HPN 2022 March

HOSPITAL PROFESSIONAL NEWS IRELAND

HPN March 2022 Issue 94 HOSPITALPROFESSIONALNEWS.IE

Ireland’s Dedicated Hospital Professional Publication

IN THIS ISSUE: ▼

NEWS: Startling New Figures on Stroke Page 7 MEDICINES: Modernisation of Medicines Management Systems Page 12

VENCLYTXO® REGIMENS ARE NOW AVAILABLE FOR THE TREATMENT OF ALL ADULT PATIENTS WITH CLL1 INDICATIONS1: VENCLYXTO® in combination with obinutuzumab is indicated for the treatment of adult patients with previously untreated chronic lymphocytic leukaemia (CLL) (see section 5.1).* VENCLYXTO® in combination with rituximab is indicated for the treatment of adult patients with CLL who have received at least one prior therapy*. VENCLYXTO® monotherapy is indicated for the treatment of CLL in the presence of 17p deletion or TP53 mutation in adult patients who are unsuitable for or have failed a B cell receptor pathway inhibitor or in the absence of 17p deletion or TP53 mutation in adult patients who have failed both chemoimmunotherapy and a B cell receptor pathway inhibitor.* VENCLYXTO® in combination with a hypomethylating agent is indicated for the treatment of adult patients with newly diagnosed acute myeloid leukaemia (AML) who are ineligible for intensive chemotherapy.† Full Summary of Product Characteristics is available at www.medicines.ie. ▼ 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 CATEGORY: POM (S1A). MARKETING AUTHORISATION NUMBERS/PRESENTATIONS: 10mg film-coated tablet, 14 tablets, EU/1/16/1138/002; 50mg film-coated tablet, 7 tablets, EU/1/16/1138/004; 100mg film-coated tablet, 7 tablets, EU/1/16/1138/005;100mg film-coated tablet, 14 tablets, EU/1/16/1138/006; 100mg film-coated tablet, 112 tablets, EU/1/16/1138/007. 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. † Indications are not reimbursed. * Indications are reimbursed.

References: 1. VENCLYXTO® Summary of Product Characteristics, available at www.medicines.ie.

IE-VNCCLL-220013 Date of Preparation: February 2022

This Publication is for Healthcare Professionals Only

REPORT: Hospital Pharmacists Ready for Strike Action Page 14 CPD: Management of Hidradenitis Suppurativa Page 31 FEATURE: Novel Agents in HER2-Positive Breast Cancer Page 36 GI FOCUS: Artificial Intelligence in Colonoscopy Page 44 GI FOCUS: Coeliac Disease Page 59

Strength of Balance

Indicated for the treatment of moderate to severe active rheumatoid arthritis in adults who have responded inadequately to, or are intolerant to one or more disease modifying anti-rheumatic drugs.1 May be used as monotherapy or in combination with methotrexate.1 Refer to Summary of Product Characteristics (SmPC) before prescribing, and for full prescribing information.

JYSELECA® filgotinib 100 mg or 200 mg film-coated tablets. Indication: Jyseleca is indicated for the treatment of moderate to severe active rheumatoid arthritis in adult patients who have responded inadequately to, or who are intolerant to one or more disease modifying anti rheumatic drugs (DMARDs). Jyseleca may be used as monotherapy or in combination with methotrexate (MTX). Dosage: Adults: 200 mg once daily. Taken orally with/without food. It is recommended that tablets are swallowed whole. Laboratory Monitoring: Refer to the SmPC for information regarding laboratory monitoring and dose initiation or interruption.

Elderly: A starting dose of 100 mg once daily is recommended for patients aged 75 years and older as clinical experience is limited. Renal impairment: No dose adjustment required in patients with estimated creatinine clearance (CrCl) ≥ 60 mL/min. A dose of 100 mg of filgotinib once daily is recommended for patients with moderate or severe renal impairment (CrCl 15 to < 60 mL/min).

Not recommended in patients with CrCl < 15 mL/min. Hepatic impairment: Mild/moderate hepatic impairment: no dose adjustment required. Severe hepatic impairment: not recommended. Children (< 18years): Safety and efficacy not yet established. Contraindications: Hypersensitivity to the active substance or to any of the excipients. Active tuberculosis (TB) or active serious infections. Pregnancy. Warnings/Precautions: See SmPC for full information. Immunosuppression: Combination use, with immunosuppressants e.g. azathioprine, ciclosporin, tacrolimus, or biologic DMARDs (bDMARDs) or other Janus kinase (JAK) inhibitors is not recommended as a risk of additive

immunosuppression cannot be excluded. Infections: Infections, including serious infections such as pneumonia and opportunistic infections e.g. tuberculosis (TB), oesophageal candidiasis, and cryptococcosis have been reported. Risk benefit should be assessed prior to initiating in patients with risk factors for infections (see SmPC). Patients should be closely monitored for the development of signs and symptoms of infections during and after filgotinib treatment. Treatment should be interrupted if the patient is not responding to antimicrobial therapy, until infection is controlled. There is a higher incidence of serious infections in the elderly aged 75 years and older, caution should be used when treating this population. Tuberculosis: Patients should be screened for TB before initiating filgotinib, and filgotinib should not be administered to patients with active TB. Viral reactivation: Cases of herpes virus reactivation (e.g., herpes zoster), were reported in clinical studies (see SmPC). If a patient develops herpes zoster, filgotinib treatment should be temporarily interrupted until the episode resolves. Screening for viral hepatitis and monitoring for reactivation should be performed. Malignancy: Immunomodulatory medicinal products may increase the risk of malignancies. Malignancies were observed in clinical studies (see SmPC). Fertility: In animal studies, decreased fertility, impaired spermatogenesis, and histopathological effects on male reproductive organs were observed (see SmPC). The potential effect of filgotinib on sperm production and male fertility in humans is currently unknown. Haematological abnormalities: Do not start therapy, or temporarily stop, if Absolute Neutrophil Count (ANC) <1 × 109 cells/L, ALC <0.5 × 109 cells/L or haemoglobin <8 g/dL. Temporarily stop therapy if these values are observed during routine patient

JYSELECA, GALAPAGOS and the JYSELECA and GALAPAGOS logos are registered trademarks of Galapagos NV. © 2022 Galapagos NV. All rights reserved.

JYSELECA – a preferential JAK1 inhibitor for moderate to severe RA1 JYSELECA shows more than 5x greater potency for JAK1 over JAK2/3 and TYK21* Balancing sustained efficacy2-6 with acceptable tolerability1,7

*This is based on biochemical assays, the clinical consequence of this is unknown.

Common adverse events (≥1/100 to <1/10) include: nausea, upper respiratory tract infection, urinary tract infection, dizziness.1

Visit strengthofbalance.co.uk to learn more management. Vaccinations: Use of live vaccines during, or immediately prior to, filgotinib treatment is not recommended. Lipids: Treatment with filgotinib was associated with dose dependent increases in lipid parameters, including total cholesterol, and high-density lipoprotein (HDL) levels, while low density lipoprotein (LDL) levels were slightly increased (see SmPC). Cardiovascular risk: Rheumatoid arthritis patients have an increased risk for cardiovascular disorders. Patients should have risk factors (e.g., hypertension, hyperlipidaemia) managed as part of usual standard of care. Venous thromboembolism: Events of deep venous thrombosis (DVT) and pulmonary embolism (PE) have been reported in patients receiving JAK inhibitors including filgotinib. Caution should be used in patients with risk factors for DVT/PE, such as older age, obesity, a medical history of DVT/PE, or patients undergoing surgery, and prolonged immobilisation. Lactose content: Contains lactose; patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take filgotinib. Pregnancy/ Lactation: Filgotinib is contraindicated in pregnancy. Filgotinib should not be used during breast-feeding. Women of childbearing potential must use effective contraception during and for at least 1 week after cessation of treatment.

Driving/Using machinery: No or negligible influence, however dizziness has been reported. Side effects: See SmPC for full information. Common (≥1/100 to <1/10): nausea, upper respiratory tract infection, urinary tract infection and dizziness. Uncommon (≥1/1000 to <1/100): herpes zoster, pneumonia, neutropenia, hypercholesterolaemia and blood creatine phosphokinase increase.

Serious side effects: See SmPC for full information Legal category: POM Pack:

30 film-coated tablets/bottle Price: UK Basic NHS cost: £863.10; Ireland: POA Marketing authorisation number(s): Jyseleca 100mg film-coated tablets EU/1/20/1480/001 EU/1/20/1480/002 Jyseleca 200mg film-coated tablets EU/1/20/1480/003 EU/1/20/1480/004 Further information: Galapagos UK, Belmont House, 148 Belmont Road, Uxbridge UB8 1QS, United Kingdom 00800 7878 1345 medicalinfo@glpg.com Jyseleca® is a trademark. Date of Preparation: January 2022 IE-RA-FIL-202112-00003 Additional monitoring required Adverse events should be reported.

For Northern Ireland, reporting forms and information can be found at yellowcard.mhra.gov.uk or via the Yellow Card app (download from the Apple App Store or Google Play Store).

Adverse events should also be reported to Galapagos via email to Drug.safety.UK.Ireland@glpg.com or 00800 7878 1345 Adverse events should be reported.

For Ireland, reporting forms and information can be found at www.hpra.ie and can be reported to HPRA on +353 1 6764971.

Adverse events should also be reported to Galapagos via email to Drug.safety.UK.Ireland@glpg.com or 00800 7878 1345

References: 1. JYSELECA SPC. Available at: www.medicines.org.uk / www.medicines.ie. Last accessed: January 2022. 2. Combe B, et al. Ann Rheum Dis 2021;doi:10.1136/annrheumdis-2020-219214.

3. Genovese MC, et al. JAMA 2019;322 (4):315–325. 4. Westhovens R, et al. Ann Rheum Dis 2021;doi:10.1136/annrheumdis-2020-219213. 5. Combe B, et al. Poster presented virtually at ACR, November 3–10, 2021. 6. Buch MH, et al. Poster presented virtually at ACR, November 3–10, 2021. 7. Genovese MC, et al. Poster presented virtually at the European League Against Rheumatism (EULAR) 2020 E-Congress, June 3–6, 2020.

January 2022 IE-RA-JY-202201-00001

BRING

PROTECTION TO LIFE

BY REDUCING THE RISK OF THE COMPOSITE OF DECLINING KIDNEY FUNCTION, ESKD, AND RENAL OR CV DEATH*1 FORXIGA is now approved for adult patients with CKD.2

treatment

GFR

FORXIGA 10 mg Once daily.

No titration required

*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 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.

ABRIDGED PRESCRIBING INFORMATION

FORXIGA (dapagliflozin) 5MG & 10MG FILM-COATED TABLETS. ®

Consult Summary of Product Characteristics (SmPC) before prescribing.

Indications: 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.

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.

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.

Contraindications: Hypersensitivity to dapagliflozin, or excipients.

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 Veeva ID: IE-3514 Date of Prep: February 2022

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.

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.

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.

Ability to Drive and Use Machines: Alert patients on the risk of hypoglycaemia when dapagliflozin is used in combination with a sulphonylurea or insulin.

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).

Legal Category: Product subject to prescription which may be renewed (B).

Marketing Authorisation Number: EU/1/12/795/002; EU/1/12/795/007.

Marketing Authorisation Holder: AstraZeneca AB, SE-151 85 Södertälje, Sweden.

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.

Date of API preparation: 11/2021 Veeva ID: IE-3322

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 References: 1. Heerspink HJL et al. N Engl J Med. 2020;383(15):1436–1446.

2. FORXIGA 10 mg film-coated tablets. Summary of product characteristics. November 2021.

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.

March Issue Issue 94

5

Contents

Foreword

Irish National Audit of Stroke National Report P6

Editor Hospital pharmacist members of Fórsa have voted overwhelmingly in favour of industrial action in a dispute over the Department of Public Expenditure and Reform’s (DPER) refusal to sanction an improved hospital pharmacy service which would deliver cost savings of ¤55m per year.

‘Postcode Lottery’ of waiting lists P8 Modernisation of Medication Management in Irish Hospitals P12

The union has served notice of a one-day strike action, by 500 hospital pharmacists, to the HSE and voluntary hospital representatives. At the time of going to press, the strike action was scheduled to take place on Wednesday 16th February.

Fórsa official Catherine Keogh explains, “DPER has refused to sanction measures that had already been backed by the Department of Health and the HSE. These are measures which would save the taxpayer ¤55m per year, and those savings have been validated by the employer.

7

Hospital Pharmacists agree on Strike Action P14 Contemporary diagnostic and therapeutic approaches to ATTR cardiac amyloidosis P16 ‘Smart’ new way of educating on Diabetes P29

12

Record Funding for Cancer Research in Ireland P78 REGULARS CPD: Hidradenitis Suppurativa P31

Turn to page 14 for the full story.

Feature: HER2-Positive Breast Cancer P36

16

In other news, patients waiting to be assessed by a hospital Consultant face little short of a postcode lottery with dramatic variations in outpatient waiting lists across the country, new analysis has revealed. The Irish Hospital Consultants Association (IHCA) has found wide disparities between outpatient waiting lists at different hospitals, when examined on a population basis, with some hospitals in the South and West having waiting lists 20-times greater than others.

GI Focus: Colonic Polyps P39 GI Focus: Colon Capsule Endoscopy P47 GI Focus: Early Rectal Cancer P56 Clinical R&D: P82 Hospital Professional News is a publication for Hospital Professionals and Professional educational bodies only. Subscription rate for Hospital Professional News ¤60 plus vat per year.

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.

PUBLISHER IPN Communications Ireland Ltd Clifton House, Lower Fitzwilliam Street, Dublin 2 (01) 669 0562 GROUP DIRECTOR Natalie Maginnis n-maginnis@btconnect.com EDITOR Kelly Jo Eastwood DIGITAL MARKETING & EDITORIAL EXECUTIVE Danielle Norton danielle@hospitalprofessionalnews.ie

The career structure implementation is badly needed, say Ireland’s hospital pharmacists – who are working as specialists without the commensurate support and recognition. “The path has been long and challenging,” states the Hospital Pharmacists Association of Ireland. The grades that hospital pharmacists are working to were last reviewed in 1978. They were fit for that time but things have moved on.

29

EDITORIAL editorial@hospitalprofessionalnews.ie ACCOUNTS Rachel Wilson cs.ipn@btconnect.com

Consultants have renewed their call on Government to effectively address the record hospital waiting lists by ending the discrimination introduced in 2012 against Consultants appointed after that date, thereby increasing staffing levels and providing the health service with the ability to deliver timely access to essential care for Ireland’s patients.

MARKETING & ADVERTISING EXECUTIVE Ashling Goodall ashling@hospitalprofessionalnews.ie

Our Special Focus for this issue falls under the remit of Gastroenterology and associated conditions. We have some excellent clinical content submitted by renowned experts in this field. On page 39 Dr Telal Khair and Dr Brian Christopher give an overview of colonic polyps while on page64 Theresa Lowry-Lenehan talks about Crohn’s Disease from presentation to management. We also carry some news on this subject on page 69.

CONTRIBUTORS

I hope you enjoy the issue.

BUSINESS ACCOUNT MANAGER/CPD LEAD Sibongile Mude - swan@ipn.ie

Diana Hogan-Murphy | Professor Emer Joyce Dr Carlos N. Perez-Garcia | Kate Rafferty Theresa Lowry-Lenehan | Dr Telal Khair Professor Anne Marie Tobin | E Gibbons Maeve A. Hennessy | Catherine M Kelly Dr Brian Christopher | Ismail Mohd Syafiq B Hall | Aisling Bracken | Tsu Jung Yang Professor Gerard Clarke | Ashley Costello Lisanne J.H.Smits | Elaine Neary Dr Julie Martin-Grace | Dr Carla Moran Lorraine Dolan | Dr Kevin McCarroll

DESIGN DIRECTOR Ian Stoddart Design HOSPITALPROFESSIONALNEWS.IE

@HospitalProNews HospitalProfessionalNews

HOSPITAL PROFESSIONAL NEWS IRELAND Ireland’s Dedicated Hospital Professional Publication

HOSPITALPROFESSIONALNEWS.IE | HPN • MARCH 2022

6

News

Prioritise Access to Biosimilars The European Commission needs to prioritise equitable access to biosimilar medicines in Europe.

That is the recent message from Medicines for Europe.

Isabell Remus, Chair of the Biosimilar Medicines Sector group of Medicines for Europe, says, “The access gaps will not close by themselves, this requires conscious policy-making that puts biosimilar medicines – and patients — at the centre. This can only happen with strong political leadership to drive the right mix of policies. The European Commission has been a strong ally in the past 15 years and we very much count on its leadership

to keep shaping the right environment for biosimilars over the next 15 years.”

Over 15 years ago, the world’s first biosimilar was launched. This was very much a European success story, with the European Medicines Agency leading the way to bringing more affordable biologics to patients. Biosimilars have had a tremendous impact on: • Patient access: Biosimilars paved the way for millions of patients to access life changing therapies, providing earlier and broader access across oncology, immunology and endocrinology.

• Healthcare system sustainability: Through savings, healthcare systems can focus resources on innovative products to improve the lives of even more people. To date, biosimilar medicines have saved 18 billion Euro in Europe.

• Innovation: Biosimilars bring competition to the market, one of the most powerful triggers for further investment in research and innovation.

However, more needs to be done to achieve equitable access to biologics in Europe.

As stressed in the IQVIA 2021

Impact of Biosimilar Competition report: “Not all European countries have been either willing or able to increase access to biological medicines in the available therapy classes”.

There remains a lot that countries across Europe can do to increase the use of biosimilars and close access gaps, for the full benefits of patients. The Pharmaceutical Strategy for Europe must help unlock the full potential of biosimilar medicines. These calls have been echoed by the European Parliament in the report on the EU pharmaceutical strategy and EU beating cancer plan.

Report on Antimicrobial Resistance The European Centre for Disease Prevention and Control (ECDC) and the World Health Organization (WHO) Europe have released a joint report covering antimicrobial resistance (AMR) surveillance data in 2020. The report provides a pan-European overview showing that each year more than 670 000 infections are due to bacteria resistant to antibiotics and approximately 33 000 people die as a direct consequence.

The report presents a regional and European Union/European Economic Area (EU/EEA) overview, including traffic light maps for priority drug-bug combinations of public health relevance, as well as 42 country and area profiles. This marks an important step in further harmonising the AMR reporting in the European Region. Results presented in the report show clearly that AMR is widespread in the WHO European Region. While assessing the exact magnitude of AMR remains challenging in many settings, the presence of specific AMR patterns across clinical settings covered by the surveillance networks is apparent.

As antimicrobial-resistant bacteria cannot be contained within borders, these results underline the need for concerted action to combat AMR throughout the WHO European Region. Resistance to last-line antibiotics is a major issue. When these antibiotics are no longer effective, there are very limited treatment options that might not work in all situations, sometimes leading to fatal outcomes. Resistance to last-line antibiotics also compromises the effectiveness of life-saving medical interventions such as cancer treatment and organ transplantation. Robust investments in interventions to address AMR are urgently needed and would have a significant positive impact on population health and future healthcare expenditures in the region.

¤22m investment at Connolly Hospital RCSI University of Medicine and Health Sciences has announced an investment of ¤22 million in the development of a new education and research centre at Connolly Hospital in Blanchardstown, Dublin.

The building will provide increased capacity for RCSI’s translational research and will be the location for a new paediatric allergy research centre.

Due for completion in February 2024, the new centre will join the Smurfit Building, Education and Research Centre at Beaumont Hospital as RCSI’s second clinical centre of academic excellence in Ireland. The construction contract for the new facility was signed today by RCSI University of Medicine and Health Sciences and Felix O’Hare & Co. Ltd. Connolly Hospital is an integral part of the RCSI campus and

this future-focused development reflects the university’s commitment to the hospital and the broader RCSI Hospital Group. It will greatly enhance the student experience for the Graduate Entry Medicine students based at Connolly and for other RCSI students while on clinical placement at the hospital.

The building will provide increased capacity for RCSI’s translational research and will be the location for a new paediatric allergy research centre.

Professor P. Ronan O’Connell, RCSI President, said, “The development of this new clinical centre of academic excellence represents a significant investment for RCSI that will further strengthen our academic partnership with Connolly Hospital as well as the wider RCSI Hospital Group. The opening of the new centre will be

MARCH 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE

transformative for our educational programmes, will greatly enhance the RCSI student experience and will enrich the local community.

“We want to play our part in building a health service with the capacity to meet the needs of our growing and aging population and

which provides a fulfilling career for healthcare professionals. This new Centre will help us to reimagine the way we are educating our students so they can respond to changes in the scope of their practice and thrive in professionally and personally rewarding careers,” added Professor O’Connell.

News

7

EAHP’s in-person congress: only weeks away Do you want to learn more about the changing roles of the hospital pharmacy profession? Don’t miss EAHP’s 26th Congress organised as an in-person event in Vienna, Austria from the 23rd to the 25th of March 2022. EAHP’s Scientific Committee, under the lead of Thomas De Rijdt, has prepared an interesting and innovative Congress programme that caters

to the educational needs of the profession and takes into account the latest developments in hospital pharmacy.

Different seminars will be hosted.

They will provide attendees with insights on for example working with limited resources, the role of the hospital pharmacist in disaster management, waste

reduction, gene and cell therapies, compounding for paediatrics and medication safety. Hands-on workshops will focus on teamwork in the hospital, pharmacoeconomics, quality improvement and quality assurance, the prescribing cascade and patient-centred medication reviews. The Student Programme will explore

contemporary ethical challenges in hospital pharmacy practice, while the Pharmacotherapy Session will be looking at advances in heart failure pharmacotherapy. Participants can also join three different keynotes, wander around the exhibition area and listen to the oral presentations of the poster award nominees.

Startling new Figures on Stroke Just 50 per cent or one in two stroke patients arrived at hospital within three hours of the onset of stroke symptoms, and 21 per cent waited more than 12 hours, the latest data shows.

These figures were contained in the Irish National Audit of Stroke (INAS) National Report 2020 which was launched recently by the National Office of Clinical Audit (NOCA).

According to NOCA, “Stroke is a medical emergency which requires urgent treatment. The sooner a person arrives at hospital, is assessed by a doctor and receives a brain scan, the less damage is likely to happen.

This results in better outcomes and less disability.”

The fact that stroke patients are not attending hospital in a timely manner has led NOCA to recommend once again that a national stroke awareness campaign be developed in Ireland.

There are approximately 6,000 strokes admitted to Irish hospitals per year – the 2020 Stroke audit analysed data on 5,153 stroke patients which represented 93 per cent of all stroke cases in 23

hospitals. Of the 5,153 stroke cases analysed by NOCA, 85 per cent were ischaemic strokes, 57 per cent were male and 43 per cent were female.

Professor Joe Harbison, Clinical Lead on the Irish National Audit of Stroke

While stroke is looked upon as a disease of the older person, over a quarter of the cases in 2020 were in people aged under 65 years of age.

The 2020 audit also revealed that just 71 per cent of stroke patients were admitted to a stroke unit and of those, 75 per cent spend their entire hospital stay in the Unit.

The national target is that 90 per cent of stroke patients should be admitted to a stroke Unit.

