functional ability compared to men. In practical terms, deterioration of spinal mobility appears to have less of an impact on restriction of function in men compared to women with axSpA. Why this variation occurs is not
Despite the higher prevalence of several disease manifestations and worse PROs in women with axSpA, medication use was statistically similar between the sexes. This pattern of medication use is not unique to the ASRI, with similarities in the frequency of use of DMARDs and biological therapy in men and women observed in other large cohort studies.8, 18 A 2020 publication examining medication use before and after the recognition of nr-axSpA found no change in use of DMARDs or biologics between males and females.42 This raises the question: Are women with axSpA less likely to be offered treatment? If so, why? Could it be that women’s symptoms are less likely to be considered inflammatory and thus less responsive to treatment? Most importantly, are women with axSpA being undertreated?
insight into observed variations in outcomes between sexes and could potentially lead to improved management of axSpA in women.
As suggested by the experience with the ASDAS, differences in reporting of disease activity could be due to the methods used to capture this information. Tools such as the BASDAI and BASFI were developed and validated for AS in predominantly male cohorts.13, 41 The development of
Studies on pregnancy in axSpA vary widely, but a high prevalence of active disease during pregnancy, peaking in the second trimester, has been reported.47
In this large registry-based study of axSpA, women had a higher prevalence of a number of articular and extra-articular manifestations compared to men. They also reported significantly worse disease activity and quality of life. However, the overall pattern of symptom severity as captured by the BASDAI was similar in men and women. Despite better mean spinal mobility overall compared to men with axSpA, limitation of spinal mobility in women with axSpA corresponded to a greater impairment in functional ability. These results suggest that further evaluation of the tools and outcome measures currently used to monitor disease activity are needed to accurately assess the burden of axSpA in women. In addition, further studies are required to examine the impact of significant hormonal changes on disease activity and disease progression in women with axSpA.
sex-specific scores indicative of active disease could help to better compare scores between men and women. In addition, evaluation of outcome measures regarding their ability to capture the burden of articular and extra-articular manifestations in both sexes may provide further insights into the variation in outcomes observed between sexes.
Oestrogens have been shown to inhibit production of tumour necrosis factor-α and decrease differentiation of Th17 cells,44 which has significant effects on the inflammatory pathway. However, studies examining the effect of female sex hormone supplementation have failed to show any effect on outcomes in axSpA.45 In addition, we must consider the significant hormonal shifts that the female body undergoes over the course of a lifetime and how they affect disease activity. These include menstruation, pregnancy, and menopause, as data suggest that the overall effects of hormones are concentration dependent.46
of symptoms in the BASDAI.22 This revealed that the level of pain corresponded to BASDAI total scores in men, while in women the level of pain was linked to assessment of peripheral and axial symptoms when considered separately. These findings led to the recommendation of sex-specific approaches when considering the results of the BASDAI.
Research on menstrual variation in disease activity is incredibly limited; however, one study reported an inverse relationship between oestrogen level and erythrocyte sedimentation rate.48 Further research into the effect of sex hormones in axSpA has the potential to offer significant
This study has several potential limitations. Data for the analysis contained within this study were cross-sectional in nature owing to the current design of the ASRI. As such, it was not possible to comment on disease progression over time or treatment response. Plans to collect longitudinal data for the ASRI are in place and will further enrich this valuable epidemiological resource. At the time of analysis, ASDAS results were not available for a large proportion of the ASRI population, preventing comparative analysis of the performance of the ASDAS and the BASDAI in our population. This has been studied in detail in numerous axSpA populations previously, and thus sex-specific patterns in reporting of the ASDAS are well established. As fluency in English was required for participation, it is possible that this resulted in exclusion of certain smaller populations from enrolment in the ASRI; however, English fluency in Ireland is 97.5% so this is unlikely.49 Ireland does not have centralized medical records, so it was not feasible to report the percentage of axSpA patients in Ireland captured within the ASRI. However, recruitment was from all major geographic regions of the country and included all levels of the socioeconomic spectrum to reflect the true population as accurately as possible and limit selection bias.
References available on request
Recent increased use of the Ankylosing Spondylitis Disease Activity Score (ASDAS) has demonstrated less variation between sexes37, 38 when assessing disease activity in axSpA. A meta-analysis examining the performance of the ASDAS and BASDAI concluded that the ASDAS may not be sensitive enough in the detection of active peripheral disease.39 As peripheral involvement is more common in females with axSpA,5 this introduces a significant sex bias. The ASDAS has proven to be a remarkable tool in detecting disease activity and even in predicting response to biological therapies in males with axSpA.40 However, given the known variation in patterns of disease activity between axSpA in women and men, it may be time to reconsider our evaluation of disease activity in females with axSpA.
It has been well established that men with axSpA tend to have greater limitation of spinal mobility, as captured in the BASMI,23, 24 although this finding seems contradictory to the worse outcomes observed in women with the disease. It stands to reason that level of function would have a strong positive correlation with spinal mobility in axSpA; in clinical terms, patients with greater limitation of spinal mobility tend to have an increased level of functional impairment and vice versa. The results of this analysis by sex indicate that this correlation is more significant if compared separately within each sex, and is notably stronger in females.
The importance of thorough investigation of CWP was highlighted in an Israeli study of known fibromyalgia patients, which found that 10.2% met ASAS criteria for axSpA while up to 25% had imaging findings suggestive of inflammatory disease.33 In patients with a known underlying axSpA, distinguishing between disease activity and CWP can be quite difficult.34, 35 To further complicate this diagnostic dilemma, symptoms of inflammatory pain can vary by sex, with women more likely to describe widespread pain while men report back pain.36 However, it is crucial to ensure adequate treatment of axSpA prior to attributing symptoms to CWP.
1. The presence of a fragility fracture
Medication use: Long term use of certain medications, such as glucocorticoids and some anticonvulsants can lead to loss of bone density and fractures. Depo Provera contraceptive has been proven to cause bone loss, particularly high risk if given during adolescence when bone is being laid down.
Modifiable and Non-modifiable Risk Factors for Osteoporosis
Ethnicity: White and Asian women are at highest risk. African American and Hispanic women have a lower but significant risk. Poor diet increases the risk for osteoporosis. Low calcium and Vitamin D intake contributes to diminished bone density, early bone loss and an increased risk of fractures.
Modifiable and Non-modifiable Risk Factors for Osteoporosis
Diagnosis
Diagnosis
Osteoporosis can be diagnosed by:
reaches their late 20’s, at which point, bones have reached their maximum strength and density, known as peak bone mass. As people age the rate of bone resorption by osteoclast cells exceeds the rate of bone formation, so bone weakens.”
According to Theresa Lowry Lehnen, Clinical Nurse Specialist and Associate Lecturer South East Technological University, osteoporosis is multifactorial in origin. “It occurs when there is an imbalance between new bone formation and old bone resorption,” she explains.
It is commonly known as the “Silent Disease”, and is characterised by low bone mass and structural deterioration of bone tissue, leading to bone fragility and an increased risk of Osteoporosisfractures.is the most common metabolic bone disease in Ireland and increases the risk of 'fragility fractures'. These fractures occur mainly at the hip, vertebrae, and distal forearm and are associated with significant morbidity, mortality, and reduced quality of life, attributed not only to the fracture itself but also to the high prevalence of comorbidities in this patient population.
Age: The risk of developing osteoporosis as bones become thinner and weaker increases with age.
Endocrine: Too much thyroid hormone can cause bone loss. This can occur in hyperthyroidism or if too much thyroid hormone medication is used to treat an underactive thyroid. Osteoporosis has also been associated with overactive parathyroid and adrenal glands and hypogonadism.
HOSPITALPROFESSIONALNEWS.IE | HPN • MAY 2022
Theresa adds that the greatest cause of osteoporosis is oestrogen deficiency which results in increased bone turnover in which resorption exceeds formation. “Corticosteroids can also induce osteoporosis in which trabecular bone is particularly affected from suppression of osteoblastic activity,” she says.
Genetic: A family history of osteoporosis is a very strong risk factor People whose parents have a history of fractures also seem to have reduced bone mass and may be at greater risk for fractures.
Causes of Osteoporosis
“Bone turnover is regulated by the interaction between osteoblasts and osteoclasts. Osteoblasts form new bone and osteoclasts are responsible for bone resorption. Both types of cell are under hormonal regulation. Up to 90 percent of peak bone mass is acquired by age 18 in females and age 20 in males. The amount of bone mass in the skeleton can keep increasing until a person
2. Measurement of bone mineral density (BMD)
3 Bone biopsy: Bone biopsy is a diagnostic procedure restricted to untypical, unclear and complicated cases in evidencebased guidelines on diagnosis and treatment of osteoporosis. Bone Biopsy is not routinely used and should never be undertaken without consultation with a specialist in osteoporosis and metabolic bone disease.
39
Eating disorders, severely restricting food intake, low BMI and being underweight weakens bone in both men and women.
Osteoporosis: The Silent Disease
Non modifiable Risk Factors
Osteoporosis can be diagnosed by:
Theresa continues, “Most fractures occurring after 50 years of age are osteoporotic. All persons presenting with a fragility fracture after 50 years
Sex hormones: The reduction of oestrogen levels in women at menopause is a strong risk factors for developing osteoporosis. Men have a gradual reduction in testosterone levels as they age. Treatments for prostate cancer that reduce testosterone levels in men and treatments for breast cancer that reduce oestrogen levels in women accelerate bone loss.
Modifiable Risk Factors
Sex: Women are much more likely to develop osteoporosis than men. Women have less bone tissue and lose bone faster than men because of the changes that occur with menopause
It is estimated that up to 300,000 people in Ireland have osteoporosis. Although more common in females who have gone through the menopause, it can also affect men and even children.
Body size: People who have small body frames tend to have a higher risk of developing osteoporosis because they have less bone mass to draw from as they age
Lifestyle factors: An inactive lifestyle can lead to weakened bones and increased risk of osteoporosis. Cigarette smoking and excessive consumption of alcohol increases the risk of bone loss and fractures
Interview with Theresa Lowry Lehnen (GPN, RNP, PhD) Clinical Nurse Specialist and Associate Lecturer South EastUniversityTechnological(SETU)
RHEUMATOLOGY FOCUS: OSTEOPOROSIS
According to the Irish Osteoporosis Society (IOS), 20% of people aged 60 and above who sustain a hip fracture will die within 6 to 12 months, due to secondary complications and 50% of people over the age of 60 who sustain a fractured hip will lose their independence. Only 15% of people in Ireland are diagnosed with bone loss, leaving an estimated 280,000 people undiagnosed.
Osteopenia is the early stage of osteoporosis and places a person at risk of developing osteoporosis. The Irish Osteoporosis Society divides osteopenia into three categories:
2. Moderate Osteopenia is a T-score of -1.5 to -1.9 which usually requires lifestyle changes. Causes should be found and addressed and the person may require medication, depending on the cause, or if they have had a fragility fracture.
1. Mild Osteopenia is a T-score of -1 to -1.49 and usually requires lifestyle changes; however, causes should be investigated and addressed.
MAY 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE 40 RHEUMATOLOGY FOCUS: OSTEOPOROSIS
treatment. “There is a direct relationship between the lack of oestrogen after menopause and the development of osteoporosis. Early menopause before age 45 and any long phases in which the woman has low hormone levels and no or infrequent menstrual periods can cause loss of bone mass. Oestrogen therapy and oestrogen with progesterone hormone therapy are approved for the prevention of osteoporosis in postmenopausal women provided there are no contraindications. HRT is not suitable for people who have a history of breast cancer in their family, particularly in early menopausal patients or patients who have had a history of deep vein thrombosis,” she says.
Selective Estrogen Receptor Modulators (SERMs)
Recommended Daily Allowances of Calcium and Vitamin D Age (years) Calcium (mg/day) Vitamin D (µg/day) Babies 0 1 N/A 5 (as supplement) Children 1 3 800 10 4 6 800 0 10 7 10 800 0 10 Males & Females 11 14 1200 0 15 15 18 1200 0 15 Males & Females 19 64 800 0 10 65+ 800 10 Pregnancy 1200 10 Lactation 1200 10 Reference: Irish Nutrition + Dietetic Institute (INDI, 2013) HRT Hormone Replacement Therapy Reference: Irish Nutrition + Dietetic Institute (INDI, 2013
Theresa continues, “SERMs, brand name Evista® work in a similar manner to oestrogen on bone, by preventing bone loss in postmenopausal women who do not have hot flushes and provided there are no other contraindications. It is used for the prevention and treatment of osteoporosis in postmenopausal women and to reduce risk of invasive breast cancer in postmenopausal women at high risk or with osteoporosis. Evista helps to maintain bone density and reduce fracture rates, specifically at the spine. It is administered as a 60mg tablet once daily. Evista can be taken with or without food or drink and at the same time as calcium and vitamin D supplements. Appropriate weight bearing exercise is also necessary.”
“The treatment selected for each individual is based on their risk of fracture or re-fracture, causes of
HRT – Hormone Replacement Therapy
3. Marked Osteopenia is a T-score of -2 to -2.49 which requires lifestyle changes. Causes should be found and addressed and the person may require medication, depending on the cause, or if they have had a fragility fracture.
Oestrogen replacement for women going through the menopause can help to maintain bone density and reduce fracture rates while they are on the
Monoclonal Antibody
Denosumab, brand name Prolia, is a monoclonal antibody which binds to RANK Ligand, inhibiting the maturation of osteoclasts, therefore protecting the bone from degradation. “Prolia is indicated for the treatment of osteoporosis in postmenopausal women and in men at increased risk of fractures. In postmenopausal women Prolia reduces the risk of vertebral, non-vertebral and hip fractures. Prolia is also indicated for the treatment of bone loss associated with hormone ablation in men with prostate cancer at increased risk of fractures. It is the first choice of drug for those at high risk of hip fracture or who have had a hip fracture over the age of 75 with T scores < 2.5 at femoral neck or with a humeral fracture. The recommended dose of Prolia is 60 mg administered as a single subcutaneous injection once every 6 months into the
of age or menopause should be considered as possibly osteoporotic. A detailed history of the fracture occurrence, physical examination and evaluation for other fractures is carried out while noting any presence of back pain, kyphosis, and height loss. Baseline laboratory tests include: Full blood count: Serum chemistry levels: Liver function tests: Thyroid-stimulating hormone level: 25-Hydroxyvitamin D level: Serum protein electrophoresis: 24-hour urine calcium/creatinine: Testosterone (total and/or free) and luteinizing hormone/folliclestimulating hormone.
osteoporosis, age, DXA scan results and medical history. Assessment of bone markers before and at three and six months after the commencement of treatment will give an earlier indication of the response to treatment.”
Treatment
Calcium and vitamin D are essential for the prevention and treatment of osteoporosis. “Bone is a major store of calcium and phosphate. Every cell in the body requires calcium. Vitamin D helps to regulate cell growth and the immune system and is essential for the absorption of calcium. It increases the body’s ability to absorb calcium by 30-80%. Vitamin D is the only vitamin required by the body that does not have to be consumed through food or supplements as it is manufactured through the skin, when exposed to sunlight,” adds Theresa. “Supplements are generally only recommended when the daily amounts of calcium and Vitamin D from dietary sources are not being met.
Osteoporosis is treatable and fractures are preventable. “The primary goal of osteoporosis therapy is to reduce the risk of fracture,” she says. “A comprehensive osteoporosis treatment program includes a focus on proper nutrition, exercise, and safety issues to prevent falls that may result in fractures. In addition, medication to slow or stop bone loss, increase bone density, and reduce fracture risk may be prescribed.
Calcium and Vitamin D supplements
“Additional testing should include measurement of bone mineral density (BMD) and if there is height loss and/or back pain, imaging of the spine. On average BMD is lower in women than in men, because women have smaller bones and smaller trabeculae. Women, as they also go through the menopause lose more bone in their lifetime than men; 50% in females Vs 35-40% in males.”
“Many of the consequences of osteoporosis, particularly vertebral fractures, are associated with severe pain. Patients with established osteoporosis should be treated for pain relief
The HSE has estimated that the number of Orthopaedic Consultants will need to almost double to around 230 posts by 2028 to address current shortfalls and meet increased patient demand.
Theresa reflects that other treatments for osteoporosis can include Kyphoplasty and Vertebroplasty:
and physiotherapy offered for the secondary effects of osteoporosis. Pharmaceutical and non- pharmaceutical measures can be used to alleviate pain. Patients should be advised of all the options, and encouraged to try different approaches until they find what works best for them.
References available on request
Today, in 2022, there are just 2.4 Orthopaedic Consultants per 100,000 population. In contrast, in the UK and New Zealand, there are more than 6 Orthopaedic Consultants per 100,000 people.
HOSPITALPROFESSIONALNEWS.IE | HPN • MAY 2022 41
“Kyphoplasty is a surgical treatment involving a balloon being placed into the fractured vertebrae, followed by “bone cement” being injected into the balloon. Vertebroplasty is a non-surgical treatment involving a needle with “bone cement” inserted into the fractured body of the vertebrae under imaging guidance. The decision to perform these techniques is made by a multi-disciplinary team to ensure that this is the correct approach to managing the collapse.
“Parathyroid hormone(PTH) teriparatide, brand name Forsteo is a recombinant
“The solution to this problem is clear and very well communicated by hospital Consultants across Ireland: we must quickly appoint additional permanent Consultants and address the long-standing issues of pay inequity and poor working conditions. The longer this Government reneges on its commitments to Consultants and dithers on a resolution, the more frustrated and ill hundreds of thousands of Irish patients will become.
Calls to Increase Number of Orthopaedic Consultants
The Hanly Report, published when Bertie Ahern was still Taoiseach and Micheál Martin was Minister for Health, made it clear that Ireland needed at least 4 Orthopaedic Consultants per 100,000 population to provide a minimum standard of care.
“In 2022, the results of that failure are clear. Sick patients are waiting longer, outcomes are worsening, and we are still no closer to ensuring a minimum standard of timely orthopaedic care due to the severe shortage of Orthopaedic surgeons and the hospital facilities they need. Given the backlog of care caused by the pandemic and the continuing Government policy which discriminates against new Consultants contracted since 2012, this problem is simply going to get worse.
“Having someone wait for more than eighteen months to be seen so that we can provide them with a solution is heart-breaking,” said Ms Conroy.
“This should not be an issue in twenty-first-century Ireland. The UK and New Zealand, the latter with a population similar to ours, are able to appoint a sufficient number of Orthopaedic Consultants. Other developed countries consistently provide timely, effective care to patients, as well as reasonable, efficient, and empathetic working environments for their doctors and other healthcare staff.
“There is simply no reason we cannot do the same in Ireland.”
There are currently over 11,700 patients nationally waiting for Orthopaedic surgery and 76,000 waiting for an orthopaedic outpatient appointment. This represents an increase of 24,700 (48%) over the past 7 years, and of 7,300 (11%) since the beginning of the pandemic. In Kerry alone, Ms Conroy said, there are more than 2,000 people waiting for an orthopaedic outpatient appointment.
human parathyroid hormone 1-34 and a bone forming agent that stimulates the formation of new bone. Foresto is a ‘high tech’ medication that can only be prescribed by a Consultant. It is given as a daily 20mcg, subcutaneous injection in the thigh or abdomen for 24 months. The patient should then have a repeat DXA scan and a new treatment plan should be implemented at the end of the course of treatment. PTH is usually recommended for those with severe osteoporosis or fractures and those who cannot tolerate other medications. Forsteo can help with the pain of vertebral fractures and the reduction of vertebral and nonvertebral fractures in women.”
“Excessive wait times can lead to the development of chronic pain. If a patient with a rotator cuff injury hasn't used their arm properly for a year, they'll have a huge amount of dysfunction, making recovery from any intervention extremely difficult. People in these situations definitely have worse outcomes, on top of a standard nine to 12-month recovery.”
Rheumatology News
“Prevention of osteoporosis should ideally start in utero. Childhood and teenage years, are critical periods for developing a strong healthy bone, especially before puberty, between the ages of 8 and 12 years. If good peak bone strength is achieved in early childhood, the risk of osteoporosis in later life is reduced.”
Professor Alan Irvine, President of the IHCA
Ms Eimear Conroy, Consultant Orthopaedic Surgeon at University Hospital Kerry, said that the chronic lack of orthopaedic consultants, available hospital beds, and theatre operating space are the main causes of the unacceptable delays in providing care. This is resulting in very serious consequences for patients.
Professor Alan Irvine, President of the IHCA, said: “When the Hanly Report was published almost twenty years ago, its author said that failure to implement its recommendations was “not an option.”
“ParathyroidBisphosphonatesHormone – (PTH) brand name preotac is a bone forming agent that stimulates the formation of new bone administered as a daily 100mcg dose, subcutaneous injection in the thigh or abdomen for 24 months. It can only be prescribed by a Consultant, as it is a ‘high tech’ drug for severe osteoporosis. It is contraindicated in patients with cancer. Patients need to have follow up tests done at 1, 3 and 6 months, for elevated serum or urinary calcium. The patient should then have a repeat DXA scan and a new treatment plan should be implemented at the end of the course of treatment.
The HSE needs to almost double the number of Orthopaedic Consultant posts to reach the recommendation of a major health report published in 2003, almost two decades ago, and meet current and projected demand.
thigh, abdomen or upper arm. Patients must be adequately supplemented with calcium and vitamin D.”
Pandemic backlog, triaging, and consultant numbers
Órla Tynan
biologic therapies differs, with Rituximab and anti-IL-6R only utilised for treatment of RA, while anti-IL-17A and antiIL-12/IL23 are utilised for PsA. Furthermore, the multifaceted nature of synovial inflammation, joint destruction, enthesitis, axial disease, and skin manifestations often makes diagnosis, prediction of disease progression and prediction of response difficult. However, currently there are few biomarkers that distinguish disease pathotype or response to therapy. Thus there is a need for the identification of noninvasive, convenient, and reliable biomarkers for the diagnosis and prediction of treatment response outcomes in autoimmune disease.
‘MicroRNA (miRNA)’ which are small endogenous regulatory RNA molecules have emerged as potential therapeutic targets and biomarkers in autoimmunity. MiRNA bind to complementary sequences on messenger RNA (mRNA), and they function generally by suppressing the translation of target proteins (Figure 1A). In the context of Inflammatory Arthritis, their effects generally down regulate proteins involved in keeping the immune response in-check, thus once unchecked this allows for an uncontrolled immune response which leads to cartilage
42 RHEUMATOLOGY FOCUS: RA/PA
Inflammatory Arthritis (IA) constitutes a diverse range of autoimmune conditions sharing characteristic features including soft tissue swelling, joint inflammation and subsequent bone and cartilage destruction of a debilitating nature. Unfortunately, the prevalence of IA in Ireland is 1-2%, of which Rheumatoid Arthritis (RA) and Psoriatic Arthritis (PsA) encompass two of the most common forms. While common pathogenic mechanisms are involved in driving inflammation in both arthropathies there are significant differences, including the presence/absence of autoantibodies, synovial vascularity, presence of skin psoriasis, immune cell infiltrates, molecular signalling, the pattern of periarticular inflammation, bone erosion and new bone formation at the entheseal complex of peripheral and spinal joints. These differences may explain distinct clinical manifestations of the two diseases, and more importantly, explain different responses to specific therapies impacting on disease outcomes and prognoses. While there are common treatments that are utilised as first line treatment for RA and PsA, including methotrexate and tumor necrosis factor inhibitors (TNFi), their response to other
Professor Ursula Fearon
MAY 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE
Serum MicroRNA Signatures as Diagnostic Tools that Distinguish Rheumatoid and Psoriatic Arthritis
Therefore, in this study we examined the expression profile of miRNAs, specifically focusing on a defined immunology miRNA panel, to identify a potential circulatory miRNA signature that could distinguish RA from PsA, in addition to evaluating the potential implication for disease pathogenesis. To do this we utilised the clinically amenable FirePlex Biofluids miRNA assay. While previous approaches employed to detect circulating miRNA relied on laborious isolation techniques and required high sample volume to obtain sufficient miRNA and thus limited the potential use in the clinical setting, the FirePlex platform allows for miRNA detection in very small volumes of blood (~20μl) that can be measured by automated flow cytometric analysis, thus allows for robust, reproducible results that can easily be assessed in clinical labs on hospital sites.
We obtained serum samples from patients with active RA and PsA, in addition to healthy controls (HC) and performed an immunological miRNA analysis using the FirePlex miRNA Immunology-V2 panel (FirePlex Bioworks Inc.). We identified a miRNA signature of seven miRNA (miR-126-3p, miR-29b-3p, miR-22-3p, miR-223-3p, miR320a, let-7g-5e, and let-7g-5p) that were significantly elevated in RA serum compared to both PsA patients and HC. Further computational bioinformatic analysis demonstrated that the miRNA expression distribution was associated with a dominant skew towards 3 specific miRNA in RA vs PsA: miR-29b-3p, miR-223p and miR-223-3p. In contrast, we identified three miRNA that were significantly elevated in PsA compared to RA which included miR-203a-3p, miR-185-5p, and miR-151a-5p. To examine sensitivity/specificity of miRNA to either RA or PsA we performed Receiver Operating Characteristic (ROC) curves, that demonstrated high sensitivity and specificity of each miRNA signature to either that of RA or PsA.
clinicalindemonstratedstudy“ThishasthepotentialforserummiRNAstobeinstrumentaladiagnosticcapacityinasetting”
Written by Professor Ursula Fearon and Órla Tynan, Molecular Rheumatology, Trinity Biomedical Sciences Institute, Trinity College Dublin
degradation and bone erosions. Over the last 10 years numerous studies have demonstrated that altered miRNA expression in Inflammatory Arthritis influences immune cell regulation, enhances pro-inflammatory signaling pathways, and leads to the overproduction of proinflammatory proteins that are critical to driving the pathogenic mechanisms involved in joint destruction and subsequent joint disability. However, more recent studies have identified that, in addition to their localization within the cell, miRNAs are also present in extracellular fluids such as serum, plasma, and synovial fluid, and through the circulation can be transported to specific cell types or tissues to carry out their function. Interestingly, it is now known that circulatory miRNAs are more stable than cellular miRNAs and are emerging as potential non-invasive biomarkers for disease.
20ul 20ul 20ul FirePlex Bioworks Inc Fireplex Computational Analysis Analysis RA PsA HC miR 29b 3p miR 22 3p miR 223 3p miR 203 mi miR151a5p185p miR 29b 3p, miR 203 miR 22 3p, miR 185p miR 223 3p, miR 151a5p BA
In summary, this study has demonstrated the potential for serum miRNAs to be instrumental in a diagnostic capacity in a clinical setting. The benefit of a serum miRNA signature as a biomarker utilising this method is that it is a minimally invasive approach requiring a minimal amount of blood that would be sufficient for diagnosis using the FirePlex assay. This assay has clinical potential as it is a highly reproducible test which requires only minimal serum that can simultaneously detect a panel of selected miRNAs, without the need for laborious RNA purification and amplification steps which can lead to lack of reproducibility in the clinical setting. This platform would also
As highlighted above, miRNA regulate their function by targeting different proteins. Therefore, we next utilised computational analysis (DIANA miRPATH tool) to identify the specific genes and inflammatory pathways targeted by the identified miRNA signatures, followed by STRING software analysis which allowed the identification of target gene interactions. Functional pathway analysis of the RA miRNA signature (miR29b-3p, miR-22-3p and miR223-3p) showed significant association with pathways that regulate key pathogenic mechanisms involved in synovial inflammation. Specifically, the miRNA signature was involved in mediating a diverse number of cellular processes including metabolism, cell growth, invasion, and proliferation, all of which contribute to the uncontrolled proliferation and activation of stromal cells within the inflamed joint, particularly for RA which is known to have a more aggressive synovial invasive layer compared to that of PsA. While few studies have examined these miRNA in RA, studies have shown that increased levels have been associated with RA disease activity and development of RA in susceptible individuals demonstrating positivity for ACPA antibodies. Furthermore, the RA miRNA have also been associated with regulation of
be an efficient, convenient, and cost-effective approach. The serum miRNA signatures identified in this study discriminated RA from PsA, and importantly from that of healthy subjects (Figure 1B). However, further investigations are required in larger multicentre patient cohorts for validation. If they prove to be consistent, it would be interesting to examine in future approaches if the circulatory miRNA signatures could be useful not only in the monitoring of disease progression but also as pharmacodynamic biomarkers of treatment response. In conclusion these findings are valuable, and the identification of reliable biomarkers that may facilitate pathotype diagnosis would facilitate interventions with more targeted therapeutic approaches, thus alleviating symptoms, and potentially inducing earlier disease remission whilst ultimately enhancing patient quality of life.
Acknowledgements: These studies would be impossible to perform without patient involvement, therefore we would like to thank all patients who contributed to this study.
HOSPITALPROFESSIONALNEWS.IE | HPN • MAY 2022 43
in the PsA joint (elongated, tortuous and dilated) is similar to the dysfunctional blood vessel patterns observed in malignant tumors. This is in stark contrast to RA where the blood vessel pattern is defined by straight, regular branching synovial vessels. The implications for these different blood vessel patterns are still unclear but must be involved in differential recruitment of immune cells to the joint, in addition to differential levels of nutrients entering the synovial cavity.
matrix withthecartilagekeyandinvasivemetalloproteinases,signallingpathways,chondrocytedysfunction,mechanismsassociatedwithbreakdown.Interestingly,miRNAsignatureassociatedPsAregulateangiogenic function and specific signalling pathways associated with blood vessel migration, leukocyte adhesion and trans-endothelial cell migration, a feature more pronounced in PsA. Indeed, many of the pathways associated with the PsA miRNA are also associated with cancer, and specifically involved in driving angiogenic processes. In particular, studies have shown that miR-151a-5p is associated with the Notch signalling pathway, which we know is increased in the PsA joint and in psoriasis skin lesions and is critically involved in the regulation of the pathogenic dysfunctional blood vessel pattern observed in PsA. Furthermore, miR-185-5p is associated with high levels of the VEGF receptor, which activates the Notch signalling pathway in endothelial cells that line the blood vessels. The PsA miRNA were also associated with the Hippo signalling pathway which again target genes associated with angiogenic growth factor regulation and cellular adhesion. Interestingly, the distinct synovial blood vessel pattern observed
RA PsA HC
Dr Daire O’Leary
need for invasive investigations. However, these scores have not been validated outside the original study populations and therefore have not been widely adopted. Diagnosis is highly reliant on access to radiology. In most children with CNO, multifocal lesions are seen on whole body MRI. The presence of multiple lesions affecting the metaphyses of long bones or the clavicles in an otherwise systemically well child, in particular one with a chronic disease course, may mean that a bone biopsy is not required. Where the diagnosis is uncertain, bone biopsy is required to exclude infection and malignancy. Bone biopsy may be necessary if the child is systemically unwell, if a single or atypical lesion is found on whole body MRI or if there is likely to be a significant delay in obtaining a whole body MRI. Timely access to MRI is particularly challenging for children who require a general anaesthetic in order to stay still for the duration of the scan.
prognosis. The course of this disease is poorly understood with few studies involving long-term follow-up. There is also significant phenotypic variation both within and between published cohorts. The majority of children have multiple lesions with relapsingremitting symptoms. A minority have a single lesion and an even smaller minority have a single symptomatic episode. While most series report good outcomes for children with CNO, there are short- and long-term complications. Some of these complications depend on the site of bony inflammation – for example, scoliosis in children with vertebral involvement or limblength discrepancy in those with inflammation of the growth plate of long bones. Other complications do not appear to depend on the site of inflammation, however. Some children develop amplified pain or functional pain disorders which can have a serious impact on school attendance. There are additional phenotypic differences which complicate the prognosis. Some children have inflammatory disease affecting sites other than their bones. Children may
Written by Dr Daire O’Leary, Dr Orla Killeen National Centre for Paediatric Rheumatology, Children’s Health Ireland at Crumlin UCD Centre for Arthritis Research, School of Medicine, UCD
investigation and referral through primary and secondary care before reaching a diagnosis. Some of this diagnostic journey is currently unavoidable because there are no specific markers of disease which allow us to differentiate CNO from important differential diagnoses. Therefore, infectious and malignant causes of these symptoms must be excluded before CNO is considered.