Speaking at the launch of the audit Ms Joan McCormack, Cardiovascular Programme Audit Manager at NOCA said that accessing stroke unit care was “a really important part” of the provision of stroke care.

“It’s known the patients who receive stroke unit care are more likely to be alive, living at home and independent, looking after themselves one year after their stroke and this is across all age ranges, sex, strokes severity,” she said.

Depression and anxiety are common post stroke however, the 2020 INAS report found that just 5 per cent of the stroke patients analysed in the audit had access to psychological support poststroke which Ms McCormack said, “highlighted the lack of access to psychology in hospitals in Ireland.”

Launching this year’s report, Professor Joe Harbison, Clinical Lead on the Irish National Audit

of Stroke (INAS) said “This years’ report is the largest and most complete we have produced in the last 10 years despite the challenges of compiling it during the COVID-19 pandemic. It shows continued improvement in some areas, especially in getting patients to urgent treatment faster. In other areas, such as admission to stroke units and provision of therapies, substantial room for improvements remain.”

HOSPITALPROFESSIONALNEWS.IE | HPN • MARCH 2022

8

News

‘Postcode Lottery’ of Waiting Lists to an even wider population than those directly in the area: for example in such treatment areas as cancer, cardiology, gynaecology, ophthalmology, orthopaedics, neurology or surgery.

Consultants say that the limitations of the NTPF data means a clear and accurate picture of patients waiting for appointments and treatment at each of Ireland’s hospitals is almost impossible to derive.

A new analysis has revealed that patients that are waiting to be assessed by a hospital Consultant face little short of a postcode lottery with dramatic variations in outpatient waiting lists across the country. (11 February 2022).

The Irish Hospital Consultants Association (IHCA) has found wide disparities between outpatient waiting lists at different hospitals, when examined on a population basis, with some hospitals in the South and West having waiting lists 20-times greater than others.

Nationally, around one in eight people are currently on a hospital outpatient waiting list. However, a new analysis by the IHCA suggests this is a much higher rate in some areas, as Consultants warn that timely access to healthcare

should not be determined by a person’s address.

The warning comes as the latest National Treatment Purchase Fund (NTPF) figures released today confirm there are 893,043 people on some form of hospital waiting list, including 97,954 children. This is an increase of 30,323 in the past year, or around 83 people added to public hospital waiting lists every single day since January 2021.

An analysis of outpatient waiting lists per hospital, reveals some stark geographical disparities. The six constituencies with the largest waiting lists are seen below.

However, the IHCA said that this analysis does not take into account the fact that many of the larger hospitals provide specialty services

While outpatient waiting lists at 625,513 have increased by 2,500 compared to this time last year, the increases are far greater in other lists for planned procedures, pre-admissions and inpatient and outpatient suspensions maintained by the NTPF but not widely publicised. These lists increased by more than 32,000 (25%) since January 2021 and now total 161,246.

Consultants have renewed their call on Government to effectively address the record hospital waiting lists by ending the discrimination introduced in 2012 against Consultants appointed after that date, thereby increasing staffing levels and providing the health service with the ability to deliver timely access to essential care for Ireland’s patients.

Commenting on the NTPF figures, IHCA President Professor Alan Irvine, said, “The analysis of individual hospital waiting lists today paint a very stark picture for many people who now face longer waits just because of their address.

“The fact that the number of people waiting to be assessed by a hospital Consultant at the four hospitals in Cork South-Central is equivalent to more than half the local population is shocking; especially when compared to the overall figure of 13% of the national population who are on an outpatient waiting list.

“A patient’s access to care should not depend on where they live.

The Government needs to address this ‘postcode lottery’ and realise that any waiting list plan which does not simultaneously address the Consultant recruitment and retention crisis is destined to fail. All our patients deserve better.

“These figures should be a wakeup call to Government to urgently address the twin deficits of a shortage of Consultants and a lack of sufficient public hospital capacity to resolve the record waiting lists we continue to experience.

“To attract and recruit the highly trained specialists needed to fill the one in five permanent hospital Consultant posts across the country that are either vacant or filled on a temporary basis, it is essential a new Independent Chair is agreed with the IHCA to facilitate the resumption of Consultant contract discussions.

“Minister for Health Stephen Donnelly must also deliver on the ‘unambiguous commitment’ he made to end the pay inequity issue for all Consultants contracted since 2012. This is crucial if we are to fill the over 700 permanent Consultant posts that are vacant or filled on a temporary basis and bring these waiting lists down.”

Outpatient Waiting Lists Jan 2022

Patients waiting as a % of local population (per 100,000)

Cork University Hospital, Cork University Maternity Hospital, Mercy Hospital, South Infirmary

70,862

58% (57,962)

Limerick City

University Hospital Limerick, St John’s Hospital

47,55

42% (41,928)

Dublin Central

Mater Hospital, Rotunda

44,956

40% (39,517)

Galway West

Galway University Hospitals

56,916

39% (39,276)

Waterford

University Hospital Waterford

43,002

37% (37,015)

Dublin Bay South St Vincent’s University Hospital, Royal Victoria Eye & Ear

41,655

34% (34,376)

Total

304,946

42% (41,676)

Constituency

Hospitals

Cork SouthCentral

MARCH 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE

50mgs once daily

50mgs once daily

Her 10th shopping trip since the day she started BETMIGA1

Prescribing Information: Please read the Summary of Product Characteristics (SPC) before prescribing. Presentation: Prolonged-release tablet, containing mirabegron 25mg/50mg. Indication: Symptomatic treatment of urgency, increased micturition frequency and/or urgency incontinence as may occur in adult patients with overactive bladder (OAB) syndrome. Posology and method of administration: The recommended dose is 50 mg once daily. A lower dose of 25mg is recommended for specific patient populations (renal and hepatic impairment) as well as in specific patient populations in combination with strong CYP3A inhibitors such as itraconazole, ketoconazole, ritonavir and clarithromycin.

Renal impairment: End stage renal disease (GFR < 15 mL/min/1.73 m2 or patients requiring haemodialysis): Not recommended. Severe renal impairment (GFR 15 to 29 mL/min/1.73 m2): Reduce dose to 25 mg. Severe renal impairment and concomitant strong CYP3A inhibitors: Not recommended. Moderate renal impairment (GFR 30 to 59 mL/min/1.73 m2): 50 mg. Moderate renal impairment and concomitant strong CYP3A inhibitors: Reduce dose to 25 mg. Mild renal impairment (GFR 60 to 89 mL/min/1.73 m2): 50 mg. Mild renal impairment and concomitant strong CYP3A inhibitors: Reduce dose to 25 mg. Hepatic impairment: Severe hepatic impairment (Child-Pugh Class C): Not recommended. Moderate hepatic impairment (Child-Pugh B): Reduce dose to 25 mg. Moderate hepatic impairment and concomitant strong CYP3A inhibitors: Not recommended. Mild hepatic impairment (Child-Pugh A): 50 mg. Mild hepatic impairment and concomitant strong CYP3A inhibitors: Reduce dose to 25 mg. The tablet is to be taken once daily, with liquids, swallowed whole and is not to be chewed, divided, or crushed. It may be taken with or without food Contraindications: Hypersensitivity to the active substance or to any of the excipients (see the SPC for a list of excipients). Severe uncontrolled hypertension defined as systolic blood pressure ≥180 mm Hg and/or diastolic blood pressure ≥110 mm Hg. Special warnings and precautions for use: Renal impairment: Betmiga has not been studied in patients with end stage renal disease (GFR < 15 mL/min/1.73 m2 or patients requiring haemodialysis) and, therefore, it is not recommended for use in this patient population. Data are limited in patients with severe renal impairment (GFR 15 to 29 mL/min/1.73 m2); based on a pharmacokinetic study a dose reduction to 25 mg is recommended in this population.

This medicinal product is not recommended for use in patients with severe renal impairment (GFR 15 to 29 mL/min/1.73 m2) concomitantly receiving strong CYP3A inhibitors. Hepatic impairment: Betmiga has not been studied in patients with severe hepatic impairment (Child-Pugh Class C) and, therefore, it is not recommended for use in this patient population. This medicinal product is not recommended for use in patients with moderate hepatic impairment (Child-Pugh B) concomitantly receiving

Date of preparation: June 2019

strong CYP3A inhibitors. Hypertension: Mirabegron can increase blood pressure. Blood pressure should be measured at baseline and periodically during treatment with mirabegron, especially in hypertensive patients. Data are limited in patients with stage 2 hypertension (systolic blood pressure ≥ 160 mm Hg or diastolic blood pressure ≥ 100 mm Hg). Patients with congenital or acquired QT prolongation: Betmiga, at therapeutic doses, has not demonstrated clinically relevant QT prolongation in clinical studies. However, since patients with a known history of QT prolongation or patients who are taking medicinal products known to prolong the QT interval were not included in these studies, the effects of mirabegron in these patients is unknown. Caution should be exercised when administering mirabegron in these patients. Patients with bladder outlet obstruction and patients taking antimuscarinic medicinal products for OAB: Urinary retention in patients with bladder outlet obstruction (BOO) and in patients taking antimuscarinic medicinal products for the treatment of OAB has been reported in postmarketing experience in patients taking mirabegron. A controlled clinical safety study in patients with BOO did not demonstrate increased urinary retention in patients treated with Betmiga; however, Betmiga should be administered with caution to patients with clinically significant BOO. Betmiga should also be administered with caution to patients taking antimuscarinic medicinal products for the treatment of OAB. Interactions: Pharmacokinetic interactions: Mirabegron is a substrate for CYP3A4, CYP2D6, butyrylcholinesterase, uridine diphosphoglucuronosyltransferases (UGT), the efflux transporter P-glycoprotein (P-gp) and the influx organic cation transporters (OCT) OCT1, OCT2, and OCT3. Pharmacokinetic interactions involving the potential for other medicinal products to affect mirabegron exposures: Increases in mirabegron exposure due to drug-drug interactions may be associated with increases in pulse rate. Strong CYP3A inhibitors See Posology and administration above for dose adjustments recommended during concomitant use of strong CYP3A inhibitors in patients with renal or hepatic impairment. Mirabegron exposure (AUC) was increased 1.8-fold in the presence of the strong inhibitor of CYP3A/P-gp ketoconazole. CYP2D6 inhibitors: No dose adjustment is needed for mirabegron when administered with CYP2D6 inhibitors (or in patients who are CYP2D6 poor metabolisers). Inducers: Inducers of CYP3A (such as rifampicin) or P-gp may decrease the plasma concentrations of mirabegron. No dose adjustment of mirabegron is required as this effect is not expected to be clinically relevant.

Pharmacokinetic interactions involving the potential for mirabegron to affect exposures to other medicinal products: Inhibition of CYP2D6: Moderate and time dependent inhibition of CYP2D6 by mirabegron may result in clinically relevant drug interactions. CYP2D6 activity recovers within 15 days after discontinuation of mirabegron. Caution is advised if mirabegron is co-administered with medicinal

products metabolized by CYP2D6 with a narrow therapeutic index such as thioridazine, Type 1C antiarrhythmics (e.g.flecainide, propafenone) and tricyclic antidepressants (e.g., imipramine, desipramine). Caution is also advised if mirabegron is co-administered with CYP2D6 substrates that are individually dose titrated. Inhibition of P-gp: Mirabegron is a weak inhibitor of P-gp. For patients who are initiating a combination of Betmiga and digoxin, the lowest dose for digoxin should be prescribed initially. Serum digoxin concentrations should be monitored and used for titration of the digoxin dose to obtain the desired clinical effect. The potential for inhibition of P-gp by mirabegron should be considered when Betmiga is combined with sensitive P-gp substrates e.g. dabigatran. Fertility, pregnancy and lactation: The effect of mirabegron on human fertility has not been established.

Betmiga is not recommended during pregnancy and in women of child-bearing potential not using contraception. Mirabegron should not be administered during breast feeding. Refer to SPC for full guidance. Driving and use of machines: Betmiga has no or negligible influence on the ability to drive and use machines.

Undesirable effects: Summary of the Safety Profile: the safety of Betmiga was evaluated in 8433 patients with OAB, of which 5648 received at least one dose of mirabegron in the phase 2/3 clinical program, and 622 patients received Betmiga for at least 1 year (365 days). In the three 12-week phase 3 double blind, placebo controlled studies, 88% of the patients completed treatment with this medicinal product, and 4% of the patients discontinued due to adverse events. Most adverse reactions were mild to moderate in severity. The most common adverse reactions reported for patients treated with Betmiga 50 mg during the three 12-week phase 3 double blind, placebo controlled studies are tachycardia and urinary tract infections.

The frequency of tachycardia was 1.2% in patients receiving Betmiga 50 mg.

Tachycardia led to discontinuation in 0.1% patients receiving Betmiga 50 mg. The frequency of urinary tract infections was 2.9% in patients receiving Betmiga 50 mg.

Urinary tract infections led to discontinuation in none of the patients receiving Betmiga 50 mg. Serious adverse reactions included atrial fibrillation (0.2%). Adverse reactions observed during the 1-year (long term) active controlled (muscarinic antagonist) study were similar in type and severity to those observed in the three 12-week phase 3 double blind, placebo controlled studies. The following adverse reactions were observed with mirabegron in the three 12-week phase 3 double blind, placebo controlled studies. The frequency of adverse reactions is defined as follows: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); not known (cannot be established from the available data) Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. The adverse events

References: 1. Freeman R, et al. Current Medical Research and Opinion 2017. https://doi.org/10.1080/03007995.2017.1419170.

are grouped by MedDRA system organ class. Infections and infestations: Common: urinary tract infection Uncommon: vaginal infection, cystitis Psychiatric disorders: Not known: Insomnia*, confusional state* Nervous system disorders: Common: headache* dizziness* Eye disorders: Rare: eyelid oedema Cardiac disorders: Common: tachycardia Uncommon: palpitation, atrial fibrillation Vascular disorders: Very rare: Hypertensive crisis* Gastrointestinal disorders: Common: nausea*, constipation*, diarrhoea* Uncommon: dyspepsia, gastritis Rare: lip oedema Skin and subcutaneous tissue disorders: Uncommon: urticaria, rash, rash macular, rash papular, pruritus Rare: leukocytoclastic vasculitis, purpura, angioedema* Musculoskeletal and connective tissue disorders: Uncommon: joint swelling Renal and urinary disorders: Rare: urinary retention* Reproductive system and breast disorders: Uncommon: vulvovaginal pruritus Investigations Uncommon: blood pressure increased, GGT increased, AST increased, ALT increased (*observed during post-marketing experience). Reporting of suspected adverse reactions: see below. Legal category: POM (S1B) Marketing Authorisation number: EU/1/12/809/003 - 25mg EU/1/12/809/010 - 50mg. Marketing Authorisation holder: Astellas Pharma Europe B.V. Sylviusweg 62, 2333 BE Leiden, The Netherlands. Further information is available from: Astellas Pharma Co., Ltd, 5 Waterside, Citywest Business Campus, Dublin 24. Phone: +3531 467 1555. Summary of Product Characteristics with full prescribing information available upon request. Job number: BET_2019_0002_IE Date of preparation of API: 27 May 2019.

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 Astellas Pharma Co. Ltd Earlsfort Terrace, IRL - Dublin 2 Tel: + 353 1 467 1555 Tel: +353 1 6764971 E-mail: Irishdrugsafety@astellas.com Fax: +353 1 6762517 Website: www.hpra.ie E-mail: medsafety@hpra.ie.

Approval code: BET_2019_0004_IE

10 News

Rare Diseases Ireland Calls for Levelling of Health Playing Vicky McGrath, CEO, Rare Diseases Ireland

took part in the survey via an online questionnaire during the month of October and the first week of November 2021.

Almost six in ten (59%) of the respondents are living with a rare condition, with just over a third (34%) being parents or guardians of people with rare conditions.

More than a third (37%) of people with rare diseases, who responded to a recent survey by Rare Diseases Ireland (RDI), have had to wait more than five years for a diagnosis of their condition. Indeed, many have been investigated for multiple conditions and seen by multiple specialists along the way. Details of the survey are contained in a new report just published by RDI, Rare Reality: Living with a Rare Disease in Ireland – Healthcare Experiences.

For those surveyed who had undertaken genetic testing (64%), the disparity between going public and private was clear with private providers delivering the vast majority (75%) of results within three months, while almost one in five (18%) had to wait more than two years if availing of the public system.

A total of 111 people with rare diseases and family members

The survey comes following almost two years of the nation’s health services dealing with the impact of COVID-19. While this has been clearly necessary to keep people safe, according to RDI, the time has now come to level the playing field across all conditions. Indeed, the Programme for Government made a number of pledges in relation to rare diseases which have yet to see any action, including work on publishing an updated National Rare Diseases Plan, as well as commitments to establish a National Genetics and Genomics Medicine Network, as recommended in the Smith Report, 2015, and to support the medical genetics service in Children’s Health Ireland at Crumlin.

Survey Highlights Among the key takeaways from the survey are: • Diagnosis: while more than nine in 10 (92%) of respondents

had received a diagnosis with a named rare condition, the time to final diagnosis (or time already spent seeking a diagnosis for those that remained undiagnosed at time of survey) is long – 21% had waited two to five years, 14% had waited between five and 10 years and 23% had waited over 10 years.

• Genetic services: more than three in five respondents (64%) had experience of genetic testing for their rare condition, and in a little over three-quarters (77%) genetic testing provided a definitive diagnosis.

• Treatment: of the respondents that received treatment directly related to their rare condition (57%), the vast majority (84%) were provided treatments to relieve symptoms, and just under half (48%) had treatment to slow down or stop deterioration of their rare disease. A small number had a treatment to prevent (5%) or cure (11%) the condition.

Vicky McGrath, CEO, Rare Diseases Ireland, comments, “Patients are waiting too long for a diagnosis and are adding to waiting list numbers as they are referred from consultant to consultant, undergoing a battery of investigations and tests. Delays mean that not only does the person not get the care that they need, but that they may also be provided with unnecessary and potentially harmful treatment.

Care is fragmented with patients or their guardians having to link up services and specialties themselves.

“It is clear that resourcing of genetic services is key to addressing the tortuous diagnostic journey for many.

Strategic development of genetic services must be a priority for leadership at the Department of Health and HSE. Their repeated failure to allocate adequate resources and appoint someone to the role of HSE National Director of National Genetic and Genomic Medicine Network is enormously frustrating.”

New Appointments at PMI assisted by Fiona O'Hara, IQVIA as Vice President. Huge thanks also to Margaret Drysdale, Takeda who has now completed her term as President and will take on the role of Ex Officio.

The Pharmaceutical Managers’ Institute are delighted to formally welcome their new President

and Vice President. Deirdre Kelly, Consilient Health has started her term as President and will be

MARCH 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE

Meanwhile, The PMI will be hosting a breakfast briefing on March 9th, 2022 between 8-9am. In December both the Irish Pharmaceutical Healthcare Association( IPHA) and Medicines for Ireland (MFI) signed Framework Agreements on the supply and pricing of medicines with the State. These agreements set the reimbursement terms and conditions for all new and existing medicines – originator and generic,

biosimilar, and hybrid medicines – for the period 2021 - 2025.

Fully understanding these Frameworks and their key implications will be of vital importance to anyone involved with pricing, reimbursement applications or indeed has a general interest in Market Access.

The PMI will welcome Brenda Dooley and Cillian Copeland from AXIS Consulting who will give a full breakdown of both the IPHA and MFI Frameworks along with the various changes they bring.

This online briefing will be an essential event for anyone involved in the pharmaceutical industry, and is complimentary to active PMI members.

HELP YOUR PATIENTS

THE ITCH & RASH OF MODERATE TO SEVERE ATOPIC DERMATITIS 1 RINVOQ demonstrated in an integrated analysis of the MEASURE UP 1 & 2 monotherapy studies at Week 16: • 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, 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 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

©2022 AbbVie Inc.

All rights reserved.

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 following the final dose of upadacitinib. Female paediatric patients and/or their parents/caregivers should be informed about the need to contact the treating physician once the patient experiences menarche while taking upadacitinib.

Upadacitinib should not be used during breast-feeding. The effect of upadacitinib on human fertility has not been 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

IE-RNQ_AD-220017 | February 2022

12

Medicines

Modernisation of Medication Management Systems in Hospitals in Ireland Electronic medication management systems inclusive of electronic prescribing Emphasis on patient safety, defined as the prevention of errors and adverse effects to patients and advanced pharmacy software and associated with healthcare, is placed on a system of care delivery that prevents errors, learns from errors that do occur,systems and is built on a culture of safety that involves healthcare professionals, robotic have been shown to organisations, and patients. Electronic medicines systems inclusive of electronic prescribing and improve patient safety, workflow andpatient cost advanced pharmacy software and robotic systems have been shown to improve safety, workflow and cost efficiencies, and governance by increasing traceability and enhancing efficiencies, and governance by increasing accountability.

These systems represent not only a technical development, but also a mindset, a method of thinking, an attitude, and a commitment to improve healthcare. Successful reform and traceability and enhancing accountability. delivery is highly dependent on realising the potential of these systems as a change catalyst.

Written by Dr Diana Hogan-Murphy, Medication Safety Pharmacist, University Hospital Galway Medication management in hospitals is complex. It incorporates the entire process of how medicines are selected, procured, delivered, prescribed, administered, and reviewed to achieve informed and desired

patient outcomes. At the forefront of medication management is medication safety, an important and topical issue that has been highlighted by the World Health Organization and various national organisations.

As well as assessing and fostering readiness for system implementation, fundamentals required to modernise processes include sufficient funding; a hospital formulary; skilled staff in adequate numbers; good, safe, usable, reliable, interoperable, readily available, and value for money hardware and software; testing at scale; clinical champions; organisational support; a

Storage

Preparation multidisciplinary implementation team; contingency plans; comprehensive staff training; and ongoing and evaluations.

Prescribing, dispensing dosing, transcribing

Administration

Procurement

Selection

MARCH 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE

Medication management

Monitoring, evaluation, education

leadership

13 of electronic prescribing and advanced pharmacy software and robotic systems have been shown to improve patient safety, workflow and cost efficiencies, and governance by increasing traceability and enhancing accountability. These systems represent not only a technical development, but also a mindset, a method of thinking, an attitude, and a commitment to improve healthcare. Successful reform and delivery is highly dependent on realising the potential of these systems as a change catalyst.

methodologies used to detect or Whilst the use of medicines is technologies which is lower than currently increasing in number measure their occurrence as well countries which spend up to A modernisation of the hospital pharmacist career structure is equallypeer required.

There is a strong and complexity which requires as the huge number that are never three per cent of their healthcare more decision-making capability discovered, acknowledged, or budget on health technologies. desire among the hospital pharmacy community to improve patient safety, quality of service, and and potentially amplifies reported. Recent events including Emphasis on patient safety, the cyberattack medication error risks, medication are COVID-19 service efficiency.

Pharmacists experts inand medicines management defined and integral the successful as the to prevention of errors on the HSE information systems management systems in Irish and adverse effects patients have highlighted the key role hospitals have remained largely underrepresented when compared to wider hospital current disparity intothe level of deployment of these systems and play a pivotal role instrategies. supportingThe acute clinical care pathways. associated with healthcare, that health information plays in paper-based and unchanged is placed on a systemstructures of care the group delivery, management, and over the lastwe feware decades.

Itprofessional the clinical pharmacy provision within hospitals risks implementation.

Without However, a small within thesystem broader hospital context and delivery that prevents errors, planning of health services and the is estimated that three million learns from errors that do occur, need for continuous investment and assurances medication errors that can take theoccur leadinon all aspects of medicines management that pharmacy is and is built on a culture of and strengthening of our security hospitals in Ireland per annum. safety that involves healthcare However, estimating the true infrastructure.

Similar to previousrelated represented at senior levels to ensure medicines management projects are expert led within professionals, organisations, and incidence of medication-related years, in 2021 less than 0.8 per patients. will Electronic medication errors can be problematic due cent of thefor public health budget all hospitals, the large investment required modernising current systems be at risk. to the various definitions and management systems inclusive was spent on eHealth and health

Key drivers of system implementation • •

•

• • • • • • •

Implementation of the Hospital Pharmacy Review/Career Structure agreement Developing, communicating, and maintaining strong management support throughout the organisation and identifying champions, preferably senior prescribers and recognised specialist pharmacists Estimating necessary financial resources such as hardware, software, additional human resources, training, and technical support with an emphasis on patient safety benefits and efficiencies to justify financing Fostering a culture of change by placing value on the system and promoting and supporting implementation highlighting benefits to both system users and patients Adequate, timely, and ongoing on-site training and technical support with protected time for training Reconfiguring roles, responsibilities, and work tasks Assessing and managing unrealistic expectations and concerns pre-implementation with clear goals and anticipated benefits Ensuring system backup as well as considering workflow design as part of the implementation process Developing formal goals, objectives, and key indicators of success Anticipating challenges in the implementation process

Electronic medicines management systems should be viewed by all stakeholders as a positive

As well as assessing and fostering readiness for system implementation, fundamentals required to modernise processes include sufficient funding; a hospital formulary; skilled staff in adequate numbers; good, safe, usable, reliable, interoperable, readily available, and value for money hardware and software; testing at scale; clinical champions; organisational support; a multidisciplinary implementation team; contingency plans; comprehensive staff training; and ongoing evaluations.

A modernisation of the hospital pharmacist career structure is equally required. There is a strong desire among the hospital pharmacy community to improve patient safety, quality of service, and service efficiency. Pharmacists are experts in medication management and integral to the successful deployment of these systems and play a pivotal role in supporting acute clinical care pathways. However, we are a small professional group within the broader hospital context and underrepresented when compared to wider hospital strategies. The current disparity in the level of the clinical pharmacy provision within hospitals risks system implementation. Without structures that can take the lead on all aspects of medication management and assurances that pharmacy is represented at senior levels to ensure medication management related projects are expert led within all hospitals, the large investment required for modernising current systems will be at risk.

Electronic medication management systems should be viewed by all stakeholders as a positive practice shift towards process optimisation and healthcare quality effectiveness. We can learn from others as the late runners into this space to ensure we achieve the best balance of features, safety, usability, and value. The vision is not for duplication of current systems but for innovation which will map future successes of system adoption and improve patient safety and efficiency.

HOSPITALPROFESSIONALNEWS.IE | HPN • MARCH 2022

practice shift towards process optimisation and healthcare quality effectiveness. We can learn from

14 Report

Hospital Pharmacists Back Industrial Action Hospital pharmacist members of Fórsa have voted overwhelmingly in favour of industrial action in a dispute over the Department of Public Expenditure and Reform’s (DPER) refusal to sanction an improved hospital pharmacy service which would deliver cost savings of ¤55m per year.

The union has served notice of a one-day strike action, by 500 hospital pharmacists, to the HSE and voluntary hospital representatives. At the time of going to press, the strike action was scheduled to take place on Wednesday 16th February.

Fórsa official Catherine Keogh explains, “DPER has refused to sanction measures that had already been backed by the Department of Health and the HSE. These are measures which would save the taxpayer ¤55m per year, and those savings have been validated by the employer.

“Our hospital pharmacist members have backed industrial action which reflects the depth of feeling among our members that these blocked measures will radically improve

the service, as well as deliver significant savings.”

Range of Measures The union said a range of measures, including the sanctioned use of ‘biosimilar’ medicines, new senior posts, and a new grading structure for hospital pharmacists have all been developed to improve and modernise hospital pharmacy services, and bring them in line with international best practice.

Ms Keogh added, “Our hospital pharmacist members have backed industrial action by more than 94% on a strong ballot turnout, reflecting the depth of feeling among our members that these measures will radically improve the service, as well as deliver significant savings.”

pay scale for entry-level hospital pharmacists. This would make these posts more competitive in a labour market where entry-level retail pharmacy positions are more attractive due to a starting pay premium of at least 30% above entry-level hospital pharmacy, and often much higher.”

The Issues The length of the negotiations coupled with failed implementation despite clear safety, quality and financial benefits is of great regret to members of the profession who have worked tirelessly and diligently to improve services, expand roles and bring expertise in the use of medicines from the pharmacy to the side of the patient.

A ballot to strike last December was deferred due to the outbreak of the Omicron variant of Covid-19.

Ms Keogh said that the union had, in order to avoid strike action, sought recourse to the Labour Court, but DPER has instructed the HSE not to attend.

The Hospital Pharmacists Association of Ireland (HPAI) has been lobbying on this matter extensively. They say the career structure implementation is badly needed - pharmacists are working as specialists without the commensurate support and recognition. “The path has been long and challenging,” they state.

Ms Keogh said, “Among the measures are a shortening of the

The grades that hospital pharmacists are working to were

MARCH 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE

last reviewed in 1978. They were fit for that time but things have moved on.

The HPAI, on their website give an overview as to developments thus far. “The past work leading to the current negotiations give the best chance of change that we have had in those 40 years. This is why it is vital that if we are serious about laying the foundations for our future we support this initiative,” they have stated.

Hospital Pharmacy Review The Hospital Pharmacy Review (sometimes known as the Career Structure Review) was published in November 2011. The review aimed to create a structure for Hospital Pharmacy to best facilitate a consistent delivery of pharmacy services in line with best practice and recognised international standards. The current structures and grades, Basic, Senior, Chief II and Chief I were implemented in 1978 and in no way reflect the current complexity and specialist knowledge that is required to manage medicines in a modern hospital. In 1986 the HPAI notified Health Service Management of the

15 need to conduct a new review in order to match changes in practice in European countries and further abroad.

The Review itself suffered much delay. In 1990 the PSI launched their “Commission of Inquiry into Pharmacy” which recommended a career structure overhaul. Unfortunately there was no restructuring after this report, however the 1990’s saw Hospital Pharmacists introduce specialisations that had a profoundly positive effect on patient safety and cost effectiveness.

These specialisations included clinical pharmacy and aseptic compounding. In the next decade, specialisations were extended to include medication safety pharmacists and antimicrobial pharmacists. In the last decade, IT developments, cluster pharmacy services and automation projects, although isolated, emerged within hospital pharmacy and pointed to the next generation of creative developments.

A second review of structures within hospital pharmacy was approved by the Department of Health and Children in 2001. In 2005, the Department of Finance agreed to the finalisation of outstanding reviews, such as that of hospital pharmacists, where service improvements

were involved. Further delays were however incurred due to the establishment of the Health Service Executive (HSE) on January 1st 2005 and the commencement of the Pharmacy Act on the 22nd May 2007. In late 2009, Dr. Ambrose McLoughlin was appointed as Chair of the Review of Hospital Pharmacy.

In December 2011 the Hospital Pharmacy Review was signed off by the HSE and the HPAI and the expectation was that the Review would then proceed to implementation. However, despite the repeated efforts of the HPAI negotiation team, not a single aspect of the Review has yet been implemented.

The Composite Report Brian Rattigan, Vice President, describes below the background to the composite report which was finalised in 2017.

‘The Pharmacy Review was completed and agreed in November 2011. New job descriptions for the management and specialist grades were agreed 12 months later.

‘Despite repeated and sincere efforts by IMPACT/HPAI to initiate the implementation phase, the HSE did not engage in a meaningful way.

‘IMPACT issued a directive in May 2014 to all Hospital Pharmacist members of the union (note not limited to HPAI members) ‘Compliance with this directive

by Hospital Pharmacists was effective in leading to a meeting in September 2016 with Liam Woods, Interim Director, Acute Hospital Services, HSE . He approved the mechanism to establish a Steering Group to oversee the implementation of the Pharmacy Review in early 2017.

‘The Steering group also created a Joint HSE/IMPACT Working Group and subsequently four Subgroups. The Acute Hospital Drugs Management Programme were well represented on the management side. The Steering Group agreed the reports (the Composite Report) for the Implementation of the Pharmacy Review in August 2017 .

‘By agreement of both sides, a process was arranged for HPAI/IMPACT to lodge documentation which matched the job descriptions of the 4 new grades with higher salary scales.

This meeting took place on October 11th 2017 at which the management side pledged to: (a) Give by return their response within 3 weeks (b) Give by return their draft initial business plan for DPER to validate the service improvements and cost savings achieved with Implementation of the Pharmacy Review. (c) Invite IMPACT/HPAI to work with them to strengthen the submission to DPER and most likely to also attend at the submission.

‘At this meeting on October 11th 2017, the management side stated they already had provided financial space in the HSE financial estimates for 2018.

‘HPAI /IMPACT lodged their documentation on October 13th.

The HSE did not honour any of their 3 commitments.

‘Hence in mid 2018 IMPACT (now called FORSA) sought the intervention of the Workplace Relations Commission.’

Under the auspices of the WRC, FORSA reached an agreement with the HSE on an employer/ union agreement in respect of the Hospital Pharmacy Career Structure in acute hospitals.

FORSA balloted Hospital Pharmacist members on this proposal in September 2020.

The membership accepted the agreement and FORSA moved to seek immediate implementation.

After several months with no implementation (coinciding with the announcement of a national emergency due to covid-19) FORSA wrote to the HSE in January 2021 as it became apparent that the employer wished to direct the agreement into the Building Momentum Public sector pay agreement.

The employer replied in April 2021 with a letter confirming that the agreement could be funded outside of the 1% allowed under building momentum Continued WRC meetings between HPAI/FORSA and the employer side made no meaningful progress leading up to November 2021.

At the November 2021 WRC meeting the employer side declared that they were not in a position to fund the agreement outside of the building momentum agreement.

In agreement with the WRC FORSA requested that the employment side enter the Labour Court to seek a binding resolution on the issue, The employer declined to do this in a letter in December 2021 In December 2021 FORSA issued a Directive instructing hospital pharmacist members to cease the provision of financial and other data.

Update: Industrial action scheduled for 16th February will not proceed Planned industrial action by 500 of Fórsa’s hospital pharmacist members, which was due to take place 16th February did not proceed following a referral of the dispute to the Labour Court.

In a memo to members this evening (Thursday), Fórsa’s head of Health and Welfare Éamonn Donnelly said the union received confirmation this afternoon that the parties can proceed to the Labour Court: “The matter will be referred to the Court immediately.

Accordingly, the need to take strike action has been averted and the strike will not proceed on 16th February,” he said.

In a ballot last month Fórsa’s hospital pharmacist members voted overwhelmingly in favour of industrial action in a dispute over the Department of Public Expenditure and Reform’s (DPER) refusal to sanction an improved hospital pharmacy service, which would deliver cost savings of ¤55m per year, a figure which already been validated by the Department of Health and the HSE.

HOSPITALPROFESSIONALNEWS.IE | HPN • MARCH 2022

16 ATTR Amylodosis

Contemporary diagnostic and therapeutic approaches to ATTR cardiac amyloidosis Written by Dr Carlos N. Perez-Garcia, Advanced Heart Failure and Cardiac transplant fellow and Professor Emer Joyce, Heart Function and Transplant Cardiologist - Mater Misericordiae University Hospital, Dublin, Ireland - Clinical Professor, UCD School of Medicine Dr Carlos N. Perez-Garcia, Advanced Heart Failure and Cardiac transplant fellow- Mater Misericordiae University Hospital, Dublin, Ireland Carlos graduated in Medicine (First Class Honours)- La Laguna University, Santa Cruz de Tenerife, Spain (2008-2014) and completed General Cardiology training at Clinico San Carlos University Hospital in Madrid, Spain (2015-2020).

He has Higher Diplomas in Statistics in Health Sciences- Autonomous University of Barcelona, Spain (2018), and in Inherited CardiomyopathiesFrancisco de Vitoria University, Madrid, Spain (2020-2021).

Professor Emer Joyce is a Consultant Cardiologist specializing in Heart Failure, Mechanical Circulatory Support and Cardiac Transplantation at the Mater University Hospital Dublin. She is the National Lead for Advanced Heart Failure and recent Cardiology Chair of the National Amyloidosis Working Group. She is has a PhD on advanced cardiac imaging from Leiden University, Netherlands and is Clinical Professor at University College Dublin and an Associate Editor of the Journal of Cardiac Failure.

Carlos is a current PhD student- Complutense University of Madrid, Spain.

Introduction The term ‘amyloidosis’ describes a group of disorders characterized by abnormal protein folding, leading to the aggregation and accumulation of these misfolded proteins, or ‘amyloid fibrils’ in the tissues of affected organs.

These amyloid fibrils display the pathognomonic property of apple-green birefringence when viewed under cross polarized light after staining with Congo red.1 The deposit of these insoluble proteins into tissues leads to marked interstitial expansion, direct cell toxicity and cell death. In case of heart involvement, amyloidosis is associated with a particularly high morbidity and mortality.2.3 Although there are more than 30 known amyloidogenic proteins, only 9 accumulate in the myocardium, and the two most frequent etiologies of cardiac amyloidosis (CA) are misfolding of either the transthyretin tetramer (ATTR) or immunoglobulin light-chains secreted by clonal plasma cells (AL), which combined account for 95% of cases of CA.4 Although the focus of this article is centered on the diagnostic and therapeutic advances in ATTR-CA, it is critical that a diagnosis of AL amyloidosis is appropriately ruled out in all patients suspected of having cardiac amyloidosis.

ATTR-CA is being increasingly recognized by the general medical and cardiology community due to a combination of greater awareness of the clinical syndrome and associated cardiac imaging findings alongside recent emergence of a validated noninvasive pathway for its diagnosis.

Patients can be classified in two groups: either hereditary (hATTRCA) or wild type (wtATTR-CA), depending on the presence or absence, respectively, of a mutation in the TTR gene.5 More than 120 mutations have been reported in the TTR gene, located on chromosome 18, and, despite the fact that it is an autosomaldominant disorder, its penetrance is incomplete and considerable phenotypic and geographical heterogeneity is characteristic.

Clinical syndromes can vary extensively from a neurologicalpredominant phenotype to a cardiac-predominant phenotype or a spectrum of both.6 The Thr60Ala or ‘T60A’ variant is the dominant variant in Ireland and in the landmark study by Reilly et al. in 1995, was found to affect up to 1% of the population of North Donegal over the age of 45, with an estimated penetrance of 80%. This variant causes both neurologic and cardiac phenotypes, with typical onset of symptoms in the 5th and 6th decades.7

MARCH 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE

The true prevalence of wtATTRCA is likely to be significantly higher than previously described, possibly occurring in 1-3% of those >75 years of age, increasing to 14% of those >85 years.8 Recent studies also estimate that wtATTR accounts for 13% of elderly patients hospitalized with heart failure (HF) with preserved ejection fraction and 16% of patients undergoing transcatheter aortic valve replacement.9,10 It is not yet clear exactly why the normal genetic sequence TTR protein becomes unstable and aggregates, but it is thought likely related to aging.

Current diagnostic strategies for ATTR-CA Traditionally CA has been an underdiagnosed condition, primarily due to lack of recognition compounded by non-specific symptoms and the presence of co-morbidities in this age cohort.

Delayed diagnosis is common, with an average lead-in time from initial symptoms to definitive diagnosis of at least 6 months.11,12 A recent European study revealed that 35% of a wtATTR-CA cohort had been previously misdiagnosed with other cardiovascular diseases commonly recognized in clinical practice, including hypertensive cardiomyopathy (35%), hypertrophic cardiomyopathy

(23.5%), ischaemic heart disease (11.8%), and aortic stenosis (8.8%).13 Recent advances in cardiac imaging, diagnostic strategies, and therapies have enabled earlier recognition and treatment of CA, which is critical due to the fact that CA is progressive and life-threatening if left untreated.

Currently, the diagnosis of CA can be divided in two phases: an initial screening phase and a definitive diagnosis phase1, and it requires a comprehensive approach considering clinical red flags, biomarkers, ECG, multimodality imaging and, in certain cases, may still require invasive tissue biopsy including native heart biopsy.

1. Screening of cardiac amyloidosis. When to suspect it?

From a clinical perspective, CA typically appears associated with several cardiac and extracardiac manifestations which are variable depending on the type of CA and can be useful to suspect the disease. These signs and symptoms are known as red flags and are shown in Figure 1A. At a cardiac level, the presence of HF with an unexplained increased left and right ventricular wall thickness, disproportionally elevated natriuretic peptides, persistently positive troponin in the absence of acute coronary syndrome, low

wtATTR-CM: A DISEASE THAT OFTEN GOES UNDETECTED1 Introducing the wtATTR-CM estimATTR—an online tool that was developed based on an artificial intelligence/machine learning (AI/ML) algorithm to learn how combinations of clinical conditions are associated with this underrecognised disease.2-4 Wild-type transthyretin amyloid cardiomyopathy (wtATTR-CM) is an underrecognised, progressive, infiltrative disease that can often be overlooked as a cause of heart failure.1,3,4 Once diagnosed, untreated patients with wtATTR-CM have a median survival of ~3.5 years.5-7 The wtATTR-CM estimATTR is an easy-to-use educational tool that was built leveraging AI/ML and can estimate the probability of wtATTR-CM in hypothetical heart failure scenarios. The tool allows you to test various combinations of clinical conditions in a hypothetical patient, see what combinations are associated with wtATTR-CM, and help distinguish from heart failure due to other causes.2 This tool is for educational purposes only, and it is not to be used in a clinical setting for the suspicion or diagnosis of wtATTR-CM in individual patients.

www.estimattr.ie

References: 1. Witteles RM, Bokhari S, Damy T, et al. Screening for transthyretin amyloid cardiomyopathy in everyday practice. JACC Heart Fail. 2019;7(8):709-716. 2. Huda A, Heitner S, Calambur V, et al. A machine learning framework for predicting risk of wild-type transthyretin amyloid cardiomyopathy. Poster presented at: XVII International Society of Amyloidosis Symposium; September 14-18, 2020; virtual. 3. 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.

4. 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.

5. Connors LH, Sam F, Skinner M, et al. Heart failure resulting from age-related cardiac amyloid disease associated with wildtype transthyretin: a prospective, observational cohort study. Circulation.

2016;133(3):282-290. 6. 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. 7. Grogan M, Scott CG, Kyle RA, et al. Natural history of wild-type transthyretin cardiac amyloidosis and risk stratification using a novel staging system. J Am Coll Cardiol. 2016;68:1014-1020.

PP-RDP-IRL-0154 October 2021

18 ATTR Amylodosis Figure 1A. Screening phase

QRS voltages or early conduction system disease are also findings that could evoke CA. Other clinical clues to take into consideration are the presence of low-flow, low-gradient aortic stenosis, the need for downtitration or discontinuation of antihypertensive therapies, as well as the intolerance of beta-blockade in newly diagnosed HF.1,9 • 12- lead electrocardiogram (ECG) An abnormal ECG is present in >90% of patients with CA. As mentioned above, discordant low QRS voltages in the limb leads in spite of left ventricle increased wall thickness is suggestive of CA, and its presence portends a worse outcome in CA patients.14 A pseudo infarction pattern, defined as QS waves in any two consecutive leads, is also a typical finding described in CA. Interestingly, these two findings may be present irrespective of increased ventricular wall thickness and both of them are more frequent in AL than in ATTR-CA (only 25% to 40% of patients with ATTR-CA meet low-voltage criteria), hence their absence does not exclude the possibility of CA.15,16 Apart from that, as previously mentioned, the presence of conduction system disease or atrial fibrillation are significantly frequent.

• Echocardiography Echocardiography is an essential tool in the screening of CA, typically revealing increased left and right ventricular wall thickness with a characteristic speckled appearance, valvular thickening, bi-atrial enlargement, reduced mitral annular tissue velocities (<5 cm/s), and not rarely, pericardial effusion.1, 5 In terms of cardiac deformation, the decreased global longitudinal LV strain (absolute value < -15%) is suggestive of CA, and there is a distinctive pattern of apical sparing in which the left ventricular apical region shows more normal strain compared with progressively worse values at the mid and basal regions (‘cherry-on-top’ pattern on the bull's eye plot of global longitudinal strain, Figure 1A).5, 17 This apical sparing pattern was shown to have 93% sensitivity and 82% specificity in the diagnosis of cardiac amyloidosis.18 • Cardiac magnetic resonance Because of its tissue characterization capabilities, cardiac magnetic resonance (CMR) is a versatile imaging technique to assess CA by late gadolinium enhancement (LGE) sequences and extracellular volume (ECV) mapping. In CA, the pattern of LGE is heterogenous. It typically begins as subendocardial and progresses to transmural

MARCH 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE

involvement in the later stages of disease. Furthermore, gadolinium kinetics are usually abnormal, characterized by a suboptimal myocardial nulling.16,19 Several investigations have shown that the presence of LGE on CMR is a robust predictor of outcome, independent of other known cardiac biomarkers.20 The use of pre-and post-gadolinium T1 mapping allows for the quantification of ECV, which is the percentage of myocardium composed of the extracellular space. ECV is markedly elevated in CA, being strongly supportive of the diagnosis when it is ≥0.40%, and correlating with histologic amyloid burden.1, 21 The degree of myocardial edema, measured with the use of T2 imaging, has also been shown to be an independent prognostic marker.22 2. Definitive diagnosis phase.

Diagnostic algorithm.

When CA is suspected on the basis of clinical or imaging findings, a timely, definite diagnosis must be obtained in order to avoid delayed treatments and disease progression. The current algorithm (Figure 1B) requires that all the patients with suspected CA must undergo screening for monoclonal proteins by quantification of serum free light chains together with serum and urine immunofixation, in order to identify the potential need

for further hematological and/ or histological investigation to exclude AL-CA. As illustrated in our algorithm, this should always be the first step following clinical suspicion of CA. If there is no monoclonal protein detected and free-light chain ratio is normal, the second step will be a cardiac scintigraphy with a bone-avid radiotracer (99mTc-PYP, DPD or HMDP), which can confirm the diagnosis of ATTR-CA via a non-invasive diagnosis pathway.1, 17, 23 However, if 1 or more of these initial 3 hematological tests are abnormal, the referral for Hematology investigation and /or cardiac or extracardiac biopsy of involved organs are recommended.1, 23 • Cardiac scintigraphy The ability of myocardial scintigraphy (typically in Ireland using Tc-99m3,3-diphosphono-1,2 propanodicarboxylic acid [DPD)]) to provide a non-invasive diagnostic pathway for ATTR-CA, if certain criteria are met, is one of the principal game changers that has emerged for this condition over recent years. The theoretical basis of why these tracers bind to TTR is still not well understood, but has been attributed to the presence of microcalcifications that are more common in ATTR than AL cardiac tissue. Therefore, it is more specific to ATTR-CA,

19 Figure 1B. Definitive diagnosis phase

although scintigraphy can return a positive result in 7-9% of ALCA cases. Other rare causes of potential false positive results like hydroxychloroquine-induced restrictive cardiomyopathy have been reported.25, 26 Interestingly, quantification of tracer retention in the myocardium reflects the severity of myocardial involvement, and it is assessed by a semiquantitative scheme (Perugini score), which compares cardiac tracer uptake with bone uptake of the rib, grading from 0 (no uptake) to 3 (cardiac uptake exceeds rib).27 When grade ≥2 uptake is present in the absence of a serum or urine monoclonal light chain protein, it has been demonstrated that a reliable diagnosis of ATTRCM can be made non-invasively with 99% of specificity.28 This diagnostic pathway has greatly increased our ability to diagnose ATTR-CA and has consequently improved patient access to potentially life-prolonging ATTR therapies.