Figure 1 Distribution of bony lesions in the Irish cohort with CNO
Table 1: Demographics of the Irish population with CNO
Table
Chronic nonbacterial osteomyelitis (CNO), which is also known as chronic recurrent multifocal osteomyelitis (CRMO) is a rare inflammatory bone disease (OMIM 259680). It predominantly affects children and adolescents. These children usually present with localised bone pain which may be associated with swelling or loss of function depending on the site involved. Less commonly, they may also present with pathological fracture of the affected bone. Most children are otherwise well and the onset of bone pain or swelling may be gradual. However, some are systemically unwell with fever and markedly raised inflammatory markers. In adults, similar bony inflammation is seen in Synovitis Acne Pustulosis HyperOstosis (SAPHO) syndrome; CNO and SAPHO may be represent different phenotypes of the same inflammatory process.
1 Demographics of the Irish population with CNO Characteristic % Median (range) Female 72.8 Age at onset 9.2 years (3.1 14.3) Age at diagnosis 10.5 years (5.9 15.5) Diagnostic delay 0.7 years (0.1 2) Duration of follow up Presenting symptom: 3.03 years (0.64 8.47) • Pain 100 • Fever 13.6 • Clinically unifocal 52.3 Total sites (clinical and radiological) 4 (1 19) Unifocal disease 9.1
Diagnostic scoring systems have been developed to try to reduce the time from symptom-onset to diagnosis. In particular, these scoring systems aim to remove the
44 RHEUMATOLOGY FOCUS: CNO
MAY 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE
Chronic Nonbacterial Osteomyelitis: Challenges of a Rare Rheumatic Disease
Until recently, CNO was thought to affect 1 in a million children and adolescents. However, more recent research suggests it is as common as bacterial osteomyelitis in this age-group, affecting 1 in 100,000. Therefore, many children undergo a lengthy period of
Once the diagnosis of CNO is made, it is very difficult to provide families with an accurate
Challenges of a rare disease
Dr Orla Killeen
• Fever 13.6
• Pain 100
Diagnostic delay 0.7 years (0.1 2)
Total sites (clinical and radiological) 4 (1 19)
have inflammatory arthritis which occurs at sites distant from their bony lesions. Others have skin inflammation such as psoriasis or severe acne. It remains unclear whether children with bone disease alone follow the same natural history of disease as those with inflammation elsewhere.
Presenting symptom: 3.03 years (0.64 8.47)
While there were similarities between the Irish cohort and those previously published, there were also some interesting differences. Demographic characteristics
CNO in the Irish population
Differences arose in terms of the frequency with which other inflammatory diseases were identified and the response to treatment. Overall, 40% of the Irish cohort have extraosseous manifestations of CNO which is more frequent than in other cohorts. In particular, cutaneous inflammation was more common; psoriasis affects just over 20% of the Irish cohort. Most other studies report psoriasis rates of less than 10%. A positive family history of arthritis, inflammatory bowel disease and psoriasis is also more common in the Irish cohort with reports of these diseases in over 2/3 of families.
HOSPITALPROFESSIONALNEWS.IE | HPN • MAY 2022 45
It is unclear whether the presence of more extraosseous inflammation and psychosocial complications indicate a more inflammatory CNO phenotype in the Irish cohort, which in turn requires a higher rate of progression to DMARDs. However, it highlights the importance of including Irish families in research. Since March 2021, the National Centre for Paediatric Rheumatology, CHI at Crumlin, offers children with CNO and other rheumatic diseases the opportunity to participate in the paediatric rheumatology biobank, supported by the Arthritis Research Coalition (ARC). Collecting and analysing data through the biobank will help us determine if the Irish experience of rheumatic diseases mirrors that of other populations. It will help physicians decide if research from other populations will benefit the children and adolescents attending our services. In addition, it will increase opportunities for families to participate in research collaborations internationally which will be essential in understanding rare diseases such as CNO.
Duration of follow up
To date, we have detailed demographic, clinical, laboratory and radiologic data on over 50 of these children and adolescents. This information reveals some interesting information about Irish children and adolescents with CNO. A comparison of the data with other case series demonstrates the importance of providing the opportunity for Irish people to participate in rare disease research.
Figure 1: Distribution of bony lesions in the Irish cohort with CNO
Unifocal disease 9.1
In Ireland, over 100 children and adolescents have been diagnosed with CNO in the last 15 years. These children attend the National Centre for Paediatric Rheumatology in Children’s Health Ireland at Crumlin and Temple Street.
Table 1 Demographics of the Irish population with CNO Characteristic % Median (range)
Age at onset 9.2 years (3.1 14.3)
Figure 1 Distribution of bony lesions in the Irish cohort with CNO
• Clinically unifocal 52.3
The phenotypic variability and unpredictable clinical course lead to further challenges developing treatment pathways. To date, there has only been a single pilot randomised controlled trial (RCT) comparing different treatment modalities for CNO. Many children respond symptomatically to treatment with nonsteroidal anti-inflammatories (NSAIDs). Many relapse once NSAIDs are weaned or flare despite ongoing NSAID use. After NSAIDs, a wide range of second-line treatments have been used in different case series; systemic corticosteroids, disease-modifying antirheumatic drugs (DMARDs), bisphosphonates and anti-tumour necrosis factor (anti-TNF) biologic agents. A consensus treatment plan was recently published by the Childhood Arthritis and Rheumatology Research Alliance which provides recommendations for the first 12 months of treatment in children who do not achieve remission with NSAIDs. However, in the absence of RCT’s, the choice of second-line treatment depends on family and physician preference. Variation in how treatment response and remission are defined and reported in different case series further compounds the difficulty agreeing a treatment plan.
including median age of onset, time to diagnosis and a female preponderance were similar to those previously reported (Table 1). The incidence of unifocal disease was lower than that seen in most cohorts. However, all patients in the Irish study underwent at least one whole-body MRI which reduces the likelihood of asymptomatic lesions remaining undetected. The frequency at which different bones were involved is also similar to that seen in other studies (Figure 1).
previous publications. This led to a higher proportion of patients progressing to non-biologic and biologic DMARDs. Response and remission rates following methotrexate monotherapy were lower than those reported in other cohorts. Response and remission rates for anti-TNF agents were similar to those in other cohorts. At last follow-up, over 90% of patients were clinically improved or in remission. Overall, complications occurred in almost half the cohort. Psychosocial complications were more frequent than physical complications. Physical complications occurred exclusively in those with vertebral involvement; vertebral compression fractures or loss of vertebral height. The psychosocial complications were pain amplification syndrome (PAS) and prolonged school absenteeism. Twenty percent of children developed pain amplification syndrome. Ten percent had prolonged school absenteeism and PAS while 10% had prolonged school absenteeism without PAS. Prolonged school absenteeism in the years following diagnosis excluded absenteeism for scheduled outpatient care. Psychosocial complications were more frequently reported than in other cohorts.
Treatment response rates to NSAIDs and bisphosphonates are lower in the Irish cohort than
Age at diagnosis 10.5 years (5.9 15.5)
Female 72.8
escalation in resources and policy to support quality osteoporosis services for so Irish people.
Yes (Limited Irish Data)
Table 1. The 10 W.H.O. Principles of Screening and how they Relate to Osteoporosis in Ireland (1, 2)
Yes: International Guidelines
There should be a recognizable latent or early symptomatic phase
Yes: >75,000 performed annually
Why Ireland would Benefit from a National Screening for Osteoporosis
Osteoporosis can be diagnosed in the setting of a fragility fracture, particularly of the proximal femur or spine.2, 6 These are the clinical events of this disease, the majority of which occur following a fall. Thus all patients should be assessed and considered for appropriate pharmacologic intervention and fall prevention, in addition to addressing any underlying causes or modifiable risk factors following these events.2, 7 Unfortunately despite overwhelming evidence showing diagnosis and treatment are the most effective way to reduce subsequent fracture risk,2, 6, 8 there is a considerable gap between the evidence and recommended management and what is actually taking place in practice.8-10 For example data from the H.I.P.E. portal, the public hospital inpatient administration system shows fewer than 20% of those adults aged 50 years and older admitted with a major osteoporotic fracture over the past 15 years are diagnosed with osteoporosis. In Galway University Hospitals the treatment gap was similar, but following the establishment of a fracture liaison service this number increased to >80% for hip fracture patients between 2009 and 2018 (Proceedings from World Congress of Orthopedic
David O’Sullivan
Written by Professor John J. Carey, Consultant Physician, Galway University Hospitals. Email: john.j.carey@nuigalway.ie and Dr. David O’Sullivan, House Officer in Orthopedic Surgery, Galway University Hospitals.Dr.
Professor John J. Carey
Yes: Several Medications
Yes: >60 DXA Facilities
The cost of case finding (including diagnosis and treatment) should be economically balanced in relation to possible expenditure on medical care as a whole.
Osteoporosis is the commonest skeletal disease worldwide. Failure to attain or loss of skeletal mass and quality result in weak bones leading to fractures. Osteoporotic fractures are one of the leading causes of morbidity and mortality in older European adults, and one fragility fractures (FF) one of the most expensive.1-3 A recent European report notes Ireland has one of the highest rates of fracture but will experience the greatest increase in numbers over the coming decade. While Ireland
Yes: WHO 1994 Report :843, WHO 2003 Report: 921.
Yes: Low BMD (T score < 2.5) There should be a suitable test or examination.
Yes: Established care with Practitioner
performed well on certain domains, we did not on national policy, guidelines or investment.4 If we are to address the rapidly increasing burden of this illness and the associated costs for patients, their social network and our country, fundamental shifts in knowledge, policy and how our healthcare system is run are needed. In 2008 the H.S.E. estimated the direct cost for caring for Irish people with FF will be ¤2billion, a doubling from 2020.5 As things currently stand we do not have the resources to manage what is already happening. Providing poor quality care has limited benefit, increases costs and harm to patients. We need a rapid
46 RHEUMATOLOGY FOCUS: OSTEOPOROSIS
Facilities for diagnosis and treatment should be available.
The condition should be an important health problem.
The natural history of the condition, including development from latent to declared disease, should be adequately understood
There should be an agreed policy on whom to treat as patients
Screening Principle
MAY 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE
Screening is a process to identify asymptomatic people at increased risk of a disease before it occurs, so interventions can be implemented to reduce their chance of developing it, or the severity of illness when it occurs. Screening is not the same as early diagnosis. Effective screening programmes are an imperfect filtration process which can identify those at risk, while minimising the harms and costs associated with overdiagnosis and ineffective interventions.12 Testing people with fractures is therefore not screening, rather diagnosing or monitoring. In 1968 the World
Yes: DXA, ?Modified OST
There should be an accepted treatment for patients with recognized disease.
The test should be acceptable to the population
What is Screening?
Osteoporosis Ireland
Yes: >200,000 people, >32,000 FF Annually
Case finding should be a continuous process and not a “once and for all” project.
Nurses 2018). Recently a national steering committee was established to address these deficiencies. A recent audit reviewed international standards for fracture liaison services, and a brief overview of where things stand at present in Ireland.8 This group are essential to garner support for resources, logistics and audit for these patients, which will require considerably greater support than currently exists in any public facility. Fracture liaison services are critical to bridging some of these gaps in care, and while effective, this is secondary prevention.11 A more fundamental approach though is primary prevention delivered via evidencebased, planned and resourced screening programmes.12
Table 1. The 10 W.H.O. Principles of Screening and how they Relate to Osteoporosis in Ireland1, 2
Health Organisation (WHO) published 10 criteria which must be met in order for a screening programme to be effective. These are still valid today, as recently cited in 2020 by the WHO,12 and are thus worth looking at from an Irish perspective, as outlined in Table 1. Unfortunately loose use of the terms ‘screening’ and ‘testing’ in the medical literature can lead to confusion, and some authors and papers use these terms interchangeably even for those with fractures.
The WHO have agreed and published a number of reports for screening postmenopausal women for osteoporosis, in particular Reports 843 in 1994, and 921 2003. These outline in extensive detail the epidemiology and natural history of osteoporosis, describe analogies to other disease areas such as cancer and cardiovascular disease, and propose standards for screening those deemed to be at risk. The 1994 report proposed what is still the accepted standard today, a T-score of <-2.5 as the diagnostic threshold for the diagnosis in postmenopausal
The United States Preventive Services Task Force (USPSTF) has undertaken a number of comprehensive and quantitative assessments of the effectiveness of screening, most notably in 2002 and 2018 . Using published data from 2002, we can see in figure 1 the importance of picking an appropriate age for screening.13 If one were to screen all women aged 50 years and older (or men presumably), the number needed to screen to prevent 1 hip or 1 vertebral fracture would be almost 10 fold higher than starting screening at age 65-70 years! And the rate of overdiagnosis would be much greater in the younger agegroup. If 1 additional risk factor is added, such as body weight, then the number needed to screen can be reduced. This latter aspect is important as it enables best use of resources, and will reduce the cost and harm associated with a screening programme.
screen can be reduced by around 30%.14, 15 Waiting times for public DXA in Ireland are long, years in some centres. Access to quality DXA is even longer. We have recently validated the OST for Irish men and women showing it works similarly well to other populations and could reduce the number of men and women referred for screening DXA.16 Although many DXA facilities provide an excellent service, poor quality DXA services are endemic in Irish practice. New legislation, coupled with site inspections by H.I.Q.A. and standards and training programmes provided by the Irish DXA Society are addressing these shortcomings.
women. These criteria have been modified and improved over the following 3 decades by the International Society for Clinical Densitometry (ISCD), such that further clarifications have been added, and they may also be used for men aged 50 years and older. These details are available through the ISCD website (https:// iscd.org/learn/official-positions/) which are an essential guide on who should be referred for DXA testing, how it should be done, how DXA testing should be reported and how to interpret the reports in clinical practice.
In the same year as the first USPSTF report was published, a group of researchers in Asia developed the Self-AssessmentOsteoporosisToolorOST for short. This tool combines age and weight to help identify those most likely to have osteoporosis. By adding weight, multiple authors have shown the number needed to
Today major screeningMostandinterpretationduelessorosteoporosis,factorsyoungeragedrecommendandappropriate,postmenopausalorganisationsinternationalagreescreeningwomenisandbothclinicallycost-effective.Themajorityscreeningallwomen65yearsandolder,andwomenwithmajorrisksuchasafamilyhistoryofcorticosteroiduserheumatoidarthritis.Thereisconsensusformen,inparttosomeambiguityaroundtheoftheepidemiologytreatmenteffectivenessinmen.agreehoweverthatsomeisappropriateasmen
Fracture risk algorithms are also used but their goal is to assess the risk of fracture, not those with low BMD, which is arguably more important. Both FRAX® (https:// asp?country=48)www.sheffield.ac.uk/FRAX/tool.andQFracture populations.have(https://qfracture.org/index.php)®beenstudiedinlargeIrish9,17Bothtoolsusesimilardatatoestimatethe10yearriskofmajorosteoporoticfractureandhipfracture,andhaveimportantstrengthsandlimitations.9,17,18The10yearriskcanthusbeestimatedviawebsiteswithorwithoutBMDdata.Becausefractureriskisprobabilisticandheuristic,thesetoolsprovideareasonableandrationalestimation.However,theperformanceofscreeningtoolsislessrobustin
Figure 1. Number of Postmenopausal US women requiring a screening DXA scan in order to prevent a spine or hip fracture at various ages13
HOSPITALPROFESSIONALNEWS.IE | HPN • MAY 2022 47
Hip Spine
make up between 20% and 30% of all FF, but acknowledged the uncertainty around who exactly should be screened, and what interventions might be used. In the USA, UK and ISCD guidelines screening is recommended for
Figure 1. Number of Postmenopausal US women requiring a screening DXA scan in order 800070006000500040003000200010000 50 65 70 75 Number Needed to Screen
men aged 70 – 75 years and older, and younger men with major risk factors, similar to postmenopausal women.
50 year old 70 ear old
For comparison we can calculate her 10 year risk of Major Osteoporotic Fracture and Hip Fracture without a DXA: MOF: 12% and Hip: 5%
48 RHEUMATOLOGY FOCUS: OSTEOPOROSIS
younger populations19 who are generally at considerably lower risk, which further emphasizes the importance of age in the criteria for establishing an effective strategy. Thus it is clear today that for the first time in Ireland we now have the availability of the essential components required to devise
Her OST is 2 = NO DXA.
Osteoporosis and the resulting fragility fracture is a national crisis
Note: In our publication we identified the most appropriate OST cut-off to be ‘0’ for women. How to Calculate OST = (Body weight in kg x Age in years) x 0.2 rounded to the nearest integer14
Sixteen public hospitals were invited to participate in the survey with a 100% response rate. Ten sites (62.5%) reported the existence of FLS and managed 3,444 non hip fractures during 2019, representing 19% of the expected non-hip fragility fracture numbers occurring annually in Ireland.
TResults:score = 0: MOF: 6% and Hip: <1%
= 0: MOF: 2% and Hip: <1%
In summary
A new Irish survey has highlighted the need for a national policy to implement effective high-quality Fracture Liaison Services (FLS) across Irish hospitals with the aim of reducing the risk of fractures in patients.
Six of the ten sites surveyed reported their services being established more than a decade but due to inadequate resourcing, they were failing to meet the thirteen standards as outlined in the International Best Practice Framework - “Capture the Fracture”. However, elements of a high quality FLS service were being attained including a comprehensive falls risk assessment.
2. A DXA scan for those who are below the threshold;
Mr Paddy Kenny – Joint National Clinical Lead for the National Clinical Programme for Trauma and Orthopaedic Surgery (NCPTOS) said “The publication and findings of the facilities survey demonstrates the need for the implementation of FLS nationally as a matter of urgency. FLS has been proven internationally to be effective clinically and economically for the management of secondary fracture prevention. This service will result in reduced hospital admissions. The programme fully supports the establishment of the FLS Database which will be publishing its preliminary report and recommendations later this year.”
1. A Modified OST with Irish thresholds;
T score = 3.0: MOF: 7% and Hip: 4%
This process is probably best outlined in an example where we consider the OST, DXA and FRAX tools for 2 women who differ only in age as shown in Table 2. Those identified as being at high risk, above an agreed and appropriate threshold, could then benefit from appropriate evidence based interventions to reduce their risk of fracture, reduce the risk of unnecessary testing and treatment as exists today, provide a more accurate and efficient programme to reduce the burden of illness for patients and the cost of healthcare for all.2, 4-6
and roll out a national screening strategy for osteoporosis, based on science, international standards and Irish data. There are 3 essential steps for the process, whose exact deployment details have yet to be worked out, and where modifications will be needed over time.
Fracture Liaison Services (FLS) provide the best method of identifying, treating and monitoring these patients and are proven to reduce fracture numbers, improve treatment for patients and substantially reduce the cost burden to the health service.
T score = 2.0: MOF: 4% and Hip: 1%
Dr Frances Dockery joint clinical lead for the Fracture Liaison Service Database said: “We urgently need a policy to support the national implementation of FLS across Irish trauma hospitals.
Note: In our publication we identified the most appropriate OST cut off to be ‘0’ for women (14).
In Ireland the predicted increase by 2030 in fragility fractures is 58%, the highest of all EU countries.
Rheumatology News
Table 2. Example of a 3 Step Screening Process for 2 Women, both 60kg and 170cm tall (BMI = 21).
If She had a DXA, we can calculate her risk for various BMD
TResults:score
If She had a DXA, we can calculate her risk for various BMD
T score = 2.0: MOF: 10% and Hip: 3%
MAY 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE
T score = 3.0: MOF: 17% and Hip: 6%
Urgent Need for National Policy
References available on request
Her OST = 2.0, so she should get a DXA scan.
To further allay Concerns, one can calculate her 10 year risk of Major Osteoporotic Fracture and Hip Fracture without a DXA: MOF: 3% and Hip:<1%
Table 2. Example of a 3-Step Screening Process for 2 Women, both 60kg and 170cm tall (BMI = 21)
The national survey, the first to be completed in Ireland, indicates that the implementation, and resourcing, of a national FLS would bring fracture prevention services in Irish hospitals in line with international standards. A national FLS would offer substantial cost savings to the health service and improve outcomes and quality of life for patients.
which is deteriorating rapidly. We do not have the resources to manage the current illness burden, which is rising rapidly as people live longer, often with more complex needs. While secondary prevention works, and needs more work and resources too, a national screening strategy could be even more clinically and cost-effective by reducing this burden with evidence-based primary prevention. Support and policy for quality DXA services are required rather than just more DXA scanning. We have the tools, we have the data, but action is needed now.
3. A Fracture Risk Estimation with or without the DXA test, which can be reviewed and repeated at appropriate intervals or if a patients circumstances change.
The survey found that no trauma sites in Ireland are capturing all fracture patients. 50% of all sites reported that patients received their first prescription for osteoporosis medication within four months of a fracture.
Method of administration: Movymia should be administered once daily by subcutaneous injection in the thigh or abdomen. It should be administered exclusively with the Movymia Pen reusable, multidose medicine delivery system and the injection needles which are listed as compatible in the instructions provided with the pen. The pen and injection needles are not included with Movymia. However, for treatment initiation a cartridge and pen pack should be used. Movymia must not be used with any other pen. Patients must be trained to use the proper injection techniques. Contraindications: Hypersensitivity to the active substance or excipients. Pregnancy and Breast-feeding Pre-existing hypercalcaemia, severe renal impairment, metabolic bone diseases other than primary osteoporosis or glucocorticoid-induced osteoporosis, unexplained elevations of alkaline phosphatase, prior external beam or implant radiation therapy to the skeleton, patients with skeletal malignancies or bone metastases. Warnings and precautions: In normocalcaemic patients, slight and transient elevations of serum calcium concentrations have been observed following teriparatide injection. Serum calcium concentrations reach a maximum between 4 and 6 hours and return to baseline by 16 to 24 hours after each dose of teriparatide. Therefore, if blood samples for serum calcium measurements are taken, this should be done at least 16 hours after the most recent teriparatide injection. Routine calcium monitoring during therapy is not required. Teripa ratide may cause small increases in urinary calcium excretion, but the incidence of hypercalciuria did not differ from that in the placebo-treated patients in clinical trials. Teriparatide should be used with caution in patients with active or recent urolithiasis because of the potential to exacerbate this condition. In short-term clinical studies with teriparatide, isolated episodes of transient orthostatic hypotension were observed. Typically, an event began within 4 hours of dosing and spontaneously resolved within a few minutes to a few hours. When transient orthostatic hypotension occurred, it happened within the first several doses, was relieved by placing subjects in a reclining position, and did not preclude continued treatment. Caution should be exercised in patients with moderate renal impairment. Experience in the younger adult population, including premenopausal women, is limited. Treatment should only be initiated if the benefit clearly outweighs risks in this population. Women of childbearing potential should use effective methods of contraception during use of teriparatide. If pregnancy occurs, teriparatide should be discontinued. The recommended treatment time of 24 months should not be exceeded. Contains sodium. Interactions: Digoxin, digitalis. Fertility, pregnancy and lactation: Women of child bearing potential should use effective methods of contraception during use of teriparatide. If pregnancy occurs, Movymia should be discontinued. Movymia is contraindicated for use during pregnancy and breast-feeding. The effect of teriparatide on human foetal development has not been studied. The potential risk for humans is unknown. Driving and operation of machinery: Teriparatide has no or negligible influence on the ability to drive and use machines. Transient, orthostatic hypotension or dizziness was observed in some patients. These patients should refrain from driving or the use of machines until symptoms have subsided. Undesirable effects: Nausea, pain in limb, headache, dizziness. Refer to Summary of Product Characteristics for other adverse effects. Pack size: 1. Reporting of suspected adverse reactions: Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2; Tel: +353 1 6764971; Fax: +353 1 6762517. Website: www.hpra.ie; E-mail: medsafety@hpra.ie. Marketing authorisation holder: STADA Arzneimittel AG, Stadastrasse 2-18, 61118 Bad Vilbel, German. Marketing authorisation number: EU/1/16/1161/001-003. Medicinal product subject to medical prescription. Date last revised: July 2019.
1. Movymia® SmPC. 2. Movymia® EPAR – public assessment report, available at: https://www.ema.europa.eu/documents/assessment-report/movymia-epar-public-assessment-report_en.pdf 3. Brixen KT et al. Basic Clin Pharmacol Toxicol. 200494(6):260–70. 4. Lyman GH et al. N Engl J Med. 2018378(21):2036–2044. 5. Janjigian YY et al. Future Oncol. 201814(23):2403–2414.* Forsteo® October 2019. 2019/ADV/TER/122H
DON’T WAIT STRIKESOSTEOPOROSISUNTILAGAIN MOVYMIA®: THE NEW TERIPARATIDE BIOSIMILAR FROM CLONMEL HEALTHCARE Rebuild bone before it breaks again—with Movymia®1 RELIABLE: Movymia®’s quality, safety and efficacy is highly similar to its reference product1,2,* EFFECTIVE: Anabolic MoA effectively rebuilds bone through the stimulation of osteoblasts1,3 AFFORDABLE: Allows more eligible patients to benefit due to its cost advantage4,5 RE-USABLE: One high quality reuseable pen for the entire treatment period1 MOVYMIA 20 MICROGRAMS/80 MICROLITERS SOLUTION FOR INJECTION Each dose of 80 microliters contains 20 micrograms of teriparatide. One cartridge of 2.4 ml of solution contains 600 micrograms of teriparatide (corresponding to 250 micrograms per ml). Presentation: Glass cartridge. Indications: Movymia is indicated in adults. Treatment of osteoporosis in postmenopausal women and men at increased risk of fracture. In postmenopausal women, a significant reduction in the incidence of vertebral and non-vertebral fractures but not hip fractures has been demonstrated. Treatment of osteoporosis associated with sustained systemic glucocorticoid therapy in women and men at increased risk for fracture. Dosage: The recommended dose is 20 micrograms administered once daily. Patients should receive calcium and vitamin D supplements if dietary intake is inadequate. The maximum total duration of treatment is 24 months. The 24 month course should not be repeated over a patient’s lifetime. Following cessation of teriparatide therapy, patients may be continued on other osteoporosis therapies. Teriparatide must not be used in severe renal impairment. Use with caution in moderate renal impairment and impaired hepatic function. Teriparatide should not be used in paediatric patients (less than 18 years), or young adults with open epiphyses. Method of administration: Movymia should be administered once daily by subcutaneous injection in the thigh or abdomen. It should be administered exclusively with the Movymia Pen reusable, multidose medicine delivery system and the injection needles which are listed as compatible in the instructions provided with the pen. The pen and injection needles are not included with Movymia. However, for treatment initiation a cartridge and pen pack should be used. Movymia must not be used with any other pen. Patients must be trained to use the proper injection techniques. Contraindications: Hypersensitivity to the active substance or excipients. Pregnancy and Breast-feeding Pre-existing hypercalcaemia, severe renal impairment, metabolic bone diseases other than primary osteoporosis or glucocorticoid-induced osteoporosis, unexplained elevations of alkaline phosphatase, prior external beam or implant radiation therapy to the skeleton, patients with skeletal malignancies or bone metastases. Warnings and precautions: In normocalcaemic patients, slight and transient elevations of serum calcium concentrations have been observed following teriparatide injection. Serum calcium concentrations reach a maximum between 4 and 6 hours and return to baseline by 16 to 24 hours after each dose of teriparatide. Therefore, if blood samples for serum calcium measurements are taken, this should be done at least 16 hours after the most recent teriparatide injection. Routine calcium monitoring during therapy is not required. Teripa ratide may cause small increases in urinary calcium excretion, but the incidence of hypercalciuria did not differ from that in the placebo-treated patients in clinical trials. Teriparatide should be used with caution in patients with active or recent urolithiasis because of the potential to exacerbate this condition. In short-term clinical studies with teriparatide, isolated episodes of transient orthostatic hypotension were observed. Typically, an event began within 4 hours of dosing and spontaneously resolved within a few minutes to a few hours. When transient orthostatic hypotension occurred, it happened within the first several doses, was relieved by placing subjects in a reclining position, and did not preclude continued treatment. Caution should be exercised in patients with moderate renal impairment. Experience in the younger adult population, including premenopausal women, is limited. Treatment should only be initiated if the benefit clearly outweighs risks in this population. Women of childbearing potential should use effective methods of contraception during use of teriparatide. If pregnancy occurs, teriparatide should be discontinued. The recommended treatment time of 24 months should not be exceeded. Contains sodium. Interactions: Digoxin, digitalis. Fertility, pregnancy and lactation: Women of child bearing potential should use effective methods of contraception during use of teriparatide. If pregnancy occurs, Movymia should be discontinued. Movymia is contraindicated for use during pregnancy and breast-feeding. The effect of teriparatide on human foetal development has not been studied. The potential risk for humans is unknown. Driving and operation of machinery: Teriparatide has no or negligible influence on the ability to drive and use machines. Transient, orthostatic hypotension or dizziness was observed in some patients. These patients should refrain from driving or the use of machines until symptoms have subsided. Undesirable effects: Nausea, pain in limb, headache, dizziness. Refer to Summary of Product Characteristics for other adverse effects. Pack size: 1. Reporting of suspected adverse reactions: Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2; Tel: +353 1 6764971; Fax: +353 1 6762517. Website: www.hpra.ie; E-mail: medsafety@hpra.ie. Marketing authorisation holder: STADA Arzneimittel AG, Stadastrasse 2-18, 61118 Bad Vilbel, German. Marketing authorisation number: EU/1/16/1161/001-003. Medicinal product subject to medical prescription. Date last revised: July 2019. 1. Movymia® SmPC. 2. Movymia® EPAR – public assessment report, available at: https://www.ema.europa.eu/documents/assessment-report/movymia-epar-public-assessment-report_en.pdf 3. Brixen KT et al. Basic Clin Pharmacol Toxicol. 200494(6):260–70. 4. Lyman GH et al. N Engl J Med. 2018378(21):2036–2044. 5. Janjigian YY et al. Future Oncol. 201814(23):2403–2414.* Forsteo® October 2019. 2019/ADV/TER/122H DON’T WAIT STRIKESOSTEOPOROSISUNTILAGAIN MOVYMIA®: THE NEW TERIPARATIDE BIOSIMILAR FROM CLONMEL HEALTHCARE Rebuild bone before it breaks again—with Movymia®1 RELIABLE: Movymia®’s quality, safety and efficacy is highly similar to its reference product1,2,* EFFECTIVE: Anabolic MoA effectively rebuilds bone through the stimulation of osteoblasts1,3 AFFORDABLE: Allows more eligible patients to benefit due to its cost advantage4,5 RE-USABLE: One high quality reuseable pen for the entire treatment period1 MOVYMIA 20 MICROGRAMS/80 MICROLITERS SOLUTION FOR INJECTION Each dose of 80 microliters contains 20 micrograms of teriparatide. One cartridge of 2.4 ml of solution contains 600 micrograms of teriparatide (corresponding to 250 micrograms per ml). Presentation: Glass cartridge. Indications: Movymia is indicated in adults. Treatment of osteoporosis in postmenopausal women and men at increased risk of fracture. In postmenopausal women, a significant reduction in the incidence of vertebral and non-vertebral fractures but not hip fractures has been demonstrated. Treatment of osteoporosis associated with sustained systemic glucocorticoid therapy in women and men at increased risk for fracture. Dosage: The recommended dose is 20 micrograms administered once daily. Patients should receive calcium and vitamin D supplements if dietary intake is inadequate. The maximum total duration of treatment is 24 months. The 24 month course should not be repeated over a patient’s lifetime. Following cessation of teriparatide therapy, patients may be continued on other osteoporosis therapies. Teriparatide must not be used in severe renal impairment. Use with caution in moderate renal impairment and impaired hepatic function. Teriparatide should not be used in paediatric patients (less than 18 years), or young adults with open epiphyses. Method of administration: Movymia should be administered once daily by subcutaneous injection in the thigh or abdomen. It should be administered exclusively with the Movymia Pen reusable, multidose medicine delivery system and the injection needles which are listed as compatible in the instructions provided with the pen. The pen and injection needles are not included with Movymia. However, for treatment initiation a cartridge and pen pack should be used. Movymia must not be used with any other pen. Patients must be trained to use the proper injection techniques. Contraindications: Hypersensitivity to the active substance or excipients. Pregnancy and Breast-feeding Pre-existing hypercalcaemia, severe renal impairment, metabolic bone diseases other than primary osteoporosis or glucocorticoid-induced osteoporosis, unexplained elevations of alkaline phosphatase, prior external beam or implant radiation therapy to the skeleton, patients with skeletal malignancies or bone metastases. Warnings and precautions: In normocalcaemic patients, slight and transient elevations of serum calcium concentrations have been observed following teriparatide injection. Serum calcium concentrations reach a maximum between 4 and 6 hours and return to baseline by 16 to 24 hours after each dose of teriparatide. Therefore, if blood samples for serum calcium measurements are taken, this should be done at least 16 hours after the most recent teriparatide injection. Routine calcium monitoring during therapy is not required. Teripa ratide may cause small increases in urinary calcium excretion, but the incidence of hypercalciuria did not differ from that in the placebo-treated patients in clinical trials. Teriparatide should be used with caution in patients with active or recent urolithiasis because of the potential to exacerbate this condition. In short-term clinical studies with teriparatide, isolated episodes of transient orthostatic hypotension were observed. Typically, an event began within 4 hours of dosing and spontaneously resolved within a few minutes to a few hours. When transient orthostatic hypotension occurred, it happened within the first several doses, was relieved by placing subjects in a reclining position, and did not preclude continued treatment. Caution should be exercised in patients with moderate renal impairment. Experience in the younger adult population, including premenopausal women, is limited. Treatment should only be initiated if the benefit clearly outweighs risks in this population. Women of childbearing potential should use effective methods of contraception during use of teriparatide. If pregnancy occurs, teriparatide should be discontinued. The recommended treatment time of 24 months should not be exceeded. Contains sodium. Interactions: Digoxin, digitalis. Fertility, pregnancy and lactation: Women of child bearing potential should use effective methods of contraception during use of teriparatide. If pregnancy occurs, Movymia should be discontinued. Movymia is contraindicated for use during pregnancy and breast-feeding. The effect of teriparatide on human foetal development has not been studied. The potential risk for humans is unknown. Driving and operation of machinery: Teriparatide has no or negligible influence on the ability to drive and use machines. Transient, orthostatic hypotension or dizziness was observed in some patients. These patients should refrain from driving or the use of machines until symptoms have subsided. Undesirable effects: Nausea, pain in limb, headache, dizziness. Refer to Summary of Product Characteristics for other adverse effects. Pack size: 1. Reporting of suspected adverse reactions: Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2; Tel: +353 1 6764971; Fax: +353 1 6762517. Website: www.hpra.ie; E-mail: medsafety@hpra.ie. Marketing authorisation holder: STADA Arzneimittel AG, Stadastrasse 2-18, 61118 Bad Vilbel, German. Marketing authorisation number: EU/1/16/1161/001-003. Medicinal product subject to medical prescription. Date last revised: July 2019. 1. Movymia® SmPC. 2. Movymia® EPAR – public assessment report, available at: https://www.ema.europa.eu/documents/assessment-report/movymia-epar-public-assessment-report_en.pdf 3. Brixen KT et al. Basic Clin Pharmacol Toxicol. 200494(6):260–70. 4. Lyman GH et al. N Engl J Med. 2018378(21):2036–2044. 5. Janjigian YY et al. Future Oncol. 201814(23):2403–2414.* Forsteo® October 2019. 2019/ADV/TER/122H DON’T WAIT STRIKESOSTEOPOROSISUNTILAGAIN MOVYMIA®: THE NEW TERIPARATIDE BIOSIMILAR FROM CLONMEL HEALTHCARE Rebuild bone before it breaks again—with Movymia®1 RELIABLE: Movymia®’s quality, safety and efficacy is highly similar to its reference product1,2,* EFFECTIVE: Anabolic MoA effectively rebuilds bone through the stimulation of osteoblasts1,3 AFFORDABLE: Allows more eligible patients to benefit due to its cost advantage4,5 RE-USABLE: One high quality reuseable pen for the entire treatment period1 MOVYMIA 20 MICROGRAMS/80 MICROLITERS SOLUTION FOR INJECTION Each dose of 80 microliters contains 20 micrograms of teriparatide. One cartridge of 2.4 ml of solution contains 600 micrograms of teriparatide (corresponding to 250 micrograms per ml). Presentation: Glass cartridge. Indications: Movymia is indicated in adults. Treatment of osteoporosis in postmenopausal women and men at increased risk of fracture. In postmenopausal women, a significant reduction in the incidence of vertebral and non-vertebral fractures but not hip fractures has been demonstrated. Treatment of osteoporosis associated with sustained systemic glucocorticoid therapy in women and men at increased risk for fracture. Dosage: The recommended dose is 20 micrograms administered once daily. Patients should receive calcium and vitamin D supplements if dietary intake is inadequate. The maximum total duration of treatment is 24 months. The 24 month course should not be repeated over a patient’s lifetime. Following cessation of teriparatide therapy, patients may be continued on other osteoporosis therapies. Teriparatide must not be used in severe renal impairment. Use with caution in moderate renal impairment and impaired hepatic function. Teriparatide should not be used in paediatric patients (less than 18 years), or young adults with open epiphyses.