• Endomyocardial and other tissue biopsy Endomyocardial biopsy (EMB) remains the gold standard for CA diagnosis and is nearly 100% sensitive and specific if biopsy specimens are collected from multiple sites (≥4 are recommended) and tested for amyloid deposits by Congo red staining.29 Identification of

amyloid must be followed by classification of the amyloid fibril protein, so amyloid subtype is then determined with either laser dissection with mass spectroscopy, immunohistochemistry or immunoelectron microscopy in specialized centres.30 Compared to EMB, other tissue biopsies, such as gastrointestinal or abdominal fat aspirate, have remarkably varying sensitivity (for example, only 15% for fat aspirate in wtATTR-CA patients).5 As shown in our algorithm, it is important to remember that invasive tissue biopsy is always required if AL-CA is suspected; however, in ATTR-CA, invasive biopsy is generally reserved when the initial non-invasive testing is inconclusive.1, 23 In addition, it is important to remember that up to 40% of patients with ATTR-CA can have a monoclonal gammopathy of unknown significance (MGUS) and scintigraphy alone cannot ensure a diagnosis with 100% specificity.

In this setting, endomyocardial biopsy is necessary to have a definitive diagnosis of ATTR-CA.23 • Genetic testing All patients diagnosed with ATTR-CA should undergo genetic testing to screen for a pathogenic gene mutation. In the case of Ireland, Thr60Ala (T60A) is the most prevalent7, and the genetic

testing has implications, not only for the patient, but also for family members, since it facilitates an earlier diagnosis and, in case of hATTR-CA, better outcomes if treated at an earlier stage of the disease. Currently, the ideal method and intervals for organ screening for hATTR carriers remain unknown.

Current and future therapies for ATTR-CA Prompt diagnosis of the CA subtype is critical to guide specific treatment, as therapy is more effective in the earlier stages of the disease. This premise is important in all types of CA, but especially in AL in which, whenever possible, patients must be transferred to specialized centers and specific chemotherapy regimens must be undertaken by multidisciplinary teams, involving oncohematology and cardiology specialists.

Therapies for patients with ATTR-CA can be classified in two groups: those which treat complications and comorbidities (including treatment of heart failure, arrhythmias, conduction disturbances, thromboembolism, concomitant presence of severe aortic stenosis…), and those which are targeted, diseasemodifying therapies. In this section, the focus is on the latter, the emergence of which in recent years represent a watershed in

the management and outcomes of patients with ATTR-CM. In 2018, 3 large clinical trials transformed the landscape of ATTR amyloidosis treatment.31-33 On the basis of these results, the US Food and Drug Administration (FDA) approved tafamidis for the treatment of ATTR-CA (regardless of type) and both patisiran and inotersen for hATTR polyneuropathy. Considering their mechanism of action, ATTR therapies can be divided into three main categories, depending if they 1) stabilize circulating TTR molecules (stabilizers), 2) suppress TTR synthesis (liver transplantation, genetic silencers and gene editing), or 3) promote the disruption and/or extraction of the deposits. Table 1 summarizes the current available therapies for ATTR-CA. Transthyretin stabilizing molecule therapies -Tafamidis is a daily oral medication, which binds the thyroxine-binding sites of TTR with high affinity and selectivity, slowing dissociation of TTR tetramers into monomers, which consequently inhibits aggregation.

Interestingly, Tafamidis was inspired by the discovery of a stabilizing mutation in transthyretin (Thr119Met), which protects Val30Met mutation carriers from developing amyloidosis.34

HOSPITALPROFESSIONALNEWS.IE | HPN • MARCH 2022

20 ATTR Amylodosis

Drug name

Mechanism of action

Indication

Tafamidis

Stabilizer

Cardiomyopathy and/or Neuropathy

Patisiran

Genetic silencer (small interfering RNA)

Neuropathy with or without Cardiomyopathy

Main current therapies for ATTR-CA Route of administration

Dose

Oral

Tafamidis meglumine: 20 or 80 mg OD (if cardiomyop.)

Intravenous

Tafamidis free acid: 61 mg OD 0.3 mg/kg every 3 weeks, up to 30 mg

Potential side effects

Concomitant therapies

Monitoring

Clinical trial

None

None specific, but monitoring liver profile can be advisable, especially 1 month after initiation

ATTR-ACT31

None specific

APOLLO32

Weekly platelet counts.

Every 2 weeks measures of serum creatinine, eGFR urinalysis, and UPCR.

NEURO-TTR33

Mild, such as: ➤ Diarrhea ➤ Abdominal pain ➤ UTI ➤ Vaginal infection

➤ Infusion-related reactions ➤ Vitamin A deficiency

With IV infusion: ➤ Steroids (e.g.,

dexamethasone 10 mg, or equivalent)

➤ Paracetamol (500 mg)

➤ H1 blocker (e.g., diphenhydramine 50 mg)

➤ H2 blocker (e.g., ranitidine 50 mg,)

Inotersen

Genetic silencer (antisense oligonucleotide)

Neuropathy with or without Cardiomyopathy

Subcutaneous

284 mg once weekly

Diflunisal

Stabilizer

Neuropathy and/or Cardiomyopathy

Oral

250 mg BD

(off-label)

➤ Thrombocytopenia ➤ Glomerulonephritis, ➤ Infusion site reactions, ➤ Fever ➤ Vitamin A deficiency

Related to NSAID properties: ➤ Bleeding ➤ Fluid retention ➤ Renal dysfunction ➤ Gastric ulceration

➤ Daily vitamin A supplements Daily vitamin A supplements

Proton pump inhibitor

Monitor renal function, platelet count, hemoglobin 1 week after initiation and then every 3-6 months

N/A,

only observational studies including ATTR-CA

Table 1. Main current therapies for ATTR-CA. eGFR: estimated glomerular filtration rate, NSAID: non-steroidal anti-inflammatory drug, UPCR: urinary protein: creatinine ratio, UTI: urinary tract infection

Initially it was approved for the treatment of stage 1 and 2 hATTR polyneuropathy35, and it was not until the results of the phase 3 ATTR-ACT randomized clinical trial that was approved for patients with ATTR-CA, either wild type or hereditary. In this study, tafamidis (n=264) was associated with reductions in all-cause mortality and cardiovascular-related hospitalizations and reduced the decline in functional capacity and quality of life as compared with placebo (n=177). Although improvements in biomarkers were noted starting at 9 months, it was not until after 18 months that a survival benefit was observed.31 Notably, while the benefits were

consistent in those with NYHA I-II symptoms, in those with NYHA class III symptoms, increased rates of hospitalizations were observed in the tafamidis-treated group.30 Based on these data, tafamidis has been approved for all patients with ATTR-CA and is indicated per the recently updated ESC 2021 HF guidelines.36 At the time of writing, the drug has not yet been approved for reimbursement by the HSE, but this is expected to be updated shortly.

-Diflunisal is a generic nonsteroidal anti-inflammatory drug with a stabilizer mechanism. A randomized placebo-controlled trial demonstrated efficacy of diflunisal in reducing the progression of hATTR polyneuropathy37, and a

MARCH 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE

retrospective study in patients with cardiomyopathy demonstrated some evidence of cardiac stabilization.38 Nevertheless, there is no prospective data in ATTRCA and diflunisal is one of those off-label therapies in ATTR-CA, whose use is at the discretion of the treating physician. Due to its nonsteroidal anti-inflammatory properties, gastroprotection and monitoring renal function are recommended.

-Investigational transthyretinstabilizing molecule therapies: an additional oral drug that stabilizes the transthyretin tetramer similar to tafamidis, acoramidis (AG-10), is currently being tested in patients with ATTR-CA in a large, phase 3 clinical trial (ATTRIBUTE-CM).39

Inhibitory oligonucleotide therapies (genetic silencers) -Patisiran is an oligo-nucleotidebased therapeutic agent that originally circulates as a double-stranded RNA molecule, subsequently dissociating into single-stranded molecules in the cytoplasm. These strands functions as a small interfering RNA (siRNA), binding the transthyretin messenger RNA (mRNA) in the cytoplasm to form an RNA-induced silencing complex. This process leads to mRNA cleavage, inhibiting the synthesis of the TTR protein and thereby decreasing levels of both normal and mutant forms.

The effects of patisiran in hATTR neuropathy were studied in the

21 APOLLO trial, where patisirantreated patients had significant improvement in neuropathy scores and gait speed compared to baseline.32 In a subgroup analysis of patients with ATTR-CA, patisiran was associated with benefit over placebo in NT-proBNP, left ventricular wall thickness, and longitudinal strain measures.40 Following these results, patisiran has been approved for patients with hATTR polyneuropathy with or without cardiac involvement, but not for those without polyneuropathy. It is administered intravenously every 3 weeks and patients need to be premedicated with a corticosteroid, paracetamol and antihistamines to reduce the risk of an infusion reaction.

After receiving the drug, patients must be monitored for symptoms which can include flushing, back pain, nausea, abdominal pain, shortness of breath, or headache.

Currently in Ireland, both hospital and home infusions have recently emerged as possible options for approved patients through a managed medicines program. Due to the fact that transthyretin aids in vitamin K transport via a complex with vitamin A, all patients treated should be prescribed vitamin A supplementation to avoid deficiencies and, subsequently, ocular toxicity.17 -Inotersen is an antisense oligonucleotide which binds to the target mRNA in the nucleus, promoting its cleavage.

Administered as a weekly subcutaneous injection, Inotersen is associated with greater stabilization in neuropathy scores in hATTR neuropathy compared to placebo, and in a substudy of patients with ATTR-CA, inotersen demonstrated stabilization of disease as measured by left ventricular wall thickness, left ventricular mass, 6-min walk test, and echocardiographic

global systolic strain.33 In terms of adverse events, a higher risk of glomerulonephritis and thrombocytopenia were observed, and subsequently, a recent trial of inotersen in patients with ATTR-CA is currently on hold because of these findings.41 It is not currently available for reimbursement in Ireland.

Elimination of deposits Other off-label therapies in ATTR-CA include: - Doxycycline and Ursodiol: shown to disaggregate formed amyloid fibrils in in vitro studies.45 A retrospective study of 53 patients with ATTR-CA treated with both drugs showed no significant cardiac disease progression over 22 months46, and larger randomized clinical trials are currently under way to assess the safety and efficacy of this combination in ATTR and ATTRCA.47 - Epigallocatechin 3-gallate, most abundant catechin in green tea, has demonstrated disruption of transthyretin amyloid fibrils in mice models.49 One observational study of 25 patients with wtATTRCA treated with 600 mg of epigallocatechin 3-gallate daily for 1 year showed a decrease in left ventricular mass without change in left ventricular wall thickness

by CMR.50 Future therapeutic perspectives in transthyretin amyloidosis Current therapeutic options for ATTR amyloidosis rely on reducing ongoing amyloid formation through stabilization of the tetrameric form of TTR or through inhibition of TTR protein synthesis by means of degradation of TTR mRNA. Such treatments produce symptom relief and functional improvement and prolong survival, but are limited by the requirement for long-term

administration to maintain TTR knockdown. Furthermore, in the case of patients on stabilizers, disease progression persists.51 In this setting, a promising alternative are the in vivo gene-editing therapies via Cas9 endonuclease (CRISPR-Cas9), to achieve a sustained knockdown of the TTR gene. This is the case of NTLA-2001, a lipid nanoparticle with liver tropism that carries a single guide RNA (sgRNA), whose results in patients with hATTR in a phase 1, open-label, multicenter study are really optimistic. A single intravenous administration of NTLA-2001 led to a mean reduction of 52% and 87% in serum TTR protein concentrations in the groups that received a dose of 0.1 mg/ kg and 0.3 mg/kg, respectively, with no serious adverse events reported.52 These results illustrate how CRISPR-Cas9–based in vivo gene-editing therapies provide a greater TTR knockdown than currently available therapies, and represent a paradigm shift in the management of this disease.

with this disease, chaired by Dr Mark Coyne. The Working Group Report was submitted in 2020 and implementation of its findings are awaited. There is no doubt that the COVID-19 pandemic imparted further stress on patients required to travel to continue to access optimal amyloidosis care.

It is hoped that that engagement of the HSE on this report, and its recommendations, will be forthcoming, particularly in light of the advent of reimbursement of disease-specific therapies as above, which although highly welcomed, nonetheless will highlight the extreme lack of any targeted funding to support the program in Ireland – including but not limited to timely access to required testing, necessary hiring of clinical staff to support clinical coordination (across sites as well as across hospital and home) and audit of newer therapies, as well as facilities for infusions, monitoring, clinical trial provision etc.

The Irish Experience

Cardiac amyloidosis, and specifically, ATTR-CA affects a growing population of patients encountered in our clinical practice. With the advent of contemporary non-invasive imaging techniques, diagnostics in this field have substantially improved, allowing an earlier detection of affected individuals.

This alongside the emergence of effective specific therapies for ATTR-CA is expected to translate into improved outcomes, making possible a promising future for amyloid patients. It is hoped that with dedicated funding and National support and coordination, Ireland can be a future leader in ATTR amyloidosis care and best practice.

As discussed above, Irish ATTR patients, based on the prevalence of the T60A mutation, through both the National and diaspora experience, have played an important role in furthering knowledge and clinical insights into this previously underrecognized and poorly understood disease. The increased recognition and diagnosis of wtATTR-CA in Ireland also parallels international figures. Despite these facts, the current model of care for amyloidosis in Ireland still involves patients travelling to the National Amyloidosis Centre (NAC) in London. A National Working Group for Amyloidosis was established by the HSE in 2019 to create a new model of care in this country for patients

Conclusions

References available on request.

News World Cancer Day: ‘Urgent Action’ Needed On World Cancer Day, the Irish Cancer Society has called for Government to take urgent and immediate action on waiting lists so that timely care is accessible to all who need it.

This year’s World Cancer Day theme of ‘closing the care gap’ could not be more relevant in Ireland, where barriers to accessing cancer care, in the form of waiting lists, have grown considerably over the course of the pandemic.

Rachel Morrogh, Irish Cancer Society Director of Advocacy

says, “These barriers are being experienced by cancer patients right along their care pathway. We need to focus on how to address the current problems while securing the future of cancer care in the form of enhanced services and a full workforce, so that the needs of growing numbers of people with cancer are met.

“This needs to happen if patients are to stand the best chance of surviving cancer and go on to have a good quality of life.

“The speed and scale of innovation that has occurred over the last two years of the pandemic provides great hope that meaningful change can happen. Advances at both community and hospital levels, along with the spirit of collaboration, determination and leadership, enabled cancer services to keep running during the pandemic. However, keeping services running is not the same as making progress at the pace that is needed to transform cancer survival rates.

“Unless an expanded cancer system is properly protected and prioritised, and a full cancer workforce is recruited and retained, progress in cancer survival will slow. It is patients who will feel the full effects of this - physically, mentally and in their long-term quality of life. We cannot let this happen and, this is why the Irish Cancer Society is calling for political commitment and resourcing from Government to tackle waiting lists, while accelerating the implementation of the National Cancer Strategy.”

HOSPITALPROFESSIONALNEWS.IE | HPN • MARCH 2022

Now reimbursed in Republic of Ireland.

Onpattro® (patisiran) Abbreviated Prescribing Information - 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). 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 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 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

ONPATTRO®

(patisiran) is indicated for the treatment of hATTR amyloidosis in adult patients with stage 1 or stage 2 polyneuropathy1

ONPATTRO®: Your opportunity to reset treatment expectations in hereditary ATTR amyloidosis with polyneuropathy

Regardless of the mutation or predominant symptomatology, all patients with hereditary ATTR amyloidosis develop mixed symptoms2 ONPATTRO® has demonstrated benefits vs placebo across the multi-system manifestations typically seen in patients with hereditary ATTR amyloidosis with stage 1 or 2 polyneuropathy1,3,4

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 woman. Undesirable effects: The most frequently occurring adverse reactions reported in Onpattro-treated 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: 09/2021. Version Final: TTR02-IRL-00016.

References 1. ONPATTRO®. Summary of Product Characteristics, November 2020. 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 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

For Healthcare Professionals only.

ONPATTRO® is a trademark of Alnylam Pharmaceuticals, Inc. © 2021 Alnylam Pharmaceuticals, Inc. All rights reserved.

October 2021 | TTR02-IRL-00028

24 Diabetes

Diabetes Footcare and Complications New diabetes footcare statistics data published, obtained by Roisin Shortall TD, shows that 608 people with diabetes underwent a lower limb amputation in 2020, accounting for 69% of the total procedures carried out in the year. There was a further 2,536 people with diabetes hospitalised requiring foot ulceration treatment spending on average 14 days in hospital for treatment in 2020.

Despite limited access to diabetes review appointments during the past 2 years, it seems from this data that diabetes related amputations and diabetes foot ulceration in patient numbers remain high year on year.

Diabetes Ireland is encouraging adults of all ages who have diabetes to ensure they have a full and proper foot assessment by a podiatrist or other appropriate healthcare professional. People with diabetes have special reason to take good care of their feet.

Long term high blood glucose levels may make feet susceptible

Foot Ulcers

to injury and infection. This is because the protective sensation in the toes or feet, the “pain alarm system” may slowly disappear due to long term exposure to high blood glucose levels.

The latest data provides a county-by-county breakdown of both diabetes related lower limb amputations and diabetes foot ulceration in patient numbers over the period 2016-2020.

FOOT ULCERS

Cases with foot ulcers without amputation with diabetes: Total 2016

2017

2018

2019

2020

2,309

2,081

2,738

2,830

2,536

Increase by 361

Decrease by 228

Increase by 657

Increase by 92

Decrease by 294

Foot Ulcers by County

must check they have continuing early thus preventing more serious With such high numbers, Diabetes problems from occurring. It sensation in their feet and be alert Ireland is asking people with recommends should to signs as prickly pain in Cases that withpeople foot ulcer, no amputation withsuch diabetes by county diabetes to be proactive by examine their feet daily and be on the feet, numbness and peculiar Diabetes Footcare booking a foot assessment which Statistics theCounty lookout2016-2020 for small changes 2018 sensations2019 such as a feeling 2016 cuts, 2017 2020 of will identify any problems and in skin colour and temperature, walking on cotton or of wearing 43 37 also 36 38 allow treatment to be undertaken red Carlow areas and swelling.

They tight socks.36This is important Amputations as without a pain alarm system, Cavan 65 45 43 94 35 AMPUTATIONS injuries and poor fitting shoes may go unnoticed.

60 Total 61 64 75 78 Cases with lower limb amputationClare with diabetes: Diabetes Ireland now has over Cork 2019 181 183 249 255attending their 256 2016 2017 2018 2020 5,000 clients preventative footcare services Donegal629 32 48Dublin & Cork.

57 56 519 547 640 60842 in These services were set up to provide people with Dublin 573 425 671 507 access to a664 high-quality and unique Increase by 61 Increase by 28 Increase by 93 Decrease by 11 Decrease by 21 podiatry appointment service.

100 Years of Insulin

Galway

113

115

109

101

112

Amputations by County Kerry

21

32

67

64

58

Kildare

108

93

94

98

67

Kilkenny

35

42

45

66

43

Cases of lower limb amputation with diabetes by county

On January 23 1922, 14-year-old Leonard Thompson received the first successful insulin injection, which resulted in a drop in his blood glucose levels without any side effects. This day now marks a celebration of this major scientific breakthrough and the millions of lives that have been saved ever since.

One hundred years later, as well as ever more performing insulins, many new medicines and technologies have been developed, making a hugely positive impact on the lives of people living with diabetes (PwD).

We also know a lot more about the complexity of this disease, which, according to the World Health Organization (WHO), actually covers 14 distinct types, of which the most common are Type 1 and Type 2 Diabetes.

2016 2017their and people’s ability to manage Countyoptimally are influenced diabetes by a multitude of often interlinked Carlow 12 11 factors. In addition to nonmodifiable genetic factors, these Cavan 8 5 include modifiable risk factors such as a person’s socio, economic and Clare 23 21as environmental circumstances well as external elements such as Cork 42 the structural organisation of 48 care and the use of data, innovative Donegal 10 tools, technologies15and approaches by national health systems and Dublin people living with122 diabetes. 146 32 determinants 37 The Galway socio-economic of health themselves include Kerry factors that today17 represent 16 some of the most pressing challenges Kildare 18 as food 37 in our societies, such insecurity, working life conditions, access to education, Kilkenny 11 income,9 housing, and social inclusion.

Extensive research and studies have demonstrated how both the risk of developing Type 2 diabetes and diabetes-related complications

MARCH 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE

2018 It is evident2019 that these 2020 Laois 62 determinants generate huge59 inequalities which have a negative 14 Leitrim 8 818 impact on PwD’s16lives. In Europe, such inequalities exist between 5 6 10 and within countries and regions and represent an obstacle to the 21 17 fulfilment of 17 PwD’s fundamental right to the highest attainable 48 48 54 by the standard of health as stated WHO Constitution.

8

21

15

In this context, new technologies, 204 and innovative 195 186 tools approaches have the potential to revolutionise 34 26 24 diabetes prevention, care and management and improve both 22 quality of17life and the health 12 the outcomes of PwD. 35

38

26

The inherent complexity of 13 14 diabetes prevention and 9 management means, however, that the deployment of these new innovations and technologies must make inclusivity a priority and address the systemic issues of access that might affect their adoption. Alongside the increased use of novel tools and approaches, a holistic approach to diabetes prevention, care and management must also be implemented, taking into the account the need for improved integration of care; the provision of adequate support for PwD including focusing on mental health and emotional well-being;

and the deployment of effective 58 51 39 training, education and other support mechanisms for improved 27 24 18 self-management, including for example peer support and patient empowerment programmes.

On this day, the International Diabetes Federation Europe called on policy-makers and other stakeholders to come together to make diabetes a priority and improve the lives of PwD through: • The promotion of a person-centred, and outcomes-based approach • Further digitalisation of health services, and the provision of innovative tools and technologies • The adoption of an integrated care system, including strengthening primary care • The reduction of inequalities and improved access to the required diabetes medicines, supplies, technologies and care • Greater PwD empowerment and engagement in their care, and • Increased focus on prevention, health promotion and early action

COMBINING POWER AND CONFIDENCE AGAINST LDL-C* IN THE TREATMENT OF

HYPERCHOLESTEROLAEMIA

Rosuvastatin + Ezetimibe

Rosuvastatin + Ezetimibe

20 mg/10 mg

10 mg/10 mg

Rosuvastatin + Ezetimibe

40 mg/10 mg

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 Prescribing Information: Suvezen (rosuvastatin/ ezetimibe) film-coated tablets Please refer to the Summary of Product 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.

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

Single-pill combination of rosuvastatin and ezetimibe available in 3 doses**

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.

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 rosuvastatin (as rosuvastatin calcium) respectively, and 10mg ezetimibe.

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

MAT-IE-2101261 (v1.0) – August 2021

26 Diabetes

Higher Risks of Diabetes for Children? glucose metabolism caused by infection, or through precipitation of prediabetes to diabetes.

“Alternatively, Covid-19 might have indirectly increased diabetes risk through pandemic-associated increases in body mass index, a risk factor for both serious Covid-19 illness and diabetes.

Future studies addressing the role of comorbidities and increases in body mass index in post– Covid-19 diabetes are warranted.

Although this study can provide information on the risk for diabetes following SARS-CoV-2 infection, additional data are needed to understand underlying pathogenic mechanisms, either those caused

by SARS-CoV-2 infection itself or resulting from treatments, and whether a Covid-19–associated diabetes diagnosis is transient or leads to a chronic condition.

Children who have recovered from Covid-19 appear to be at an increased risk of developing Type 1 or Type 2 diabetes, researchers at the Centers for Disease Control and Prevention (CDC) have said.

A heightened risk of diabetes has already been seen among adults who recovered from Covid-19, according to some studies.

Researchers in Europe have reported an increase in the number of children being diagnosed with Type 1 diabetes since the pandemic started, the New York Times reported.

But the CDC study is among the first to examine large insurance claim databases in the US to estimate the prevalence of new diabetes diagnoses in children aged under 18 who had Covid-19 or were known to be infected with the coronavirus.

The study used two claim databases from the US health plans to look at diabetes diagnoses made in youngsters under 18 over a year or more, starting March 1, 2020, comparing those who had Covid to those who didn't.

The researchers said, “New diabetes diagnoses were 166% (IQVIA) and 31% (HealthVerity) more likely to occur among patients with Covid-19 than among those without Covid-19 during the pandemic and 116% more likely to occur among those with Covid-19 than among those with ARI during the prepandemic period. Non– SARS-CoV-2 respiratory infection was not associated with diabetes.

These findings are consistent with previous research demonstrating an association between SARS-CoV-2 infection and diabetes in adults.

“The inclusion of only patients aged <18 years with a health

MARCH 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE

care encounter possibly related to Covid-19 in the non–Covid-19 HealthVerity group could account for the lower magnitude of increased diabetes risk in this group compared with risk in the IQVIA group. In addition, patients without Covid-19 in HealthVerity had higher hospitalization rates than did those in IQVIA, suggesting more severe disease at the index encounter in the HealthVerity comparison group.

“The observed association between diabetes and Covid-19 might be attributed to the effects of SARS-CoV-2 infection on organ systems involved in diabetes risk. Covid-19 might lead to diabetes through direct attack of pancreatic cells expressing angiotensin converting enzyme 2 receptors, through stress hyperglycemia resulting from the cytokine storm and alterations in

“Among persons aged <18 years with Covid-19 and new diabetes diagnoses in this study, nearly one half had DKA at or around the time of diagnosis. This number was higher than that in comparison groups, and higher than previous reports of DKA among incident type 1 diabetes cases before the pandemic (28%). Increased frequency of DKA at time of diagnosis of type 1 diabetes during the pandemic has previously been reported and was thought to be due to delayed care-seeking for diabetes. However, the observed association of increased risk for diabetes diagnosis following SARS-CoV-2 infection would not be explained solely by delayed care.

“Health care providers should screen for diabetes symptoms in persons aged < 18 years with a history of SARS-CoV-2 infection.

These symptoms can include frequent urination, increased thirst, increased hunger, weight loss, tiredness or fatigue, stomach pain, and nausea or vomiting.”

Toujeo® is available in two pre-filled insulin devices allowing you to choose the most suitable device for your patients

Toujeo® DoubleStar™ holds more units per pen than any other basal insulin pen on the market1-4 Shared features with Toujeo® SoloStar • Pen size • 5-second hold time5,6 • 42-day shelf life after first use1 • Same technical platform *Toujeo® DoubleStar™ is recommended for patients requiring at least 20 units of basal insulin per day1

References: 1. 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.

Prescribing Information: Toujeo® (insulin glargine 300 units/ml) Please refer to Summary of Product Characteristics (SmPC) before prescribing.

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.

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.

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

References: 1. Toujeo® Summary of Product Characteristics.

Date of preparation: August 2020 | MAT-IE-2000823 (v1.0)

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.

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.

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

Think Once-Weekly Ozempic®t for People with Type 2 Diabetes who have Atherosclerotic Cardiovascular Disease1-3 Ozempic® provided a significant 26% risk reduction of MACE# in people with type 2 diabetes* and cardiovascular disease.1,2,§ This includes a 39% relative risk reduction in non-fatal stroke.1,2,‡ Ozempic® also has superior blood glucose and weight-loss efficacy across all head-to-head clinical trials in the SUSTAIN program.1-9,†,‡ * 26% CV risk reduction in patients with type 2 diabetes and high CV risk, compared to placebo, in addition to standard treatment. # Major Adverse Cardiovascular Events † Results apply to Ozempic® across SUSTAIN trials, which included placebo, sitagliptin, dulaglutide, canagliflozin, exenatide PR and glargine U100.1-9 § p=0.02 for superiority ‡ p<0.05

Ozempic® is recommended by the ADA/EASD Consensus Report for people with type 2 diabetes who have established atherosclerotic cardiovascular disease10 PR = Prolonged Release; ADA = American Diabetes Association; EASD = European Association for the Study of Diabetes.

SUSTAIN = Semaglutide Unabated Sustainability in treatment of Type 2 Diabetes. *SUSTAIN was the phase 3 clinical trial programme investigating the effects of once weekly semaglutide versus other anti-diabetic agents.

ABBREVIATED PRESCRIBING INFORMATION Ozempic®t semaglutide Please refer to the Summary of Product Characteristics (SmPC) before prescribing. Ozempic® 0.25 mg solution for injection in pre-filled pen. Ozempic® 0.5 mg solution for injection in pre-filled pen. Ozempic® 1 mg solution for injection in pre-filled pen.

One ml of solution contains 1.34 mg of semaglutide (human glucagon-like peptide-1 (GLP-1) analogue). Indication: Ozempic® is indicated for the treatment of adults with insufficiently controlled type 2 diabetes mellitus as an adjunct to diet and exercise • as monotherapy when metformin is considered inappropriate due to intolerance or contraindications • in addition to other medicinal products for the treatment of diabetes. For study results with respect to combinations, effects on glycaemic control and cardiovascular events, and the populations studied, see sections 4.4, 4.5 and 5.1 of the Ozempic® SmPC. Posology and administration: Administered once weekly at any time of the day, with or without meals.

Injected subcutaneously in the abdomen, thigh or upper arm. Starting dose: 0.25 mg once weekly. After 4 weeks the dose should be increased to 0.5 mg once weekly. After at least 4 weeks with a dose of 0.5 mg once weekly, the dose can be increased to 1 mg once weekly to further improve glycaemic control. When Ozempic® is added to existing metformin and/ or thiazolidinedione therapy or to an SGLT2 inhibitor, the current dose of metformin and/ or thiazolidinedione or SGLT2 inhibitor can be continued unchanged. When Ozempic® is added to a sulfonylurea or insulin, a reduction in dose of sulfonylurea or insulin should be considered to reduce the risk of hypoglycaemia. Blood glucose self-monitoring is necessary to adjust the dose of sulfonylurea and insulin, particularly when Ozempic® is started and insulin is reduced. A stepwise approach to insulin reduction is recommended. Children: No data available. Elderly: No dose adjustment required, therapeutic experience in patients age ≥75 is limited. Renal impairment: No dose adjustment is required for patients with mild, moderate

or severe renal impairment. Experience in patients with severe renal impairment is limited.

Not recommended for use in patients with end-stage renal disease. Hepatic impairment: No dose adjustment is required for patients with hepatic impairment. Experience with severe hepatic impairment is limited. Caution should be exercised when treating these patients with semaglutide. Contraindications: Hypersensitivity to the active substance or to any of the excipients. Special warnings and precautions for use: Should not be used in patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis. Not a substitute for insulin. Diabetic ketoacidosis has been reported in insulin-dependent patients whom had rapid discontinuation or dose reduction of insulin. There is no experience in patients with congestive heart failure NYHA class IV and is therefore not recommended in these patients.

Use of GLP-1 receptor agonists may be associated with gastrointestinal adverse reactions. This should be considered when treating patients with impaired renal function as nausea, vomiting, and diarrhoea may cause dehydration which could cause a deterioration of renal function.

Acute pancreatitis has been observed with the use of GLP-1 receptor agonists. Patients should be informed of the characteristic symptoms of acute pancreatitis. If pancreatitis is suspected, semaglutide should be discontinued; if confirmed, semaglutide should not be restarted.

Caution should be exercised in patients with a history of pancreatitis. Use of semaglutide in combination with a sulfonylurea or insulin may have an increased risk of hypoglycaemia, therefore consider reducing the dose of sulfonylurea or insulin when initiating treatment with Ozempic®. In patients with diabetic retinopathy treated with insulin and semaglutide, an increased risk of developing diabetic retinopathy complications has been observed. Caution should be exercised when using semaglutide in patients with diabetic retinopathy treated with insulin. These patients should be monitored closely and treated according to clinical guidelines.

Rapid improvement in glucose control has been associated with a temporary worsening of diabetic retinopathy, but other mechanisms cannot be excluded. When semaglutide is used

in combination with a sulfonylurea or insulin, patients should be advised to take precautions to avoid hypoglycaemia while driving and using machines. Fertility, pregnancy and lactation: Women of childbearing potential are recommended to use contraception when treated with semaglutide. Should not be used during pregnancy or breast-feeding. Discontinue at least 2 months before a planned pregnancy. Effect on fertility unknown. Undesirable effects: Very common (≥1/10): Hypoglycaemia when used with insulin or sulfonylurea, nausea, diarrhoea. Common (≥1/100 to <1/10): Hypoglycaemia when used with other oral antidiabetic medications, decreased appetite, dizziness, diabetic retinopathy complications, vomiting, abdominal pain, abdominal distension, constipation, dyspepsia, gastritis, gastrooesophageal reflux disease, eructation, flatulence, cholelithiasis, fatigue, increased lipase, increased amylase, weight decreased. Uncommon (≥1/1,000 to <1/100): Hypersensitivity, dysgeusia, increased heart rate, acute pancreatitis, injection site reactions. Rare (≥1/10,000 to <1/1,000): Anaphylactic reaction. Not known (cannot be estimated from available data): Angioedema. The SmPC should be consulted for a full list of side effects. MA numbers: Ozempic® 0.25 mg pre-filled pen EU/1/17/1251/002. Ozempic® 0.5 mg pre-filled pen EU/1/17/1251/003. Ozempic® 1 mg pre-filled pen EU/1/17/1251/005. Each pre-filled pen delivers 4 doses and includes 4 disposable NovoFine® Plus needles. Legal Category: POM. 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. Date last revised: March 2021.

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

t

References: 1. Ozempic® Summary of Product Characteristics www.medicines.ie 2. Marso SP, et al; Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. (SUSTAIN 6) N Engl J Med. 2 2016;375:1834-1844. 3. Marso SP, Bain SC, Consoli A, et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med. 2016;375(suppl1):S1-S108. 4. Lingvay I et al, Once weekly Semaglutide vs Canagliflozin in type 2 diabetes (SUSTAIN 8) : a double blind phase 3 randomised control trial: Lancet Diabetes Endocrinol 2019; 7: 834–44. 5. Ahmann AJ et al. Efficacy and safety of once-weekly semaglutide versus exenatide ER in subjects with type 2 diabetes (SUSTAIN 3): A 56-Week, Open-Label, Randomized Clinical Trial. Diabetes Care 2018;41:258-266. 6. Aroda VR et al. Efficacy and safety of once-weekly semaglutide versus once-daily insulin glargine as add-on to metformin (with or without sulfonylureas) in insulinnaive patients with type 2 diabetes (SUSTAIN 4): a randomised, open-label, parallel-group, multicentre, multinational, phase 3a trial. Lancet Diabetes Endocrinol 2017;5: 355–66. 7. Sorli C et al. Efficacy and safety of once-weekly semaglutide monotherapy versus placebo in patients with type 2 diabetes (SUSTAIN 1): a double-blind, randomised, placebo-controlled, parallel-group, multinational, multicentre phase 3a trial. Lancet Diabetes Endocrinol 2017; 5: 251–60. 8. Ahrén B et al. Efficacy and safety of once-weekly semaglutide versus once-daily sitagliptin as an add-on to metformin, thiazolidinediones, or both, in patients with type 2 diabetes (SUSTAIN 2): a 56-week, double-blind, phase 3a, randomised trial. Lancet Diabetes Endocrinol 2017; 5: 341–54. 9. Pratley RE et al. Semaglutide versus dulaglutide once-weekly in patients with type 2 diabetes (SUSTAIN 7): a randomised, open-label, phase 3b trial. Lancet Diabetes Endocrinol. 2018;6275-286.

10.Buse JB et al. 2019 update to: Management of hyperglycaemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care 2020 Feb; 43(2):487-493.

Ozempic® is indicated for the treatment of adults with insufficiently controlled type 2 diabetes mellitus as an adjunct to diet and exercise • as monotherapy when metformin is considered inappropriate due to intolerance or contraindications • in addition to other medicinal products for the treatment of diabetes. For study results with respect to combinations, effects on glycaemic control and cardiovascular events, and the populations studied, see sections 4.4, 4.5 and 5.1. of the SmPC.1 tThis medicinal product is subject to additional monitoring. This will allow quick identification of new safety information.

Novo Nordisk Limited, First Floor, Block A, The 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 Ozempic® and the Apis bull logo are registered trademarks owned by Novo Nordisk A/S. Date of preparation: October 2021. IE21OZM00098

News 29

‘Smart’ Way to Educate on Diabetes Diabetes Ireland with support from Novo Nordisk has developed a free interactive online education platform available at www.diabeteseducation.ie called Diabetes Smart. This free interactive programme has been updated to meet the increasing demand for support from people with Type 2 diabetes who want to learn more about their condition and how to manage it effectively.

Due to the significant burden placed on GP’s and the health care system over the last two years because of the Covid 19 pandemic, many people with Type 2 diabetes have not had regular review appointments with their GP or their diabetes team. Diabetes Smart is a free online resource that will give those diagnosed with Type 2 diabetes the opportunity to educate themselves about their condition and how to manage it effectively no matter how long they have been living with the condition.

The programme has been developed by diabetes healthcare professionals to support a busy lifestyle and participants can pause their interactive learning at any stage of the journey and resume with ease. It is a great educational tool for GP’s and health professionals to promote to their patients.

According to the 2021 Healthy Ireland survey, diabetes is the third most diagnosed condition

Kieran O’Leary, CEO, Diabetes Ireland, Sinead Powell, Senior Dietitian, Diabetes Ireland and Owen Treacy from Novo Nordisk unveil “Diabetes Smart” a free online education programme for people living with Type 2 diabetes.

With GPs and the health system currently heavily overstretched, this programme will provide health care providers with an educational tool they can refer their Type 2 patients to so they can learn about their condition and how to manage it more effectively

in Ireland, and it is expected that the number of people with Type 2 diabetes will increase by 60% over the next 10-15 years.i Type 2 diabetes has a profound impact on the quality of life of people living with the condition. People with Type 2 diabetes also run a greater risk of developing one or more severe health complications such as cardiovascular disease, kidney disease, blindness, and lower limb amputation, which can greatly impact their independence and quality of life. However, through effective management strategies people living with Type 2 diabetes can significantly improve their health and reduce the risk of developing more severe health issues and potentially even

reverse their condition and protect their future health.

Sinead Powell, Senior Dietitian, Regional Development Officer (Northeast Area), Diabetes Ireland speaking about Diabetes Smart adds, “We in Diabetes Ireland frequently hear how a diagnosis of diabetes can be difficult to accept as people have to learn to adapt to a whole new way of living. The pandemic has meant that some people living with Type 2 diabetes have felt more isolated or have had restricted or reduced access to healthcare professionals.

This free educational resource provides support and advice to people in the comfort of their own homes. It uses real-life stories of

people living with Type 2 diabetes to guide users in managing and taking control of their condition, so they can approach their diagnosis with a sense of purpose and help them formulate their own treatment goals.”

The Diabetes Smart programme contains six interactive modules, covering topics that explains what diabetes is, understanding the key medical information such as blood glucose levels, managing illness, and provides lots of tips on healthy eating and getting active.

The course can be completed whenever and wherever suits can be paused, and continued at any time, and is accessible via a laptop, tablet, or mobile phone.

Rise in Crude Mortality Rates for Respiratory Diagnoses The National Office of Clinical Audit (NOCA) has announced the publication of the sixth report from the National Audit of Hospital Mortality (NAHM).

Analysis of the NAHM data shows that there was a reduction in the number of cases admitted for in-hospital treatment in acute hospitals in 2020 compared with 2019. These reductions were anecdotally found to be due to people’s reluctance to go to a hospital for fear that they would contract coronavirus disease 2019 (COVID-19) while there.

There has been a rise in the crude mortality rate in the respiratory diagnoses included in this report, particularly for pneumonia, despite the decreased number of overall cases, and this rise can be directly attributed to COVID-19.

ratios (SMR) for six medical conditions1: acute myocardial infarction (AMI) / heart attack, heart failure, ischaemic stroke, haemorrhagic stroke, chronic obstructive pulmonary disease (COPD) and pneumonia. NAHM uses data from 44 publicly funded hospitals in Ireland, with 30 hospitals meeting the criteria for inclusion in this report. All hospitals were within expected ranges for the included medical conditions.

The NAHM Annual Report 2020 presents standardised mortality

• There was a slight increase in in-hospital mortality for

This report cannot be used to compare hospitals to one another.

No two hospitals are expected to be the same, as hospitals have very different case mix or patient profiles.

Key Findings:

pneumonia between 2011 and 2020, from 127 deaths per 1,000 admissions in 2011 to 131 deaths per 1,000 admissions in 2020; however, there was a significant increase between 2019 and 2020, from 103 deaths per 1,000 admissions reported in 2019 to the 131 deaths per 1,000 admissions reported in 2020. Analysis of NAHM records shows that in 19.4% of pneumonia cases, the COVID-19 flag was present, indicating that COVID-19 had been laboratory confirmed or clinically diagnosed.

• The COPD crude mortality rate has increased slightly in 2020 (38 in-hospital mortalities per 1,000 admissions recorded) compared with the relatively static rate recorded in 2018 and 2019 (37 in-hospital mortalities per 1,000 admissions recorded

in both years), with a downward trend having been recorded between 2011 and 2018.

• Heart failure in-hospital mortality decreased significantly (22%) between 2011 and 2020, from 81 deaths per 1,000 admissions in 2011 to 63 deaths per 1,000 admissions in 2020.

• There was a significant reduction (42%) in ischaemic stroke in-hospital crude mortality between 2011 and 2020, from 123 deaths per 1,000 admissions in 2011 to 71 deaths per 1,000 admissions in 2020.

• In-hospital crude mortality due to haemorrhagic stroke reduced by 21% between 2011 and 2020, from 355 deaths per 1,000 admissions in 2011 to 280 deaths per 1,000 admissions in 2020.

HOSPITALPROFESSIONALNEWS.IE | HPN • MARCH 2022

OTEZLA® can offer solutions to the challenges in this new environment

OTEZLA® has an established efficacy and safety profile for up to 5 years†1,2

No warnings regarding risk of serious infection2

No contraindications for concurrent use with live vaccination2

A short half-life of 9 hours

Minimise frequency of clinical appointments

Immunomodulatory mode of action2

No laboratory pre-screening, and no drug specific blood monitoring required2

Means that OTEZLA® is rapidly cleared from the body if administration needs to be stopped2

Confidence not compromise in immune response, down-regulation of proinflammatory cytokines and up-regulation of anti-inflammatory cytokines

Make OTEZLA® the positive choice for your psoriasis and psoriatic arthritis patients OTEZLA® (apremilast) 10mg, 20mg and 30mg film coated-tablets Brief Prescribing Information.

Refer to the Summary of Product Characteristics (SPC) before prescribing. Further information is available upon request. Presentation: 10mg, 20mg and 30mg film coated-tablets. Indications: Psoriatic arthritis: OTEZLA, alone or in combination with Disease Modifying Antirheumatic Drugs (DMARDs), is indicated for the treatment of active psoriatic arthritis (PsA) in adult patients who have had an inadequate response or who have been intolerant to a prior DMARD therapy. Psoriasis: OTEZLA is indicated for the treatment of moderate to severe chronic plaque psoriasis in adult patients who failed to respond to or who have a contraindication to, or are intolerant to other systemic therapy including ciclosporine, methotrexate or psoralen and ultraviolet-A light (PUVA). Dosage and administration: Treatment with OTEZLA should be initiated by specialists experienced in the diagnosis and treatment of psoriasis or psoriatic arthritis. The recommended dose of OTEZLA is 30mg twice daily taken orally in the AM and PM, approximately 12 hours apart, with no food restrictions. The film-coated tablets should be swallowed whole. An initial dose titration is required per the following schedule: Day 1: 10mg in the AM; Day 2: 10mg in the AM and 10 mg in the PM; Day 3: 10mg in the AM and 20mg in the PM; Day 4: 20mg in the AM and 20mg in the PM; Day 5: 20mg in the AM and 30mg in the PM; Day 6 and thereafter: 30mg twice daily in the AM and PM. No re-titration is required after initial titration. If patients miss a dose, the next dose should be taken as soon as possible. If it is close to the time for their next dose, the missed dose should not be taken and the next dose should be taken at the regular time. Patients with severe renal impairment: The dose of OTEZLA should be reduced to 30mg once daily in patients with severe renal impairment (creatinine clearance of less than 30mL per minute estimated by the Cockcroft-Gault equation). For initial dose titration in this group, it is recommended that OTEZLA is titrated using only the AM doses and the PM doses be skipped. Paediatric population: The safety and efficacy of OTEZLA in children aged 0 to 17 years have not been established. No data is available. Contraindications: Hypersensitivity to the active substance(s) or to any of the excipients. OTEZLA is contraindicated in pregnancy. Pregnancy should be excluded before treatment can be initiated. Special warnings and precautions: Diarrhoea, nausea and vomiting: Severe diarrhoea, nausea, and vomiting associated with the use of OTEZLA have been reported. Most events occurred within the first few weeks of treatment.