Figure 1: Axial HRCT image demonstrating subpleural reticulation, ground glass change and traction bronchiectasis.
Rheumatoid arthritis (RA) is an autoimmune condition characterised by chronic inflammation
Written by Dr Laura Durcan, Consultant Rheumatologist, Beaumont Hospital and Dr Wan Lin Ng, Specialist Registrar in Rheumatology, Beaumont Hospital
DISCUSSION
This patient was diagnosed with seropositive Rheumatoid Arthritis and was commenced
He was referred to the respiratory team for management of his ILD. His chest CT images which were discussed at the lung multidisciplinary meeting (MDM) were consistent with a fibrosing non-specific interstitial pneumonitis (NSIP) pattern. He did not have any respiratory symptoms and his pulmonary function test revealed forced vital capacity (FVC) of 103% predicted and diffusing capacity for carbon monoxide (DLCO) was 93% predicted. He was strongly advised to stop smoking. A year later, he had a follow-up chest
50 RHEUMATOLOGY FOCUS: RA/LUNG DISEASE
On examination, he had active synovitis in bilateral second, third and fourth MCP joints with swelling of both his wrist joints. Initial blood results revealed raised inflammatory markers, negative Rheumatoid Factor (RF), strongly positive anti-cyclic citrullinated peptide antibody (ACPA) and
negative anti-nuclear factor. Plain radiographs of his hands and feet showed mild osteopenia with no erosive changes.
Figure 1: Axial HRCT image demonstrating subpleural reticulation, ground glass change and traction bronchiectasis
MAY 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE
ILD is the most common pulmonary presentation in RA. Patients with RA-ILD present with symptoms such as breathlessness, cough, sputum production and fatigue. The median survival of patients with RA-ILD is estimated to be between 3-7 years.
A 56 year old gentleman was referred to our Rheumatology department in 2018 with pain, stiffness and swelling in his hands for several months. He reported pain and swelling in both metacarpophalangeal (MCP) joints and wrists. His past medical history included craniotomy and excision of right occipital arteriovenous malformation in 1989 with epilepsy secondary to this. He had a 20 pack-year smoking history and consumed 5 units of alcohol per week. He worked as a mechanic and did not have any family history of autoimmune conditions. The systems review was unremarkable.
CT and the images from his most recent chest CT (Figure 1) were discussed at the lung MDM. The CT images showed a probable usual interstitial pneumonia (UIP) which had progressed from fibrotic NSIP. His right upper lobe nodule had progressed with central cavitation. CT guided biopsy of the nodule was advised to determine if the nodule is secondary to a rheumatoid nodule or malignancy.
CASE
Rheumatoid Arthritis and Interstitial Lung Disease
on methotrexate. A routine chest radiograph was ordered and revealed diffuse interstitial abnormalities most marked at the lung bases. This resulted in a chest CT which demonstrated evidence of bilateral subpleural reticulation, particularly in the bases which were in keeping with early fibrosis. There were two subpleural pulmonary nodules in the right lung. He was commenced on rituximab infusion but developed an allergic reaction to it.
Dr Wan Lin Ng
Dr Laura Durcan
He had several flare-ups while on the methotrexate, and sulfasalazine was commenced but the added therapy did not improve his symptoms. The patient had a great response when adalimumab was later added to his treatment regime.
Rheumatoid arthritis (RA) is an autoimmune condition characterised by chronic inflammation, particularly at the synovium leading to damage to the bone and cartilage causing profound disability. It affects approximately 1% of the population and is twice as common in women with peak incidence at 50 years. Patients diagnosed with RA typically present with symmetrical polyarthritis of the hands and feet for a period of several months, and is often associated with early morning stiffness. RA is also associated with extra-articular manifestations. These include episcleritis, scleritis, Sjögren’s syndrome, rheumatoid vasculitis, Felty’s syndrome and interstitial lung disease (ILD). Pulmonary involvement has become a major contributor to morbidity and mortality in RA-related deaths, second only to cardiovascular disease. Pulmonary involvement in RA can precede the onset of articular manifestations in up to 20% of the patients.
DISCUSSION
Treatment
Investigation
Adjunctiverespectively.measures are recommended in addition to the traditional immunosuppressive therapies for the management of RA-ILD. Patients should be advised to smoke cessation, be enrolled on pulmonary rehabilitation therapy, receive supplemental oxygen therapy and ensure appropriate vaccination such as pneumococcal, influenza and COVID-19 vaccinations. Early palliative care intervention in this cohort of patients is increasingly important to improve patients’ symptoms, quality of life and caregivers’ psychosocial needs.
As patients with RA have approximately a 10% lifetime risk of developing RA-ILD, patients presenting with respiratory symptoms should have a thorough physical examination and relevant investigations. Pulmonary function tests (PFTs) are commonly used to screen and monitor disease activity in patients with RA-ILD. It is important to note that normal PFT results can be present in early ILD and this does not rule out mild pulmonary disease. Patients with ILD can have reduced diffusion capacity for carbon monoxide (DLCO), followed by reduced flow (forced vital capacity [FVC]) and reduced lung volumes (total lung capacity [TLC]) in more advanced diseases. A decline of ≥10% in FVC or ≥15% in DLCO likely indicates worsening ILD. The 6-minute walk test (6MWT) is a simple measure that provides prognostic information in patients with established RA-ILD.
specific interstitial pneumonia (NSIP) which has a predominantly ground-glass appearance. Other RA-ILD subtypes include organising pneumonia (OP), lymphocytic interstitial pneumonia (LIP), acute interstitial pneumonia, desquamative interstitial pneumonia and respiratory bronchiolitis ILD.
Patients with RA-ILD can be managed with immunosuppressive therapy. Patients with NSIP, OP or LIP generally respond better to corticosteroids compared to the more fibrotic patterns such as UIP and fibrotic NSIP. Rituximab, which is an anti-CD20 monoclonal antibody, has been used in the treatment of RA-ILD. The RECITAL study is an ongoing multicenter, prospective, randomised, doubleblind, controlled trial of rituximab versus cyclophosphamide to study the efficacy of rituximab in patients with connective tissue disease related ILD (CTD-ILD) which would provide great insights once completed. Results from the focuSSced study demonstrated a favourable change in FVC percentage predicted in patients with SSc-ILD treated with tocilizumab. Tocilizumab is an IL-6 receptor antibody that is
commonly used in RA and further studies should be conducted to see its role in patients with RAILD. Abatacept, which is a fully humanised monoclonal antibody against CD80/86 was associated with stabilisation of FVC in a multicenter, open-label study of patients with RA-ILD.
The option for lung transplantation should be considered for younger patients with end-stage RA-ILD. The consideration for a lung transplant is generally complicated with advanced age, immobility and multiple comorbidities. The post lung transplantation outcomes in patients with RA-ILD are comparable to patients with IPF with one-year survival post lung transplant of 67% and 69%
RA-ILD is more prevalent in males, with a male to female ratio of 2:1 (despite RA being more common in females). History of smoking and advanced age are some of the risk factors for developing RA-ILD along with high titres of RF and ACPA. 3-15% of patients with RA are found to have the presence of anti-Ro/SSA antibodies. A retrospective study demonstrated that 60.4% of patients with RA who had positive anti Ro-52 antibodies and 20% with isolated anti Ro-60 antibodies developed ILD. Interleukin-1-alpha antibody, KL-6 glycoprotein, interferonγ-inducible protein and matrix metalloproteinase-7 are some serum markers that are linked with RA-ILD. Recent studies have shown that the presence of the MUC5B variant could increase the risk of developing ILD in patients with RA. Another study demonstrated a higher risk for RA-ILD in those who carry HLA-DRB1*1502.
ILD is an increasingly important clinical manifestation in patients with RA. It remains challenging to manage patients with RA-ILD due to the paucity of data and the complex nature of the disease. Immunosuppressive therapy, antifibrotics and a multidisciplinary approach are important measures in the treatment of RA-ILD.
References available on request
with nintedanib or pirfenidone due to their elevated risk of raised liver enzymes.
Chest radiography is a cheap and readily available tool to identify pleural effusions and pneumonia but has poor sensitivity and specificity for detecting ILD. High resolution computed tomography (HRCT) is used to diagnose and monitor the disease progression in ILD. Prognosis is guided by the extent of fibrosis demonstrated on HRCT and the various subtypes. Usual interstitial pneumonia (UIP) pattern which is characterised by basilar and subpleural reticulation with or without traction bronchiectasis and honeycombing is the most common subtype in RA-ILD, followed by non-
Summary
Risk factors
HOSPITALPROFESSIONALNEWS.IE | HPN • MAY 2022 51
Bronchoalveolar lavage (BAL), although not routinely performed in this condition, may be helpful to evaluate the activity of the development processes in RAILD and to out rule infections, malignancy and haemorrhage. Surgical lung biopsy is less commonly performed in recent years to diagnose ILD as HRCT is a very reliable diagnostic tool.
Nintedanib is a tyrosine kinase inhibitor that has been shown to slow the progression of disease progression in patients with idiopathic pulmonary fibrosis (IPF) and also in patients with scleroderma related ILD in the recent SENCSIS trial. The annual rate of decline in FVC was shown to be much less with nintedanib compared with placebo in patients with SSc-ILD in the SENSCIS trial. The INBUILD trial had demonstrated the role of nintedanib in slowing the rate of decline in FVC in patients with CTD-ILDs. Pirfenidone, another anti-fibrotic agent which acts on the regulation of TGF-5 activity, TNF-α and β pathways, as well as cellular oxidation has also been proven to slow down disease progression in IPF. Ongoing studies such as the TRAIL study are being carried out to demonstrate the efficacy of these antifibrotics in patients with connective tissue disease related ILD. As shown in most literature, the main limiting factor of patients continuing on nintedanib or pirfenidone is their gastrointestinal side effects which include diarrhoea, nausea, vomiting and abdominal pain. It is worth noting that leflunomide, which is generally used in the treatment of RA should be avoided when co-prescribing
WHAT’S BEHIND AMGEVITA®
≥ 30 kg: 40 mg EOW. Ankylosing spondylitis (AS), adults: Severe active AS with inadequate response to conventional therapy. Axial spondyloarthritis without radiographic evidence of AS (nr-axSpA), adults: Severe nr-axSpA with objective signs of inflammation (elevated CRP and/or MRI), and an inadequate response to or intolerance to nonsteroidal anti-inflammatory drugs. Psoriatic arthritis (PsA), adults: Active and progressive PsA with inadequate response to DMARDs. Dosage (AS, nr-axSpA, PsA): 40 mg EOW. Reconsider treatment beyond 12 weeks if no clinical response. Psoriasis, adults: Moderate to severe chronic plaque psoriasis in candidates for systemic therapy. Dosage: 80 mg at Week 0, followed by 40 mg EOW from Week 1. Reconsider treatment beyond 16 weeks if no clinical response. Refer to SmPC. Paediatric Plaque Psoriasis, ≥ 4 years: Severe chronic plaque psoriasis with inadequate response to or if topical therapy and phototherapies are inappropriate. Dosage: 15 kg to < 30
Please refer to the Summary of Product Characteristics (SmPC) before prescribing Pharmaceutical Form: Single dose pre-filled syringe contains 20 mg adalimumab in 0.4 mL (50 mg/mL) solution, 40 mg adalimumab in 0.8 mL (50 mg/mL) solution or single dose pre-filled pen (SureClick®) contains 40 mg adalimumab in 0.8 mL (50 mg/mL) solution. Indications and Dosage: please refer to SmPC for full information. For subcutaneous injection. Treatment should be initiated and supervised by specialist physicians experienced in conditions for which AMGEVITA® is indicated. Ophthalmologists should consult with an appropriate specialist before starting treatment. Give patients a Patient Reminder Card. After training in injection technique, patients may self-inject with medical follow-up as necessary. Optimise other concomitant therapies (e.g. corticosteroids and or/immunomodulatory agents). Rheumatoid arthritis (RA), adults: In combination with methotrexate (MTX) for: 1. Moderate to severe, active RA with inadequate response to disease-modifying antirheumatic drugs (DMARDs) including MTX; 2. Severe, active and progressive RA not previously treated with MTX. Can be given as monotherapy if intolerance to or when continued treatment with MTX is inappropriate. Dosage: 40 mg every other week (EOW). Continue concomitant MTX. In monotherapy, patients may require 40 mg every week or 80 mg EOW if there is a decrease in clinical response. Reconsider treatment beyond 12 weeks if no clinical response. Consider need for dose interruption, e.g. before surgery or if serious infection occurs. Polyarticular juvenile idiopathic arthritis (pJIA), paediatrics ≥ 2 years: In combination with MTX for active pJIA with inadequate response to one or more DMARDs. Can be given as monotherapy if intolerance to or when continued treatment with MTX is inappropriate. Dosage: 10 kg to < 30 kg: 20 mg EOW. ≥ 30 kg: 40 mg EOW. Reconsider treatment beyond 12 weeks if no clinical response. Enthesitis-related arthritis (ERA), paediatrics, ≥ 6 years: Active ERA with inadequate response to or intolerance to conventional therapy. Dosage: 15 kg to < 30 kg: 20 mg EOW.
kg: 20 mg followed by 20 mg EOW starting one week after initial dose. ≥ 30 kg: 40 mg then 40 mg EOW starting one week after initial dose. Reconsider treatment beyond 16 weeks if no clinical response. Safety has been assessed in paediatric patients with plaque psoriasis for a mean of 13 months. Hidradenitis suppurativa (HS), adults and adolescents ≥ 12 years: Active moderate to severe HS (acne inversa) with inadequate response to conventional systemic therapy. Dosage, adult: 160 mg at Day 1, followed by 80 mg at Day 15. At day 29 continue with 40 mg every week or 80 mg EOW. Reintroduction after treatment interruption: 40 mg every week or 80 mg EOW. Dosage: adolescent (≥ 30 kg): 80 mg at week 0 then 40 mg EOW starting at week 1. If response is inadequate, consider increasing to 40 mg every week or 80 mg EOW. Dosage, adult and adolescent: Antibiotics may be continued if necessary. Use concomitant topical antiseptic wash on a daily basis. Reconsider treatment beyond 12 weeks if no improvement. Periodically evaluate the benefit and risk of continued treatment. Crohn’s disease (CD), adults: Moderately to severely active CD with no response despite a full and adequate course of, intolerance to or contraindication for a corticosteroid and/ or an immunosuppressant therapy. Dosage: Induction: 80 mg at Week 0, then 40 mg at Week 2. For a more rapid response: 160 mg at Week 0, then 80 mg at Week 2; risk of adverse events higher during rapid induction. Maintenance: 40 mg dose EOW. Corticosteroids may be tapered in accordance with clinical guidelines. If decrease in clinical response, can increase to 40 mg every week or 80 mg EOW. If no response by Week 4 there may be benefit from continued therapy to week 12. Reconsider treatment beyond 12 weeks if no clinical response. Paediatric CD, ≥ 6 years: Moderately to severely active CD with inadequate response to, intolerance to or contraindication to conventional therapy including primary nutrition therapy and a corticosteroid and/or an immunomodulator. Dosage: < 40 kg: Induction: 40 mg at week 0 then 20 mg at week 2. For a more rapid response: 80 mg at week 0 then 40 mg at week 2; risk of adverse events higher during rapid induction. Maintenance starting at week 4: 20 mg dose EOW. If insufficient response, consider 20 mg every week. Dosage: ≥ 40 kg: Induction: 80 mg at Week 0 then 40 mg at Week 2. For a more rapid response: 160 mg at Week 0, then 80 mg at Week 2; risk of adverse events higher during rapid induction. Maintenance starting at week 4: 40 mg dose EOW. If insufficient response, consider 40 mg every week or 80 mg EOW. Reconsider treatment beyond 12 weeks if no clinical response. Ulcerative colitis (UC), adults: Moderately to severely active UC with inadequate response to, intolerance to or contraindication for conventional therapy including corticosteroids and 6-mercaptopurine (6-MP) or azathioprine (AZA). Dosage: Induction: 160 mg at week 0 and 80 mg at week 2. Maintenance: 40 mg EOW. Corticosteroids may be tapered in accordance with clinical guidelines. If insufficient response, consider increasing to 40 mg every week or 80 mg EOW. Do not continue treatment beyond 8 weeks if no
extra-pulmonary
Screen all patients before therapy initiation PRESCRIBE AMGEVITA® BY BRAND NAME ® awarded best value biosimilar medicine in a citrate free formulation of adalimumab by the Medicines Management Programme BVBM AWA R DED DEDRAWA CITRATEFREE itcfunamaurngexcellence supply reliability yconsistentqualit gniunitnocnoitavonniAmgen has >40 EXPERIENCBIOLYEARSOGICSE Amgevita® Awarded best value biologic medicine in a citrate free formulation of adalimumab and is the only BVBM awarded for 20mg adalimumab. NOW BVBM FOR ADALIMUMAB20MG 6 AMGEVITA® HOW AND WHEN AMGEVITA® is injected a specially designed You should inject in see diagram below. The medicine travels that are inflamed and Your doctor, pharmacist you or your parent/carer injection. It’s important correctly for it to work. You may have the injection at home. You can give parent/carer can do injection is given every doctor may change works for you. You need to follow healthcare team and if you are not feeling For full and detailed administer your AMGEVITA®, instructions provided in
clinical response. Paediatric UC, ≥6 years: Moderately to severely active UC with an inadequate response to conventional therapy including corticosteroids and/or 6-MP or AZA, or who are intolerant to or have contraindications. Dosage: < 40 kg: Induction: 80 mg at Week 0 and 40 mg at Week 2. Maintenance starting at week 4: 40mg EOW. Dosage: ≥ 40 kg: Induction: 160 mg Week 0 and 80 mg Week 2. Maintenance starting at week 4: 80mg EOW. Patients reaching 18 years should continue their prescribed maintenance dose. Reconsider treatment beyond 8 weeks if no clinical response. No relevant use in children <6 years. Uveitis, adults: Non-infectious intermediate, posterior and panuveitis with inadequate response to corticosteroids, in patients in need of corticosteroid-sparing, or in whom corticosteroid treatment is inappropriate. Dosage: 80 mg at Week 0 and 40 mg EOW from Week 1. There is limited experience in initiation of treatment with adalimumab alone. Treatment can be initiated in combination with corticosteroids and/or with other non-biologic immunomodulatory agents. Concomitant corticosteroids may be tapered starting two weeks after initiating treatment with AMGEVITA® Evaluate on a yearly basis the benefit and risk of continued treatment. Paediatric uveitis, ≥ 2years: Chronic non-infectious anterior uveitis with inadequate response or intolerance to conventional therapy, or in whom conventional therapy is inappropriate. In paediatric uveitis, there is no experience in the treatment with AMGEVITA® without concomitant treatment with methotrexate. Dosage: < 30 kg: 20 mg EOW in combination with MTX. Dosage: ≥ 30 kg: 40 mg EOW in combination with MTX. A loading dose of 40 mg (< 30 kg) or 80 mg (≥ 30 kg) may be administered 1 week in advance of maintenance therapy. No clinical data on use of loading dose in patients < 6 years. Evaluate benefit and risk of continued treatment on a yearly basis.
AMGEVITA® (adalimumab) Brief Prescribing Information
Contraindications: Hypersensitivity to the active substance or to any excipients; Active tuberculosis (TB) or other severe infections such as sepsis and opportunistic infections; Moderate to severe heart failure (NYHA class III/ IV). Warnings and Precautions: Clearly record the name and batch number.
Infections: Patients taking TNF-antagonists are more susceptible to serious infections, especially if impaired lung function. Monitor for infections, before, during and for 4 months after treatment. Do not initiate treatment during an active infection, until infection is controlled. Consider risk/benefit prior to treatment in patients exposed to TB or who have travelled in areas of high risk of TB or endemic mycoses. Evaluate new infections and monitor closely. Stop treatment if new serious infection or sepsis and treat. Exercise caution in patients with a history of recurring infections or who are predisposed to infections, including the use of concomitant immunosuppressive medications.
Serious Infections: Consult SmPC for details. Serious infections, including those associated with hospitalisation or death, were reported in patients receiving treatment. TB: Reactivation and new onset TB, both pulmonary and (disseminated).
RIGHT FRONTLEFT A B C Information for Healthcare Professionals The Medicine Management Programme recommends AMGEVITA® as a citrate-free formulation of adalimumab. Prescribing AMGEVITA® has lead to significant savings for the health service, in the order of millions of euros1,2,3 AMGEVITA® 40mg SureClick® Pre-filled pen AMGEVITA® 20mg Pre-filled syringe AMGEVITA® 40mg Pre-filled syringe
WHEN IS IT GIVEN?
3. Medicines Management Programme Best-Value Biological Medicines: Adalimumab 20 mg solution for injection. adalimumab-20mg-march-2021.pdf.best-value-biological-medicines/mmp-report-bvb-medicine-about/who/cspd/ncps/medicines-management/best-value-medicines/https://www.hse.ie/eng/January2022.
Autoimmune processes: Autoimmune antibodies may form. Stop treatment if development of a lupus-like syndrome with positive antibodies against doublestranded DNA. Surgery: Consider the long half-life of AMGEVITA® for planned surgical procedures. Monitor closely for infections. There is limited safety experience in patients undergoing arthroplasty or surgical procedures. Elderly patients: Serious infections were higher in patients over 65, some of which were fatal. Consider risk of infections in these patients. Interactions: Antibody formation was lower when AMGEVITA® was given together with MTX rather than as monotherapy. Combination of AMGEVITA® with other biologic DMARDs (e.g. anakinra and abatacept) or other TNF-antagonists is not recommended. Fertility, pregnancy and lactation Only use during pregnancy if clearly needed. Women of childbearing age to consider use of adequate contraception during and for at least 5 months after the last treatment. Administration of live vaccines (e.g. BCG) to infants exposed to AMGEVITA ® in utero is not recommended for 5 months following the mother’s last injection during pregnancy. AMGEVITA ® can be used during breastfeeding. Effects on ability to drive and use machines: AMGEVITA® may have a minor influence on the ability to drive and use machines. Adverse Reactions: Very common ≥ 1/10: Respiratory tract infections, leukopenia, anaemia, lipids increased, headache, abdominal pain, nausea and vomiting, elevated liver enzymes, rash, musculoskeletal pain, injection site reaction. Common ≥ 1/100 to < 1/10: Systemic infections, intestinal infections, skin and soft tissue infections, ear infections, oral infections , reproductive tract infections , urinary tract infections, fungal infections, joint infections, skin cancer excluding melanoma, benign neoplasm, leucocytosis, thrombocytopenia, hypersensitivity, allergies, hypokalaemia, uric acid increased, blood sodium abnormal, hypocalcaemia, hyperglycaemia, hypophosphataemia, dehydration, mood alterations , anxiety, insomnia, paraesthesia, migraine, nerve root compression, visual impairment, conjunctivitis, blepharitis, eye swelling, vertigo, tachycardia, hypertension, flushing, haematoma, asthma, dyspnoea, cough, GI haemorrhage, dyspepsia, gastroesophageal reflux disease, Sicca syndrome, worsening or new onset of psoriasis , urticaria, bruising , dermatitis, onychoclasis, hyperhidrosis, alopecia, pruritus, muscle spasms , renal impairment, haematuria, chest pain, oedema, pyrexia, coagulation and bleeding disorders, autoantibody test positive , blood lactate dehydrogenase increased, impaired healing. Serious, including fatal, adverse reactions have been reported including infections/sepsis, TB, opportunistic infections, allergic reactions, HBV reactivation and malignancies. Serious haematological, neurological and autoimmune reactions have also been reported. These include rare reports of pancytopenia, aplastic anaemia, central and peripheral demyelinating events and reports of lupus, lupusrelated conditions and Stevens-Johnson syndrome. Other less common and rarely reported adverse reactions are listed in the SmPC. Pharmaceutical
in the tummy, or the tops of your legs (thighs), below.travels into your bloodstream to work on the areas and causing your symptoms.
injected under the skin (a subcutaneous injection) with designed pen called SureClick® or using a pre-filled syringe.
Adverse reactions/events should be reported to the Health Products Regulatory Authority (HPRA) using the available methods via www.hpra.ie. Adverse reactions/events should also be reported to Amgen Limited on +44 (0) 1223 436441 or Freephone 1800 535 160.
1. BVBM Amgevita Product Information Sheet. amgevita-product-information-sheet.pdf.value-medicines/best-value-biological-medicines/bvb-medicine-ie/eng/about/who/cspd/ncps/medicines-management/best-https://www.hse.AccessedJanuary2022.
Precautions: Store in a refrigerator (2 C 8 C). Do not freeze. Keep in the outer carton in order to protect from light. Out of the refrigerator, may be stored up to 25°C for up to 14 days. Legal Category: POM. Presentation and Marketing Authorisation Number. AMGEVITA® 20 mg solution for injection in pre-filled syringe: EU/1/16/1164/001 – 1 pack: cost AMGEVITA® 40 mg solution for injection in pre-filled syringe: EU/1/16/1164/003 – 2 pack AMGEVITA® 40 mg solution for injection in pre-filled pen: EU/1/16/1164/007 – 2 pack. Marketing Authorisation Holder: Amgen Europe B.V. Minervum 7061, 4817 ZK Breda, The Netherlands. Further information is available from Amgen Ireland Limited, 21 Northwood Court, Santry, Dublin D09 TX31. AMGEVITA® is a registered trademark of Amgen Inc. Date of PI preparation: December 2021 (Ref:IE-AMB-1121-00005)
4. AMGEVITA® (adalimumab) summary of product characteristics.IE-AMB-0122-00003
January
Date of preparation: 2022
AMGEVITA® AND ME
for active or inactive (latent) TB. Perform detailed medical assessment and appropriate screening tests for TB in all patients and results recorded on patient reminder card. If latent TB is suspected, consult physician with appropriate expertise Despite prophylaxis, TB reactivation has occurred on adalimumab. If active TB is diagnosed, do not initiate AMGEVITA® treatment. Other opportunistic infections: Opportunistic infections were observed in patients receiving adalimumab. Stop AMGEVITA® in patients with signs and symptoms of such infections. Consult with physician with appropriate expertise for diagnosis and administration of empiric antifungal therapy. Hepatitis B reactivation: Reactivation of HBV has occurred in chronic carriers; some cases were fatal. Test patients for HBV infection before initiating treatment. HBV carriers should consult a specialist physician and be closely monitored for reactivation of HBV infection throughout therapy and for several months after treatment. If reactivation occurs, stop treatment and initiate appropriate antiviral and supportive treatment. Neurological events: Caution in patients with pre-existing or recent-onset central or peripheral nervous system demyelinating disorders. Consider discontinuation if any of these develop. Perform neurologic evaluation in patients with non-infectious intermediate uveitis prior to initiation of treatment and regularly during treatment. Allergic reactions: Reports of serious allergic reactions including anaphylaxis. For serious allergic or anaphylactic reaction, stop AMGEVITA® immediately and initiate appropriate therapy. Dry natural rubber: The needle cover of the pen (SureClick®) is made from dry natural rubber (a derivative of latex), which may cause allergic reactions. Malignancies and lymphoproliferative disorders: A possible risk of malignancy, some fatal, including lymphomas and leukaemia, cannot be excluded (see SmPC). Examine all patients, especially those with a medical history of extensive immuno-suppressant therapy or psoriasis patients with a history of PUVA treatment, for non-melanoma skin cancer prior to and during treatment. Melanoma and Merkel cell carcinoma have also been reported. Caution in COPD patients, and in patients with increased risk for malignancy due to heavy smoking. Consider the potential risk with the combination of AZA or 6-MP and AMGEVITA® (hepatosplenic T-cell lymphoma has occurred). Caution in patients with a history of malignancy. Risk of developing dysplasia or colon cancer unknown. Screen patients with UC, history of dysplasia or colon carcinoma, for dysplasia before and during treatment. Haematologic reactions: Adverse events of the haematologic system, including medically significant cytopenia, have been reported. Advise patients to seek immediate medical attention if signs and symptoms of blood dyscrasias develop. Vaccinations: Patients may receive concurrent vaccinations, except for live vaccines. Bring paediatric patients up to date with all immunisations prior to initiating treatment. Congestive heart failure: See contraindications. Caution in mild heart failure (NYHA class I/II). Discontinue treatment if new or worsening symptoms of congestive heart failure.
detailed instructions on how to AMGEVITA®, please read the provided in the product carton.
pharmacist or nurse will show parent/carer how to give the important the injection is given work.injection in hospital or give it to yourself or your do this for you. Usually, the every 2 weeks, but your change this to best suit what the advice of your and ask to speak to them feeling well.