In some cases, patients were hospitalized. Patients 65 years of age or older may be at a higher risk of complications. Discontinuation of treatment may be necessary. Psychiatric disorders: OTEZLA is associated with an increased risk of psychiatric disorders such as insomnia and depression. Instances of suicidal ideation and behaviour, including suicide, have been observed in patients with or without history of depression. The risks and benefits of starting or continuing treatment with OTEZLA should be carefully assessed if patients report previous or existing psychiatric symptoms or if concomitant treatment with other medicinal products likely to cause psychiatric events is intended. Patients and caregivers should be instructed to notify the prescriber of any changes in behaviour or mood and of any suicidal ideation. If patients suffered from new or worsening psychiatric symptoms, or suicidal ideation or suicidal attempt is identified, it is recommended to discontinue treatment with OTEZLA. Severe renal impairment: See dosage and administration section. Underweight patients: OTEZLA may cause weight loss. Patients who are underweight at the start of treatment should have their body weight monitored regularly. In the event of unexplained and clinically significant weight loss, these patients should be evaluated by a medical practitioner and discontinuation of treatment should be considered.

Lactose content: Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicinal product. Interactions: Co-administration of strong cytochrome P450 3A4 (CYP3A4) enzyme inducer, rifampicin, resulted in a reduction of systemic exposure of OTEZLA, which may result in a loss of efficacy of OTEZLA. Therefore, the use of strong CYP3A4 enzyme inducers (e.g. rifampicin, phenobarbital, carbamazepine,

phenytoin and St. John’s Wort) with OTEZLA is not recommended. In clinical studies, OTEZLA has been administered concomitantly with topical therapy (including corticosteroids, coal tar shampoo and salicylic acid scalp preparations) and UVB phototherapy. OTEZLA can be co-administered with a potent CYP3A4 inhibitor such as ketoconazole, as well as with methotrexate in psoriatic arthritis patients and with oral contraceptives. Pregnancy, lactation and fertility: Women of childbearing potential should use an effective method of contraception to prevent pregnancy during treatment. OTEZLA should not be used during breast-feeding. No fertility data is available in humans. Undesirable effects: Psychiatric disorders: In clinical studies and post-marketing experience, uncommon cases of suicidal ideation and behaviour, were reported, while completed suicide was reported post-marketing. The most commonly reported adverse reactions with OTEZLA in these indications are gastrointestinal (GI) disorders including diarrhoea (15.7%) and nausea (13.9%). These GI adverse reactions generally occurred within the first 2 weeks of treatment and usually resolved within 4 weeks. Adverse reactions reported in the psoriatic arthritis and/or psoriasis clinical trial programme and post marketing experience include: very common (≥ 1/10) diarrhoea*, nausea*; common (≥1/100 to <1/10) bronchitis, upper respiratory tract infection, nasopharyngitis*, decreased appetite*, insomnia, depression, migraine*, tension headache*, headache*, cough, vomiting*, dyspepsia, frequent bowel movements, upper abdominal pain*, gastroesophageal reflux disease, back pain*, fatigue; uncommon (≥1/1,000 to <1/100) hypersensitivity, suicidal ideation and behaviour, gastrointestinal haemorrhage, rash, urticaria, weight loss; not known (cannot be estimated from the available data) angioedema. *At least one of these adverse reactions was reported as serious. Please consult the SPC for a full description of undesirable events. Pharmaceutical Precautions: Do not store above 30°C. Legal category: POM. Presentation and Marketing Authorisation Numbers: Initiation pack containing 27 film coated tablets (4 x 10mg, 4 x 20mg, 19 x 30mg) - EU/1/14/981/001; 30mg film coated tablets in a pack size of 56 tablets - EU/1/14/981/002.

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. OTEZLA is a trademark owned or licensed by Amgen Inc., its subsidiaries, or affiliates. Date of preparation: April 2020 (Ref: IE-OTZ-2000019).

Adverse reactions/events should be reported to the Health Products Regulatory Authority (HPRA) using the available methods via www.hpra.ie. Adverse events should also be reported to Amgen Limited on +44 (0)1223 436441. † Otezla met the primary endpoint of the pivotal trials in psoriasis: PASI-75 response vs placebo at 16 weeks. ESTEEM 1: 33.1% (N=562) vs 5.3% (N=282); ESTEEM 2: 28.8% (N=274) vs 5.8% (N=137), P<0.0001. OTEZLA met the primary endpoint of the pivotal trials in Psoriatic Arthritis: ACR 20 response vs placebo at 16 weeks. PALACE 1: 38% (N=168) vs 19% (N=168), P≤0.001. PALACE 2: 32% (N=162) vs 19% (N=159) P≤0.01; PALACE 3: 41% (N=167) vs 18% (N=169) P≤0.001.2 References: 1. Kavanaugh et al. Arthritis Research & Therapy 2019: 21;118. 2. OTEZLA (apremilast).

Summary of Product Characteristics.

© 2020 Amgen Inc. All rights reserved.

Amgen Ireland Ltd., 21 Northwood Court, Santry, Dublin 9 IE-OTZ-0820-00002 | Date of preparation: September 2020

CPD 85: HIDRADENITIS SUPPURATIVA Continuing Professional Development

AUTHOR: Professor Anne Marie Tobin

CPD

Consultant Dermatologist Tallaght University Hospital

60 Second Summary

1. REFLECT - Before reading this module, consider the following: Will this clinical area be relevant to my practice?

knowledge gap - will this article satisfy those needs - or will more reading be required?

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.

4. EVALUATE - Did this article meet my learning needs - and how has my practise changed as a result?Have I identified further learning needs?

Hidradenitis suppurativa (HS), previously known as acne inversa is a chronic inflammatory skin disease that affects approximately 1% of the Irish Population. The condition causes boils, abscesses and scarring in the axillae, groin and inframammary areas of patients.

HS may affect between 1-4% of the population, and a study from Irish dermatology departments indicated a prevalence of 1.4% amongst the patient population attending dermatology clinics.

HS begins as small pustules and boils under the arms and in the groin or buttock area, they may be predated by blackheads which are open comedones, the presence of ‘double comedones’, two blackheads beside each other, is pathognomic of the condition. Because the disease begins in puberty it is often not recognized at its beginning.

The most commonly areas affected are the axillae, inguinal creases, buttocks, natal cleft and under the breasts or abdominal pannus, any site where skin touches off itself or at sites of friction.

Historically HS was thought to be a disease of apocrine glands it is now recognized as a follicular disorder. It is thought that the initial occlusion is caused by hyperkeratinisation of the pilosebaceous unit leading to occlusion of the follicle with swelling leading to rupture of the follicle and discharge of contents into the dermis.

In a similar paradigm to psoriasis, it is now apparent that HS carries a substantial comorbidity burden, these include obesity, metabolic and cardiovascular disease, inflammatory bowel disease, inflammatory joint dIsease and psychological distress.

31

Clinical Associate Professor Trinity College Dublin Clinical Lead in Dermatology Health Service Executive

3. PLAN - If I have identified a

5. WHAT NEXT - At this time you may like to record your learning for future use or assessment. Follow the

4 previous steps, log and record your findings.

Published by HPN. Copies can be downloaded from www.irishpharmacytraining.ie Disclaimer: All material published is copyright, no part of this can be used in any other publication without permission of the publishers and author.

Amgen® has no editorial oversight of the CPD programmes included in these modules.

Management of Hidradenitis Suppurativa Hidradenitis suppurativa (HS), previously known as acne inversa is a chronic inflammatory skin disease that affects approximately 1% of the Irish Population. The condition causes boils, abscesses and scarring in the axillae, groin and inframammary areas of patients. HS is chronic, recurrent and debilitating and tends to be progressive. The disease causes significant pain and distress and has a huge impact on patients’ lives affecting their ability to work and intimate relationships.

groin or buttock area, they may be predated by blackheads which are open comedones, the presence of ‘double comedones’, two blackheads beside each other, is pathognomic of the condition.

Because the disease begins in puberty it is often not recognized at its beginning. Pustules enlarge to become abscesses which are

extremely painful and eventually discharge a mixture of pus and blood which is foul-smelling and the pain gradually resolves. As the disease progresses abscesses join up to form sinus tracts and eventually marked scarring.

Thus patients suffer both pain and the embarrassment of foul-smelling discharge.

Fig 1: Nodule, abscess, sinus tract and double comedone of HS

Epidemiology of Hidradenitis Suppurativa: HS may affect between 114% of the population, and a study from Irish dermatology departments indicated a prevalence of 1.4% amongst the patient population attending dermatology clinics1.

HS is three times more common in women and generally starts around puberty and ameliorates around menopause. One third of patients have a family history of the condition or a family history of pilonidal sinus.

Clinical presentation.

HS begins as small pustules and boils under the arms and in the Fig Fig 1: Nodule, abscess, sinus tract andand double comedone of of HSHS 1: Nodule, abscess, sinus tract double comedone

TheThe most commonly areas affected areare thethe axillae, inguinal creases, buttocks, most commonly areas affected axillae, inguinal creases, buttocks,natal natalcleft cleftand andunder under thethe breasts or abdominal pannus, anyany site where skin touches or abdominal pannus, site where skin touches offitself itselfororatatsites sitesofoffriction. friction. The The Figbreasts 1: Nodule, abscess, sinus tract and double comedone ofoff HS diagnosis of HS is aisclinical oneone and is and the presence of:of: of HS a clinical and is the presence Figdiagnosis 1: Nodule, abscess, sinus tract double comedone of HS The most commonly areas affected are the axillae, inguinal creases, buttocks, natal cleft and un ® 1.Typical Typical Primary lesions - painful deep-seated nodules (blind boils) lesions lesions: Primary lesions - any painful deep-seated (blind boils) lesions The1.most commonly areas affected are the inguinal creases, buttocks, natalofcleft and u the breasts orlesions: abdominal pannus, siteaxillae, where skin nodules touches off itself or Secondary atSecondary sites friction.

- abscesses, sinuses, bridged scars, “tombstone comedones” - abscesses, sinuses, bridged scars, “tombstone comedones” diagnosis HSdraining is draining a clinical one and is site the presence of: touches the breasts orofabdominal pannus, any where skin off itself or at sites of friction.

2.Typical Typical localization: Axillae and groin, genitals Under breasts, buttocksand andperineum perineum 2. localization: Axillae and groin, genitals Under breasts, onon buttocks diagnosis of HS is a clinical one and is the presence of: 1.Chronicity Typical lesions: Primary lesions -recurrent painfullesions deep-seated nodules (blind boils) Secondary lesi recurrences: Chronic lesions more than sixmonths months 3. 3.Chronicity andand recurrences: Chronic recurrent forfor more than six

Continuous Professional Development is supported by Amgen

32

CPD 85: HIDRADENITIS SUPPURATIVA

The most commonly areas affected are the axillae, inguinal creases, buttocks, natal cleft and under the breasts or abdominal pannus, any site where skin touches off itself or at sites of friction. The diagnosis of HS is a clinical one and is the presence of:

2A

When two adjacent follicles rupture a sinus tract/tunnel under the skin (Fig 2A and Fig2B)

1. Typical lesions: Primary lesions - painful deep-seated nodules (blind boils) Secondary lesions - abscesses, draining sinuses, bridged scars, “tombstone comedones” 2. Typical localization: Axillae and groin, genitals Under breasts, on buttocks and perineum 3. Chronicity and recurrences: Chronic recurrent lesions for more than six months

2B

Despite this, diagnosis of HS may be delayed as the chronicity of lesions may not be appreciated and patients may present in different clinical settings, primary care, emergency departments, gynaecology and surgery. It has been estimated that patients may wait eight years for diagnosis, see five different specialities over on average 17 consultations.

This delay in diagnosis leads to irreversible changes of scar, sinus tracts and fistula as the disease progresses, leading to scarring and disability.

Patients with HS may also have other cutaneous disorders such as severe acne and a pilonidal sinus where the spectrum is known as follicular triad, when patients have HS, severe acne, pilonidal sinus and folliculitis de calvens it is known as follicular tetrad.

.

a much more heterogeneous into the dermis (Fig 2A). There Stage 3 (Severe cases): When two adjacent follicles rupture a sinus tract/tunnel under thein skin 2B). signature that involves immune may also be abnormalities the (Fig Widespread involvement of area, with multiple interconnected tracts

skin’s innate immune system as

and abscesses with multiple

associated with HS. Keratinocytes

B cells.

recentshown work hasthe shown altered and abscesses Microbial colonisation plays a role and recent work has formation of biofilms in HS lesions Microbial colonisation plays a copy numbers of β-defensin, Severity of HS is most commonly role and recent work has shown •clinically Widespread spots, pustules aninfection antimicrobial may peptide, was a secondary role and HS skin that is not involved.

Bacterial serve in the graded using the Hurley Staging the formation of biofilms in HS

lesions and HS skin that is not pathogenesis of HS byinterconnected exacerbating localandinflammation viaofapatients series of pathogen associated from the follicles skin holes clinically involved. Bacterial with HS also display differing tunnels (sinus tracts) infection may a secondary bacterial pathogens identified, but serve antibiotic molecular pathways. As yet there are no definitive expression of antimicrobial

Stage 1 (Mild cases): Single or multiple abscesses

• Abscesses can be painful and • Painful bumps, pustules and treatment is a mainstay of HS treatment. develop into deep sinus tracts abscesses in the armpits, groin, under the skin. Areas of skin under the breasts, in between involved may split and produce the buttocks or inner thigh; an unpleasant odour • These bumps generally start as Pathogenesis firm, pea-sized nodules.

Historically HS was thought to be Stage 2 (Moderate cases): a disease recurrent abscesses, sinus Risk Factors for developing HS:of apocrine glands it is now recognized as a follicular tract formation disorder. It is thought that • Recurring spots, pustules and Smoking: the initial occlusion is caused abscesses in multiple areas with by hyperkeratinisation of the scarring and skin tunnelling • pilosebaceous unit leading to Scarring can occur as a result of occlusion of the follicle with long-term or repeat occurrences swelling leading to rupture of the follicle and discharge of contents in a single location

peptides compared to controls.

These follicular contents trigger an immune response leading to redness and inflammation.

Dysregulation of the innate and adaptive immune system has also been demonstrated based on clinical association with other immune-mediated disorders, its response to biologic therapy in the clinical arena, and from molecular research. Anti-TNF therapy is proving effective in HS and increased lesional expression . of IL-17 and IL-23 suggest other i pathways and cells may be involved it is clear that HS has

role in the pathogenesis of HS by exacerbating local inflammation via a series of pathogen associated molecular pathways. As yet there are no definitive bacterial pathogens identified, but antibiotic treatment is a mainstay of HS treatment.

RISK FACTORS FOR DEVELOPING HS: Smoking Smoking has been associated

a 5 to 12 fold increased risk Smoking has been associated with a 5 to 12 fold increased risk of HS Inwith 2011, the specific of HS. In 2011, the specific term “smoker’s boils “for HS lesions term “smoker’s boils “for HS lesions in patients who are smokers . Thisin stemmed from a patients who are smokers . previous randomized, matched-pair control group study showing that the percentage of active cigarette smokers among HS patients was 88.9%, with an odds ratio of 9.4 and the percentage of smokers in the matched-pair control group was 46%.

Continuous Professional Development is supported by Amgen®

33 This stemmed from a previous randomized, matched-pair control group study showing that the percentage of active cigarette smokers among HS patients was 88.9%, with an odds ratio of 9.4 and the percentage of smokers in the matched-pair control group was 46%.

Nicotine causes release of tumour necrosis factor alpha causing inflammation, promotion of follicular occlusion and epidermal hyperplasia and contains polyaromatic carbohydrates, that may activate keratinocytes and cells of the immune system.

Obesity Several studies have confirmed that patients with HS have a higher Body Mass Index (BMI) compared to the general population and this ranges from 12% to 88%, depending on the type of population. In a large retrospective, matched casecontrol study the association between obesity and HS was high with 17.3-fold higher odds of being obese when also afflicted with HS. Overweight individuals tend to have larger and increased

skin folds, leading to subsequent increased mechanical friction and maceration of the overlying skin. In addition, a warm, humid and occlusive environment in these areas favours microbial growth and colonization. In addition obesity is considered to be a state of systemic, low-grade inflammation which contributes to the inflammation in the skin.

Family history Approximately a third of patients have a family history of the disease and early onset HS is associated with a stronger genetic predisposition ( 55% vs 34 %) and more widespread disease. .

This pattern probably represents autosomal dominant inheritance with incomplete penetrance.

No definitive genes have been identified apart from rare mutations in gamma secretase gene mutation which leads to a particularly severe clinical presentation.

Hormonal influences Given that HS is three times more common in women and that some women report premenstrual flare HS can resolve after the menopause, hormonal influences

play a role. This has yet to be fully elucidated and hormonal treatments such as anti-androgens have not proved particularly useful.

High rates of Polycystic Ovarian Syndrome among patients with HS also corroborate the likelihood that hormones play a role in pathogenesis.

Co-morbidity in Hidradenitis suppurativa In a similar paradigm to psoriasis, it is now apparent that HS carries a substantial comorbidity burden, these include obesity, metabolic and cardiovascular disease, inflammatory bowel disease, inflammatory joint dIsease and psychological distress.

Obesity, Metabolic Syndrome and Cardiovascular Disease Unsurprisingly the increased rates of obesity in HS result in increased rates of metabolic syndrome and also the individual components of metabolic syndrome, including dyslipidemia, hypertension and diabetes, this in turn increases cardiovascular risk. One of the first studies to evaluate CVD risk in HS patients using a validated risk assessment tool, the Framingham

Deroofing, LASERs, local excision

Topical clindamycin

Risk Score (FRS) was an Irish study by Hughes et al. In this study patients were mainly in their thirties yet showed an increased cardiovascular risk than controls.

Inflammatory Bowel Disease An association between IBD and HS has been reported as early as in 1991. Of 1,076 patients with HS, 3.3% had IBD, with a prevalence of 2.5% for CD and 0.8% for CD. Using the estimated prevalence of IBD in the general it was indicated that the prevalence of IBD is 4-8 times higher in the included HS cohort than in the general population. HS and CD share several similar clinical and pathogenic features. Both conditions are chronic diseases of epithelia which are inhabited by commensal flora and both have demonstrated a clinical response to anti-TNF α therapy. They share a number of predisposing factors including genetic predisposition and smoking association

Fig 3. Algorithm for the treatment of hidradenitis suppurativa, adapted from European S1 Guidelines

Wide surgical excision

Systemic treatment 1. Clindamycin + rifampicine/ Tetracycline 2. Acitretin

Adjuvent therapy Pain management Treatment of superinfections Weight loss and tobacco abstinence

Continuous Professional Development is supported by Amgen®

Systemic treatment Adalimumab/ infliximab

34

CPD 85: HIDRADENITIS SUPPURATIVA Questions Which of the following statements are true regarding Hidradentis suppurativa: HS is a disease of apocrine glands The disease is more common in women HS is an autoimmune disease HS affects 5% of the population HS may be associated with severe acne Treatment of HS includes the following Steroids Antibiotics De-roofing

Inflammatory Arthritis In a French study the estimated prevalence of spondyloarthropathy was 3.7% which far exceeded that of the populationn, 0.3%.

In a retrospective, case-control study of 1,730 HS patients in Massachusetts General Hospital, it was found that 908 patients had spondyloarthritis compared to only 52 in those who did not have HS (52.5% vs. 3.0% p< 0.0001).

The pathogenesis underlying the development of SpA in HS patients is unclear. The shared features of dysregulated innate immune response and the role of microbial factors have been hypothesized.

Psychological Distress HS patients suffer significant pain and foul-smelling suppuration from abscesses or sinuses in affected areas during flares which leads to disruption of activities of daily living as well as work and embarrassment contributing to high levels of psychological distress. Multiple studies have demonstrated high levels of depression and anxiety in patients with HS. These findings support several other studies in the literature proposing a possible link between chronic inflammation and depression.

Treatment of Hidradenitis suppurativa The publication of the European S1 Guideline for the treatment of hidradenitis suppurativa in 2015 has provided some clarity on how

to manage patients at different Hurley Stage (Fig 3). It clearly suggests a triple-track approach to the management of patients of all stages, i.e. a surgical approach, a medical approach and adjuvant management of pain, suppuration and co-morbidities. The evidence supporting this Guideline was reviewed in an evidence based way and a more complex algorithm generated . This was the first attempt to provide an algorithm for the treatment of patients.

administered as 160mg at week zero, 80mg at week two and 40mg each week thereafter, starting from week four and has received a licence for the treatment of HS. Second-line agents for severe disease include infiximab 5mg/ kg, and ustekinumab. The area of biological treatment is being intensely investigated, largely using biologics licensed for other indications.

Surgical Treatment

The third track of treatment includes treating patients’ symptoms of pain, appropriate wound care and identifying and treating superinfections.

Surgical treatment consists of either lesional treatment: such as de-roofing and carbon dioxide laser ablation, or regional treatment where wide areas of hair-bearing skin are excised and the defect repaired by skin grafting or healing by secondary intention.

Medical treatment Medical treatments consist of topical clindamycin for mild disease, oral tetracyclines for a prolonged period of up to four months. The combination of rifampicin and clindamycin, both 300mg twice daily for a 10- week period, has proved highly efficacious, though patients must be warned about the risk of developing C. difficile. Adalimumab (Humira®) is recommended as a first-line treatment option in patients with moderate-to-severe HS who were unresponsive or intolerant to oral antibiotics. It should be

Adjuvant treatment

Smoking cessation is important, as research has shown that 92 per cent of patients smoke and smoking is associated with less self-reported remission. The severity of HS was associated with pack years in 846 Dutch patients.

Encouraging weight loss is also desired, as weight loss of more than 15 per cent is associated with a significant reduction of disease severity. Clearly treating HS patients requires a multidisciplinary approach involving a dermatologist, a surgeon, nursing support, smoking cessation advice and weight loss programmes.

Although there has been considerable advances in the treatment of HS the disease however remains one for which a definitive treatment have been produced.

Anti TNF NSAIDS HS lesions consist of Comedones Plaques Nodules Abscesses Sinus tracts Risk Factors for the development of HS include: Family history Alcohol Smoking Obesity Patients with HS are more likely to suffer from the following conditions: Metabolic syndrome Increased Cardiovascular risk Inflammatory Bowel Disease Depression Rheumatoid arthrtitis

Continuous Professional Development is supported by Amgen®

This is a promotional advertisement from LEO Pharma for IE healthcare professionals.

NEW

For the treatment of moderate to severe atopic dermatitis in adult patients who are candidates for systemic therapy1

TIME TO PRESS PLAY Introducing Adtralza®

Not an actual patient. For illustrative purposes only.

The first licensed biologic that inhibits IL-13 alone,1 a key driver of atopic dermatitis signs and symptoms.2 Learn more at www.adtralza.ie Prescribing Information for Adtralza® in pre-filled syringe

(tralokinumab) 150 mg solution for injection

Please refer to the full Summary of Product Characteristics (SmPC) (www.medicines.ie) before prescribing.

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. Indications: Treatment of moderate-tosevere atopic dermatitis in adult patients who are candidates for systemic therapy.

Active ingredients: Each pre-filled syringe contains 150 mg of tralokinumab in 1 mL solution (150 mg/mL). Dosage and administration: Posology: The recommended dose of tralokinumab is an initial dose of 600 mg (four 150 mg injections) followed by 300 mg (two 150 mg injections) administered every other week as subcutaneous injection.