2. Oireachtas.ie, Debates, December 2020, Written Answer by Minister for Health. question/2020-12-10/373/.https://www.oireachtas.ie/en/debates/AccessedJanuary2022.
MAKES THE DIFFERENCE
Introduction
• With this ageing demographic it is expected that the number of fractures in Ireland will rise by around 58% in this time period.
Osteoporosis is a disease which affects mostly older adults and fragility fractures often result in pain and long-term disability, as well as substantial costs to the healthcare system.
The economic cost of new and previous fragility fractures was estimated at ¤460 million in 2019, equivalent to ¤95.7 for every individual in Ireland, and an increase of 73% compared to 2010. Given the strain fragility fractures currently put on patients and on the healthcare system it is imperative that health authorities and healthcare professionals take action to address this expected increase.
Not only has this a colossal impact on the health of those who suffer, but broken bones caused by osteoporosis cost the healthcare system more than ¤460 million per annum.
In order to do this, we need the systems in place to provide systematic fracture prevention strategies for those at highest fracture risk, namely, those who have already sustained a fragility fracture and prevent their risk of further fractures.
At present, just 10 Irish hospitals operate fracture liaison services, and none of them span anything close to the expected coverage of fragility fractures numbers arriving to their Emergency and Radiology departments.
Addressing the findings within the new research, Mr Aaron Glynn, Orthopaedic Surgeon and joint clinical lead for the Fracture Liaison Service Database said,
SCOPE report
“Despite the high cost of osteoporotic fractures, the new report exposes a large and worrying treatment gap. Approximately 150,000 women aged over 50 are estimated to be at high risk of fracture and should be considered for osteoporosis treatment, but only 68% receive treatment according to the European scorecard estimate. Without treatment for osteoporosis, people at high-risk remain unprotected against potentially debilitating and life-threatening fractures which is going to grow enormously due to the ageing population.”
Dr Frances Dockery
• Hip and spine fractures in older adults are a major cause of morbidity and mortality with the report estimating that in Ireland, amongst those over 50 years, 115 of every 100,000 deaths are related to osteoporotic fractures.
Mr Aaron Glynn
MILLION IRELAND DIRECT COST OF INCIDENT FRACTURES €290.8 MILLION DISABILITYLONG-TERMCOSTS PHARMACOLOGICALINTERVENTION CHANGE IN COST PER INDIVIDUAL HUGE COST BURDEN FOR OSTEOPOROSIS-RELATED HEALTHCARE €135.7 MILLION €37.7 MILLION A NEW SCORECARD FOR OSTEOPOROSIS IN EU 27+2 REVEALS BURDEN OF DISEASE, GAPS, AND INEQUALITIES IN OSTEOPOROSIS & FRACTURE PREVENTION AND CARE 2019INSPENT INDIVIDUALS WITH OSTEOPOROSIS IN 2019 3.7% OF THE TOTAL POPULATIONPER DAY PER HOUR 32,000893.7 FRACTURES FRACTURES NEW FRAGILITY FRACTURES IN 2019 77.5%22.5% MENWOMEN 209,000 PROJECTED INCREASE IN THE NUMBER OF FRAGILITY FRACTURES BURDEN OF €464.3DISEASE 51,000 2034 32,000 2019 +58.4% SERVICE PROVISION & UPTAKE 104,000 49,000 WOMEN REMAIN UNTREATED WOMEN TREATED* 20.5 2019 €95.7 2010 €55.2 +73% Fig:1 Economic cost for osteoporosis-related healthcare in 2019 MILLION IRELAND DIRECT COST OF INCIDENT FRACTURES €290.8 MILLION DISABILITYLONG-TERMCOSTS PHARMACOLOGICALINTERVENTION CHANGE IN COST PER INDIVIDUAL HUGE COST BURDEN FOR OSTEOPOROSIS-RELATED HEALTHCARE €135.7 MILLION €37.7 MILLION A NEW SCORECARD FOR OSTEOPOROSIS IN EU 27+2 REVEALS BURDEN OF DISEASE, GAPS, AND INEQUALITIES IN OSTEOPOROSIS & FRACTURE PREVENTION AND CARE 2019INSPENT INDIVIDUALS WITH OSTEOPOROSIS IN 2019 3.7% OF THE TOTAL POPULATIONPER DAY PER HOUR 32,000893.7 FRACTURES FRACTURES NEW FRAGILITY FRACTURES IN 2019 77.5%22.5% MENWOMEN 209,000 PROJECTED INCREASE IN THE NUMBER OF FRAGILITY FRACTURES BURDEN OF €464.3DISEASE 51,000 2034 32,000 2019 +58.4% POLICY SERVICEFRAMEWORKPROVISION& UPTAKE 104,000 49,000 WOMEN REMAIN UNTREATED FOR OSTEOPOROSIS WOMEN TREATED FOR OSTEOPOROSIS 32% TREATMENT GAP 153,000 WOMEN ELIGIBLE FOR TREATMENTOSTEOPOROSIS * 20.5 OFREIMBURSEMENTOSTEOPOROSISMEDICATIONS AVAILABLE UNITS/MILLIONDXAINHABITANTS €120 FRAX® SESSIONS/ MILLION PEOPLE/YEAR YES FRAX® ASSESSMENTRISKMODELISAVAILABLE 25-50% OF HAVINGHOSPITALSFRACTURELIAISONSERVICES 2623 DXA COST Hip Fracture Risk Fracture Risk Lifetime Risk FRAX® FractureRiskProjections Burden of Disease Quality of Data National Health Priority Specialist Training Society Support Availability of DXA Access to DXA Risk GuidelineModelsQuality Service Provision FRAX® TreatmentUptakeGap Δ Treatment Gap Waiting Time for Hip Fracture Surgery Policy ServiceFrameworkUptake Liaison Service Quality Indicators Care Pathway Treatment SCORECARD YES YES YES ESTABLISHEDNATIONALFRACTUREREGISTRIES OSTEOPOROSISRECOGNISEDASASPECIALTY OSTEOPOROSISPRIMARILYMANAGEDINPRIMARYCARE RHEUMATOLOGYGERIATRICSORTHOPAEDICS OTHER OSTEOPOROSISINVOLVEDSPECIALTIESINCARE2019 €95.7 2010 €55.2 +73% *LEVEL OF REIMBURSEMENT IS MEANS TESTED Fig:2 Treatment gap for women with osteoporosis in 2019
• As the Irish population ages, it is expected that by 2034, the number of people aged above 50 years in Ireland is likely to increase by 38%.
MAY 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE
Some key additional figures from the SCOPE report
Written by Kenny Franks (left), Project Manager, Fracture Liaison Service, Royal College of Surgeons in Ireland with Mr Aaron Glynn and Dr Frances Dockery, Clinical Leads, Fracture Liaison Service Database
Establishing a Fracture Liaison Service: Supporting the Case
Fragility fractures are fractures sustained after a simple fall in people aged 50 years and over. Osteoporosis is the most common underlying condition. Fragility fractures have a significant impact on Irish people and our healthcare system.
54 RHEUMATOLOGY FOCUS: FRACTURES
Approximately 200,000 people in Ireland have osteoporosis with over 32,000 new osteoporosis-related fractures occurring annually.
The International Osteoporosis Foundation (IOF) report ‘Osteoporosis in Europe; A Compendium of Country-Specific Reports (2022)’ documents the epidemiology and economic burden of osteoporosis in 29 European countries. Their ‘Scope 21 Score Card for Osteoporosis in Europe’, estimates that in the Irish population of those aged 50 years or more, approximately 77% of women and 22% of men are affected by osteoporosis.
If it’s out there... we can source it for you For more information please contact: Free Phone 1800 440 440 I PharmaSource@uniphar.ie I www.uniphar.ie
Should the numbers increase by the predicted 25% by 2030 in Ireland, this will be the highest of all EU countries.
Speaking about the new research Mr Paddy Kenny, Joint National Clinical Lead for the National Clinical Programme for Trauma and Orthopaedic Surgery (NCPTOS), said “The publication and findings of this new survey of FLS in Ireland demonstrates the need for the implementation of FLS nationally as a matter of urgency. FLS has been proven internationally to be effective clinically and economically for the management of secondary fracture prevention. This service will result in reduced hospital admissions. The Trauma & Orthopaedic programme fully supports the establishment of the FLS Database which will be publishing its preliminary report and recommendations later this year.”
IRELAND DIRECT COST OF INCIDENT FRACTURES €290.8 MILLION DISABILITYLONG-TERMCOSTS PHARMACOLOGICALINTERVENTION CHANGE IN COST PER INDIVIDUAL OSTEOPOROSIS-RELATED HEALTHCARE €135.7 MILLION €37.7 MILLION A NEW SCORECARD FOR OSTEOPOROSIS IN EU 27+2 REVEALS BURDEN OF DISEASE, GAPS, AND INEQUALITIES IN OSTEOPOROSIS & FRACTURE PREVENTION AND CARE INDIVIDUALS WITH OSTEOPOROSIS IN 2019 3.7% OF THE TOTAL POPULATION 77.5%22.5% MENWOMEN 209,000 PROJECTED INCREASE IN THE NUMBER OF FRAGILITY FRACTURES 51,000 2034 32,000 2019 +58.4% 104,000 49,000 FOR OSTEOPOROSIS WOMEN TREATED FOR OSTEOPOROSIS 32%153,000 20.5 UNITS/MILLIONDXAINHABITANTS 25-50%€120 2019 €95.7 2010 €55.2 +73% Fig:3 Projected increase in number of fragility fractures in Ireland 2019 - 2034 Date for your Diary The Irish Society of Rheumatology Spring Meeting takes place this month, 19/20th May, 2022 at the Sligo Park Hotel. The Spring meeting for ISR will see a welcome return to Face 2 Face meetings. The Programme is in the final stages of completion and will be circulated shortly. This year ISR will celebrate its 50th anniversary, which means that the meeting will commence at 17.00 on Thursday, 19 May followed by a celebratory dinner on Thursday evening where hopefully all past Presidents will attend. The programme includes talks from Dr Ronan Kavanagh, Consultant Rheumatologist, Galway Clinic and Bon Secours Hospital, Galway speaking about ‘The Music of Rheumatology’ and Professor Hector Chinoy, Professor of Rheumatology and Neuromuscular Disease at The University of Manchester. Professor Chinoy will be discussing ‘Updates in the Management of Inflammatory Myopathy.’
New research recently published from the The Royal College of Surgeons in Ireland (RCSI) further highlights the need for the establishment of a Fracture Liaison Service (FLS) in Irish hospitals.
Six of the ten sites surveyed reported their services being established more than a decade but due to inadequate resourcing, they were failing to meet several of the thirteen standards as outlined in the International Best Practice Framework - “Capture the Fracture”.
A FLS service assesses people over the age of 50 who have sustained a fragility fracture to determine their risk of further fractures.
RHEUMATOLOGY FOCUS: FRACTURES
FLS Audit Report
The National Fracture Liaison Service Steering committee
Sixteen public hospitals were invited to participate in the survey with a 100% response rate. Ten sites (62.5%) reported the existence of FLS and these sites managed 3,444 non-hip fractures during 2019, representing 19% of the expected non-hip fragility fracture numbers occurring annually in Ireland.
They have an estimation of fracture risk, falls risks and if necessary, they are then referred for a diagnostic scan (known as a DXA), then recommendations of appropriate treatment. The patient and their GP are fully informed of the treatment recommendations.
The research findings underline the urgent need for a policy to support the national implementation of FLS across Irish trauma hospitals. Such a service would provide the best method of identifying, treating and monitoring these patients and are proven to reduce fracture numbers, improve treatment for patients and substantially reduce the cost burden to the health service.
Dr Dockery said: “We urgently need a policy to support the national implementation of FLS across all Irish trauma hospitals. Fracture Liaison Services (FLS) provide the best method of identifying, treating and monitoring these patients and are proven to reduce fracture numbers, improve treatment for patients and substantially reduce the cost burden to the health service.”
The Steering committee is tasked with implementing Recommendation 15 of “A Trauma System for Ireland: Report of the Trauma Steering Group (2018)” which states; “The HSE should develop a comprehensive Fracture Liaison Service to provide high quality, evidence-based care to those who suffer a fragility fracture with a focus on achieving the best outcomes for recovery, rehabilitation and secondary prevention of further fracture.”
This new national survey, the first to be completed in Ireland, indicates that the implementation, and resourcing, of a national FLS would bring fracture prevention services in Irish hospitals in line with international standards, improve outcomes and quality of life for patients as well as offer substantial cost savings to the health service which is much needed.
European data suggests that by 2030 there will be a 25% increase in the numbers presenting with these fractures.
The research also found that no trauma site in Ireland is identifying all patients sustaining fractures. 50% of all sites reported that it took patients up to four months after their fracture for their first prescription for osteoporosis medication.
Dr Frances Dockery joint clinical lead for the Fracture Liaison Service Database suggests that all the information, evidence and clinical feedback points to the need for a national policy for FLS.
This process, when in situ, has been proven to prevent further fractures at a population level. The fracture liaison service originated in Scotland, with the world’s first FLS opening in Glasgow approximately 20 years ago.
In 2019 Scotland became the second country in the world, after New Zealand, with 100% FLS provision across all health boards.
MAY 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE 56
President of the IOF, Professor Cyrus Cooper, is calling for greater prioritisation of osteoporosis and it’s associated challenges. Speaking about the research findings he said,
“This important report has exposed the need for greater efforts to prioritise osteoporosis and musculoskeletal disease prevention in Europe. We must take urgent action to reduce the burden and costs of osteoporotic fractures on our healthcare systems. In doing so, we will help ensure that older adults are able to enjoy mobile, independent lives as they age, free of debilitating fragility fractures.”
The National Fracture Liaison Service Steering committee was established in 2018 to develop and implement a national programme to improve patient outcomes after a fragility fracture through compliance with national and international standards.
The new research, “Fracture liaison services in Ireland - how do we compare to international standards?” calls for more widespread use of FLS in Irish hospitals.
should be informed about the need to contact the treating physician once the patient experiences menarche
THE ITCH & RASH OF MODERATE TO SEVERE ATOPIC DERMATITIS 1
HELP YOUR PATIENTS
evaluated. ADVERSE REACTIONS: Refer to SmPC for full details on adverse reactions. Very common adverse reactions (≥1/10): upper respiratory tract infections, acne. Common adverse reactions (≥1/100 to <1/10): bronchitis, herpes zoster, herpes simplex, folliculitis, influenza, anaemia, neutropaenia, hypercholesterolaemia, cough, abdominal pain, nausea, urticaria, fatigue, pyrexia, increased blood CPK/ALT/AST, increased weight and headache. This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions via HPRA Pharmacovigilance; website: www.hpra.ie. LEGAL CLASSIFICATION: POM (S1A). MARKETING AUTHORISATION NUMBER/ PRESENTATION: EU/1/19/1404/001 and EU/1/19/1404/006 – Calendar blister packs containing 28 prolonged-release tablets. MARKETING AUTHORISATION HOLDER: AbbVie Deutschland GmbH & Co. KG, Knollstrasse, 67061 Ludwigshafen, Germany. Further information is available from AbbVie Limited, 14 Riverwalk, Citywest Business Campus, Dublin 24, Ireland. DATE OF REVISION: December 2021. PI-1404-005 Abbreviations: EASI – eczema activity and severity index; NRS – numerical rating scale; QD – once daily; EU European Union. * The recommended dose of RINVOQ is 15mg once daily for adolescents weighing at least 30kg. The safety and efficacy of RINVOQ in children with atopic dermatitis below the age of 12 years have not been established. No data are available. No clinical exposure data are available in adolescents <40kg. The posology in adolescent patients 30kg to <40kg was determined using population pharmacokinetic modelling and simulation.2 Reference: 1. Langan S. et al. Atopic dermatitis. The Lancet. 2020;396(10247):345-360. DOI: https://doi.org/10.1016/ S0140-6736(20)31286-1. 2. RINVOQ Summary of Product Characteristics, available on www.medicines.ie 3. Baricitinib Summary of Product Characteristics, available on www.medicines.ie 4. Abrocitinib Summary of Product Characteristics, available on www.medicines.ie ©2022 AbbVie Inc. All rights reserved. IE-RNQ_AD-220017 | February 2022
upadacitinib
PRESCRIBING INFORMATION (PI) RINVOQ® (upadacitinib) 15 mg and 30mg prolonged-release tablets. Refer to Summary of Product Characteristics (SmPC) for full prescribing information. PRESENTATION: Each 15 mg prolonged-release tablet contains upadacitinib hemihydrate, equivalent to 15mg of upadacitinib. Each 30mg prolonged-release tablet contains upadacitinib hemihydrate, equivalent to 30 mg of upadacitinib. INDICATION: Treatment of moderate to severe active rheumatoid arthritis (RA) and active psoriatic arthritis (PsA) in adult patients who have responded inadequately to, or who are intolerant to one or more disease-modifying anti-rheumatic drugs (DMARDs). RINVOQ may be used as monotherapy or in combination with methotrexate. Treatment of active ankylosing spondylitis (AS) in adult patients who have responded inadequately to conventional therapy. Treatment of moderate to severe atopic dermatitis (AD) in adults and adolescents 12 years and older who are candidates for systemic therapy. DOSAGE AND ADMINISTRATION: Intended for use under guidance and supervision of a physician experienced in diagnosis and treatment of conditions for which upadacitinib is indicated. Dosage: RA, PsA and AS: The recommended oral dose is 15mg once daily. Consideration should be given to discontinuing treatment in patients with AS who have shown no clinical response after 16 weeks of treatment. Some patients with initial partial response may subsequently improve with continued treatment beyond 16 weeks. AD (adults): The recommended oral dose is 15 mg or 30 mg once daily based on individual patient presentation. 30 mg once daily dose may be appropriate for patients with high disease burden and for patients with an inadequate response to 15 mg once daily. The lowest effective dose for maintenance should be considered. For patients ≥ 65 years of age, the recommended dose is 15mg once daily. AD (adolescents from 12 to 17 years): The recommended oral dose is 15mg once daily for adolescents weighing at least 30 kg. Adults and adolescents 12 years and older: Upadacitinib can be used with or without topical corticosteroids. Topical calcineurin inhibitors may be used for sensitive areas such as the face, neck, and intertriginous and genital areas. Consideration should be given to discontinuing upadacitinib treatment in any patient who shows no evidence of therapeutic benefit after 12 weeks of treatment. Special Populations: Elderly: For AD, doses higher than 15mg once daily not recommended in patients aged 65 years and older. Limited data for patients aged 75 and older. Renal: No dose adjustment required in mild-moderate renal impairment. Upadacitinib 15mg once daily should be used with caution in patients with severe renal impairment. Upadacitinib 30 mg once daily is not recommended for patients with severe renal impairment. Upadacitinib has not been studied in subjects with end stage renal disease. Hepatic impairment: No dose adjustment is required in patients with mild (Child Pugh A) or moderate (Child Pugh B) hepatic impairment. Should not be used in patients with severe (Child Pugh C) hepatic impairment. Paediatric Population: No data available in the following paediatric patient populations: children with AD below the age of 12 years; children and adolescents with RA, PsA and AS aged 0 to less than 18 years. CONTRAINDICATIONS: Hypersensitivity to active substance or excipients. Active tuberculosis (TB) or active serious infections. Severe hepatic impairment. Pregnancy. SPECIAL WARNINGS AND PRECAUTIONS: See SmPC for full details. Immunosuppression: Combination use, with immunosuppressants e.g. azathioprine, ciclosporin, tacrolimus, and biologic DMARDs or other JAK inhibitors has not been evaluated in clinical studies and is not recommended as the risk of additive immunosuppression cannot be excluded. Serious infections: Serious and fatal infections have been reported. Caution when treating patients ≥65 years. Frequently reported – pneumonia and cellulitis. Bacterial meningitis has been reported. Opportunistic infections reported –TB, multidermatomal herpes zoster, oral/oesophageal candidiasis, and cryptococcosis. Do not initiate treatment in patients with active, serious infection, including localised infections. Consider the risk/benefit of treatment in patients with: chronic or recurrent infection, history of serious or opportunistic infection, those exposed to TB, those who have resided or travelled in areas of endemic TB or endemic mycoses, those with underlying conditions that may pre-dispose patients to infection. Closely monitor patients and interrupt treatment if there are signs and symptoms of infection pre and post treatment. Tuberculosis: Pre-screen patients for active or latent TB. RINVOQ should not be given to patients with active TB. Consider anti-TB therapy in patients with previously untreated latent TB or in patients with risk factors for TB infection. Consult with a physician with experience in TB therapy to assess whether initiating anti-TB therapy is appropriate for an individual patient. Monitor patients for the development of signs and symptoms of TB, including patients who tested negative for latent TB infection prior to initiating therapy. Viral reactivation: Cases of herpes virus reactivation have been reported e.g. herpes zoster. If herpes zoster is reactivated, consider interruption of upadacitinib therapy until the episode resolves. Screen for viral hepatitis and monitor regularly for reactivation before starting and during therapy with upadacitinib. Patients, positive for hepatitis C antibody/hepatitis C virus RNA and hepatitis B surface antigen/hepatitis B virus DNA were excluded from clinical studies. If hepatitis B virus DNA is detected while receiving RINVOQ, a liver specialist should be consulted. Vaccination: Use of live, attenuated vaccines during or immediately prior to therapy is not recommended. It is recommended that patients be brought up to date with all immunisations, including
, the first and only oral JAK inhibitor indicated for the treatment of both adults and adolescents ≥12 years* with moderate to severe Atopic Dermatitis in the EU2-4
RINVOQ demonstrated in an integrated analysis of the MEASURE UP 1 2 monotherapy studies at Week 16:
&
Upadacitinib should not be used during breast-feeding. The effect
• EASI 75 skin clearance rates of 76% and 65% for patients treated with RINVOQ 30 mg QD and 15 mg QD, respectively, vs 15% with placebo (p<0.001 for both comparisons)2
• Itch reduction (mean percent change from baseline in Worst Pruritus NRS) of –70% and –58% for RINVOQ 30 mg QD and 15 mg QD, respectively, vs –24% with placebo (p<0.001 for both comparisons)2
RINVOQ
prophylactic zoster vaccinations prior to starting therapy, in agreement with current immunisation guidelines. Malignancy: Immunomodulatory therapies may increase the risk of malignancies including lymphoma and nonmelanoma skin cancer in RA patients. Malignancies were observed in clinical studies. Periodic skin examination recommended for patients who are at increased risk for skin cancer. See SmPC for full details. Haematological abnormalities: Do not start therapy if Absolute Neutrophil Count <1 x 109 cells/L, Absolute Lymphocyte Count <0.5 x 109 cells/L and Hb <8 g/dL. Monitor patients and temporarily stop therapy if abnormal haematological parameters as specified are detected during routine patient management. Diverticulitis: Events of diverticulitis have been reported in clinical trials and post-marketing. Upadacitinib should be used with caution in patients with diverticular disease and especially in patients chronically treated with concomitant medications associated with an increased risk of diverticulitis. Patients presenting with new onset abdominal signs and symptoms should be evaluated promptly for early identification of diverticulitis to prevent gastrointestinal perforation. Cardiovascular Risk: RA patients have an increased risk for cardiovascular disorders. Manage patient’s risk factors for e.g. hypertension, hyperlipidaemia as per usual standard of care. Lipids: Monitor total cholesterol, low-density lipoprotein (LDL) and high-density lipoprotein (HDL) at 12 weeks and thereafter according to international guidelines. Elevated LDL in clinical trials decreased to pre-treatment levels in response to statin therapy, although evidence is limited. The effect of these lipid parameter elevations on cardiovascular morbidity and mortality has not been determined. Hepatic transaminase elevations: Monitor liver enzymes at baseline and thereafter according to routine patient management. Prompt investigation of the cause of liver enzyme elevation is recommended to identify potential cases of drug-induced liver injury. In such cases therapy should be interrupted until this diagnosis is excluded. Venous thromboembolism: Deep vein thrombosis (DVT) and pulmonary embolism (PE) have been reported in patients receiving JAKi, including upadacitinib. Use therapy with caution in patients at high risk for DVT/PE. Risk factors should be determined by patients age, obesity and medical history of DVT/PE, patients undergoing major surgery and prolonged immobilisation. If clinical features of DVT/PE occur discontinue therapy, evaluate and treat promptly. INTERACTIONS: Upadacitinib is metabolised mainly by CYP3A4 and plasma exposures may be affected by CYP3A4 inhibitors or inducers. Upadacitinib 15 mg once daily should be used with caution in patients receiving chronic treatment with strong CYP3A4 inhibitors. Upadacitinib 30 mg once daily dose is not recommended for patients receiving chronic treatment with strong CYP3A4 inhibitors. See SmPC for full details. FERTILITY, PREGNANCY AND LACTATION: Upadacitinib is contraindicated during pregnancy. Women of childbearing potential should be advised to use effective contraception during treatment and for 4 weeks the and/or their parents/caregivers while taking upadacitinib. of on fertility has not been
human
following
final dose of upadacitinib. Female paediatric patients
status gradually and maintaining simultaneous cytokine secretion for a short period of time.7 SARSCoV-2 specific T cell IL-2, TNF-α and IFN-γ cytokine polyfunctionality is dependent on viral antigen specificity and contributes to viral clearance.8 Importantly, T cell receptor (TCR) dependent and TCR independent stimulation resulted in similar cytokine secretion patterns over time, suggesting that both TCR mediated signals and bystander T cell activation could be important for the emergence of polyfunctional T cell states.7
Our understanding of polyfunctional T cells that share characteristics with multiple T cell subsets and transcend previous dogmas of well-defined polarised T cells has increased significantly, however, several key questions remain unanswered. While, the implications of polyfunctional T cell responses extend beyond autoimmunity, response to pathogens, anti-cancer responses and encompass vaccine development, characterisation of polyfunctional T cells is technically challenging and requires new data exploration, visualization and analytical approaches.5
MAY 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE
The window for effective therapeutic intervention in rheumatoid Arthritis (RA) is limited. Additionally, current T cell specific therapies for the treatment of RA are broad and affect all T cells irrespective of their contribution to disease pathogenesis and progression, therefore, not differentiating between protective and pathogenic T cell responses.1-2 More refined and targeted therapeutic approaches will improve disease progression while limiting unwanted side-effects and toxicity. Importantly, characterisation of T cell responses in the synovial tissue of at-risk individuals will help identify prognostic markers and extend the window for effective therapeutic intervention.
While the influencers of synovial tissue polyfunctionality remain elusive, the enrichment of common T cell activation and differentiation pathways in IAR and RA patient synovial tissue biopsies indicate their potential as candidate regulators of polyfunctional T cell responses. Further characterisation of the synovial pathways identified could lead to the development of methods for the therapeutic manipulation of pathogenic polyfunctional T cell responses.
Written by Achilleas Floudas, Declan Sweeney, Tracy Madigan, Maryanne Murphy-Lyons, Ursula Fearon
58 RHEUMATOLOGY FOCUS: T CELLS RA
Recent studies have highlighted the importance of deleterious polyfunctionality in autoimmune inflammation. Highly polyfunctional T cell responses have been identified in the synovial tissue of psoriatic arthritis patients and their frequency correlates strongly with disease severity.9 Increased T cell plasticity across multiple T cell subpopulations and polyfunctionality of Th cells have recently been
Loss of balance between protective and proinflammatory synovial tissue T-cell polyfunctionality predates clinical onset of Rheumatoid Arthritis
identified in children with Down syndrome associated arthritis, an aggressive form of erosive polyarticular inflammatory arthritis.10
Ex-Th17 T cells with the capacity to produce multiple pro-inflammatory cytokines simultaneously have previously been identified in the synovial fluid of patients with RA, these polyfunctional T cells are also resistant to inhibition by regulatory T cells (Treg).3-4
Polyfunctional CD4 T cells are molecularly distinct from monofunctional cells however, several questions regarding the temporal cytokine production dynamics, transcriptional control and stimulation requirements of polyfunctional T cells remain unanswered.6 Early studies suggest T cell polyfunctionality is a result of sequential cytokine release with T cells obtaining polyfunctionality
Despite accumulating evidence regarding the importance of T cell polyfunctionality in autoimmunity, little is known about the potential contribution of polyfunctional T cells to RA disease progression and the timing of their emergence in relation to the onset of clinical inflammation. Additionally, polyfunctional T cell responses can be highly heterogeneous raising the potential for immunoregulatory as well as proinflammatory states of polyfunctionality.11 We have recently performed extensive characterisation of peripheral blood and synovial tissue T cell subpopulations with emphasis on polyfunctional T cell responses in RA patient, IAR and HC synovial tissue biopsies. Synovial tissue RNAseq analysis with pathway enrichment analysis, revealed an enrichment in T cell activation and differentiation pathways prior to clinical inflammation. Importantly, we have characterised synovial polyfunctional T cell responses that pre-date the clinical onset of RA with distinct and potentially protective polyfunctionality in HC synovial biopsies. In addition, we identified highly polyfunctional synovial CD4+CD8dim T cells that correlate with disease severity in RA patients.
T cell polyfunctionality contributes early in the pathogenesis of RA and raise the possibility of future therapeutic interventions targeting CD4+CD8dim T cells and the
My appointment with a rheumatologist a few weeks later confirmed exactly what my GP had suggested to me, that I had developed rheumatoid arthritis. He explained that the rheumatoid factor could be negative; I did not know that you do not need to have a family history of RA to develop it. The rheumatologist also explained to me that women are two to three times as likely as men to develop RA and that post-partum onset is not Reassuringly,uncommon.he
Collaborative, interdisciplinary research is the only way to increase our understanding of the immunological mechanisms that underline synovial inflammation in order to bring more effective, targeted treatments to the patients. Patients have to be in the centre of research as partners, guides supporters and guardians of the path to actionable knowledge. Below is but a glimpse of evidence that support efforts in challenging current dogmas of immunological research in order to refine the currently “exploratory” treatment regimens of arthritis.
balance between protective and pathogenic polyfunctional T cells. Why challenging previous dogmas in rheumatology research is important
people with autoimmune disease differently and RA is no exception to this. Many people enjoy full periods of disease remission during pregnancy. My symptoms improved greatly during my early pregnancy and I felt better than I had in months! However, remission from my RA did not last long and my symptoms slowly started to return. My fears and anxieties about RA caused a lot of distress to me at this time and I was very worried about having another baby and coping with the pain and stiffness and a post-partum flare-up. While pregnancy can give short-term remission from active disease in RA, post-partum flare-ups are very common.
During this time, I was referred to Prof. Doug Veale and Louise Moore, an Advance Nurse Practitioner
The first meeting was a bit of a blur, trying to process the words “I’m afraid you have Rheumatoid Arthritis, which is going to get worse” He wasn’t joking, and so began my long downward journey into a World of acute pain, frustration, and false dawns which was to last for over four years.
3. Create the end product
I started to ‘google’ more on serum negative arthritis and started to realise that my GP was worried I had rheumatoid arthritis. I reassured myself that this was not the case as my blood test was negative and I had no family history of RA. I became determined not to have rheumatoid arthritis! Nonetheless, I was struggling to manage the pain
Only at step number 5 was the end user ever really involved in the product. Now swap the words for end user for patient and product for drug. This roadmap is familiar in lots of industries and many of these are either changed or changing. Why?
In product development there was always a process or roadmap that was followed:
My Arthritis Journey (by Declan Sweeney)
What you soon discover with RA is that unlike an infection where you are prescribed an antibiotic and recover, RA drugs are a completely different kettle of fish! Finding the right drug to suit you is like playing a game of ‘lucky dip’! In my case I was not so lucky, as it takes some three months to determine whether the drug in question is working, and all this time your joints, particularly your hands and feet are swelling to a point where you cannot even hold a It'stoothbrush.hardtoconvey the change it brings, not just for the individual but for the whole household. Laughter is in short supply, my three boys became withdrawn and my wife took on the role of carer, helping me to dress, and driving me to Hospital for three-day stints hooked up to a drip to control the inflammation. By this stage it had become so
advised me that I could continue breastfeeding. He prescribed medication for me called a DMARD. I found the following weeks very difficult, as I tried to accept that I had RA. I continued to try lots of alternative therapies and alternative diets and I didn’t start the medication that was recommended. I know now that this is not advisable and there is little scientific evidence to support the effectiveness of alternatives like herbs or acupuncture and strict diets for RA. I found it difficult to cope and worried so much all the time about my future living with this condition.
The end user (by Tracy Madigan)
1. Decide what the end user needs
4. Test the end product
Over the next four years, I was prescribed a plethora of strange sounding drugs, such as Methotrexate, Enbrel, Rituximab and numerous others, coupled with large doses of prednisolone increasing my normal weight from 83kg to over 100kg. Thankfully in 2018 I was prescribed Orencia, which I self-inject weekly, along with other RA drugs and a reduced dose of steroids.
The birth of our third child in October 2015 was a very exciting time for my husband Niall and I; our little boy Harry was welcomed adoringly into our family by our two other children James and Sarah who were aged six and two respectively. Harry was a great baby, he was instantly very good at breastfeeding and sleeping, almost perfect! Unfortunately, within four to six weeks of Harry’s birth, I started to feel unwell. While I was familiar with the usual post-partum aches and pains and tiredness that are common with a newborn baby, this was different and unrelenting. Every day I was noticing something different, swollen knee, ankle, my hands were feeling hot and swollen. I was noticing the stiffness was getting worse and increasing every day at an alarming rate. I made an appointment with my GP and I mentioned that I was feeling unwell. He was extremely attentive and showed great care to me as I cried, explaining that I was feeling so awful and was struggling with lifting and holding Harry. I didn’t understand why he was testing me for the rheumatoid factor at that time.
Later that week, I became aware of my neck being quite stiff, and over the next number of weeks found it increasingly difficult to get out of bed in the morning. After numerous blood tests, and X- Rays at our nearest Hospital, I was advised to see a Rheumatologist.
I sought an opinion of another rheumatologist during this time and he confirmed what my GP and the first rheumatologist advised about my post-partum onset RA. I agreed after this consultation to commence the recommended medication and a course of shortterm steroids. During this period of time, we discovered to our surprise and delight that, we were having another Pregnancybaby.affects
Arthritis as a part of my life (by Maryanne Murphy-Lyons)
My GP rang me a few days later to inform me that my blood results were clear and that the rheumatoid factor in my blood was negative. But my symptoms of hot, painful swollen joints and joint stiffness continued. My GP said to come back to him in one week, which I did. It was almost Christmas and l was feeling more and more anxious and in a lot of pain.
5. Release the product to the end user
This has been Life changing, and has enabled me to lead a somewhat normal life again, returning to golf, swimming and cycling. With the love and support of my Family, I have managed to stay mostly positive throughout this difficult period. Indeed, even with the occasional ‘flare up’, I take one look at the plight of the Ukrainian people and realise just how lucky I am!
and stiffness in my joints, while looking after Harry and my other two children.
When the lifecycle of any product starts with all stakeholders investing their time, experiences and skills the project will always be more successful.
acute that my Rheumatologist was injecting each space between my fingers and toes.
2. Design the end product
In the following weeks, lots of family and friends came to help me manage baby Harry and my other two children. I consulted with various alternative therapists to try alleviate my symptoms, acupuncture, reflexology, osteopathy to name a few! Indeed more than one person suggested to me that stopping breastfeeding would help my joints and alleviate my symptoms. Thankfully, I did not do this. I consulted with Dr Jack Newman, a world-famous expert in Canada on breastfeeding, who absolutely reassured me that I could continue breastfeeding, despite my joint pain and stiffness.
The first week in September 2014 was like previous years, new school bags and lunch boxes for the boys, the usual assortment of ‘window envelopes’ dropping through the post-box, but against that Manchester City had won the Premiership, and I had managed to knock a couple of shots of my handicap! Life was good, what could possibly go wrong?!
If you can harness the skills and experiences of the right patients at the very beginning you will find that there is power in people, especially in people so invested in the success of the product. We may be patients in the clinical sense but we are also accomplished and successful people who manage all sorts of challenges everyday and while we may not understand the full scope of the “science bit” you have no idea what we can offer along a long journey where the outcome is unknown. For the researchers I feel that the emotions and experiences we offer provide perspective, focus and a more patient orientated end product. Being involved gives us hope for future generations and a feeling that there is value in our experience.
HOSPITALPROFESSIONALNEWS.IE | HPN • MAY 2022 59
MAY 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE 60 RHEUMATOLOGY FOCUS: T CELLS RA
Samuel was born just in time for Christmas! We had a wonderful busy Christmas with our little new baby
As I learnt more about RA, I grew more confident in managing my life with the condition, as opposed to viewing it as something separate. Becoming an active participant in your own care is very important and, in my view, it has been one of the key factors in me living well with RA. It does take some energy and emotional management and
Becoming an active participant as opposed to a passive recipient in my own care gave me the confidence to learn my self-management skills. Exercise, living a healthy, balanced, but busy life with work and four young children and my RA are the norm for me now!
This is something that took me a while to learn, as I was not the most compliant patient and this did not help managing my RA. Keeping a diary of your symptoms, medication benefits and side effects all assist your doctor/nurse to provide you with the best care possible. I also found during this time that it is important to develop a relationship with your pharmacist, as they are another source of information and
I have always been a very active person and was used to exercising, but I started exercising more frequently as I found it helped my joint stiffness and also helped my coping skills. After a number of months and a couple of different medication changes, a suitable medication was found that suited me and alleviated my symptoms with minimal side effects. I was able to slowly wean-off my steroids. During this period, I also attended other professionals such as a physiotherapist and occupational therapist. This was also a very important step for me, they taught me invaluable skills and shared great insights with me on managing pain, stress and fatigue, all common and reoccurring symptoms of RA.
RA no longer impacts my life in the way it used to, it is now just part of my life.
C. Enrichment plots of RNAseq data pathway analysis for significantly upregulated gene pathways for IAR vs HC, Dot size represents number of differentially regulated genes per pathway, color intensity represents significance and x axis is indicative of the pathways fold enrichment change. D. Representative imaging flow cytometry of RA patient synovial fluid CD4+, CD8+ and CD4+CD8+ DP T cells. F. FLIM images and cumulative data of RA patient flow sorted peripheral blood CD4+ and CD4+CD8+ DP T cells.
in rheumatology in Our Lady’s Hospice Harold’s Cross, both of whom have a special interest in rheumatology and reproductive health. This referral was hugely important as it was the beginning of a turning point in the management part of rheumatoid arthritis.
A. Example of synovial tissue biopsies isolated by arthroscopic surgery.
and are not a long-term solution to managing RA.
I do still get ‘tired’ of RA, but I no longer fear it and when I am in periods of pain or fatigue I can recognise these symptoms and self-manage them.
B. SPICE algorithm visualization of synovial tissue CD4 T cell cytokine expression and frequency of polyfunctional CD4 T cells for Healthy controls, individuals at risk (IAR) and patients withArthritisRheumatoid(RA).
Identification and characterisation of polyfunctional T cell clusters
support. Professor Veale and Louise Moore were very knowledgeable and up to date in the range of medications available to manage Rheumatoid Arthritis and were able to prescribe a biologically medication that suited me.
I was 30 weeks pregnant and was very worried about coping with another new baby and RA. However, with some education and consultation with Professor Veale and Louise Moore, I was reassured that post-partum flare-ups can be very well managed and I found reassurance that she would be in touch me four to six weeks after my baby’s birth. My RA symptoms were managed with a low dose steroid for the rest of my pregnancy.
When Samuel was about five months, I was finished breastfeeding him and my symptoms of RA were still active. The following eight to nine months were difficult, as I tried various combinations of medication to manage my RA. There are a number of different medications available to manage RA and it can be trial and error to find the right combination. It can also take a number of months to see the benefit of the medications. Unfortunately, side effects are also common and it is a careful balance of medication and side effects that make the process of finding the correct medication important. What I have leant from that process as a patient is that you must be compliant and cooperative and be an active participant in your own care.
However,boy. as expected within four to six weeks of Samuel’s birth, I started to have a post-partum flare-up. I was in a much better place psychologically this time as I had the support I needed and I was not in as much pain due to the medication. I was only taking steroids at this time which offered a temporary relief from RA symptoms
Written by: Leah Rooney, MB BCH BAO MRCPI, Rheumatology SPR St Vincent’s University Hospital, Anne-Barbara Mongey, MD DCH MRCPI, Consultant Rheumatologist, St. Vincent’s University Hospital.
Table 1: SLICC Criteria
Oral/Nasal ulcers
Serositis
Low Complement
Leah Rooney
Collaborating Clinics) criteria was published in 2012 and currently it is widely used for the classification of SLE and can also be used to aid in the diagnosis of SLE in the clinical setting. For classification, a person needs to fulfil 4 or more criteria: at least one clinical and one immunologic criterion, or anyone with biopsy proven lupus nephritis with positive ANA or dsDNA (table 1).
who are considering pregnancy be assessed for both the anti-phospholipid and anti-Ro antibodies.
ANA
RHEUMATOLOGY FOCUS: LUPUS
Immunologic Criteria
Chronic cutaneous lupus
Table 1: SLICC Criteria
Anti Sm
The diagnosis of SLE requires a combination of clinical manifestations and immunologic/ laboratory abnormalities. The SLICC (Systemic Lupus International Collaborating Clinics) criteria was published in 2012 and currently it is widely used for the classification of SLE and can also be used to aid in the diagnosis of SLE in the clinical setting. For classification, a person needs to fulfil 4 or more criteria: at least
Non scarring alopecia
HOSPITALPROFESSIONALNEWS.IE | HPN • MAY 2022 61
Antinuclear antibodies (ANA) are a hallmark of SLE. They are useful as a screening test since they are positive in >98% of cases and therefore have a high sensitivity for the diagnosis of SLE. However, they have poor specificity, particularly a low titre, since up to 30% of the healthy population have a positive ANA. ANAs can represent reactivity to a number of different antigens such as double stranded DNA and a variety of extractable antigens (ENA) which can be assessed using ELISAs and other assays. Antibodies to these antigens have greater specificity for the connective tissue diseases, including SLE, although their presence alone is insufficient to make a diagnosis. Double stranded DNA (dsDNA) antibodies have a high specificity for SLE but are only present in 30% of patients.
Systemic Lupus Erythematous
SLE is a chronic disease which is characterised by the production of autoantibodies and deposition of complement, leading to systemic inflammation. Although the pathogenesis of the disease is not fully understood, genetic factors, environmental risks and hormonal influences likely all play a role. Over 30 genetic loci have been associated with SLE, smoking, ultraviolet light and viral infections have been identified as environmental triggers and the female predominance suggests hormones may play a part.
dsDNA antibodies are associated with more severe disease, particularly lupus nephritis. Their titres often correlate with disease activity and in those patients can be helpful into monitoring disease activity. Anti-Smith antibody occurs in 20% and is specific to SLE and in particular for renal involvement. Anti-Ro (SS-A) antibody is present in 30% and Anti-La (SS-B) in 15% of SLE patients, although they are also associated with Sjogren’s syndrome. Anti-Ro antibody is associated with the development of neonatal lupus, which is manifested by the development of congenital heart block and/or rash in the newborn, a result of transplacental crossing of the anti-Ro antibody into the foetal circulation. Antiphospholipid antibodies, which include antibodies to cardiolipin, β2 glycoprotein1and the lupus anticoagulant, occur in 30% of patients with SLE and are associated with the development of arterial and/or venous thrombosis, vasculopathy and foetal loss. A diagnosis of anti-phospholipidsecondarysyndrome is made when these antibodies are present in moderate or high titer (> 99th percentile) on 2 or more occasions, at least 12 weeks apart, in a SLE patient who develops one of these clinical manifestations. It is advisable that patients with SLE
Diagnosis
Antiphospholipid Antibody Arthritis
Autoantibodies associated with SLE
Acute cutaneous lupus
Clinical Criteria
Clinical manifestations
Anti DNA
Renal ThrombocytopeniaLeucopeniaHaemolyticNeurologicdisorderdisorderAnaemia
Systemic Lupus Erythematous (SLE) is an autoimmune disease with a worldwide prevalence of 50100/100,000. It is a heterogenous disease where manifestations can range from mild disease involving skin and joints to life-threatening organ involvement. It has a significant female predominance with a female:male ratio of almost 10:1. Its prevalence is 3-4 times higher in people of African, Asian and Hispanic ancestry and they tend to develop a more severe disease phenotype. The peak age of disease onset is younger in females than in males and often in childbearing years.
SLE can affect almost any organ in the body. Its manifestations can range from mild cutaneous and/ or joint disease to life-threatening renal, pulmonary, neurologic, or haematologic involvement.
one clinical and one immunologic criterion, or anyone with biopsy proven lupus nephritis with positive ANA or dsDNA (table 1).
Clinical manifestations:
Anne-Barbara Mongey
Direct Coomb’s test in absence of haemolytic anaemia
The kidney is the most common visceral organ to be affected in SLE and is clinically involved in 50% of cases. Lupus nephritis is an immune complex
Image 1:Image 1
It most commonly affects the skin and/or joints and was first described as a dermatological condition. Cutaneous lupus can present acutely as a malar rash which is a photosensitive, erythematous rash across the cheeks, chin and nose; as subacute lupus which can resemble psoriasis or annular lesions, or as discoid lupus which is a chronic form of cutaneous lupus manifested by plaques with scarring on sun exposed areas.
glomerulonephropathy where immune complexes are formed by antibodies binding to intrarenal autoantigens. Immune complexes activate endothelial and mesangial cells and the complement system, driving inflammation. The presentation of lupus nephritis is variable. Asymptomatic proteinuria is the most common but it can also present with hypertension, nephritic syndrome, nephrotic syndrome or rapid renal failure with rapidly renaltoinitiationprognosis.isThetoandRenalwork-upimportantandglomerulonephritis.progressiveUrinalysisquantifyingproteinuriaareinthediagnosticandindiseasemonitoring.biopsyisusedtodiagnoseclassifylupusnephritisandassesforactivityvschronicity.presenceofinterstitialdiseaseassociatedwithaworseEarlydiagnosisandoftreatmentisimportantoptimiseprognosisandpreservefunction.
cases arthralgias
MAY 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE 62
The majority of patients with discoid lupus do not have other systemic Musculoskeletalmanifestations.involvement or
The clinical features of CNS lupus are very heterogenous; they can be diffuse: acute confusion, cognitive impairment, headache, aseptic meningitis and psychiatric disease with psychosis or anxiety/depression, or focal: stroke/TIA, seizures, demyelination and transverse myelopathy. CNS lupus likely results from cerebrovascular endothelial dysfunction, disrupting the blood-brain barrier, allowing immune cells, cytokines and antibodies into the CNS. Twenty different autoantibodies in the serum and CSF have been identified in patients with CNS lupus, and anti-cardiolipin antibody is the most commonly Haematologicassociated.1,2abnormalities are common in SLE and are part of the classification criteria. All three blood cell lines can be affected with leucopenia (lymphopenia more common than neutropenia), thrombocytopenia, autoimmune in up to 95% of typically affects small joints of hands and wrists and pain disproportionate to the degree of joint swelling. Jaccoud-type arthropathy
SLE. This can look like rheumatoid arthritis (RA) with ulnar deviation, subluxation and swan-neck deformities, however, unlike in RA, the deformities as it is caused by ligament, tendon and joint capsule laxity and not by
Musculoskeletal involvement or myalgia occur
RHEUMATOLOGY FOCUS: LUPUS
myalgia occur in up to 95% of cases. Arthritis, and arthralgias typically affect small joints of hands and wrists and pain tends to be disproportionate to the degree of joint swelling. Jaccoud-type arthropathy can also occur with SLE. This can look like rheumatoid arthritis (RA) with ulnar deviation, MCP joint subluxation and swanneck deformities, however, unlike in RA, the deformities are reducible as they are caused by ligament, tendon and joint capsule laxity and not by joint damage (image 1).
The treatment of SLE depends on the disease severity and organ involvement. Hydroxychloroquine, an antimalarial agent, is recommended for all patients with SLE, unless contraindicated. Long term studies have demonstrated the clear benefit of hydroxychloroquine in reducing morbidity and mortality in SLE. It is used as the initial treatment of cutaneous and joint disease. Methotrexate is useful in patients with more severe joint disease.
• Cardiovascular disease is a leading cause of mortality in SLE and management of cardiovascular risk factors is important.
SLE, like other chronic inflammatory diseases, is associated with accelerated atherosclerosis and cardiovascular events are a leading cause of mortality. Effective treatment of active lupus reduces this risk and management of traditional cardiovascular risk factors, such as hypertension and smoking, is particularly important.
The most common pulmonary and cardiac manifestations in SLE is serositis – pericarditis/pleuritis with or without effusion, with patients presenting with pleuritic chest pain and sometimes associated dyspnoea. Other forms of pulmonary disease are uncommon, although patients can develop pneumonitis, chronic interstitial lung disease and rarely pulmonary hypertension without underlying parenchymal disease. Shrinking lung syndrome is rare, presenting with progressive dyspnoea, elevated diaphragm on imaging and reduced lung volumes and restrictive pattern on pulmonary function tests.3
• SLE frequently presents in females in childbearing years and is associated with increased maternal and foetal risks.
References available on request
TREATMENT OF ImmunosuppressiveSLEdrugs
Summary
Pregnancy in women with SLE is associated with increased maternal and foetal risks, including preterm birth, preeclampsia, foetal loss and SLE flares. The risk factors for adverse pregnancy outcomes include: active disease, lupus nephritis, low complement, dsDNA antibodies and antiphospholipid antibodies. Detailed pre-pregnancy planning with rheumatology and obstetrics is essential to ensure disease is optimally controlled and prescribed medications are safe in Hydroxychloroquinepregnancy.5 is commonly continued throughout pregnancy in SLE patients. Azathioprine and calcineurin inhibitors are also considered safe in pregnancy (although there have been no prospective controlled trials to prove this). Glucocorticoids can be used to treat lupus flares if required, although their dose should be minimised. Patients at risk of pre-eclampsia, especially those with lupus nephritis and those with prescribedantibodies,antiphospholipidaregenerallyaspirin.Patients with secondary antiphospholipid syndrome, particularly those with a history of foetal loss, are generally treated with a combination of aspirin and heparin.6
HOSPITALPROFESSIONALNEWS.IE | HPN • MAY 2022 63
Cardiovascular Risk
Anti-Ro antibodies can cross the placenta and result in neonatal lupus manifesting as congenital
A temporal association between the ingestion of an agent and the development of the lupus-like features is required to make the diagnosis. Unlike drug hypersensitivity, it generally requires weeks to months of exposure to an agent before drug-induced lupus develops. Remission of the clinical features with a decrease in the autoantibody titres should occur following withdrawal of the offending agent. Recurrence of the syndrome following reintroduction of the agent would provide confirmatory evidence for an association but this is seldom done in clinical practice. Many patients will develop anti-nuclear antibodies while taking certain medications but the majority do not develop a lupus-like syndrome. Hence, the development of a positive ANA in the absence of other clinical features is insufficient for the diagnosis of drug induced lupus and should not be a reason to discontinue the medication.
haemolytic anaemia and anaemia of chronic disease. The degree of lymphopenia can be associated with disease activity.
• SLE is an autoimmune disease where manifestations can range from mild disease to lifethreatening organ involvement.
Procainamide and hydralazine are drugs with the highest risk of developing drug-induced lupus, however these drugs are now infrequently prescribed. Isoniazid, methyldopa, minocycline and anti-TNF agents are also associated with drug induced lupus, and although they have a lower risk, they are more commonly prescribed and therefore seen more.
Drug induced lupus
Drug-induced lupus refers to the development of a lupus like syndrome following exposure to a causative drug. Unlike SLE, it affects males and females equally. The classic autoantibodies present in drug-induced lupus is anti-histone Drug-inducedantibodies.lupuscan manifest
heart block and/or neonatal cutaneous lupus. The presence of these antibodies in the mother is associated with a 2-3% risk of congenital heart block; when this occurs, the risk is 12-20% in subsequent pregnancies. This risk is reduced with hydroxychloroquine treatment. Patients with anti-Ro antibodies who become pregnant need to be monitored in a high-risk obstetrical unit with weekly foetal echocardiograms during their second and third trimesters. Neonatal cutaneous lupus will resolve once the maternal anti-Ro antibody leaves the neonatal circulation but the heart block can be permanent.
For renal disease, mycophenolate or azathioprine can then be used for maintaining remission.4
The mainstay treatment of druginduced lupus is to discontinue the offending drug. In patients with more severe signs and symptoms, such as serositis, a short course of steroids can be used.7
in 3 different phenotypes: systemic disease, subacute cutaneous lupus and cutaneous vasculitis. The systemic disease typically presents with arthralgia, myalgia, serositis and constitutional symptoms. Drug-induced subacute cutaneous disease presents with similar findings to acute cutaneous SLE and this diagnosis is considered in individuals who develop cutaneous lupus over the age of 50.
the agents most frequently used to treat severe disease. Mycophenolate is associated with less toxicity cyclophosphamidethanand it can be used for both induction and maintenance treatment; it is generally preferred for women of child bearing age who wish to become pregnant in the future given that cyclophosphamide can cause infertility. However, mycophenolate is teratogenic and therefore needs to be discontinued prior to a woman planning pregnancy; patients can be switched to azathioprine which is generally considered to be safe throughout pregnancy.
Lupus in pregnancy
are
B cell targeted treatments are effective in SLE. Belimumab targets B cell activating factor and inhibits mature B cells. It has been demonstrated to be effective in the treatment of mild to moderate SLE and as an addon therapy for the treatment of lupus nephritis. Rituximab is a monoclonal antibody which targets CD20, a B cell specific antigen. Although clinical trials of rituximab for the treatment of SLE did not achieve their primary endpoint, it is used in the clinical setting for SLE, including lupus nephritis, when other immunosuppressive therapies have not been effective. It is given by intravenous infusion and causes B cell depletion lasting 6-12 months. Obintuzumab which also targets CD 20, has been shown in the NOBILITY study, to improve renal outcomes, when added to the standard care for treatment of lupus nephritis. Similarly, Voclosporin, a calcineurin inhibitor, and Anifrolumab, which targets interferon, have also been approved as adjunct treatments for lupus nephritis.4
• Treatment of lupus depends on disease severity and organ manifestations and almost all patients are hydroxychloroquine.prescribed
It is generally accepted that anti-nuclear antibodies need to be present to diagnose drug-induced lupus although their presence alone is not sufficient to make the diagnosis. The autoantibody profile associated with drug-induced lupus is more restrictive compared with the vast multitude of autoantibodies seen in idiopathic SLE. Anti-histone antibodies occur most frequently. Antibodies to double-stranded dsDNA are uncommon in drug-induced lupus but they have been reported to develop in patients treated with TNF-α inhibitors, sulphasalazine, and minocycline.
Biologic drugs in SLE
Steroids are frequently used in the treatment of SLE. Their dose and mode of administration is determined by the disease severity and by organ involvement. High dose steroids are used initially for treatment of acute active lupus nephritis, pneumonitis, cerebritis or transverse myelitis, severe thrombocytopenia or haemolytic anaemia because of their quick onset of action. However, given their significant long term side effects patients are also commenced on immunosuppressive agents in order to allow tapering of steroids as soon as mycophenolateCyclophosphamidepossible.ormofetil
which affects the hands and/ or feet, although any joint lined by a synovial membrane may be involved. “Severity fluctuates over time, but chronic RA results in the progressive development of various degrees of joint destruction, deformity, and a significant decline in functional status. Extra-articular involvement of organs such as the skin, heart, lungs, and eyes can also be significant.,” she explains.
Physical examination is a key part of the assessment process. “In addition to checking general vital signs, including temperature, blood pressure, pulse rate, heart and lung function, the doctor will evaluate the patient’s joints in detail, paying particular attention to function, swelling, and pain. The physical exam will help determine the severity of the illness and help guide treatment decisions,” she adds.
Physical examination is a key part of the assessment process. “In addition to checking general vital signs, including temperature, blood pressure, pulse rate, heart and lung function, the doctor will evaluate the patient’s joints in detail, paying particular attention to function, swelling, and pain. The physical exam will help determine the severity of the illness and help guide treatment decisions,” she adds.
Imaging tests include x rays taken of symptomatic joints which can reveal signs of joint involvement (inflammation) and damage (bone erosion) indicative of RA. Other imaging tests useful in diagnosis of RA include magnetic resonance imaging (MRI) and ultrasound
64 RHEUMATOLOGY FOCUS: RA
Laboratory blood tests required to determine a diagnosis suggestive of RA or inflammatory disease include:
• Rheumatoid factor (RF)
• Anti-citrullinated protein antibodies (ACPA) (including anti-CCP and anti-MCV antibody tests)
Medical history refers to current presenting symptoms, past medical history, family medical history, medications including any OTC medications, allergies and lifestyle factors such as smoking and alcohol intake. She continues, “Presenting symptom history includes questions about the type, duration, location and pattern of pain experienced, how it affects mobility and lifestyle, and whether it is affecting sleep and causing fatigue. Past medical history and other medical illnesses will be discussed as some medical problems tend to occur along with RA and may be suggestive of the disease. A family medical history is important due to the hereditary component to RA, and information about any close relative with the condition or any other autoimmune disease will provide more information on the individual’s risk. Smoking is a high risk factor, and alcohol which effects the liver, can promote inflammation and interact with some NSAID and methotrexate medication. Therefore, a knowledge of lifestyle factors is also important in the diagnosis and treatment of RA.”
Theresa, clinical features of RA are persistent symmetric polyarthritis (synovitis)
Smoking is a high risk factor, and alcohol which effects the liver, can promote inflammation and interact with some NSAID and methotrexate medication. Therefore, a knowledge of lifestyle factors is also important in the diagnosis and treatment of RA.”
• Antinuclear antibody (ANA)
• C reactive protein (CRP)
Imaging tests include x-rays taken of symptomatic joints which can reveal signs of joint involvement (inflammation) and damage (bone erosion) indicative of RA. Other imaging tests useful in diagnosis of RA include magnetic resonance imaging (MRI) and ultrasound.
• Rheumatoid factor (RF)
The ACR/EULAR Classification Criteria, is associated with a point value. Diagnosis of RA can be made when a total of 6 points or more is reached across the separate criteria.
Rheumatoid arthritis (RA) is a chronic systemic inflammatory autoimmune condition with periods of exacerbation and remission, characterized by synovitis and joint destruction mediated by cytokines, chemokines, and metalloproteases. RA can affect any body part but most commonly the peripheral joints, aboutAssociationPracticeandLehnenWesystemicanddestructionleadingmetatarsophalangealwrist,metacarpophalangealinterphalangeal,andaswellastheanklesandjoints,toprogressiveofarticularstructuresaccompaniedbysymptoms.spokewithTheresaLowry-(PhD)CNS,GPN,RNPNationalPROIrishGeneralNursesEducationalwhotoldusmorethiscondition.
Theresa adds, “A diagnosis of RA is based on specific clinical, laboratory and imaging features and the ACR/EULAR Classification Criteria. The ACR ‘RA Disease Activity Measures’, define the ranges and level of disease activity. All patients with suspected RA should be referred urgently to a rheumatologist.”
The ACR/EULAR Classification Criteria, is associated with a point value. Diagnosis of RA can be made when a total of 6 points or more is reached across the separate criteria.
• Full blood count (FBC)
Clinical features and presentation of rheumatoid arthritis
Interview with Theresa Lowry Lehnen (GPN, RNP, PhD) Clinical Nurse Specialist and Associate Lecturer South East Technological University (SETU)
• Antinuclear antibody (ANA)
Laboratory blood tests required to determine a diagnosis suggestive of RA or inflammatory disease include:
Approximately 10% of patients with rheumatoid arthritis have an abrupt onset, but in most cases onset is insidious and initial presenting symptoms can be vague, including fatigue, malaise, morning stiffness, weight loss and low-grade fever. Progression of the illness leads to joint inflammation and swelling which causes difficulty performing activities of daily living, such as dressing, standing, walking, or use of the Accordinghands.to
• Anti citrullinated protein antibodies (ACPA) (including anti CCP and anti MCV antibody tests)
Rheumatoid Arthritis: Clinical Presentation, Diagnosis and Pharmacological Treatment (DMARD’s)
MAY 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE
• Full blood count (FBC)
• Erythrocyte sedimentation rate (ESR)
Patients with RA are at an increased risk of co-morbidities such as CVD, severe infections, and over-lapping autoimmune disease, e.g. mixed connective tissue diseases, autoimmune thyroiditis and lymphoma.
• C-reactive protein (CRP)
• Erythrocyte sedimentation rate (ESR)
“DMARDs, (Disease-modifying anti-rheumatic drugs) are also called immune-suppressive or slow-acting anti-rheumatic drugs (SAARDs). They are classed in two major groups; synthetic (sDMARDs) and biological (bDMARDs). These groups are then further subdivided and classed as conventional synthetic (csDMARDs) or targeted synthetic (tsDMARDs). Conventional synthetic (csDMARDs) include methotrexate, leflunomide and sulfasalazine.
“Combination therapy which allows for lower dosage of an individual drug, may reduce the risk of adverse effects that can occur with higher doses. Methotrexate, leflunomide and sulfasalazine have similar efficacy, however methotrexate is considered the ‘anchor drug’ for the treatment of RA. It is prescribed in up to 70% of patients as a monotherapy or as combination therapy with other DMARDs.”
DMARD’s and the pharmacological treatment of rheumatoid arthritis
Concurrent use of tsDMARDS with bDMARDs is however contraindicated and tsDMARDs cannot be used with live vaccines.
Methotrexate as the DMARD of choice in the treatment of rheumatoid Methotrexatearthritis(MTX), a diseasemodifying anti-rheumatic drug (DMARD), interferes with the production and maintenance of DNA, the genetic material in the cells of the body. It is not known exactly how methotrexate works
Current themanagementpharmacologicalofRAincludesinitiationofDMARDsby a rheumatologist and medication for symptom control such as a corticosteroid.