Every fourth week dosing may be considered for patients who achieve clear or almost clear skin after 16 weeks of treatment. Consideration should be given to discontinuing treatment in patients who have shown no response after 16 weeks of treatment. Some patients with initial partial response may subsequently improve further with continued treatment every other week beyond 16 weeks. Tralokinumab can be used with or without topical corticosteroids. The use of topical corticosteroids, when appropriate, may provide an additional effect to the overall efficacy of tralokinumab. Topical calcineurin inhibitors may be used, but should be reserved for problem areas only, such as the face, neck, intertriginous and genital areas. If a dose is missed, the dose should be administered as soon as possible and then dosing should be resumed at the regular scheduled time. No dose adjustment is recommended for elderly patients, patients with renal impairment or patients with hepatic impairment. For patients with high body weight (>100 kg), who achieve clear or almost clear skin after 16 weeks of treatment, reducing the dosage to every fourth week might not be appropriate. The safety and efficacy of tralokinumab in children below the age of 18 years have not yet been established.

Method of administration: Subcutaneous use. The pre-filled syringe should be not shaken.

After removing the pre-filled syringes from the refrigerator, they should be allowed to reach room temperature by waiting for 30 minutes before injecting. Tralokinumab is administered by subcutaneous injection into the thigh or abdomen, except the 5 cm around the navel. If somebody else administers the injection, the upper arm can also be used. For the initial 600 mg dose, four 150 mg tralokinumab injections should be administered consecutively in different injection sites. It is recommended to rotate the

injection site with each dose. Tralokinumab should not be injected into skin that is tender, damaged or has bruises or scars. A patient may self-inject tralokinumab or the patient’s caregiver may administer tralokinumab if their healthcare professional determines that this is appropriate. Contraindications: Hypersensitivity to the active substance or to any of the excipients. Precautions and warnings: If a systemic hypersensitivity reaction (immediate or delayed) occurs, administration of tralokinumab should be discontinued and appropriate therapy initiated. Patients treated with tralokinumab who develop conjunctivitis that does not resolve following standard treatment should undergo ophthalmological examination. Patients with pre-existing helminth infections should be treated before initiating treatment with tralokinumab. If patients become infected while receiving tralokinumab and do not respond to antihelminth treatment, treatment with tralokinumab should be discontinued until infection resolves. Live and live attenuated vaccines should not be given concurrently with tralokinumab. Fertility, pregnancy and lactation: There is limited data from the use of tralokinumab in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity. As a precautionary measure, it is preferable to avoid the use of tralokinumab during pregnancy. It is unknown whether tralokinumab is excreted in human milk or absorbed systemically after ingestion. Animal studies did not show any effects on male and female reproductive organs and on sperm count, motility and morphology. Side effects: Very common (≥1/10): Upper respiratory tract infections.

Common (≥1/100 to <1/10): conjunctivitis, conjunctivitis allergic, eosinophilia, injection site reaction. Uncommon (≥1/1,000 to <1/100): keratitis. Precautions for storage: Store in a refrigerator (2°C-8°C). Do not freeze. Store in the original package in order to protect from light. Legal category: POM. Marketing authorisation number and holder: EU/1/21/1554/002. LEO Pharma A/S, Ballerup, Denmark. Last revised: June 2021 Reference number: REF-19238(1) Reporting of Suspected Adverse Reactions Adverse events should be reported.

Reporting forms and information can be obtained from: HPRA Pharmacovigilance, Website: www.hpra.ie Adverse events should also be reported to Drug Safety at LEO Pharma by calling +353 1 4908924 or e-mail medical-info.ie@leo-pharma.com

IL, interleukin.

References: 1. Adtralza® SPC. 2. Bieber T. Allergy 2020;75:54–62.

Further information can be found in the Summary of Product Characteristics or from: LEO Pharma, Cashel Road, Dublin 12, Ireland.

E-mail: medical-info.ie@leo-pharma.com ® Registered trademark

Date of preparation: February 2022 IE/MAT-54463 V1

36 Breast Cancer

Novel Agents in HER2-Positive Breast Cancer Written by Maeve A. Hennessy, Kate Rafferty, Catherine M. Kelly Dept. of Medical Oncology, Mater Misericordiae University Hospital

Maeve Hennessy

Kate Rafferty

Catherine Kelly

“Two new and exciting clinical trials for HER2-positive breast cancer are now open and recruiting in Ireland, providing access to novel therapies for Irish patients, and aiming to address important unanswered questions in both early (Destiny-Breast05) and advanced (Destiny-Breast12) HER2positive breast cancer” Overexpression of human epidermal growth factor receptor 2 (HER2) occurs in approximately 15-20% of breast cancers. This subset of breast cancer has historically been characterised by high rates of recurrence and a more aggressive biology. HER2targeted therapies have altered the clinical course of both early and metastatic HER2-positive breast cancer, reducing the risk of recurrence in the adjuvant setting and prolonging survival in those with advanced disease.1,2 Trastuzumab, a humanized monoclonal antibody that binds to the extracellular domain of HER2 receptors, was the first anti-HER2 monoclonal antibody to demonstrate improved outcomes when added to chemotherapy, for both patients with metastatic and early HER2-positive breast cancer.1,2 Since then, we have seen the development of an array of novel HER2-targeted agents which have changed the treatment paradigm. We review the evidence and discuss recent key advances in the management of HER2positive breast cancer.

Anti-HER2 therapies in metastatic HER2-positive breast cancer The standard of care for the first line management of HER2-positive metastatic breast cancer was established in the CLEOPATRA trial, which demonstrated significant improvements in overall survival (OS), up to 57 months, for dual anti-HER2 blockade with the monoclonal antibodies trastuzumab, pertuzumab in combination with taxane-based chemotherapy.3 The antibody drug conjugate (ADC) trastuzumab emtansine (T-DM1) has been the preferred agent in the second line on the basis of the EMILIA study, where it demonstrated improved progression free survival (PFS) and OS as compared with lapatinib/capecitabine, with less toxicity.4 Following on from the development of T-DM1, improvements in drug engineering led to the development of a second-generation ADC, trastuzumab deruxtecan (T-DXd).5 This contains an identical humanised monoclonal HER antibody sequence to T-DM1,

MARCH 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE

however is conjugated to a different cytotoxic agent, a novel topoisomerase 1 inhibitor. T-DXd has a higher drug-to-antibody ratio (8 versus 3.5) allowing higher potency and increased drug delivery. In addition, the highly permeable payload membrane allows a ‘bystander effect’, which means that the drug can be released by tumour cells on neighbouring heterogenous nonHER2 tumour cells.5,6 Trastuzumab deruxtecan has recently shown durable activity in heavily pre-treated patients with HER2-positive metastatic breast cancer and has since shown improved outcomes over T-DM1 in the second line for patients with HER2-positive metastatic breast cancer in the phase III Destiny-Breast03 trial.7,8 DestinyBreast03 was an international phase III trial which compared T-DXd versus T-DM1 in patients with HER2-positive metastatic breast cancer who were initially treated with trastuzumab and a taxane. Five-hundred and twentyfour patients were included and were randomised to either T-DXd

at 5.4mg/kg or T-DM1 at 3.6mg/ kg every 3 weeks. Progression free survival was the primary endpoint. At a median followup of 16 months, median PFS was not reached with T-DXd and was 6.8 months with T-DM1 (HR 0.28, p<0.001). The response rate was 79.7% for T-DXd versus 34.2% for T-DM1 (p<0.0001).

Importantly, a benefit was noted across all subgroups including patients with brain metastases.8 An updated subgroup analysis presented at San Antonio Breast Cancer Symposium 2021, showed that 82 patients with stable brain metastases at baseline had an improvement in median PFS, 15 months with T-DXd versus 3 months with T-DM1 (HR 0.25, 95% CI 0.31-0.45).9 Previous trials of T-DXd had documented interstitial lung disease (ILD) as a significant adverse event, however the rate of ILD in Destiny-Breast03 was less than what was reported in the earlier studies where patients had been more heavily pre-treated, (10.5%, with 9.7% being grade 1 or 2) and no grade 4 or 5 ILD reported. These impressive results were seen as practice changing and T-DXd is now the preferred second-line treatment based on this study, and in particular in the case of central nervous system (CNS) involvement.8 T-DXd with or without pertuzumab is now being evaluated in the first line against the CLEOPATRA regimen.10 The inclusion of patients with CNS involvement in clinical trials evaluating novel therapies for metastatic HER2 is vital, especially given that approximately one third of patients with HER2positive metastatic breast cancer will ultimately develop brain metastases.11 Further clinical trials are ongoing to assess treatment options in this important cohort of patients and are active and recruiting in Ireland. DestinyBreast12 is an open-label international phase IIIb/IV study assessing the safety and efficacy of T-DXd in patients with or without brain metastasis. The trial aims to recruit a total of 500 eligible participants across 19 countries, and is currently open in three sites in Ireland: Cork University Hospital, St Vincent’s University Hospital, and the Mater Misericordiae University Hospital. Eligible participants must be at least 18 years of age, have unresectable/ advanced or metastatic HER2-

38 Breast Cancer Destiny-Breast05 is an exciting phase III international, multicentre, randomised, open-label trial that is studying this cohort of patients, i.e., those with HER2positive breast cancer who have residual invasive disease in the breast or axillary lymph nodes following neoadjuvant therapy, and will examine treatment with T-DXd versus T-DM1. The primary objective of the trial is to compare the invasive disease-free survival (IDFS) between T-DXd and T-DM1.

This trial is open in Ireland and is being run in the following institutions: Mater Misericordiae University Hospital, Cork University Hospital, St James’s Hospital, St Vincent’s University Hospital and University Hospital Limerick. This study will help to provide further evidence to inform treatment selection for this group of patients who are at a higher risk of disease recurrence.

positive breast cancer and evidence of disease progression on trastuzumab, pertuzumab, or T-DM1 (≤ 2 lines/regimens of therapy in the metastatic setting).

Participants will be stratified according to presence or absence of brain metastasis at baseline and will receive intravenous T-DXd at 5.4 mg/kg every 3 weeks until progressive disease or development of unacceptable toxicity.

Small molecules such as tucatinib, an oral anti-HER2 tyrosine kinase inhibitor (TKI), are another class of drug being explored in the treatment of HER2-positive breast cancer. Tucatinib has been shown to effectively cross the blood brain barrier and has demonstrated activity in patients with CNS metastases, as seen in the HER2CLIMB trial.12 In this international trial, 612 patients with HER2-positive metastatic breast cancer previously treated with trastuzumab, pertuzumab, and T-DM1, with or without brain metastases, were randomised to receive either tucatinib or placebo, in combination with trastuzumab and capecitabine. 291 patients (47.5%) had brain metastases at baseline. The tucatinib plus trastuzumab/capecitabine arm had more than double the response rate as compared with the control arm (47% vs 20%, p=0.03). There

was also an impressive intracranial response with intracranial PFS 9.9 months versus 4.2 months p<0.001).12 Therefore, tucatinib may be a valid option in the second line if patients have brain metastases and this novel TKI is now being examined in earlier settings to prevent CNS relapse.

Anti-HER2 therapy In early stage HER2-positive breast cancer For patients with early stage HER2-positive breast cancer, a neoadjuvant approach is standard of care for HER2-positive tumours greater than 2cm and/ or lymph node involvement.13 Upfront systemic therapy has the advantage of assessing response to treatment and allowing further personalisation of treatment in the adjuvant setting. Currently, this takes the form of anthracycline/ taxane-based chemotherapy plus dual anti-HER2 blockade with trastuzumab and pertuzumab.

However, increasingly the role of anthracyclines in contemporary dual anti-HER2 treatment regimens is limited and non-anthracycline regimens are now the most frequently administered (neo) adjuvant regimens. Neoadjuvant therapy is followed by surgical resection, plus or minus adjuvant radiotherapy, completion of anti-HER2 therapy and endocrine therapy depending on the

MARCH 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE

tumour hormone status. The introduction of a dual HER2 blockade neoadjuvantly has resulted in improved rates of pathologic complete response (up to 60%), which has been shown to translate to better long-term outcomes for patients.14,15 Patients with residual invasive breast cancer post neoadjuvant chemotherapy plus HER2-targeted therapy have a worse prognosis than those who have no residual cancer. The management of patients with residual disease following neoadjuvant therapy has been informed by the landmark KATHERINE study, which was published in the New England Journal of Medicine (NEJM) in 2019.16 In this randomised phase III trial, 1468 patients with HER2positive breast cancer who had residual disease post neoadjuvant taxane-based chemotherapy and anti-HER2 therapy were randomly assigned to either trastuzumab or T-DM1 for 14 cycles. The T-DM1 arm had an improved invasive disease-free survival (IDFS) compared to the trastuzumab arm, (88 vs. 77%; HR = 0.50; 95% CI 0.39–0.64), and T-DM1 was approved by the FDA and EMA in this setting as a result.16 Trastuzumab emtansine has only recently (January 2022) been funded in Ireland for this indication.

Significant progress has been made in recent years in the management of HER2-positive breast cancer, with many patients with advanced disease now experiencing longterm responses. The spectrum of active therapies means that treatment is becoming increasingly effective and individualised. Two new and exciting clinical trials for HER2-positive breast cancer are now open and recruiting in Ireland, providing access to novel therapies for Irish patients, and aiming to address important unanswered questions in both early (DestinyBreast05) and advanced (DestinyBreast12) HER2-positive breast cancer. Finding effective drugs to treat patients with brain metastases has been a long term challenge, and there are now some excellent options for patients, many of whom have stable extracranial disease, but progressive disease in the CNS. It is likely that in the coming years the current anti-HER2 therapies being used in the neoadjuvant and metastatic setting will be replaced by new highly active antibody drug conjugates and combinations of potent small molecule tyrosine kinase inhibitors. Additionally, treatments approved for other breast cancer subtypes associated with improvements in survival, such as immunotherapies in triple negative breast cancer and CDK4/6 inhibitors in hormone receptorpositive breast cancer, are also being explored in HER2-positive breast cancer. In summary, the recent advances in the treatment of HER2-positive breast cancer have been impressive, resulting in significantly improved outcomes and the future is promising for patients with this diagnosis.

References available on request

is article section is not intended to cover the entire all need to know ps asPlease the topic toothis wide to besection discussed here. to Important secti GIfully FOCUS: POLYPS noteisthat article isCOLONIC not intended cover the enti 39 s article ultimately, Gastroenterology service involvement with aboutand colonic polyps as the topic is too wide to be fully discussed he ppropriate future in management going forwardGastroenterology especially with regard are discussed this article and ultimately, service Colonic Polyps – Current Understanding, follow up on appropriate future management going forward esp propriateness isthe warranted.

Implications, Endoscopic approach & Surveillance surveillance and appropriateness is warranted.

Background Colonic polyps (Image 1) are common finding at colonoscopy.

There are different polyps aetiologies including hyperplastic, inflammatory, part of polyposis syndromes, pre-malignant and neoplastic. The endoscopic removal of colorectal polyps reduces the incidence of colorectal cancer (CRC) and is considered an essential skill for all endoscopists who perform colonoscopy1,2,3.

Therapeutic polypectomy is a specialised procedure with timely intense training for trainees. Complex cases will need to be performed by expert endoscopists at tertiary centres and may need multi-disciplinary meeting discussion with fellow endoscopists and colorectal colleagues prior to intervention.

Endoscopy

Written by

complications, aftermath of the procedure i.e. endoscopist’s impression of total complete polypectomy with histological confirmation (i.e. R0 resection margin), Gastro Histopathology multidisciplinary team discussion, surveillance pathway and so on must all be taken into account.

paration and anticipation is the key in endoscopy. Indications for be At mentioned,for preparation and anticipation is the key in endoscop anticoagulation patients undergoing colonoscopy should always anti-platelets or anticoagulation for patients undergoing colonos s aton endoscopy will totally change the ball game approach altogethe reviewed as findings at endoscopy will totally change the ball game therapeutic intervention. These should all be reviewed even at the from diagnostic to therapeutic intervention. These should all be revi al phase with the appropriates to hold these medications beforehan colonoscopy referral phase with the appropriates to hold these med m intervention is indicated i.e. anticoagulation bridging, switching to whether any interim intervention is indicated i.e. anticoagulation br discussion with specific relevant specialties i.e. cardiology / haemat Diagnostic and therapeutic colonoscopic procedures totally gives a different perspective approach for any endoscopist and all cases are individualised. Proper consent with risk and benefit involved with the diagnostic procedure itself and the possibility of intervention should always be discussed with the patient preprocedure. Multifactorial aspects including co-morbidities, being on antiplatelets / anticoagulations factor, presence of pacemaker or Implantable Cardioverterdefibrillators (ICD), potential

As with any other medical specialities, there are specific societies guideline committee that review and revise all the up to date, evidence-based approach and management of colonic polyps. These would include the European Society of Gastrointestinal Endoscopy (ESGE), British Society of Gastroenterology (BSG), American Society of Gastrointestinal Endoscopy (ASGE), United European Gastroenterology (UEG) and not forgetting our own, Irish Society of Gastroenterology (ISG) to name a few.

Please note that this article section is not intended to cover the entire all need to know about colonic polyps as the topic is too wide to be fully discussed here.

Important sections are discussed in this article and ultimately, Gastroenterology service involvement with follow up on the appropriate future management going forward especially with regards to surveillance and appropriateness is warranted.

Dr Telal Khair is a senior Gastroenterology Registrar currently practising in St James’s Hospital, Dublin.

MBBS, MRCP (UK)

Endoscopy

Dr Brian Christopher is a Consultant Gastroenterologist and General Physician at St James’s Hospital, Dublin.

MB, BCh, BAO (HONS), MRCPI, MRCPS (Glasg), FESBGH, FRCP (Glasg)

A graduate of National University of Ireland, Galway (NUIG), Brian completed his higher specialist training (HST) and obtained CSCST from RCPI. He was conferred European Section and Board Fellowship in Gastroenterology and Hepatology. Part of his sub-speciality of interest is in advanced interventional endoscopy

aspirin etc. or even discussion with specific relevant specialties i.e. c colleagues.

At mentioned, preparation and anticipation is the key in endoscopy. Indications for being on anti-platelets or anticoagulation for patients undergoing colonoscopy should always be reviewed as findings at endoscopy will totally change the ball game approach altogether from diagnostic to therapeutic

onicImage polyps’ morphology 1: Variable colonic polyps’ morphology Image 1: Variable colonic polyps’ morphology

Adapted from KevinMD, retroflexion.com (Sessile lesion)

Adapted from World Endoscopy Organization (pedunculated polyp i.e. with stalk)

Adapted from KevinMD, retroflexion.com from W nMD, retroflexion.com Adapted from WorldAdapted Endoscopy HOSPITALPROFESSIONALNEWS.IE | HPN • MARCH 2022

of flexible arms everts and flatten folds to provide an enhanced view of the entire colon and increase polyp and adenoma detection rate4.

40

GI FOCUS: COLONIC POLYPS

Image 2: Practical use of Endocuff in colonoscopy Image 2: Practical use of Endocuff in colonoscopy

M. Bugajski et al, Gi Endoscopy January 18’

S. Mehdizadeh et al, MD

M. Bugajski et al,

S. (Endocuff Mehdizadeh etgreen) al, MD arms visible in

Gi Endoscopy January 18’

Image from Endocuff Vision

Image from Endocuff

(Endocuff arms visible in green)

intervention. These should all be reviewed even at the colonoscopy referral phase with the appropriates to hold these medications beforehand and whether any interim intervention is indicated i.e. anticoagulation bridging, switching to aspirin etc. or even discussion with specific relevant specialties i.e. cardiology / haematology colleagues.

Standard position change during procedure should always be undertaken to optimize the yield of polyps’ detection. The use of other polyp detection enhancing methods i.e. computerised artificial intelligence (AI), endocuffs etc.

(Image 2) are all depending on the availability in the local endoscopy department unit.

preparation is crucial as endoscopists must be able to have definite clear views of the entire colon including the key landmarks.

colonoscopy by manipulating colonic folds. A single row of flexible arms everts and flatten folds to provide an enhanced

view of the entire colon and increase polyp and adenoma detection rate4.

Antiplatelet / Anticoagulation Guidelines

The current BSG / ESGE guidelines Antiplatelet / Anticoagulation Guidelines (2021) development committee included representatives from British Society of Haematology, British Cardiovascular Intervention Society and representatives from the charities Anticoagulation UK and Thrombosis UK5 (Image 3 & 4).

Vision

using the Paris classification system and sized in milimeters6 (moderate quality evidence; strong recommendation). Any polyps should be thoroughly inspected with the standard endoscopy white light and enhancing view modalities available i.e. narrow band imaging (NBI) for Olympus scopes or Blue Light Imaging (BLI) for Fuji scopes.

The current BSG / ESGE guidelines (2021) development committee included representatives Endocuff is a device attached to Good High Quality Colonoscopy the distal end of a colonoscope, from British Society of Haematology, British Cardiovascular Intervention Society and designed to maintain and A good quality colonic mucosal maximize the mucosa view during representatives charities Anticoagulation UK and Thrombosis UK5 (Image 3 & 4). view after standard bowelfrom the Endoscopic Classifications

Image 3: BSG / ESGE Guideline on

Gross endoscopic morphology update Andrew Image 3: BSG / ESGE Guideline on Antiplatelets update 2021, Andrew M. Antiplatelets Veitch et al.M.2021, of polyps should be described Veitch et al.

Image 4: BSG / ESGE Guideline on Anticoagulation update 2021, Andrew M. Veitch et al.

MARCH 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE

42

GI FOCUS: COLONIC POLYPS Image 4: BSG / ESGE Guideline on Anticoagulation update 2021, Andrew M. Veitch et al.

Image 4: BSG / ESGE Guideline on Anticoagulation update 2021, Andrew M. Veitch et al.

Endoscopic Classifications

Gross endoscopic morphology of polyps should be described using the Paris classific system and sized in milimeters6(moderate quality evidence; strong recommendatio polyps should be thoroughly inspected with the standard endoscopy white light and enhancing view modalities available i.e. narrow band imaging (NBI) for Olympus sco Blue Light Imaging (BLI) for Fuji scopes.

A thorough endoscopic inspection examination will provide the initial, approximate assessment including the infiltration depth i.e. beyond mucosa and is imperative to next step. The Paris classification (Image 5), based on earlier Japanese classification developed to allow morphological classification of superficial lesions7,8. The NICE (N International Colorectal Endoscopic) Classification is based on narrow-band images colonic polyps. The classification uses staining, vascular patterns, and surface patter distinguish between hyperplastic and adenomatous colon polyps9. The Japan NBI Ex Team (JNET), which comprises 38 members specialized in colonoscopy, attempted t establish a new NBI classification system for colorectal tumour diagnosis that would overcome the limitations of the NICE classification system10 (Image 6).

A thorough endoscopic inspection examination will provide the initial, approximate assessment including the infiltration depth i.e. beyond mucosa and is imperative to plan the next step.

The Paris classification (Image 5), based on earlier Japanese classifications, was developed to allow morphological classification of superficial lesions7,8. The NICE (NBI International Colorectal Endoscopic) Classification is based on narrow-band images of colonic polyps. The classification uses staining, vascular patterns, and surface patterns to distinguish between hyperplastic and adenomatous colon polyps.9 The Japan NBI Expert Team (JNET), which comprises 38 members specialized in colonoscopy, attempted to establish a new NBI classification system for colorectal tumour diagnosis that would overcome the limitations of the NICE classification system10 (Image 6).