ACR recommendations for the measurement of RA disease activity
DMARD’s and the pharmacological treatment of rheumatoid arthritis
References available on request
Theresa highlights, “The lowest dose possible for the shortest period of time is recommended when using corticosteroids. NSAIDs are typically prescribed to control pain and inflammation in the RA patient. The ACR and EULAR guidelines recommend that if used NSAIDs be prescribed in the lowest dose that provides symptom relief, and the dose reduced when a good response to DMARDs is achieved.
Methotrexate is the most common DMARD used to treat rheumatoid arthritis, says Theresa. “It may be used in the early stages to prevent progression of the illness and in combination with other DMARDs. It is effective in relieving joint inflammation and pain, slowing RA progression, and preventing disability by delaying joint destruction.
Rheumatoid arthritis patients taking methotrexate must be monitored closely for signs of infection and require regular FBC, LFT and renal function blood tests. She adds, “Intensive monitoring is required when initiating therapy, changing doses and in patients with co-morbidities. FBC, LFTs and U&Es are required every two weeks when initiating therapy until blood tests are stable for 6 weeks.
“DMARDs, (Disease modifying anti rheumatic drugs) are also called immune suppressive or slow acting anti rheumatic drugs (SAARDs). They are classed in two major groups; synthetic (sDMARDs) and biological (bDMARDs). These groups are then further subdivided and classed as conventional synthetic (csDMARDs) or targeted synthetic (tsDMARDs). Conventional synthetic (csDMARDs) include methotrexate, leflunomide and sulfasalazine
“Targeted synthetic DMARDs (tsDMARDs) example Tofacitinib and Baricitinib are a new therapeutic class that inhibit JAK (Janus kinase inhibitors). They can be used in combination with methotrexate or as monotherapy if patients have contraindications or are intolerant of methotrexate. Concurrent use of tsDMARDS with bDMARDs is however contraindicated and tsDMARDs cannot be used with live vaccines.
“Patients must be closely monitored when taking methotrexate as it is associated with many adverse side effects including infections, gastrointestinal problems, leukopenia, headache, dizziness; fatigue, raised LFTs, rash and alopecia. Some side effects may be reduced by taking folic acid at a dose of at least 5mg/ week, taken on a different day from the methotrexate.
HOSPITALPROFESSIONALNEWS.IE | HPN • MAY 2022 65
“Targeted synthetic DMARDs (tsDMARDs) example Tofacitinib and Baricitinib are a new therapeutic class that inhibit JAK (Janus kinase inhibitors). They can be used in combination with methotrexate or as monotherapy if patients have contraindications or are intolerant of methotrexate.
“Combination therapy which allows for lower dosage of an individual drug, may reduce the risk of adverse effects that can occur with higher doses. Methotrexate, leflunomide and sulfasalazine have similar efficacy, however methotrexate is considered the ‘anchor drug’ for the treatment of RA. It is prescribed in up to 70% of patients as a monotherapy or as combination therapy with other DMARDs.”
in rheumatoid arthritis, but it can reduce inflammation and slow progression of the illness.
“Patient education about their weekly methotrexate regimen, folic acid requirement and the risk of drug interactions is important as a number of medications such as salicylates, toxicity.anactionDrugtotrimethoprimsulphonamides,hypoglycaemics,phenytoin,andhavethepotentialinteractwithmethotrexate.interactionscanenhancetheofmethotrexateresultinginincreasedriskofmethotrexateLivevaccinesshould
“Methotrexate produces a beneficial effect in 2-6 weeks and is given once weekly. The initial weekly dose is 7.5-15 mg but can be increased up to 25mg per week if required, based on assessment of response and side effects. It can be administered by oral, intramuscular or subcutaneous routes.”
be avoided, however, flu and pneumococcal vaccination is recommended. Screening for TB and infections such as hepatitis B and C should be performed prior to initiating treatment and screening for varicella zoster is also recommended by some experts. It is advisable that if a person with RA develops an infection, requires antibiotic treatment or develops shingles or chicken pox, that they stop taking their anti-rheumatic medication until the infection has cleared. Advice on smoking cessation, contraception when applicable, and the risks associated with alcohol consumption while taking methotrexate should be provided for the patient.”
Current pharmacological management of RA includes the initiation of DMARDs by a rheumatologist and medication for symptom control such as a corticosteroid.
“This is followed by monthly blood tests until the dosage and illness is stable for 1 year. Thereafter, blood test monitoring may be reduced in frequency to every 2-3 months based on clinical judgement and discussion with the specialist team.
Theresa highlights, “The lowest dose possible for the shortest period of time is recommended when using corticosteroids. NSAIDs are typically prescribed to control pain and inflammation in the RA patient. The ACR and EULAR guidelines recommend that if used NSAIDs be prescribed in the lowest dose that provides symptom relief, and the dose reduced when a good response to DMARDs is achieved.
ACR recommendations for the measurement of RA disease activity
We developed multiple-choice and Likert-based survey questions pertaining to telemedicine (15 in total; see Supplementary Material) as part of a 77-question trainee survey for the COVID-19 GRA. The survey was piloted with five rheumatology trainees (from the United States and the United Kingdom; two were pediatric rheumatology trainees) and revised according to feedback. The survey was available in English, Spanish, and French via the
Rapid Adoption of Telemedicine in Rheumatology Care During the COVID 19 Pandemic Highlights Training and Supervision Concerns Among Rheumatology Trainees
Highlights Training and Supervision
Methods
The novel coronavirus disease 2019 (COVID-19) pandemic demanded a rapid, unplanned change in the mode of delivery of health care services. Providers were required to balance the dual necessities of reducing nonemergent in-person clinical contact while maintaining patient access to care. The majority of rheumatology care occurs in the outpatient setting, which saw a rapid increase in the use of telephone or video calling to deliver care remotely, also known as telemedicine.1 This has implications not only for patient care but also for rheumatology training. There is a paucity of data regarding rheumatology trainee experiences with telemedicine during the pandemic. The COVID-19 Global Rheumatology
EULAR, and Pan-American League of Associations for Rheumatology. Regional/country representatives from the GRA were also asked to disseminate invitations to rheumatology trainees from their country. United States fellowship program directors were encouraged to send invitations to their fellows. Additionally, respondents were recruited on social media using invitations from official Twitter accounts of the GRA, ACR, and EMEUNET. All surveys were completed between August 19, 2020, and October 5, 2020.
Telemedicine
Written by Su-Ann Yeoh, Kristen Young, Michael Putman, Sebastian Sattui, Richard Conway, Elizabeth Graef, Adam Kilian, Maximilian Konig, Jeffrey Sparks, Manuel Ugarte-Gil, Laura Upton, Francis Berenbaum, Suleman Bhana, Wendy Costello, Jonathan Hausmann, Pedro Machado, Philip Robinson, Emily Sirotich, Paul Sufka, Jinoos Yazdany, Jean Liew, Rebecca Grainger, Zachary Wallace, Arundathi Jayatilleke, on behalf of The Global Rheumatology Alliance
Alliance (GRA), an international collaborative of the rheumatology community, was formed to collect data in rheumatology relevant to COVID-19.2 The objective of this study was to assess the use of telemedicine before and during the COVID-19 pandemic and the impact of telemedicine on rheumatology trainees' experiences during the COVID-19 pandemic.
REDCap (Project R) platform to adult and pediatric rheumatology trainees. Data from the United Kingdom/European Economic Area (EEA) were hosted on a REDCap database at University College London in the United Kingdom, and non-United Kingdom/EEA data were hosted at Temple University Hospital in the United States. All members of the GRA, American College of Rheumatology (ACR) fellows-in-training listserv, and the Emerging European League Against Rheumatism (EULAR) Network (EMEUNET) trainee listserv were contacted by email and invited to participate. A request to share the survey among their membership was made to the International League of Associations for Rheumatology Executive Committee, comprising the leadership from the ACR, African League of Associations for Rheumatology, Asia Pacific League of Associations for Rheumatology,
Rapid Adoption of Telemedicine in Rheumatology Care During the COVID-19 Pandemic Highlights Training and Supervision Concerns Among Rheumatology Trainees
A total of 302 respondents from 33 countries (Figure 1) completed the survey, with 116 (38%) from the United States, 89 (29%) from Europe, and 97 (32%) from the rest of the world (ROW). The majority of respondents (252 [83%]), were enrolled in single-track adult rheumatology training, 29 (10%) were in single-track pediatric rheumatology training, and 7% (n = 21) were in dual adult/pediatric training. The majority (279 [92%]) were in full-time training before the COVID-19 pandemic. Most respondents reported being in the first 3 years of training (n = 204, 68%; Year 1: n = 64; Year 2: n = 85; and Year 3 n = 55), 60 (20%)
Rapid Adoption of in Rheumatology Care During the COVID-19 Pandemic Concerns Among Rheumatology Trainees
Results
Telemedicine in Rheumatology Care
MAY 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE
Figure 1: Map displaying the distribution of survey respondents
66 RHEUMATOLOGY FOCUS: TELEMEDICINE
Respondents were included if they were physicians who reported, 1) rheumatology training as part of their job description, 2) were aged 18 or more, and 3) consented to participate in the survey. Respondents were excluded if they completed rheumatology training prior to 2020. The survey was voluntary and did not include personal identifiers, protected health information, or incentives for participation. To allow for the variation in the duration of rheumatology training across regions, we included eight options for the training stage (from training Years 1 to 7 or beyond and whether respondents had completed their training in 2020).
ACR Open Rheumatology, Volume: 4, Issue: 2, Pages: 128-133, First published: 17 November 2021, DOI: (10.1002/acr2.11355)
59
64
3 32(5)(50) 7 28(11)(44)
5411210047112(42)(89)(48) 32
Half of the trainees (n = 125 [51%]) reported supervision via postvisit discussions during the pandemic, which was similar to the proportion of trainees (n = 18 [46%]) who had
postvisit discussion supervision when using telemedicine before the pandemic (Table 1). Some trainees reported real-time observation for part (n = 71 [29%]) or the entirety (n = 43 [17%]) of the telemedicine visit. Almost one-quarter (59 [24%]) of those who used telemedicine during the pandemic reported having no telemedicine supervision. Telemedicine was reported to negatively or slightly negatively impact the supervision of 50% of trainees (n = 123), whereas only 9% reported a slight or very positive impact on supervision (n = 21). For clinical teaching quality, most respondents (n = 171 [70%]) reported that telemedicine had a negative or slightly negative impact, and only 23 (9%) reported a slight or very positive impact on each of these areas (Figure 2).
Just more than one-third (n = 97 [39%]) of trainees reported that they had received training in telemedicine; the majority found telemedicine training somewhat or very helpful (n = 89 [92%]). A higher proportion of United States trainees (n = 69 [62%]) reported having received training compared with 135 (21%) trainees from Europe and the ROW combined (P < 0.001 using Fisher's exact test). Technology and platform use were more frequently addressed by this training (n = 85 [88%]) compared with clinical skills (n = 37 [38%]) and billing (n = 39 [40%]).
Most trainees using telemedicine evaluated new patients during the pandemic (n = 161 [65%]). A larger proportion of trainees (n = 170 [69%]) agreed or strongly agreed that they felt comfortable using telemedicine to evaluate follow-up patients compared with evaluating new patients (n = 41 [25%]) (P < 0.01 using Fisher's exact test) and also compared with managing changes in treatment using telemedicine (n = 80 [33%]) (P < 0.01 using Fisher's exact test) (Figure 2) on page 68.
None,after,communicationWrittenafter,discussionVerbal(fullobservation,Real-timen(partobservationReal-timeSupervision,nAudio–video,nAudio-only,Modality,nTelemedicine,(%)n(%)(%)nofvisit),(%)visit),n(%n(%)n(%)n(%) (nEurope=89) 15 (17) 15 14 (93) 1 0015(7)(0)(0) 8 (53) 0 (0) 7 (47) United States (n = 116) 9 (8) 9 3 (33) 7 (78) 49 (44) 2 (22) 3 (33) 0 (0) 2 (22) (nROW=97) 15 (15) 15 8 (53) 7 15(47) 3 (20) 2 (13) 7 (47) 1 (7) 5 (33) (nAll=
15
(nROW=97) (73) 5171 (72) (41) (21) (11) (39) (nAll= 302) 247 (82) (62) (55) (17) (51 (13) (24)
7 64(11) 2
29
9 22(13)(31)
136
71
125
Clinical training in telemedicine and supervision
Experience in telemedicine
HOSPITALPROFESSIONALNEWS.IE | HPN • MAY 2022 67
39
For pediatric-only rheumatology trainees, 27 (93%) reported using telemedicine during the pandemic, whereas, for those in combined adult/peds training, 19 (90%) reported using telemedicine during the pandemic. Eighty percent of adult rheumatology trainees (n = 201) reported using telemedicine.
•Abbreviation: ROW, rest of the world. • ROW data include Asia (n = 50), Central and South America (n = 23), Canada (n = 12), Australia (n = 8), and Africa (n = 4). Prepandemic Pandemic Table 1. Telemedicine use, supervision, and training by region
28
This large international survey of rheumatology trainees found limited prepandemic experience 302) (13) (64) (38)
Patients evaluated using telemedicine
United States (n = 116) 112 (97) (29) (58) (13) (8)
71247(29) 43
(nEurope=89) (72) (88) (3)
Discussion
39 25
39 7 (18) 4 18(10)(46) 1 14(3)(36)
Reported use of telemedicine increased from 39 trainees (13%) before the pandemic to 247 trainees (82%) during the pandemic. Differences were observed in the modalities used; United States trainees predominantly used video telemedicine compared with trainees from Europe and the ROW combined (P < 0.001 using Fisher's exact test), who predominantly used audio-only telemedicine compared with United States trainees (P < 0.001 using Fisher's exact test) (Table 1).
5664
were in Years 4 and above, and 38 (13%) completed training in 2020.
9
8
154247
15
65
Supervision of telemedicine visits occurred most frequently by verbal discussion after the consultation.
1571
31
AUTHOR CONTRIBUTIONS
Telemedicine in Rheumatology Care
Figure 2: Rheumatology trainee comfort levels in using telemedicine during the pandemic
ACKNOWLEDGMENTS
The authors would like to thank all rheumatology trainees who participated in the survey, as well as the COVID-19 Global Rheumatology Alliance for mentorship and feedback.
All authors were involved in drafting the article or revising it critically for important intellectual content, and in the final approval of the version of the article to be published.
COVID 19 Pandemic
The key strength of our survey is that it is the only international rheumatology trainee survey during the pandemic of which we are aware. Our survey was designed by a multiregional team and piloted by trainees and program directors.
The ideal context for trainee telemedicine experiences, then, may be in the assessment of stable follow-up patients. Providing access to rheumatology care to new patients via telemedicine must be balanced with the educational needs of trainees, wherein inperson or bedside rheumatology teaching still plays an important role and cannot fully be replaced by telemedicine-only training.
MAY 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE 68 RHEUMATOLOGY FOCUS: TELEMEDICINE
of telemedicine, which increased during the pandemic to 83% of respondents with a perceived negative impact on training. Similar increases in telemedicine use have been reported by other trainees.3,4 Telemedicine training was not widespread or comprehensive, and trainees reported a negative impact of telemedicine on their clinical training and supervision. A significantly larger proportion of trainees reported feeling comfortable with evaluating follow-up patients compared with new patients or those requiring treatment changes. These findings provide insights to drive curricular design for training in and during telemedicine.
The negative impact of telemedicine on clinical teaching reported by most trainees should prompt rheumatology programs to examine preexisting curricula and ensure that telehealth competencies are incorporated such as that recommended by the Association of American Medical Colleges.6 In addition, allocating in-person visits to less-experienced (eg, first year) trainees until they become confident7 and ensuring that trainees possess the necessary foundational knowledge and skills before virtual visits8 may improve the training experience.
Although telemedicine training was infrequent, it was generally helpful, though focused on technological competence. Increasing focus on telemedicine-specific clinical skills will be required, which could include essential remote physical examination skills, simulated appointments with relevant rheumatological clinical scenarios, content about legislation, and ethics relevant to managing telemedicine visits. In addition, peer mentoring or discussion groups may be useful in terms of providing a safe space to discuss difficult or challenging cases or aspects of clinical assessment that are problematic. A future telemedicine curriculum could be designed using previously identified learning needs and effective educational strategies.9
Medical education institutions have already begun incorporating telemedicine into their curricula,10 paralleling an exponential growth in telemedicine practice. Since the pandemic, the United States Accreditation Council of Graduate Medical Education has adopted residency training requirements (Common Program Requirements) embedding telemedicine training.11 Foci will include telemedicinespecific clinical competencies in a virtual setting, virtual communication skills, and more nuanced aspects such as “webside manner”.8 Globally, telemedicine implementation will differ according to resource setting,12 community needs, and regulations.13
Similar to our gastroenterologyresults,trainees reported minimal supervision during pandemic telemedicine.3 Half of the trainees indicated that telemedicine negatively impacted their supervision. There are various means by which supervision can be delivered, including real-time observation with a supervisor physically present with the trainee or through co-attendance in remote consultation; the latter has been a successful model for remote supervision of rural medical trainees.14 A successful model of remote supervision focuses on establishing a learning relationship between supervisor and junior, a stimulus for learning, and an understanding of the practicalities of remote supervision. These principles will be useful as a guide for programs and supervisors to foster a conducive learning environment for trainees.14
In conclusion, our findings emphasize the need for telemedicine to be included in the rheumatology curriculum, especially regarding teaching telemedicine-specific clinical skills, supporting trainees evaluating new or complex patients using telemedicine, and ensuring adequate supervisory arrangements.
Rapid Adoption of Telemedicine in Rheumatology Care During the COVID-19 Pandemic Highlights Training and Supervision Concerns Among Rheumatology Trainees
Our study has limitations. Selection and response bias were difficult to minimize, but a wide recruitment strategy was used. Survey respondents were mostly United States and European trainees, limiting generalizability. We were unable to obtain information about factors that may contribute to variable training and trainee experiences, such as regional infrastructure of telemedicine, local severity of the COVID-19 pandemic, and local policy. Finally, our study was one of several surveys being distributed to trainees, which may have contributed to survey fatigue and decreased participation.
References available on request
Rapid Adoption of During the Highlights Training and Supervision Concerns Among Rheumatology Trainees
ACR Open Rheumatology, Volume: 4, Issue: 2, Pages: 128-133, First published: 17 November 2021, DOI: (10.1002/acr2.11355)
The rapid telemedicine adoption during the pandemic was focused on meeting clinical needs and was not optimized for trainee experiences, in which some trainees reported not having telemedicine-specific training and, at times, supervision. The negative impact on clinical training is likely not to be merely due to the rapid adoption of telemedicine but also due to the limited opportunities for in-person clinical encounters, crucial for training in rheumatic diseases. Standard rheumatological assessments rely on physical examination, especially during diagnosis and treatment
escalation/de-escalation, which may explain why more trainees reported higher comfort levels using telemedicine for follow-up compared with new patients. In addition, only one-third of respondents were comfortable making treatment changes using telemedicine. Similarly, in a COVID-19 tele-rheumatology audit, clinicians were less likely to make a diagnosis via telemedicine, de-escalate immunosuppressive treatment, and discharge patients.5
To further explore the underpinning mechanisms of these divergent macrophage activation states, we performed
Dr Megan Hanlon, Irish Research Council Research Fellow, Molecular Rheumatology, Trinity Biomedical Sciences Institute, Trinity College Dublin
Arthritis is a leading cause of joint deformity that affects roughly 15% of the population. Rheumatoid Arthritis (RA) is a chronic and progressive form of inflammatory arthritis that typically affects 1 in 100 people and twice as many women as men. RA is associated significant co-morbidities societallycostandanddisease,atherosclerosis,includingcardiovasculardiabetesandobesityreducespatientmobilityqualityoflife.TheeconomicofRAbothindividuallyandisanestimatedcost
Combined this data suggests that RA myeloid cells are imprinted with disease-specific hyperinflammatory and bioenergetic signatures and retain this functional commitment, such that differentiation into macrophages conserves this phenotype and results in impaired phagocytic ability. Mechanistically we have identified a key a role for a novel metabolite NAMPT whereby inhibition of NAMPT activity switches the inflammatory and metabolic phenotype of RA macrophages to promote resolution of inflammation. Thus, this study highlights the potential role of circulating monocytes as a blood surrogate marker for tissue inflammation and also identifies new candidate targetable pathways for better treatment options.
MAY 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE
One of the hallmarks of RA pathology is inflammation of the synovial joint which results in swelling pain and subsequent joint damage. One such cell type that is a key player in joint destruction is the ‘macrophage’, with many studies demonstrating a correlation between increased numbers of sub-lining macrophages and RA disease activity. In fact, synovial macrophages are the only celltype identified to date that are consistently associated with treatment response, regardless of treatment Macrophagestype.can be derived from circulating monocytes and so in this study we isolated circulating monocytes from the blood of active RA patients and healthy individuals. Firstly, we demonstrate increased levels of pro-inflammatory mediators in RA monocytes compared with healthy individuals. Interestingly this distinctive hyper-inflammatory signature of RA circulating monocytes is maintained upon differentiation into macrophages. Ex vivo RA macrophages clearly memorise the inflammatory phenotype of their precursor cells as indicated by significant increases in inflammatory markers
70 RHEUMATOLOGY FOCUS: INFLAMMATION
in RA macrophages compared to healthy. This suggests that if macrophages retain memory bias of their monocyte precursors, analysis of circulatory monocytes may be clinically translatable in terms of early diagnosis, disease stratification and treatment response.
Building upon this inflammatory data, we also examined the metabolic capacity of monocytederived macrophages in RA and healthy controls. RA macrophages display heightened mitochondrial respiration along with increased frequency of elongated mitochondria compared with healthy macrophages. In addition, RA macrophages have boosted glycolysis with significant increased expression of key glycolytic markers. This data suggests that RA macrophages are in a highly energetic state in comparison to healthy macrophages. This hyper-energetic phenotype allows macrophages in disease to produce energy quickly to allow for rapid immune activation.
in depth transcriptional analysis pro and anti-inflammatory macrophages in RA patients. Here we demonstrated an enrichment of members of the JAKSTAT signalling pathway (Tofacitinib is a current target of this pathway), particularly STAT3 as well as enrichment of many members of the NAD salvage pathway particularly NAMPT enriched in RA proinflammatory macrophages. Using specific inhibitors for both STAT3 (STATTIC) and NAMPT (FK886), we investigated the role of these two molecules as central players in macrophage polarisation towards inflammatory functions. Here we found that both STAT3 and NAMPT inhibition resulted in inhibition of both the hyperinflammatory, and hypermetabolic phenotype observed in these RA macrophages. Interestingly, NAMPT inhibition also results in reciprocal inhibition of STAT3 gene expression suggesting interplay between these two signalling pathways. Finally phagocytic function of RA macrophages was assessed whereby pro-inflammatory macrophages display decreased phagocytic function compared with anti-inflammatory. This reduction in phagocytosis is reversed upon NAMPT inhibition, with little effect observed with STAT3 blockade.
Photo: Trevor Butterworth
of ¤19,596 per patient/year, and overall cost of ~¤544 million. Despite significant advances in the treatment of RA such as the development of new targeted biotherapies in recent years, there is still no cure for RA Patients of this debilitating disease require life-long treatment. In addition, it is currently impossible to predict which patients will develop severe, erosive disease and those who will respond well to treatments such as Methotrexate, Rituximab or Tofacitinib, resulting in a ‘trial and error’ approach to treatments. Therefore, better understanding of the disease at the site of inflammation ‘the synovial membrane’ will allow for the development of a ‘personalised medicine’ approach to therapy.
Manipulation of Rheumatoid Arthritis Macrophages Primed for Inflammation
Case
illustrating A) Chondritis of right pinna B) Inflammatory process of left orbital apex 71RHEUMATOLOGY FOCUS: VEXAS
A 69 year old male presented to the emergency department with diplopia and a painful, tender and erythematous right ear. He also reported pain and swelling in his right calf and a patchy erythematous rash on his trunk and arms. He had a complex past medical history which included: frequent admissions for investigation of pyrexia of unknown origin, lingular pneumonia, neutrophilic dermatosis, pancytopenia and macrocytic anaemia. He had seen a heamatologist 6 months previously who had performed a bone marrow aspirate- the results were described as reactive. On examination he was febrile. His left eye showed signs of hypertopia and proptosis. Extraocular movements were painful. He had a
In this article I will describe a recent case encountered at the Mater Misericordiae University Hospital. I describe how genomics was used to discover VEXAS and how this discovery will have important implications for disease discovery in general. Finally I will outline the various ways in which VEXAS can present and discuss potential treatment options.
papular erythematous rash on his trunk and Investigationsarms.revealed elevated ESR, CRP, Ferritin and D-dimer. Longstanding macrocytic anaemia was evident along with neutropenia, lymphopenia and monocytaemia. Ultrasound of right lower limb was positive for superficial vein thrombosis. MRI brain confirmed presence of chondrits of the right ear and showed high signal intensity in the left orbital apex suggestive of an inflammatory process. [Figure 1] Histopathology from punch biopsy of the diffuse papular rash was consistent with a leucocytoclastic vasculitis.
HOSPITALPROFESSIONALNEWS.IE | HPN • MAY 2022
Written by Dr John Stack, Consultant Rheumatologist, Mater Misericordiae University Hospital MRI Brain
VEXAS (Vacuoles, E-1 enzyme, X-linked, Auto-inflammatory, Somatic) is a newly discovered haemato-immune disease that was first described in 2020. It results from an acquired, somatic mutation of the UBA1 gene resulting in impaired ubiquitylation with resultant fever, cytopenia, neutrophilic dermatosis, pulmonary infiltrates, chondritis and vasculitis. It occurs almost exclusively in men with a median age of onset of 64. Presence of vacuoles in myeloid precursor cells is a universal finding on bone marrow aspiration. Severe cases will progress to develop myelodysplastic syndrome (MDS). The disease is associated with a high mortality and treatment pathways have yet to be fully defined.
Retrospective review of the bone marrow aspirate performed 6 months prior confirmed vacuolation of the myeloid precursor cells. [Figure 2 on page 72] Genetic testing showed presence of
Fig MRI1Brain illustrating: A) Chondritis of right pinna B) Inflammatory process of left orbital apex A B Figure 1:
VEXAS: a Genotype-First Approach to Novel Disease Discovery
Introduction
Future implications
Using sanger sequencing the authors were able to demonstrate that the UBA1 mutation was only
VEXAS- treatment options and prognosis
VEXAS disease discovery- from genotype to phenotype
In summary VEXAS is a novel haemato-immune disease caused by a somatic mutation in the X-linked UBA1 gene. The diagnosis should be considered in men in their fifth to seventh decades presenting with unexplained systemic inflammation and cytopenias who are found to have vacuoles in the myeloid precursor cells on bone marrow aspirate.
2: Bone marrow aspirate demonstrating vacuoles in precursormyeloidcells Fig Bone2 marrow aspirate demonstrating vacuoles in myeloid precursor cells
Figure
to be a poor prognostic indicator and autologous stem cell transplantation should be considered for such patients.
MAY 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE
Diseases are usually discovered by first identifying individuals with the same phenotypic features. The genetic basis of disease is then determined by identifying loci of genetic variation (e.g. polymorphisms and mutations) within the same group of phenotypically similar patients. The group of researchers who discovered VEXAS inverted this process by using a genotype-first approach.1 They examined a group of seemingly disparate group of individuals with varying phenotypic features who had consented to participate in the ‘Undiagnosed Diseases Programme’ (patients who had been screened for periodic fever syndromes with no underlying genetic cause found). The exome sequence of 2560 persons was examined. They focussed on 841 genes associated with protein ubiquitylation, an important cell-signalling mechanism which the authors hypothesised if impaired would give rise to auto-inflammation. They identified 3 individuals, all of whom were men in their fifth to seventh decades, who were heterozygous for a mutation affecting the methionine-41 codon (p.Met41) of the X-linked UBA1 gene. The fact that these men were heterozygous for an X-linked gene raised the possibility of sequencing error. Men have only one X-chromosome so how could they possess two copies of a gene which is X-linked? The answer was that this mutation is somatic i.e. acquired in adulthood and expressed in some cell types but not in others.
expressed in specific haemopoetic cell lineages – myeloid cells , but not lymphocytes or fibroblasts. The findings were subsequently corroborated in a cohort of 141,600 patients, in which 25 patients with the UBA1 mutation were identified. All of the cases were men with a median age of 64 years. Vacuoles in the myeloid precursor cells were present on bone marrow in 100% of cases. The name VEXAS therefore refers to the genetic basis of this disease and the biological pathway affected by this mutation.
The discovery of VEXAS is an important milestone for rheumatology as it is the first inflammatory disease identified which results from a somatic mutation acquired in adulthood. Whilst somatic mutations are well recognised causes of cancer, the discovery of VEXAS implies that somatic mutations may play a causative role in a much wider range of disease than was previously thought. The genotype to phenotype approach described above highlights the power of modern genomics not just in diagnosing disease but also discovering new diseases and is likely to be replicated in other disease domains. Although formal epidemiological studies have yet to be performed, the estimated disease prevalence of VEXAS is thought to lie between 1 in 20,000 and 1 in 30,000 persons- so not as rare as one might assume. This fact along with its protean manifestations mean that many specialists are likely to encounter VEXAS at some point over the coming years.
mutation in the UBA1 gene confirming the diagnosis of TheVEXAS.patient was pulsed with IV methylprednisone 500mg x3 over consecutive days with complete resolution of diplopia by day 5. His fever and inflammatory rash also resolved. He was then switched to prednisone 40mg reducing slowly but unfortunately relapsed when the dose was reduced to 20mg daily. He was then started on a Janus Kinase inhibitor, tofacitinib 11mg daily and remains well presently.
Clinical features of VEXAS
Conclusion
Patients with VEXAS appear to respond (at least initially) to corticosteroids -albeit requiring very high doses. Biological drugs used in the treatment of other auto-inflammatory disease have been described with varying success in treating VEXAS. A cases series of 19 patients highlighted the potential efficacy of a variety of immunomodulatory drugs in the treatment of VEXAS by comparing time to next treatment.3 Median time to next treatment was 8 months for Tocilizumab (anti-IL6 receptor), 3.4 months for adalimumab, 3.9 months for corticosteroids, 12.7 months for cyclosporine and 21.9 months for azacytidine. Patients treated with Janus kinase (JAK) inhibitors such as tofacitinib and ruxolitinib remained on treatment at the time of reporting and therefore time to next treatment could not be determined, but it does suggest promising efficacy for JAK inhibitors. Randomised clinical trials have yet to be performed.
VEXAS appears to be associated with a high mortality. 10 out of 25 patients (40%) included in the original NEJM paper died from complications of their disease. A more recent retrospective case series of 116 French patients reported 5 year survival rates according to 3 different clusters.2 Clusters 1 and 3 were characterised as mild to moderate disease with 5-year survival probability of 84.2% and 89.6% respectively. Patients in cluster 2 were characterised by higher prevalence of chondritis and MDS and a 5-year survival probability of 50.5%. Presence of MDS in particular appears
References available on request FOCUS: VEXAS
Patients with VEXAS can present with a variety of autoinflammatory and haematological abnormalities. Within the original cohort, the majority (96%) had a history of recurrent fever and macrocytic anaemia (96%). Inflammatory skin disease was also common as was chondritis, venous thromboembolism and lung inflammation. Interestingly 60% of patients had previously been classified as having relapsing polychondritis , 32% with Sweets syndrome, 24% with myelodysplastic syndrome, 20% with multiple myeloma, 12% with polyarteritis nodosa and 4% with giant cell arteritis. More recently described clinical features include: inflammatory eye disease (as in case above), sensorineural hearing loss, myocarditis, colitis, expandlistandmimickinglymphadenopathy,hepatosplenomegaly,arthritisrheumatoidarthritisorchitis/epididymitis.2Theofclinicalfeaturesislikelytoasmorepatientswith
72 RHEUMATOLOGY
VEXAS are identified.
Part of the improvement in colorectal cancer cure rates is doubtless due to the National Bowel Screening Programme (“Bowelscreen” launched in 2013) as the earlier the disease is detected the more likely treatment (and indeed surgery alone) is likely to cure the disease. Sadly however, generally, uptake of this service offered for free by the state is less then that seen with Breast cancer screening, especially among men within the age group being offered bowel screening.
Written by Professor Ronan Cahill, Professor of Surgery, School of Medicine, University College Dublin
Research published by National Cancer Registry researchers (and funded by the Irish Cancer Society) suggested that men who decided
While breast and prostate cancer have a strong hormonal component and so a potential hormonal therapy in addition to surgical and medical oncology therapies, care for colorectal cancer most often involves surgery. This is most especially for those with organ confined or regional only disease (i.e. Stage 1, 2 and 3) where surgery alone can often prove definitive therapy. Surgery is also increasingly a component of care of those with metastatic disease (stage IV) who either need palliation (including potentially a stoma) or who show response to chemo and immunotherapies especially with regard to liver metastases.
73 HOSPITALPROFESSIONALNEWS.IE | HPN • MAY 2022 73
This is awful for any such affected patients and others worrying regarding their symptoms as it often means that they will need more invasive therapies with less confidence of cure. While increasingly greater proportions of such patients can still be cured despite their later stage presentation, their disease will therefore present a much more daunting prospect for them and their families and comes at much higher cost for the health care system in terms of effort and expense.
An Overview of Colorectal Cancer
These patients as well as those with node positive either colon and rectal cancer undergoing primary surgery without any radiological evidence of any other metastases commonly also receive postoperative (adjuvant) chemotherapy too. To best guide patients through these treatment pathways, a multidisciplinary team is needed including regular meetings among these specialists where patient care can be planned, understood and updated/amended as Thanksneeded.tothese types of treatments, alone or in combination, survival from colorectal cancer has improved over recent years, most especially rectal cancer thanks to personalized, sophisticated treatment plans alongside centralization of care among our eight designated cancer centres in It’sIreland.interesting to consider would similar efforts improve too the outcomes of colon cancers. Indeed in surgery there are efforts to develop a more radical resection standard safely following evidence in selected series regarding improved survival rates following such an operation.
This is a shame as premalignant and some earliest stage cancers in polyps can even be cured at colonoscopy by our accredited, expert gastroenterologists and other localized cancers (T1 and T2, N)) can be cured by minimally invasive surgery whether done by standard or robotic-assisted laparoscopy. Sadly too, the COVID-19 pandemic has impacted diagnostic services a lot in Ireland for both symptomatic and asymptomatic patients and as a result presentations with colorectal cancer have lately tended to be more advanced then previously.
as this helps improve disease free survival following surgery.
Colorectal cancer is the commonest solid organ cancer that affects both genders. For context, there were 2,819 people diagnosed with this disease in 2020 versus 3,890 men with prostate cancer and 3,704 (mostly) women with breast cancer while 2,573 people were diagnosed with lung cancer. A recent seven country study in the Lancet using data from 21 population-based cancer registries in Australia, Canada, Denmark, New Zealand, Ireland and the UK showed overall declining or stable incidences for both colon and rectal cancer. Overall the risk of colon and rectal cancer has increased among more recent birth cohorts with higher numbers now presenting under the age of Interestingly50. and importantly improvements in treatments for patients in colorectal cancer means there were estimated to be over 17,000 people living with a history of colorectal cancer in 2014 focusing attention on survivorship programmes for this disease like those seen for other malignancies. Increasingly too patient advocacy groups along with a patientpublic engagement initiatives are enabling a greater degree of “patient voice” contribution into the care processes and pathways for this disease in Ireland.
Excision for rectal cancer) includes Central Vascular Ligation in its performance while still being completed laparoscopically. This may be something that selected patients can be offered nationally perhaps even initially at selected centres to try and better disease control and survival rates at a single (and indeed ideally index) procedure. At least the value of such a surgical approach could be better evaluated prospectively in such a way to understand its usefulness in real-world settings rather than research trials with outcome being measured perhaps by means of a registry used to show such operative care can be reliably and usefully performed for Irish patients at a regional or national basis.
Indeed, such resection following systemic treatment at this stage of disease can provide cure for approximately 25% of such patients initially commenced on “palliative therapy”. Nonmetastatic rectal cancer patients may too receive pretreatment (neoadjuvant) with chemoradiotherapy ahead of surgery if there is any evidence on their staging investigations of disease involvement near the intended surgical resection planes
Colorectal Cancer
not to take part had overall a poor knowledge of bowel cancer were often rather fatalistic about cancer of any type while women who decide not to take part often held negative beliefs and emotions about the screening test itself.
This approach known as Complete Mesorectal Excision (matching as a corollary Complete Mesorectal
Males too get HPV-caused cancers and can transmit to their partners, so our gender-neutral scheme is also a major aid to reducing community levels of HPV, thereby preventing six types of cancer including cervical.
Screening has been hugely successful at bringing down the levels of cervical cancer in this country, with rates more than half those seen prior to the introduction of a national testing programme. However, cervical pre-cancer and cancer remains all too
74 MAY 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE Cervical
We are fortunate in Ireland that the HPV vaccine is delivered for free through the national schools vaccination programme, and all teenagers in first year are eligible. With compulsory involvement among schools, a school-based programme boosts equity of access.
In line with the agreed pillars of this strategy, we can group the needs and opportunities for a comprehensive burden elimination strategy into the three areas: vaccination, screening, and treatment and care.
Screening
Each year over three hundred women are diagnosed with cervical cancer, and those living with and beyond extend into their Globallythousands.andnationally, attention about this malignancy has increased in recent years. Buoyed by the recognition that the advent of vaccination and HPV testing means that cervical cancer is increasingly preventable, ambitious targets have been set by international health and policy organisations such as the EU parliament and WHO.
Valiant efforts by parents, schools and the National Immunisation Office have kept HPV vaccination levels high, but there is no question that COVID has impacted uptake rates in several ways. At a cost of approximately ¤800, missing the free programme likely puts later access out of the reach of many young people. Hence, a national catch up is strongly indicated now.
However, truly eliminating the burden of cervical cancer will require a broader range of action by us all over multiple decades.
Asymptomatic HPV infections are common when young people first become sexually active, and the vaccine works when immunity is established prior to such exposure, hence the vital importance of a national programme for vaccination of young people which establishes that protection.
Vaccination
Almost all squamous cell cervical cancers are directly caused by
one of approximately a dozen HPV virus strains, HPV-16 being particularly carcinogenic and accounting for 50% of that burden alone, with other factors such as smoking amplifying that risk.
In the fantastically multicultural community of modern Ireland, these efforts will also need to be
EliminatingCancertheBurden of Cervical Cancer
communicated through means more suitable to the information sources commonly used by discreet communities, bearing in mind that some in society have significant reason to question state authorities based on historical and legacy challenges from their country of origin.
There are also emerging indications that vaccination of older women, especially those immediately being treated for HPV-caused cervical cell abnormalities, may greatly reduce the chances of recurrence and later cancer risk.
Safe and effective vaccines have been widely available now for more than a decade and are already causing a precipitous fall in pre-cancer and early cancer rates among high uptake populations.
Withcommon.over7,000
women needing intervention to prevent the emergence of cervical cancer annually, this translates to an approximate 1 in 10 lifetime risk of cervical pre-cancer treatment which has a health burden in its own right, with just less than a 1 in 100 lifetime risk of a cancer diagnosis, and a 3 in 1000 risk of cervical cancer death.
The successful transition of that programme to HPV-based testing will more sensitively and accurately identify those in need of intervention before cancer emerges, however there will still
Written by Dr Robert O’Connor, Director of Research & Yvonne O’Meara, Psychotherapist, Irish Cancer Society
“Screening has been hugely successful at bringing down the levels of cervical cancer in this country, with rates more than half those seen prior to the introduction of a national testing programme. However, cervical pre-cancer and cancer remains all too common”
Vaccine hesitancy is not going away, and maintaining high uptake will require an ongoing multiannual effort to educate parents as their children come to the relevant age and ‘immunise’ them with facts against emotive and highly targeted misinformation and disinformation.
The importance of Patient and Public Involvement, or PPI, is fundamental to improving quality of life for these women. www.thisisGO.ie has been developed as an institutionally neutral platform with extensive voluntary input from PPI and health care professionals throughout Ireland.
The effectiveness of screening will continue to rely heavily on maintaining high colposcopy standards, and this will be challenged initially by increased demand driven by HPV positivity, and then declining demand as the impact of vaccination and HPV detection reduces positivity rates.
Patients can be left with a variety of life-changing side effects including chronic sexual dysfunction, lymphoedema, infertility, itstreatmentManygynaecologicaltheofbeenCervicalradiotherapy,andmenopause,treatment-inducedandgastrointestinalurinarytoxicityfromamongothers.cancerpatientshavefoundtohaveworsequalitylifescoreswhencomparedtogeneralpopulationandothercancersurvivors.patientsreceivemultiplemodalities,eachwithownlong-termeffects.Given
Equally, the platform is designed to be of use to professionals working in the field, with relevant information shared through a hybrid approach of papers, videos and Articlespodcasts.onsubjects including breaking bad news and how to take a psychosexual history are particularly relevant to professionals working directly in oncology, but also to those who may not be. A phase two of the platform focusing on the ovarian cancer was also recently launched to coincide with World Cancer Day in February, with further content set to be added on other gynaecological conditions throughout the course of 2022.
While effective for many, the current administration of an uncomfortable test by a third party can be a significant hurdle for some people with a cervix, or the many in our community who have sadly been exposed to sexual trauma. Screening rates can also be lower in underprivileged communities facing challenges with healthcare access.
People using the platform will find it useful right across the disease trajectory from diagnosis to treatment, through to living well with and beyond cancer.
Phase one of www.thisisGO. ie focused on cervical cancer and has received universal praise from patients and health care professionals. It has been designed as a safe online space where women and their families can access accurate, reliable, evidence-based information about their cancer, treatment options, long and short-term complications, psychological and social issues.
the high five-year survival for cervical cancer, evaluation, and improvement of long-term quality of life are essential.
Ignorance of the personal and relationship burdens of cervical cancer treatment has left many suffering devastating consequences, often in lonely isolation. This was one of the drivers behind the Irish Cancer Society establishing its Women’s Health Initiative, a programme established in Cork and Dublin and now extending to Galway researching the best way to provide state-of-the-art customised interventions to assist women to manage and overcome the impacts of cancer treatment, especially in cervical cancer.
ThisisGO.ie
A vastly disproportionate burden of cervical cancer is found among those who cannot make use of the screening currently available. There are now strong indications that the use of an adjunct of HPV-based self-sampling may open up even wider access to prevention and early detection by such individuals.
New treatments and combinations of treatment are gradually pushing up survival and giving hope to those impacted, but these often come at a devastating cost.
The need for improvements in treatment and care often gets least attention in the conversation around cervical cancer.
The idea is quite simple. Users create a personalised profile and get information tailored to their situation, with information provided on their disease site, stage and treatment modalities received.
Treatment and care
Due to the physical location of cervical cancer, it can be embarrassing and more challenging for women to talk about these side
The scope of the information available is vast. There is a very useful symptom tracker for patients as well as a detailed service directory which allows women access local supports in all areas of the country.
Management of this cancer may be through surgery, radiotherapy, or chemotherapy or a combination of these. Short and long-term side effects are an inevitable component in each patient’s care pathway.
75 HOSPITALPROFESSIONALNEWS.IE | HPN • MAY 2022
The Irish Cancer Society’s Women’s Health Initiative research programme has taken great strides in addressing the needs of such women.
Donal Brennan, Professor of Gynaecological Oncology in UCD who leads the Dublin arm of the programme, has along with his team designed, populated, and launched an online resource addressing the needs of these women, their partners and health care professionals supporting them. This web-based virtual platform is called www.thisisGO.ie.
Despite all that we know about the symptoms of cervical cancer, it is clear that symptomforandprofessionalseducationprogresshurdlescommunicationeducational,andaccessremain,andcontinuedwillrequireongoingofthepublicandastowarningsignsreadyandrapidaccesswomentocompassionateassessment.
effect to their treating teams. Often, these women suffer in silence, unsure how to manage these side effects. Some of these can be easily addressed if they are spoken about and normalised during a patient consultation. The most obvious of these is vaginal dryness.
It also contains practical articles on topics such as ‘How to talk to children about cancer’, death and dying, vulvovaginal health, diet and exercise, lymphoedema management, decoding the science, and menopause, to mention some of the most commonly searched topics.
be challenges to reap the full benefits of such testing.
Dr Ahmed Al Badi
programmed cell death ligand 1(PD-L1) expression which causes exhaustion of effector T cells when they attempt to attack the cancer cell.(4) Testing for PD-L1 tumour proportion score (TPS Tumour cells positive for PD-L1/ viable tumour cells*100%) is now one of the pillars of the initial treatment of NSCLC. Immune checkpoint inhibitors (ICI) such as Pembrolizumab disrupt PDL1 signalling and activate the immune system to attack the cancer in a substantial minority of patients.
CTLA-4 is an immune checkpoint found in naïve T cells being exposed to antigen by antigen presenting cells early in T cell maturation. Their use leads to rapid expansion of T cell clones some of which may recognize self-antigen causing autoimmune disease. PD-L1 inhibitors tend to have a lower risk of irAE thanCTLA-4 inhibitors as the T cells have already been through selection in the lymph node and are quiescent but unleashed to attack the cancer cells. In moderate to severe cases treatment cessation and steroids yield good responses. Differential diagnoses
The KEYNOTE-024 trial compared the use of first line pembrolizumab to platinum based chemotherapy in advanced NSCLC with PD-L1 >50% and no driver mutations; the group that received pembrolizumab showed a significant overall survival (OS) and longer progression free survival (PFS).(5) In Ireland first line monotherapy with ICI is limited to frail patients who would not tolerate chemotherapy and who have a TPS score >50%. In the USA based on KEYNOTE-042 lung cancer with any PD-L1 score can receive single agent immunotherapy as they accept inferior response rates and financial toxicity more readily. TPS is an imperfect biomarker.
Dr Brian Healey Bird, Senior Lecturer in Clinical Education University College Cork
either a chemoimmunotherapy group (cisplatin or carboplatin plus pemetrexed combined with pembrolizumab) compared to a placebo. This was followed by pembrolizumab maintenance therapy or placebo. chemoimmunotherapyThearms had increased OS with all subgroups of TPS as demonstrated below. Similar results were demonstrated in the KENOTE-407 trials with squamous cell carcinoma NSCLC (Carboplatin and Paclitaxel ± pembrolizumab or placebo). In Ireland Pembrolizumab, Nivolumab and Atezolizumab are all funded for second line treatment of NSCLC post chemotherapy alone.
IntroductionAdvancedCancerNSCLC
Immune Related Autoimmune Side Effects
Immunotherapy is now the first line treatment of choice for stage IV Non-Small Cell Lung Cancer (NSCLC) without driver mutations.(3) This article will review these agents combined with chemotherapy or as single agents, and the associated immune related
Lung cancer is the commonest cancer diagnosis in both sexes. Half of these diagnoses are locally advanced or associated with distant metastasis.(2)
The KEYNOTE-189 trial randomized a patient population of non-squamous NSCLC to
Immunotherapy capitalises on the body’s ability to recognize self and non self and destroy non self. Tumour cells escape immune surveillance by upregulation of
Written by Dr Ahmed Al Badi and Dr Brian Healey Bird
Figure 1. KEYNOTE 189 – Study Schema and Flow chart adapted from Johnson ML. Approach To Patients With Metastatic Non-Small Cell Lung Cancer In 2019(6). Lower table shows the distribution of PDL1 TPS in each arm of the study
autoimmune side effects (irAE) We will also explore treatment options following immunotherapy, including novel agents targeting KRAS G12C mutations. 2 cases will be used to illustrate these learning points.
76 MAY 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE Lung
Immunotherapy
FDA ≥ 1% (636) 27 31)(24 5.46.2)(4.3
CTLA 4 is an immune checkpoint found in naïve T cells being exposed to antigen by antigen presenting cells early in T cell maturation. Their use leads to rapid expansion of T cell clones some of which may recognize self antigen causing autoimmune disease.. PD L1 inhibitors tend to have a lower risk of irAE thanCTLA 4 inhibitors as the T cells have already been through selection in the lymph node and are quiescent but unleashed to attack the cancer cells. In moderate to severe cases treatment cessation and steroids yield good responses. Differential diagnoses including sepsis, thrombosis and chemotherapy side effects need to be considered especially in patient with other comorbidities and polypharmacy.
77 HOSPITALPROFESSIONALNEWS.IE | HPN • MAY 2022
including sepsis, thrombosis and chemotherapy side effects need to be considered especially in patient with other comorbidities and Rashespolypharmacy.(14)andpruritisare common and tend to effect about 40% of patients. These occur early in treatment at the 2–3-week
FDAEMA,Ireland, ≥ 50% (132) 62.170.4)(53.3 14.4)(9.111.1
in 1.8% of patients at around 6-7 weeks. Bowel rest and hydration can be sufficient but in moderate to severe disease steroids and hospitalization is warranted. 0.5-1mg/kg of prednisolone with a 4–6-week taper to avoid early relapse is recommended. Consider infectious pathogens and a CT scan early. If the diagnosis is
Immune Related Autoimmune Side Effects
0.017)0.99,(0.67 20
FDAEMA,Ireland, ≥ 20% (412) 33 38)(29 7.8)(5.16.2 0.94
can happen quite early at 42 days in 6.6% of patients. Usually, presentation is mild symptoms of hypothyroidism but can initially be preceded by hyperthyroid symptoms. This is because it is commonly associated with thyroid autoantibodies and progresses like a thyroiditis. Symptomatic therapy with Levothyroxine for hypothyroidism or non-selective beta blockers for the temporary hyperthyroidism may be beneficial. These patients may recover with time. Other endocrine dysfunction is extremely rare but one emergency to look out for would be adrenal insufficiency in 0.7% of patients who may present with non-specific symptoms or in an adrenal crisis. The latter need hospitalization, aggressive fluid resuscitation and stress dose steroids.(14) Patients whose immune system attacks pancreatic islet cells may present with Diabetic Keto Acidosis.
(14) Rashes and pruritis are common and tend to effect about 40% of patients. These occur early in
Adapted from Healey Bird B, Nally K, Ronan K, Clarke G, Amu S, Almeida AS, et al. Cancer Immunotherapy with Immune Checkpoint Inhibitors-Biomarkers of Response and Toxicity; Current Limitations and Future Promise. Diagnostics. 2022;12(1):124.(13) Table 1. Summary of Selected trials of Pembrolizumab in NSCLC 3 TRIAL ARM PD L1 TPS IHC Score using Dako Pembrolizumab)receivingpatients(Number22C3of CI)RateResponseOverall(95%(%) CI)(05%monthsPFSMedianin PFS p(95%alonetocomparedHRchemoCI,value) (95%monthsOSMedianinCI) OS p(95%alonetocomparedHRchemoCI,value) Approval Single 024KEYNOTESquam)(AdenoPembroliAgentzumaband(5,7-9) ≥ 50% (154) 44.8 10.3 0.5 0.001)0.68,(0.37< (95%26.3 CI 40.4)18.3 0.62 0.002)0.81,(0.48 FDAEMA,Ireland, 042KEYNOTE(10) All (636)patients 16.7 0.81 0.0036)0.93,(0.71 FDA ≥50% (298) 39 (34 45) 7.19)(5.9
Consider discussion with the respective specialties to consider other differentials but if related to immunotherapy treatment discontinuation (temporarily or permanently) and steroids can help treat these side effects.(14) 0.81 24.9)(15 0.69 0.003)0.85,(0.56 1.11,)(0.8 22.1)(15.317.7 0.77 0.002)0.92,(0.64 1.07 1.21)(0.94 19.7)(13.916.7 0.81 0.0018)0.93,(0.71 18.2)(10.713.4 0.92 1.11,)(0.77 9 9.9)(8.1 0.48 0.58)(0.4 2225.2)(19.5 0.560.70)(0.45 0.360.51)(0.26 NRNR)(20.4 0.590.86)(0.39 0.73)(0.36 25.9)(17.721.8 0.620.92)(0.42
uncertain a colonoscopy may be useful. In unresponsive cases a switch to infliximab within 72 hours may be Hepatitisconsidered.(14)occursinabout 10% of patients, usually after 8-12 weeks from initiation. This is usually a rise in liver function tests (LFTs) but can manifest as a fever. Consider alternative diagnoses such as thromboembolic events, alcoholic or viral hepatitis and metastatic disease as causes for liver function derangement. A CT scan and hepatitis panel can aid this differential. Normalisation of LFTs can be aided with 0.5mg-1mg of Prednisolone as a 3-week taper. Treatment can be recommenced for mild to moderate hepatitis secondary to immunotherapy after recovery of liver function tests (which may take up to 8 weeks) but should be discontinued in severe Thyroidhepatitis.(14)dysfunction
1 (128)49% 49.258.2)(40.3 9.213.1)(7.8 0.51
mark and in most cases can be observed and symptomatically managed. Interestingly Vitiligo rashes are usually associated with a good response to immunotherapy. Blistering rashes need a broader differential and other causes investigated.(14)
FDA 1 (338)49%
FDA Pembro and (11,KEYNOTE(ChemoAdenoCA)18912) All (410)Pembrolizumabreceivingpatients 48 53)(43.1
< (127)1% 32.341.2)(24.3 6.28.1)(4.9 0.640.89)(0.47 22.8)(13.817.2 0.520.74)(0.36 KEYNOTESCC)(FirstChemotherapyandPembrolizumabLine407 All (278)Patients 63.8)(51.957.9% 8.3)(6.26.4 <0.001)0.70;(0.450.56 NE)(13.215.9 <0.001)0.85;(0.490.64; FDAEMA,Ireland, ≥50% (73) 71.5)(48.160.3 10.3)(6.18.0 0.58)(0.240.37 NE)(11.3NR 1.10)(0.370.64 1 (103)49% 59.5)(39.549.5 11.4)(6.07.2 (0.390.56 0.8) NE)(12.814.0 0.90)(0.360.57 ≥1% (183) 0.65)(0.380.49 (95)<1% 72.8)(52.663.2 6.5)(6.16.3 0.98)(0.470.68 NE)(13.115.9 0.98)(0.380.61 Adapted from Healey Bird B, Nally K, Ronan K, Clarke G, Amu S, Almeida AS, et al. Cancer Immunotherapy with Immune Checkpoint Inhibitors Biomarkers of Response and Toxicity; Current Limitations and Future Promise. Diagnostics. 2022;12(1):124.(13)
Diarrhoea and colitis can happen
Pneumonitis can occur in 5% of patients. Patients can present with shortness of breath, coughing, or reduced exercise tolerance. It is a potentially fatal complication. CT is imaging of choice and can show bilateral ground glass opacities. Prednisolone at 1-2mg/kg with a long taper over 4-6 weeks to avoid relapse can help reduce inflammation. Consider infectious causes and a bronchoscopy to out rule these especially in moderate to severe disease or in poor Otherresponse.(14)irAEstolook out for include inflammatory arthritis, cytopenia and ocular manifestations .
Lung Cancercombined6
75.9%.(16)
Baseline 3 Months of chemo/Pembro Disease progression after 3 months of maintenancePembro
Immunotherapy combined with chemotherapy
switch for guanosine triphosphate (GTP) the active form and guanosine diphosphate (GDP) the inactive form. The G12C mutation selects the active form GTP which promotes downstream oncogenic and uninhibited cell growth.
The use of Sotorasib was explored in the CodeBreaK100 trial currently in phase 1/2. They have recruited patients with an ECOG 0 1, having advanced or metastatic NSCLC, disease progression after first line treatment which is either platinum based chemotherapy or receipt of PD 1/PD L1 monotherapy or a combination treatment. They measured the primary endpoints of objective response either complete or partial. Responsiveness was reported as per the RESIST standards (see below). In 126 patients, 124 were selected. There was an objective response in 37.1% (95% confidence interval [CI], 28.6 46.2), 3.2% had a complete response the remaining had a partial response. Disease control defined as a minimum 5 week period with stable disease occurred in 80.6% of patients (95% CI, 72.6 to 87.2). Most patients tolerated sotorasib well and there were no major safety concerns. (7)
Through irreversible binding and inhibition of KRAS this mutation is suppressed. Some studies report that as many as 13% of lung adenocarcinoma tumours harbour this mutation(17)
Disease progression
No response as above criteria but no disease progression.
The use of Sotorasib was explored in the CodeBreaK100 trial currently in phase 1/2. They have recruited patients with an ECOG 0-1, having advanced or metastatic NSCLC, disease progression after first line treatment which is either platinumbased chemotherapy or receipt of PD-1/PD-L1 monotherapy or a combination treatment. They measured the primary endpoints of objective response either complete or partial. Responsiveness was reported as per the RESIST standards (see below). In 126 patients, 124 were selected. There was an objective response in 37.1% (95% confidence interval [CI], 28.6-46.2), 3.2% had a complete response the remaining had a partial response. Disease control defined as a minimum 5-week period with stable disease occurred in 80.6% of patients (95% CI, 72.6 to 87.2). Most patients tolerated sotorasib well and there were no major safety concerns. (7)
Beyond First- and Second-Line Treatment
More than 30% decrease in sum of longest diameters (SLD)
Sotorasib targets the KRAS G12C mutation. KRAS a guanosine triphosphatase that acts as a switch for guanosine triphosphate (GTP) the active form and guanosine diphosphate (GDP) the inactive form. The G12C mutation selects the active form GTP which promotes downstream oncogenic and uninhibited cell growth. Through irreversible binding and inhibition of KRAS this mutation is suppressed. Some studies report that as many as 13% of lung adenocarcinoma tumours harbour this mutation(17)
RECIST Complete1.1response
After recovery from the complication a staging scan was performed in early 2021 to discuss treatment options. This unfortunately showed disease progression.
Disease progression after 3 months of Pembro maintenance
Beyond First- and Second-Line Treatment
literature on sotorasib and discussion with the patient she was commenced on sotorasib 960mg once a day. She has tolerated it very well for almost one year now and her scan at 6 weeks showed an interval reduction in tumour burden.
chemotherapy/ICI) from seven German centres. The study concluded that of 93 patients enrolled overall response rate (ORR) was 41.4% with disease control rate (DCR) of
After recovery from the complication a staging scan was performed in early 2021 to discuss treatment options. This unfortunately showed disease Followingprogression.reviewofthe
A 60 year old female former smoker presented initially in August 2018 with back pain. She had imaging which revealed a small lung primary with a metastatic T8 pathological fracture. Tissue samples revealed lung adenocarcinoma. Next Generation Sequencing showed a KRAS G12C mutation and immunohistochemistry a PD-L1 TPS of 1-49% She underwent vertebrectomy and spinal reconstruction followed by Stereotactic Body Radiotherapy (SBRT) to the small lung primary. She was then referred to medical oncology. At that time Ireland did not have immunotherapy available in first line lung cancer. She was given 4 cycles of Carboplatin and Pemetrexed and remained free of progression for 15 months, On progression she received pembrolizumab as monotherapy. Her immunotherapy was halted due to grade 3 colitis managed with inpatient IV hydrocortisone and discharged with a 3-week oral taper of prednisolone. This was unsuccessful and the patient was readmitted due to refractory colitis and required an infliximab infusion.
Following review of the literature on sotorasib and discussion with the patient she was commenced on sotorasib 960mg once a day. She has tolerated it very well for almost one year now and her scan at 6 weeks showed an interval reduction in tumour burden.
Baseline
After recognizing the therapeutic benefits of immunotherapy it may be helpful to review the current strategy to treat stage IV lung cancer. Targeted therapies for druggable mutations must be screened for early on.(15) However, if there are no targetable mutations then immunotherapy (ideally combined with cytotoxic chemotherapy) is the best option. The options are pembrolizumab alone or pembrolizumab combined with chemotherapy doublet of choice (cisplatin or carboplatin with pemetrexed for Adenocarcinoma).
78 MAY 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE
3 Months of chemo/Pembro
No new lesions or progression of non-target lesions.
Stable disease
More than 20% increase in SLD, progression of non target lesions or new lesions.
a KRAS G12C mutation and immunohistochemistry a PD-L1 TPS of 1-49% She underwent vertebrectomy and spinal reconstruction followed by Stereotactic Body Radiotherapy (SBRT) to the small lung primary. She was then referred to medical oncology. At that time Ireland did not have immunotherapy available in first line lung cancer. She was given 4 cycles of Carboplatin and Pemetrexed and remained free of progression for 15 months, On progression she received pembrolizumab as monotherapy. Her immunotherapy was halted due to grade 3 colitis managed with inpatient IV hydrocortisone and discharged with a 3-week oral taper of prednisolone. This was unsuccessful and the patient was readmitted due to refractory colitis and required an infliximab infusion.
ImmunotherapyChemotherapyCombinationandandbeyond.
After 2 cycles of chemotherapy, she was admitted with febrile neutropenia and pancytopenia. This was attributed to her cytotoxic chemotherapy, and she had a dose reduction and continued full dose pembrolizumab. She had a restaging CT TAP which showed some decrease in tumour bulk in November of 2021. After 3 further months of maintenance pembrolizumab a staging CT was performed, and the disease had progressed in the aforementioned regions. She was switched to Docetaxel and Nintedanib. This decision was based on a retrospective, real world analysis of Docetaxel plus Nintedanib after treatment failure (chemotherapy followed by ICI or combined chemotherapy/ICI) from seven German centres. The study concluded that of 93 patients enrolled overall response rate (ORR) was 41.4% with disease control rate (DCR) of 75.9%.(16)
A 60-year-old female former smoker presented initially in August 2018 with back pain. She had imaging which revealed a small lung primary with a metastatic T8 pathological fracture. Tissue samples revealed lung adenocarcinoma. Next Generation Sequencing showed
References available on request.
A 60-year-old female ex-smoker with a 15-pack year (PY) smoking history presented in July of 2021 with haemoptysis and shortness of breath on exertion. CT thorax abdomen and pelvis (CT TAP) showed a malignant mass in left hilum with central mediastinal invasion, invasion into left atrium, left pulmonary vein and left upper lobe collapse. There was a small ipsilateral effusion which contained malignant cells. A bronchoscopy was performed, and tissue was sent for an Next Generation Sequencing panel and PD-L1 TPS. There were no actionable mutations and PD-L1 TPS was over 90%. She
received carboplatin/pemetrexed and pembrolizumab.
Sotorasib targets the KRAS G12C mutation. KRAS a guanosine triphosphatase that acts as a
References available on request
Disappearance of lesions and pathological lymph nodes
Partial response
Case 1.
“Uncontrolledpressure.high blood pressure is a leading cause of heart attacks and stroke. Because there are no obvious symptoms, very often people assume it’s nothing to worry about. However, high blood pressure needs to be treated and managed so as to avoid a serious heart event or a catastrophic stroke,” says Professor Sharif.
The number of adults aged 30-79 years with hypertension or high blood pressure has increased from 650 million to 1.28 billion in the last thirty years, according to the first comprehensive global analysis of trends in hypertension prevalence, detection, treatment
Startlingly, it is estimated that over half of all adults in Ireland over the age of 45 are living with high blood pressure. High blood pressure is a sign that the heart and blood vessels are being overworked which in turn increases the risk of having a heart attack or a stroke. It can also lead to other conditions such as aneurysm, heart failure, problems with your vision and kidney failure.
The number of adults aged 30-79 years with hypertension or high blood pressure has increased from 650 million to 1.28 billion in the last thirty years, according to the first comprehensive global analysis of trends in hypertension prevalence, detection, treatment
A team of consultants in Galway, including Professor Faisal Sharif, Consultant Cardiologist, are now leading the way in treating this problem at the Difficult to Treat Hypertension Clinic, based in Merlin Park Hospital, which assesses patients and investigates the reason for poor blood pressure control. Despite lifestyle changes and medication changes, if the blood pressure remains elevated patients can be referred for medical device based treatment for high blood pressure. One such treatment is known as Renal Denervation (RDN). RDN is a minimally invasive procedure specifically used to treat resistant hypertension. This procedure can be performed with multiple emerging technologies, including radio-frequency, ultrasound, and chemical ablation methods to modify sympathetic nerves in the renal arteries, which decreases blood “Uncontrolledpressure.high blood pressure is a leading cause of heart attacks and stroke. Because there are no obvious symptoms, very often people assume it’s nothing to worry about. However, high blood pressure needs to be treated and managed so as to avoid a serious heart event or a catastrophic stroke,” says Professor Sharif.
79 HOSPITALPROFESSIONALNEWS.IE | HPN • MAY 2022 News
79 HOSPITALPROFESSIONALNEWS.IE | HPN • MAY 2022 News
Taking Control of Blood Pressure
organised by the World Hypertension League (WHL) which is an umbrella organisation composed of 85 hypertension societies and leagues from all over the world.
The UK was one of the top ten countries with the lowest prevalence of high blood pressure among women in 2019 at 23 per cent while in Ireland this figure was 26.6 per cent. The study found that the country with the highest prevalence of high blood pressure in men was Paraguay at 62 per cent compared to 22 per cent in Eritrea which had the lowest prevalence among men.
Taking Control of Blood Pressure
C M Y CM MY CY CMY K
and control, led by Imperial College London and the World Health Organization (WHO), and published in The Lancet. Nearly half these people did not know they had high blood pressure.
World Hypertension day is celebrated annually on the 17th May. The main aim of the day is to educate the public and increase awareness of hypertension, which is also commonly known as high blood Hypertensionpressure.is a major cause of a range of health problems such as strokes, heart attacks and kidney disease, and can also contribute to dementia. Many people who suffer from hypertension are not aware that they have it as there can be no symptoms, often people only find out after suffering a heart attack or Thestroke.dayis
organised by the World Hypertension League (WHL) which is an umbrella organisation composed of 85 hypertension societies and leagues from all over the world.
The theme for this year is Know Your Numbers, and the WHL would like to encourage as many people as possible to get involved in May Measurement Month. In this initiative which started in 2017, volunteer manned screening sites will be setting up in a range of venues around the world to check the blood pressure of as many people as possible.
Thestroke.dayis
Startlingly, it is estimated that over half of all adults in Ireland over the age of 45 are living with high blood pressure. High blood pressure is a sign that the heart and blood vessels are being overworked which in turn increases the risk of having a heart attack or a stroke. It can also lead to other conditions such as aneurysm, heart failure, problems with your vision and kidney failure.
A team of consultants in Galway, including Professor Faisal Sharif, Consultant Cardiologist, are now leading the way in treating this problem at the Difficult to Treat Hypertension Clinic, based in Merlin Park Hospital, which assesses patients and investigates the reason for poor blood pressure control. Despite lifestyle changes and medication changes, if the blood pressure remains elevated patients can be referred for medical device based treatment for high blood pressure. One such treatment is known as Renal Denervation (RDN). RDN is a minimally invasive procedure specifically used to treat resistant hypertension. This procedure can be performed with multiple emerging technologies, including radio-frequency, ultrasound, and chemical ablation methods to modify sympathetic nerves in the renal arteries, which decreases blood
and control, led by Imperial College London and the World Health Organization (WHO), and published in The Lancet. Nearly half these people did not know they had high blood pressure.
World Hypertension day is celebrated annually on the 17th May. The main aim of the day is to educate the public and increase awareness of hypertension, which is also commonly known as high blood Hypertensionpressure.is a major cause of a range of health problems such as strokes, heart attacks and kidney disease, and can also contribute to dementia. Many people who suffer from hypertension are not aware that they have it as there can be no symptoms, often people only find out after suffering a heart attack or
The theme for this year is Know Your Numbers, and the WHL would like to encourage as many people as possible to get involved in May Measurement Month. In this initiative which started in 2017, volunteer manned screening sites will be setting up in a range of venues around the world to check the blood pressure of as many people as possible.
The UK was one of the top ten countries with the lowest prevalence of high blood pressure among women in 2019 at 23 per cent while in Ireland this figure was 26.6 per cent. The study found that the country with the highest prevalence of high blood pressure in men was Paraguay at 62 per cent compared to 22 per cent in Eritrea which had the lowest prevalence among men.
SRS is a novel radiation technique developed by a Swedish neurosurgeon, Lars Leksell, for lesions not amenable to surgical resection. SRS is a distinct
Brain metastases have a significant impact on quality of life and clinical outcomes of patients with cancer. Although the incidence of brain metastases in patients with breast cancer is low, brain metastases are relatively common in patients with metastatic breast cancer, particularly in patients with human epidermal growth factor receptor 2 (HER2)-positive or triple-negative breast cancer (TNBC) subtype. Despite the extracranial efficacy of many systemic therapies for patients with breast cancer, the bloodbrain barrier limits penetration of many systemic agents into the brain, and patients often experience intracranial progression. Therefore, radiation, in the form of whole brain radiotherapy (WBRT) or now more commonly stereotactic radiation, is the mainstay of the therapy for many patients with breast cancer and brain metastases. The management choice in patients with newly diagnosed brain metastases depends on number of brain metastasis, histological subtype, performance status, estimated prognosis, and extent of extracranial disease.
Hippocampal avoidance Whole Brain Radiation (HA WBRT)
of being able to integrate with systemic treatment. Patients with brain metastasis treated with SRS can be treated without chemotherapy treatment breaks thus optimizing extracranial disease control in addition to their intracranial disease.
Despite the efficacy and improvements radiation delivery, many patients ultimately progress intracranially, both locally and in distant or uninvolved regions of the brain. The challenge and unanswered question for doctors and patients is how to sequence all the treatments, both local and systemic, to optimize the patient's quality of life and survival. This is an area of intense clinical research. The treatment of patients with breast cancer brain metastases should be discussed by a multidisciplinary team of breast cancer experts including a neurosurgeon, medical oncologist, and radiation oncologist. Important clinical features that help determine appropriate first line therapy include number of brain metastasis, resectability, breast cancer subtype, performance status, and the presence of extracranial disease.
Written by Dr Daniel Cagney, Clinical Director, Radiation Oncology, Mater Private Hospital Dublin
Brain metastases tend to be spherical with sharp demarcation from brain tissue. They are thus ideal for SRS because precision targeting can be easily generated using radiosurgical systems. Compared with resection, SRS is advantageous as it can treat surgically inaccessible lesions and multiple lesions. In general, asymptomatic patients with up to four lesions smaller than 4 cm are regarded as suitable for SRS. Local tumour control rates with SRS are consistently greater than 80%. Patients with newly diagnosed brain metastases may be treated with wholebrain radiotherapy alone versus whole-brain radiotherapy and SRS boost. In practice we tend to omit whole brain radiotherapy from this treatment paradigm due to enhanced toxicity, impact on quality of life and no improvement in overall survival. Whole brain radiotherapy is then reserved for future salvage use if required. SRS, unlike whole brain radiotherapy, has the additional advantage
80 MAY 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE Breast
Stereotactic Radiation (SRS)
Thankfully brain radiation treatment has evolved over the past decade to lead to better outcomes for patients from a cancer perspective but also side effects and toxicities have been reduced. This article highlights two such developments.
discipline that utilises x-rays to inactivate defined target(s) in the head and spine without the need to make an incision. The target is identified by high-resolution imaging. SRS is mainly performed in a single session, using a mask and a stereotactic image guidance system, but can be conducted up to a maximum of five days.
Whole-brain radiotherapy (WBRT) remains an important treatment modality in many patients with brain metastases because it reduces symptoms, improves intracranial control, and diminishes the chance of death. However, numerous patients experience cognitive deterioration after WBRT, which highlights concerns about the toxicity of WBRT. Preclinical and clinical studies have suggested that relatively low doses of radiation to neural stem cells within the subgranular zone of the hippocampus may contribute to radiotherapy (RT)–induced cognitive toxicity. A recent prospective multi-institutional randomized phase III trial investigated the role of WBRT with or without HA in patients with brain metastases. The use of HA during WBRT (Figure 1) was shown to effectively spare the neurocognitive damage from radiation to better preserve cognitive function and patientreported symptoms. This is fantastic news for patients with breast cancer and brain metastases. However even with the use of HA-WBRT, patients can still experience side effects. Thus, in patients with limited number of brain metastases stereotactic radiation is the preferred treatment course.
Hippocampal avoidance Whole Brain Radiation (HA-WBRT)
Hippocampal avoidance Whole brain radiotherapy (HA-WBRT)
RadiotherapeuticCancer Management of Breast Cancer Brain Metastases
both laya healthcare members and non-members the new diagnostic imaging services
81 HOSPITALPROFESSIONALNEWS.IE | HPN • MAY 2022
• An automated respiratory monitoring solution has been deployed to 23 hospitals across the country providing >10 hours’ notice of a patient desaturation. The same solution is now being tested with COPD patients in the community in Donegal.
NEW DIAGNOSTIC IMAGING SUITE
Results from the confirmatory PRIME trial will be presented at an upcoming medical congress. Data from both trials will form the basis of regulatory submissions around the world for Dupixent in prurigo nodularis, which are planned to begin in the first half of 2022.
The randomized, placebocontrolled PRIME2 trial met primary and all key secondary endpoints with data presented at AAD 2022 showing:
A number of examples from the Digital Living Labs will be demonstrated at the conference, these include:
In total, 21 scientific abstracts evaluating the safety and efficacy of Dupixent in patients with atopic dermatitis in different age groups, as well as investigational indications – prurigo nodularis and chronic spontaneous urticaria – will be presented at the congress.
are helping to meet the increasing demand for healthcare services and provide access within a community-based setting. The additional services announcement also ties in with Laya Health and Wellbeing Clinic in Galway marking its second anniversary, which has seen over 8,000 people use the Clinic’s services since opening (1,000 of which were non-members), with footfall increasing by 58% year-on-year.
• A Remote Heart Failure Monitoring Solution in conjunction with Centric Healthcare and Roche, which could reduce hospitalisation rates and improve clinical review rates.
laya healthcare has announced the opening of a brand-new, fully functioning Diagnostic Imaging Suite, which will provide MRI, X-ray and Dexa scanning services at its Health and Wellbeing Clinic in AvailableGalway.to
• A unique integrated rapid screen, Personal Electronic Health Record and wellness device and app, which proactively identifies risk and provides tools to help people manage their wellness and health. Early detection of disease and early intervention can dramatically improve patient quality of life and longevity. Partners in this living lab include Careplus Pharmacies, Google, Fitbit, Full Health M.
• Nearly three times as many Dupixent patients achieved clear or almost clear skin at week 24: 45% of Dupixent patients compared to 16% of placebo patients (p<0.0001).
• A falls detection systems allows a fall of an elderly person to be detected in real time and a conversation to be initiated with the person within 5 seconds through a smart watch and their GPS coordinates to be dispatched in real-time if necessary for emergency services – deployed in Wexford in association with Wexford County Council, HSE and Tunstall. Proactive Monitoring of a patients’ vital signs allows early intervention for chronic disease exacerbations.
Detailed positive results from the Phase 3 PRIME2 trial evaluating the safety and efficacy of Dupixent® (dupilumab) was presented in a late-breaking session at the American Academy of Dermatology (AAD) 2022 Annual Meeting. The companies previously announced topline results from PRIME2 and a second trial called PRIME investigating the use of Dupixent in adults with uncontrolled prurigo nodularis. In both trials, Dupixent significantly reduced itch and skin lesions compared to placebo.
LATE-BREAKING PHASE 3 DATA ON DUPIXENT® (DUPILUMAB)
• 37% of Dupixent patients experienced a clinically meaningful reduction in itch from baseline compared to 22% of placebo patients (p=0.0216) at week 12, the primary endpoint.
• Nearly three times as many Dupixent patients experienced a clinically meaningful reduction in itch from baseline at week 24: 58% of Dupixent patients compared to 20% of placebo patients (p<0.0001).
LATEST TECHNOLOGIESHEALTH SHOWCASED
The potential use of Dupixent in prurigo nodularis is currently under clinical development, and the safety and efficacy have not been fully evaluated by any regulatory authority.
Professor Martin Curley, Director, Digital Transformation and Open Innovation, HSE explains, “We are building on an ecosystem of over 50 Digital Living Labs located across hospital and community health services. Digital Health Living Labs provide test beds for new digital technologies through high impact projects. In collaboration with our partners, these innovative projects focus on enhanced benefits and services for patients in hospitals and local communities as well as delivering value for money and providing real world evidence of the value of innovation and technology.
• A mobile X-Ray solution (Mobile Medical Devices) which brings the X-Ray machine to a nursing home or an elderly patient’s home after a fall. Transfers to hospital reduced by 88%, improving quality of life and reducing costs.
There are currently three Laya Health and Wellbeing Clinics open across Ireland – Cherrywood, Dublin; Limerick; and Galway. By 2023, laya healthcare plans to have a network of five Clinics offering urgent care, wellbeing, and advanced healthcare services to patients nationwide. Since the first Clinic opened, over 52,000 people – of whom 15% were non laya healthcare members – have been seen across the network of three Clinics.
The Laya Health and Wellbeing Clinics are open 365 days a year from 10am to 10pm providing urgent care services within one hour for adults and children as young as 12 months. Video consultations for minor illnesses are also available.
Dr Jose Miguel Flores, radiographer Virdea Santos, Alliance Medical regional manager David Dooley, staff nurse Paul Grealish, and Site Manager Leanne O’Shea at the launch
Clinical R&D
The Irish Digital Health Leadership Strategy Group (IDHLSG) together with the HSE Digital Transformation team, recently hosted a national conference in Tullamore bringing together key interested parties to discuss current initiatives and opportunities in relation to digital innovation. The conference, supported by key industry, academic and clinical leaders, exhibited a range of examples of digital health solutions, some of which are already demonstrating multiple benefits through their pilot initiatives around the country.
“A key aim of the technologies is to keep people safe and well in their homes for as long as possible, and in parallel use digital technologies to improve patient flow from hospital to a community setting and their home.”
With an easy referral pathway, the new addition to the diagnostic imaging services adds to the Health and Wellbeing Clinic’s existing portfolio of advanced services, which includes urgent care with treatment typically within one hour as well as Heartbeat cardiac screenings for members over the age of 12. It also makes access to healthcare experts for laya members and the general public, much easier and quicker.
The safety results of the trial were generally consistent with the known safety profile of Dupixent in its approved dermatology indications. For the 24-week treatment period, overall rates of adverse events were generally similar between Dupixent and placebo groups (57% Dupixent, 51% placebo). Adverse events that were more commonly (>5%) observed with Dupixent were herpes viral infections (7% Dupixent, 0% placebo). A lower rate of skin infections were observed with Dupixent (5% Dupixent, 9% placebo). Additionally, 3% of Dupixent patients and 30% of placebo patients discontinued prior to week 24.
• A Remote allowMonitoringRespiratorySolutionwhichpatientstoremainin their homes instead of hospitalisation, deployed in Cork University Hospital, Beaumont Hospital, and the Mater Hospital.
A positive trend in overall survival (OS) was also observed (HR=0.69; 95% CI, 0.53 to 0.88; P=0.003), and all other secondary endpoints demonstrated a benefit in favour of darolutamide. Importantly, the incidence of treatment-emergent adverse events (AEs) with greater than or equal to 5 percent frequency or of grade 3–5 was comparable between darolutamide and placebo arms; only fatigue occurred in more than 10 percent of patients (darolutamide plus ADT resulted in 13.2 percent versus 8.3 percent in patients with placebo plus ADT). Quality of life outcomes were similar between the treatment groups.
said Dr Tristan Cooper, Medical Director at Bayer Ireland.
*Refer to 20 mg SmPC. **Refer to 40 mg FamotidineSmPC.Clonmel is available on all reimbursement schemes including the GMS. The GMS codes are Famotidinebelow:Clonmel 20mg Film-coated Tablets x 60; Famotidine44452 Clonmel 40mg Film-coated Tablets x 30; 44453
• Symptomatic treatment of mild reflux oesophagitis*
Dr Thorsten Giesecke, General Manager, Commercial Business, Janssen Sciences Ireland UC, said: “Multiple sclerosis is a debilitating and degenerative disease. At Janssen, we are dedicated to helping people living with MS and ponesimod is testimony to this commitment, with a particular focus on improving the treatment landscape in relapsing MS, where medical unmet needs among the MS community remain.”
Please contact Clonmel Healthcare on 01-6204000 if you require any additional information. PA 126/344/001-2. PA Holder: Clonmel Healthcare Ltd., Clonmel, Co. Tipperary. Date prepared: March 2022. 2022/ADV/FAM/068H.
The report makes a number of includingrecommendations,callingforthe urgent implementation of a statutory home care scheme, which is included in the current Programme for Government, but has not yet been delivered. Such a scheme should include the licensing and regulation of home care providers.
FAMOTIDINE CLONMEL
Within the OPTIMUM study, overall, the number of treatment-emergent adverse events reported was similar between the ponesimod and teriflunomide treated groups, and the majority were mild/ moderate and did not warrant treatment discontinuation.1
Nubeqa® (darolutamide), which is an oral androgen receptor inhibitor (ARi), has been reimbursed by the HSE and is available in Ireland from 1st April under the High-Tech Drug Arrangements. It is indicated for the treatment of adult men with non-metastatic castration resistant prostate cancer (nmCRPC) who are at high risk of developing metastatic disease.
DYSFUNCTIONAL “EIRCODE LOTTERY” IN IRISH HOME CARE SYSTEM
• Treatment of mild to moderate reflux oesophagitis**
Nubeqa has a distinct chemical structure which inhibits the growth of prostate cancer cells while limiting the burden of side effects on patients’ everyday lives.
“We are pleased that Nubeqa® (darolutamide) is now available for patients in Ireland. Darolutamide’s efficacy in preventing the spread of prostate cancer together with its favourable tolerability profile may allow these largely asymptomatic nmCRPC patients to continue their daily living without adding any burden;”
Following the recall of Ranitidine products in Ireland in 2019, Clonmel Healthcare is delighted to announce the re-introduction of Famotidine Clonmel 20mg and 40mg film-coated tablets, available on prescription to the Irish Famotidinemarket.Clonmel is a H2receptor antagonist indicated for the following:
• Zollinger-Ellison-Syndrome
Currently,people.home care in Ireland is not allocated equally across Ireland – with assessment and decision criteria varying not only between regions, but sometimes within them – so that those with comparable needs living in different parts of the country can receive completely different home care, leading to an “Eircode lottery”.
The compound, which is developed jointly by Bayer and Orion Corporation, a globally operating Finnish pharmaceutical company. Bayer is responsible for global commercialisation, with a co-promotion of Bayer and Orion Corporation in certain European markets, including Ireland; France; Germany; Italy; Spain; the UK; Scandinavia and Finland.
PONVORYTM (PONESIMOD), A ONCE DAILY, ORAL THERAPY APPROVED FOR REIMBURSEMENT IN IRELAND Janssen, the Pharmaceutical Companies of Johnson & Johnson, has announced that PONVORYTM (ponesimod) has been granted reimbursement in Ireland for the treatment of adults with relapsing multiple sclerosis (RMS) with active disease defined by clinical or imaging features.4
BAYER’S INREIMBURSED(DAROLUTAMIDE)NUBEQA®ISANDAVAILABLEIRELAND
Reimbursement in Ireland follows EC approval of ponesimod based on data from the Phase 3 OPTIMUM trial, a multicentre, randomised, parallel-group,double-blind,active-controlled superiority study of 1,133 adult patients (aged 18-55 years) in 28 countries.1 The trial was designed to evaluate the efficacy and safety of once daily oral ponesimod (20mg) vs. oncedaily teriflunomide (14mg), an approved first-line oral treatment, in adult patients with RMS.1 The large, Phase 3 study showed superior efficacy of ponesimod 20mg on the primary endpoint, annualised relapse rate (ARR), with a rate reduction of 30.5 percent (p<0.001) compared with teriflunomide.1 Ponesimod also showed statistically significant superiority on one of the secondary endpoints, combined unique active lesions (CUALs).1 Ponesimod significantly reduced the number of new inflammatory lesions on brain MRI by 56 percent (p<0.0001) at week 108 when compared to teriflunomide.1
The most commonly reported adverse events in either the ponesimod 20mg group or the teriflunomide 14mg group were Alanine Aminotransferase (ALT) enzyme elevations (19.5% vs. 9.4%), nasopharyngitis (19.3% vs. 16.8%), headache (11.5% vs. 12.7%), upper respiratory tract infection (10.6% vs. 10.4%) and alopecia (3.2% vs. 12.7%).1 The safety profile of ponesimod is consistent with the known safety profile of other S1P receptor modulators, although a head-tohead comparison, other than with teriflunomide, is not available.
Full prescribing information is available on request or alternatively please go to www.clonmel-health. ie. Medicinal product subject to medical prescription.
82 MAY 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE
Clinical R&D
A report by the newly formed Home Care Providers Alliance, whose members collectively provide more than half of all home care packages and home support in Ireland, has today (24 March) criticised the arbitrary “Eircode lottery” home care assessment currently in place in Ireland.
• Benign gastric ulcer
The marketing authorisation in the European Union, granted by the European Commission, was based on results from the pivotal Phase III ARAMIS trial in patients with non-metastatic castrationresistant prostate cancer (nmCRPC). The results of the trial showed a statistically significant improvement in metastasis-free survival (MFS) with darolutamide plus androgen deprivation therapy (ADT) compared to placebo plus ADT (HR=0.41, 95% CI 0.34-0.50; P<0.001). This translates to a 59 percent reduction in the risk of metastasis or death. The median MFS was 40.4 months in the darolutamide arm compared with 18.4 months for the placebo arm –an overall improvement in median MFS of 22 months.
The Alliance is calling for a number of measures to help address the ongoing recruitment and retention crisis within the sector. This includes Government reviews of the social welfare system to incentivise part-time workers to take on additional hours, the inclusion of home carers as a critical skill for the purposes of non-EEA permits and strengthened “earn as you learn” programmes.
Further prescribing information can be found at medicines.ie/medicines/ponvory-https://www. 2-mg-3-mg-4-mg-5-mg-6-mg-7mg-8-mg-9-mg-10-mg-20-mgfilm-coated-tablets-35163/spc
• Duodenal ulcer
The report, “The Future of Home Care”, outlines the dysfunction in the current home care system, including the inconsistent ways in which care needs are delivered across Ireland, the lack of centralised independent standards and regulation, and State policies that hamper employment and recruitment efforts within the sector. These issues have contributed to a home care waiting list of more than 5,000
• Prevention of recurrent duodenal ulcers*
This medicine is indicated for treatment of: Gastrointestinal stromal tumour (GIST) Sunitinib Accord is indicated for the treatment of unresectable and/or metastatic malignant gastrointestinal stromal tumour (GIST) in adults after failure of imatinib treatment due to resistance or intolerance.
Former Director General of the HSE, Tony O’Brien, who chaired the meetings of the Home Care Providers Alliance, said, “The Home Care Providers Alliance has come together to identify issues of concern to the entire sector and propose solutions to help end the dysfunction at the heart of the system.
83 HOSPITALPROFESSIONALNEWS.IE | HPN • MAY 2022
Metastatic renal cell carcinoma (MRCC) Sunitinib Accord is indicated for the treatment of advanced/metastatic renal cell carcinoma (MRCC) in adults.
Accord Healthcare is delighted to announce the launch of another High-Tech medicine to their already extensive portfolio of High-Tech medicines: Sunitinib 12.5 mg, 25 mg & 50 mg which comes in packs of 28 hard capsules.
Think High Techs, Think Accord
At the launch of the “Future of Home Care” Report by the Home Care Providers Alliance, are: Catherine Cox, Head of Communications and Policy, F.C.I.; Noel O’Meara, Chair of N.C.C.N.; Tony O’Brien, Chair of Home Care Providers Alliance meetings; and Collette Gleeson, Board Member, H.C.C.I.
who need home care, and their families, will continue to face the same challenges many years into the future.
The current model of home care provision also prioritises price over quality of care in assessing providers, according to the Home Care Providers Alliance, and this needs to change to prioritise the provision of high-quality care that recipients want and deserve.
overdue. The introduction of a model that promotes quality care and addresses staffing issues is essential to ensure the care needs of the future are met.
“The promised implementation of a Statutory Home Support Scheme, which includes the regulation of providers is long
“Addressing the recruitment and retention challenges in the sector is crucial to the long-term provision of health care. Without a sustainable workforce, those
Pancreatic neuroendocrine tumours (pNET) Sunitinib Accord is indicated for the treatment of unresectable or metastatic, well-differentiated pancreatic neuroendocrine tumours (pNET) with disease progression in adults.
ACCORD HEALTHCARE LAUNCH SUNITINIB
Please refer to the Summary of Product Characteristics (SPC) for further information. The SPC will be available from the launch date at www.hpra. ie and for Healthcare Professionals at Sunitinibwww.accord-healthcare.ie.Accordwillbeavailable from both full line wholesalers from launch. For further information please contact Accord in Cork on 021 461 9040 or visit www.accord-healthcare.ie
“The time to act is now.”
The Home Care Providers Alliance has been formed by organisations, representative bodies, and companies from across the voluntary, community and private care sectors to identify issues of mutual concern to the sector. The membership of the Home Care Alliance includes Family Carers Ireland (FCI), Home and Community Care Ireland (HCCI) and the National Community Care Network (NCCN).
The Home Care Providers Alliance also believes insufficient focus is placed on the quality of care delivered, and that home care provision needs to go beyond providing the bare minimum service. Rather than assistance with just the most basic of care needs, those in receipt of home care should be able to avail of services that also meet nutritional, exercise, mental health and social needs.
PREGNANCY AND LACTATION: Women of Childbearing potential: An effective method of contraception during treatment and for at least 21 weeks after treatment should be used. Pregnancy: Limited data available. It is preferable to avoid the use of Skyrizi during pregnancy as a precautionary measure. Lactation: It is not known whether Skyrizi is excreted in breast milk. Human IgGs are known to be excreted in breast milk during the first few days after birth, which decreases to low concentrations soon afterwards; consequently, a risk to the breast-fed infant cannot be excluded during this short period. A decision should be made whether to discontinue/abstain from Skyrizi therapy, taking into account the benefit of breastfeeding to the child and the benefit of Skyrizi therapy to the woman. Fertility: The effect of Skyrizi on human fertility has not been evaluated. ADVERSE REACTIONS: See SmPC for full details on adverse reactions. Very common adverse reactions (≥1/10): Upper respiratory infections. Common adverse reactions (≥1/100 to <1/10): Tinea infections, headache, pruritus, fatigue and injection site reactions.
Sustaining high skin clearance or complete skin clearance is associated with incremental and durable benefits in HRQoL and mental health of psoriasis patients.2
▼ This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions via HPRA Pharmacovigilance; Website: www.hpra.ie. Suspected adverse events should also be reported to AbbVie Limited on 01-4287900.
Skyrizi® Summary of Product Characteristics, available on www.medicines.ie. Date of preparation: April 2022 | IE-RISN-220005
High skin clearance matters to patients: Patients who achieve and maintain high levels of skin clearance (PASI 90-99 or PASI 100) have significantly better HRQoL than those with lower levels of skin clearance (PASI 75-89).2
When it comes to your patient’s psoriasis treatment goals
* Nothing on the skin: Defined as 75% achievement of PASI90 at Week 16 and ≥50% achievement of PASI 100 at Week 52 in UltIMMa-1 and UltIMMa-2.1
75
LEGAL CLASSIFICATION: POM (S1A). MARKETING AUTHORISATION NUMBERS/PRESENTATIONS: Skyrizi 75 mg solution for injection in pre-filled syringe (Pack of 2 pre-filled syringes): EU/1/19/1361/001; Skyrizi 150 mg solution for injection in pre-filled pen: EU/1/19/1361/002; Skyrizi 150 mg solution for injection in prefilled syringe: EU/1/19/1361/003. Not all presentations may be marketed. Further information is available from: AbbVie Ltd., 14 Riverwalk, Citywest Business Campus, Dublin 24, D24XN32. DATE OF REVISION: November 2021 PI/1361/004
HRQoL, Health-Related Quality of Life; PASI, Psoriasis Area Severity Index.
REFERENCES: 1. Gordon KB, et al. Lancet 2018; 392: 650-661. 2. Ryan C et al. Poster presented at the 27th European Academy of Dermatology & Venerology (EADV) Congress 2018; September 12–16; Paris, France.
What means everything to the patient? The potential for nothing left on their skin.1,2
PRESCRIBING INFORMATION (PI). SKYRIZI®▼ (risankizumab) mg solution for injection in prefilled syringe; Skyrizi 150 mg solution for injection in pre-filled pen and Skyrizi 150 mg solution for injection in prefilled syringe. Refer to Summary of Product Characteristics (SmPC) for full information before prescribing. PRESENTATION: Skyrizi 150 mg solution for injection in pre-filled pen/syringe: each prefilled pen/syringe contains 150 mg risankizumab in 1 mL solution. Skyrizi 75 mg solution for injection in pre-filled syringe: each pre-filled syringe contains 75 mg risankizumab in 0.83 ml mL solution. INDICATION: Plaque Psoriasis: For treatment of moderate to severe plaque psoriasis in adults who are candidates for systemic therapy. Psoriatic Arthritis: alone or in combination with methotrexate (MTX), is indicated for the treatment of active psoriatic arthritis in adults who have had an inadequate response or who have been intolerant to one or more disease-modifying antirheumatic drugs (DMARDs). DOSAGE AND ADMINISTRATION: Intended for use under guidance and supervision of a physician experienced in diagnosis and treatment of psoriasis. Dosage: The recommended dose of Skyrizi is 150 mg by subcutaneous injection at weeks 0, 4, and every 12 weeks thereafter (either as two 75 mg pre-filled syringe injections or one 150 mg pre-filled pen or pre-filled syringe injection). Two 75mg pre-filled syringes should be injected for the full 150 mg dose. Consider discontinuation of treatment in patients showing no response after 16 weeks of treatment. Some patients with initial partial response may subsequently improve with continued treatment beyond 16 weeks. Special Populations: Elderly: No dose adjustment required. Renal or hepatic impairment: No dose adjustment required. Paediatric Population: No data available. Overweight patients: No dose adjustment required. CONTRAINDICATIONS: Hypersensitivity to any of the active substances or excipients. Clinically important active infections (e.g. active tuberculosis). SPECIAL WARNINGS AND PRECAUTIONS: See SmPC for full details. In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded. Skyrizi may increase the risk of infections. In patients with a chronic infection or history of recurrent infections, or known risk factors for infection, Skyrizi should be used with caution. Treatment with Skyrizi should not be initiated in patients with any clinically important active infection until the infection resolves or is adequately treated. Patients should be evaluated for tuberculosis infection prior to initiating treatment. Anti-TB therapy should be considered prior to initiating Skyrizi in patients with a past history of latent or active TB in whom an adequate course of treatment cannot be confirmed. Completion of all appropriate immunisations should be considered prior to initiating therapy. If a patient has received live vaccination (viral or bacterial), it is recommended to wait at least 4 weeks prior to starting treatment with Skyrizi. Patients treated with Skyrizi should not receive live vaccines during treatment and for at least 21 weeks after treatment. If a serious hypersensivity reaction occurs, administration of Skyrizi should be discontinued immediately and appropriate therapy initiated. Excipients with known effect (75
mg solution for injection only): Skyrizi contains 68.0 mg sorbitol and less than 1 mmol sodium (23 mg) per 150 mg dose. INTERACTIONS: The safety and efficacy of Skyrizi in combination with immunosuppressants, including biologics or phototherapy have not been evaluated.