The Size/Morphology/Site/Access (SMSA) scoring system was developed to predict in polypectomy based on four polyp characteristics: size (S), morphology (M), site (S Various polypectomy techniques the lesion has been lifted with a of diffic developed(A). to predict access Thedifficulty score is expressed as four categories with increasing degree and devices are available, their in polypectomy based on four use often varying based on local polyp characteristics: size (S), preference and availability12,13,14. morphology (M), site (S) and Endoscopic mucosal resection access (A). The score is expressed (EMR) is a technique performed as four categories withclassification increasing Image 5 : Paris with a polypectomy snare after degree of difficulty11.

The Size/Morphology/Site/Access (SMSA) scoring system was

Image 5 : Paris classification

MARCH 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE

submucosal fluid injection (the “inject-and-cut” technique) (Image 7 & 8). There are other techniques involved i.e. conventional (cEMR) vs underwater (uEMR) EMR, Endoscopic submucosal

43

Image 6: JNET Endoscopic classification

Image 6: JNET Endoscopic classification Y. Sano et al, Digestive Endoscopy, April 2018

(SMSA) level 4. (Moderate quality evidence; strong recommendation) Surveillance Rutter et al.16 has recently published the updated endorsed BSG/PHE/ACPGBI guidelines (2020) for post polypectomy surveillance. This guideline takes into account the introduction of national bowel cancer screening.

Conclusion

dissection (ESD), full thickness 2 ESGE suggests a completely snare-resected • Colonic polyps involve extensive Y. Sano et al, Digestive Endoscopy, April 2018 CSP for sessile polyps 6 – 9mm in size because of Image lesion in safest minimum resection device (FTRD) approach, 7:the EMR Technique planning management from the its superior safety profile, although number of pieces, with adequate but, these are beyond the scope of point of pre-intervention with initial evidence comparing efficacy with margins and without need for discussion in this article. diagnostic intention which may hot snare polypectomy (HSP) adjunctive ablative techniques. convert to therapeutic intervention En-block (full complete Various resection polypectomy techniquesis and devices are available, their use often varying based on lacking. (Moderate quality (Low quality evidence, strong intra-procedure.

12,13,14 resection in one piece) as evidence, weak recommendation.) recommendation.) local preference and availability .

Endoscopic mucosal resection (EMR) is a technique opposed to piecemeal resection • High quality colonoscopy is a performed with a polypectomy 3snare theHSP lesion has a submucosal ESGEafter suggests (with or been lifted 6 ESGEwith recommends careful fluid pivotal element for polyp initial is preferable as the one-piece without submucosal detection and subsequent proper lesion assessment prior to EMR to specimen enable our injectionwill (the “inject-and-cut” technique) (Imageinjection) 7 & 8). for There are other techniques removal of sessile polyps 10 – 19 management. identify features suggestive of poor Histo-pathologist to determine involved conventional (cEMR) (uEMR) submucosal mmvsinunderwater size. In most cases deepEMR, Endoscopic outcome. Features associated whether thei.e. excision was complete • Polypectomy is a high risk thermal injury is a potential with incomplete resection or the i.e.

R0 resection. dissection (ESD), full thickness resection device (FTRD)risk approach, but, these are beyond endoscopic procedure and proper and thus submucosal injection recurrence include lesion size > 40& Endoscopy Adapted from GastroMedicine informed consent pre-procedure is scope of discussion in this article.

Not all lesions are amenable prior to HSP should be considered. mm, ileocecal valve location, prior imperative. for en-block resection as larger (Low quality evidence, strong failed attempts at resection, and En-block (full complete resection in one piece) as opposed to piecemeal resection lesions will resection need to be excised in recommendation.)

References available on request size, morphology, site, and access pieces due to technicality factors is preferable as the one-piece specimen will enable our Histo-pathologist to determine 4 ESGE recommends HSP mentioned i.e. SMSA scoring for pedunculated polyps. To whether the excision was complete i.e. R0 resection. system factors. prevent bleeding in pedunculated Image 8: EMR Technique, Adapted from Y.Hazewinkel et al, Nature Review Image 8: EMR Technique, Adapted from Y.Hazewinkel et al, Nature Reviews Main ESGE recommendations15 polyps with head ≥ Not all lesions are amenable forcolorectal en-block resection as larger lesions will need to2011 be excised Gastro & Hep, Sept Sept 2011 20 mm or a stalk ≥ 10 mm in 1 ESGE recommends cold diameter, ESGE recommends in pieces due to technicality factors mentioned i.e. SMSA scoring system factors. snare polypectomy (CSP) as the pre-treatment of the stalk with preferred technique for removal injection of dilute adrenaline and/ of diminutive polyps (size ≤ 5mm). or mechanical haemostasis.

This technique has high rates of (Moderate quality evidence, strong complete resection, adequate recommendation.) tissue sampling for histology, and low complication rates.

5 ESGE recommends that the (High quality evidence, strong goals of endoscopic mucosal recommendation.) resection (EMR) are to achieve

Image 7: EMR Technique

Image 7: EMR Technique

Adapted from GastroMedicine & Endoscopy

Adapted from GastroMedicine & Endoscopy HOSPITALPROFESSIONALNEWS.IE | HPN • MARCH 2022

44

GI FOCUS: COLONSCOPY

Artificial Intelligence in Colonoscopy – A Brave New World Written by E. Gibbons, B Hall, Department of Gastroenterology, Connolly Hospital, Blanchardstown

Eimear Gibbons

Barry Hall

Abstract

optic-enhancing technologies since that time, up to 25% of adenomatous polyps can still be missed at colonoscopy.1 The adenoma-carcinoma sequence describes the transformation of normal colorectal epithelium to adenomatous polyp to invasive cancer. This temporal sequence of events offers an opportunity for endoscopic intervention at a precancerous stage. Despite this, colorectal cancer (CRC) is the third most common cancer in Ireland, accounting for 11% of all cancer related deaths.2 Artificial intelligence (AI), in particular deep machine learning, is showing potential to improve polyp detection in colonoscopy.

Artificial intelligence (AI) has shown potential to improve polyp detection in colonoscopy.

Advanced machine learning models are highly effective at image recognition, hence their applicability to polyp detection.

In 2018, the World Endoscopy Organisation published a consensus statement on postcolonoscopy cancer (PCCRC), identifying PCCRC rates as an important performance indicator for an endoscopy service. In one large community-based US study with 1000 identified PCCRCs, almost half had potentially modifiable factors related to polyp surveillance or removal, and examination completeness. These modifiable factors represent areas where AI technology can assist in improving outcomes. The three leading endoscopy manufacturers are currently developing AI systems which will be integrated into future endoscopy processing stacks. The authors have recently trialled the Medtronicdeveloped GI-Genius system.

The combination of advances in AI technologies, commercial interest and a growing body of supporting evidence suggests that the use of AI to augment day to day endoscopy will become a reality in the near future.

Two physicians in the United States, Dr William Wolff and Dr Hiromi Shinya performed the first colonic polypectomy in 1969. Despite advances in operator technique and

AI is a broad term which refers to the use of computer algorithms to augment human intelligence.

Deep learning, a subset of the machine learning field within AI, is a multi-layered mathematical algorithm which creates networks known as artificial neural networks.

Unlike traditional machine learning, deep learning can progressively learn independently from human intervention, therefore enabling improved accuracy over time without manually rebuilding the algorithm. Advanced machine learning models such as convolutional neural networks are highly effective at image recognition, hence their applicability to polyp detection.

In 2018, the World Endoscopy Organisation published a consensus statement on postcolonoscopy cancer (PCCRC), identifying PCCRC rates as an

MARCH 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE

important performance indicator for an endoscopy service.3 In one large community-based US study with 1000 identified PCCRCs, almost half had potentially modifiable factors related to polyp surveillance or removal, and examination completeness.4 Individual endoscopist adenoma detection rates (ADR) are an independent predictor of the risk of interval cancer.5 ADR is defined as the proportion of colonoscopies where one or more adenomas are detected.

With every 1% increase in an endoscopist’s ADR, their risk of an interval cancer decreases by 3%.6 These modifiable factors represent areas where AI technology can assist in improving outcomes.

The three leading endoscopy manufacturers are currently developing computer-aided diagnostic (CADx) and computeraided detection (CADe) systems which will be integrated into future endoscopy processing stacks. The authors have recently trialled the Medtronic-developed GI-Genius system. An 11% increase in the polyp detection rate was captured during this period.

There are a growing number of studies demonstrating the potential of these AI systems in colonoscopy. Most systems have been evaluated by using either images or video of real procedures.

Multiple systems have the ability to be used in real time, yet only a small number of studies have been performed during real time colonoscopy to date. One of these studies showed an improvement in ADRs with 29.1% in those with a CADe system versus 20.3% in those without. The increase seems to have been due to a higher number of diminutive adenomas and hyperplastic polyps, however, and a cost benefit analysis of the increased yield of diminutive polyps is yet to be fully explored.7 An Italian team using GI-Genius

by Medtronic, randomly assigned 685 individuals to undergo colonoscopy either with CADe or without and found adenomas five mm or smaller were detected in a significantly higher proportion of examinations in the CADe group (33.7%) than in the control group (26.5%). This study found no increase in withdrawal time despite the extra polyps identified,

an important consideration for service provision.8 There is also growing evidence to support the use of CADx systems in a ‘resect and discard’ strategy for tiny, hyperplastic rectal polyps, with studies showing a negative predictive value ranging from 95% to 98% for diminutive rectosigmoid adenomas.9 Despite the increasing body of evidence, large randomised controlled trials are needed. A systematic review and meta-analysis of the use of AI systems in detection of polyps in Endoscopy this year identified only five randomised trials for analysis.10 The combination of advances in AI technologies, commercial interest and a growing body of supporting evidence suggests that the use of AI to augment day to day endoscopy will become a reality in the near future. As this happens it will raise a number of key ethical and regulatory issues, including data protection and ownership of missed diagnoses.

The relative novelty of this field also poses a challenge in terms of interpreting data presented.

Widespread understanding of the technical aspects of AI doesn’t currently exist among medical professionals, while developers of this technology can be unfamiliar with clinical relevance and implications for daily practise. Important areas that need further investigation include the effect CAD systems will have on length of procedures, their impact on surveillance, and cost of procedure itself, as well as the cost of additional histopathology. For GI endoscopy to really harness the power of this technology, a multidisciplinary approach will be necessary to ensure progress continues and focus remains on clinically relevant patient outcomes.

Declarations Funding: Not applicable Conflicts of interest/ Competing interests: Not applicable Availability of data and material: Not applicable Code availability: Not applicable References available on request

45

GI FOCUS: GI/SARS

Gastrointestinal Manifestations of Covid-19 Introduction Severe acute respiratory syndrome coronavirus 2 (SARS-CoV 2) was declared a global pandemic by The World Health Organisation (WHO) on the 11th of March 2020 making it the fifth documented pandemic since the 1918 influenza outbreak.1, 2 Following its rapid spread throughout the population, it has been responsible for >300 million cases and >5.5 million deaths worldwide as of 31 January 2022.3 Human coronaviruses were first characterised in the 1960’s; making coronavirus disease 2019 (COVID-19) the seventh member of the coronavirus family to cause disease in humans and the third to be associated with disease encompassing severe acute respiratory syndrome.2, 4 The other coronaviridae with potential to cause severe disease in humans are (SARS-CoV-1) and Middle East respiratory syndrome coronavirus (MERS-CoV).5, 6 In addition to the better known respiratory and systemic involvement, gastrointestinal (GI) manifestations have also been reported with SARS-CoV 2. This is not unique to coronaviridae or, indeed, other respiratory viridae; GI disease is seen with SARS-Cov-1, MERS-CoV , adenovirus, influenza amongst others (7-9). This review aims to briefly explore GI manifestations associated with previous coronavirus infections followed by exploration of the commonly reported GI manifestations of COVID-19 and the suggested underlying pathophysiology responsible.

Ashley Costello BPharm, MPharm Graduate Entry Medical School, University Of Limerick

Aisling Bracken B.Sc. Graduate Entry Medical School, University Of Limerick

Gerard Clarke MD FRCPI Graduate Entry Medical School, University Of Limerick

Table 1. GI manifestations of SARS-CoV-1 Table 1. GI manifestations of SARS-CoV-1 Article Booth et al, 2003

SARS CoV-1 GI manifestation 23.6% diarrhoea 19.4% Nausea or Vomiting 3.5% Abdominal pain

Sample size (N=) (N=144)

Peiris et al, 2003

73% diarrhoea

(N=75)

Tsang et al, 2003 Liu et al, 2004

30% patients diarrhoea 66% patients had diarrhoea 9% patients had vomiting 11% had nausea 9% abdominal tenderness

(N=10) (N=53)

Jang et al, 2004

13.8% diarrhoea 17.2% Nausea & Vomiting 19.6% diarrhoea 19.6% Nausea and vomiting 38.4% diarrhoea Diarrhoea 75%, vomiting 63%

(N=29)

SARS-CoV-1; GI Manifestations Diarrhoea, nausea, vomiting and abdominal pain are frequently reported in many series.

Diarrhoea has been described as its modal GI symptom with prevalence figures that range from 13.8% to 73%.10-15 A retrospective analysis of GI manifestations of patients with RT-PCR confirmed SARS-Cov-2 in Hong Kong reported diarrhoea at initial presentation in 20.3% while 38.4% cumulatively had diarrhoea throughout the illness (16). Nausea and vomiting were other common manifestation with studies reporting rates of 63%, 19.4%, 11.3%, 17.2%, 19.6% (10-13, 17). Abdominal pain was reported in a small number of studies; 3.5% and 9.0%.10, 11 A summary of GI manifestations associated with SARS-CoV-1 is described in Table 1.

MERS-CoV In 2012, MERS-CoV was identified as a zoonotic disease causing a respiratory disease in humans. However, MERS-CoV infection also displayed high levels of GI involvement. In fact, GI symptoms were the most common extra-pulmonary symptoms of MERS with approximately one third of patients experiencing abdominal pain, nausea, vomiting and diarrhoea (18, 19). Mackay and colleagues described fever and gastrointestinal symptoms which formed a prodrome, followed by more severe systemic and respiratory syndrome.20 A summary of MERS-CoV associated GI manifestations is represented by Table 2.

Lee et al, 2003 Leung et al, 2003 Srikantiah et al, 2005

(N=138) (N=138) (N=8)

Table 2. GI manifestations of MERS-CoV Table 2. GI manifestations of MERS-CoV MERS-CoV Article MERS-CoV GI manifestation Sample size (N=) InAssiri 2012,etMERS-CoV was identified as a zoonotic respiratory disease in al, 2013 (18) Diarrhoea in 26%disease causing a (N=47) humans. However, MERS-CoV infection also displayed high levels of GI involvement. In fact, Vomiting in 21% GI symptoms were the most common extra-pulmonary symptoms of MERS with Abdominal pain 17% approximately one third of patients experiencing abdominal pain, nausea, Assiri et al, 2013 (21) Diarrhoea in 22% (N=23) vomiting and diarrhoea (18, 19). Mackay and colleagues described fever and gastrointestinal symptoms Vomiting 17% which formed a prodrome, followed by more severe systemic and respiratory syndrome Al-Tawfiq et al, 2014 (22) Diarrhoea in 7% (N=15) (20). A summary of MERS-CoV associated GI7% manifestations is represented by Table 2.

Vomiting in

Arabi et al, 2014 (23)

Saad et al, 2014 (24)

Diarrhoea in 17% Nausea in 8% Acute abdomen in 25%; 1 with ischemic bowel and 2 negative laparotomies Diarrhoea in 30% Vomiting in 30%

(N=12)

(N=70)

HOSPITALPROFESSIONALNEWS.IE | HPN • MARCH 2022

46

GI FOCUS: GI/SARS Table 3. Summary of the GI manifestations of COVID-19.

Pathophysiology of GI involvement

Table 3. Summary of the GI manifestations of COVID-19

SARS-CoV-2 gains access to host cells via binding to angiotensin-converting enzyme 2 (ACE2) receptors found in the lungs and utilises a serine protease TMPRSS2 for S protein priming.25 While ACE2 receptors are present in the lungs, they are also expressed in both hollow and solid intestinal organs. They are present in both the upper and lower GI tract, expressed at concentrations almost 100fold higher compared to their respiratory counterparts.26, 27

COVID-19 GI manifestations Gastrointestinal manifestations are reported in a high proportion of individuals with COVID-19 infection. The majority of these include diarrhoea, nausea, vomiting, anorexia and abdominal pain. A summary of articles describing these symptoms are displayed in Table 3.

Pan and colleagues found that 103 (50.5%) of participants reported a digestive problem (N=204).30 Jin and colleagues found that 74 (11.4%) presented with at least one Gi symptom (N=651).31 Lin and colleagues reported GI symptoms in 58 (61.1%) (N=95).32 Abdominal pain has been reported at lower rates than other GI symptoms but was common among patients in ICU.33 A small proportion of patients presenting with abdominal pain had a significant underlying cause for this such as acute pancreatitis, acute appendicitis, intestinal obstruction, and bowel ischemia.9 The time of onset of GI symptoms is variable;

Diarrhoea

Nausea

Han C Et al, 2020 (34).

67 (32%)

Vomiting

Abdominal Pain 9 (4.4%)

Other

-

Nausea & Vomiting 24 (11.7%) -

35 (34%)

-

4 (3.9%)

-

2 (1.9%)

lack of appetite in 81 (78.6%)

Chen N et 2 (2%) al, 2020 (35).

N=99 Yue H et al, 1(1.2%) 2020 (36).

(N=86)

-

-

1 (1%)

-

-

-

-

-

-

-

Huang C et al, 2020 (37).

-

-

-

-

-

(N=206)

Pan L et al, 2020 (30).

(N=204)

Upon binding with the target host cell, both the ACE2 receptor and COVID-19 virus are endocytosed leading to an overall reduction in surface ACE2 concentration.9 ACE2 receptors play particular roles in gut epithelial cells; including amino acid homeostasis maintenance, antimicrobial peptide expression and the ecology of the gut microbiome.

Therefore, a reduction of surface ACE2 receptors may interrupt these processes and lead to inflammation. Digestive symptoms of COVID-19 are likely to be a result of its mechanism of action.

SARS-CoV-1 and SARS-CoV-2 possess high degrees of genomic similarity and both utilise ACE2 as means of an entry receptor (28).

However, SARS-CoV-2 binding affinity to ACE2 is significantly higher (10-20 times) compared with SARS-CoV-1.29

Article (N=)

(N=38) Jin X et al, 2020 (31) (N=651)

1 (3%)

53( 8.14%)

Lin L et al, 2020 (32) (N=95)

24.2%

17.9%

Luo S et al, 2020 (38).

68 (37%)

134 (73%)

Anorexia 17.9%

119 (65%)

37 (20%)

(N=183)

Wang D et al, 2020 (33).

Han et al described that of the 67 (32%) of individuals with diarrhoea, 19.4% of these experienced it as their first symptom.34 Lin et al described that of the 58 (61.1%) of patients with GI symptoms , only 11.6% of them had symptoms on admission while the rest manifested later in the course of the illness.32 Gut Microbiome in Covid-19 Research has demonstrated that microorganism inhabitation not only occurs in the gut, but also in the lungs. Although the concentration of microorganisms in the lungs are at lower levels compared to those found in the gut, the result is the creation of a local microbiome.42 Since the emergence of lung microbiome research, studies have investigated the lung microbiota composition of individuals with pulmonary diseases such as asthma, chronic obstructive pulmonary disease (COPD), cystic fibrosis, idiopathic lung disease and lung cancer and compared it to the composition found in healthy individuals.43-47 The relationship between the gut microbiota and pulmonary system is referred to as the

MARCH 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE

(N=138) Young et al, 2020 (39).

(N=18)

Poor appetite in 70 (34%).

Low appetite in 32 (15.5%)

14 (10.1%)

16 (9%)*

14 (10.1%)

5 (3.6%)

*Both abdominal pain and diarrhoea.

3 (2.2%)

27 (16.5%)

13 (7.9%)

17 (10.4%)

Loss of appetite in 180 (98%).

3 (17%)

Hu Zhang et 62 (37.8%) al, 2020.(40) (N=164) Zhou F et 9 (5%) al, 2020 (41)(N=191)

Gut Microbiome in Covid-19

93 (56.7%) had inappetence,

7 (4%)

“gut-lung axis’. This axis enables

the gut microbiota influences GI

be able to infect GI epithelial

viridae, coronaviridae in general,

Research has demonstrated microorganism inhabitation not only expression occurs in the gut, but ACE2 receptor which bidirectional cross-talkthat between also in therespiratory lungs. Although the concentration of microorganisms the lungs are at lower in turn mayininfluence COVID-19 GI and systems; 52 levels compared to those found in the gut, the result is the creation a local microbiome infectivity andofseverity. whereby inflammation occurring (42). Since the emergence of lung microbiome research, studies have investigated the lung in the lungs can also affect the microbiota composition of individuals with pulmonary diseases such as asthma, chronic Summary 48, 49 As previously gut microbiota. obstructive pulmonary disease (COPD), cystic fibrosis, idiopathic lung disease and lung mentioned, SARS-CoV-2 may common with many cancer and compared it to the composition found In in healthy individuals (43-47).respiratory The relationship microbiota and pulmonary system is referred to as the can cells throughbetween bindingthe togut ACE2 and SARS CoV-2 in particular “gut-lung axis’.

This axis enables bidirectional cross-talk GI the and respiratory infectbetween cells of gastrointestinal receptors expressed there; systems; whereby inflammation also affect the gut microbiota tractcanvia the ACE2 receptor. which in turn play a role inoccurring gut in the lungs (48, 49). As previously mentioned, SARS-CoV-2 may be able to infect GI epithelial cells 50 This microbiome regulation.

The majority of manifestations are through binding to ACE2 receptors expressed there; which in turn play a role in gut relationship raises a fascinating microbiome regulation (50). This relationship raises a fascinating perspective when mild and self-limiting.

However, in a perspective when considering GI considering GI manifestations of COVID-19 and poses the number question on small ofwhether cases,COVID-19 especially manifestations of COVID-19 and (51). Segal et al. reported that there is infection has an impact on the gut microbiota those in critical care, very serious poses the on whether evidence thatquestion the gut microbiota influences GI ACE2 receptor expression which in turn may and potentially fatal complications COVID-19 infection hasand an severity impact(52). influence COVID-19 infectivity

on the gut microbiota.51 Segal et al. reported that there is evidence that

Summary

can arise.

Refences available on request

In common with many respiratory viridae, coronaviridae in general, and SARS CoV-2 in particular can infect cells of the gastrointestinal tract via the ACE2 receptor.

47

GI FOCUS: ENDCOSCOPY

Colon capsule endoscopy is a viable alternative to colonoscopy for the investigation of intermediate- and low-risk patients with gastrointestinal symptoms: results of a pilot study Written by Ismail, Mohd Syafiq1,2; Semenov, Serhiy1,2; Sihag, Sandeep1; Manoharan, Thilagaraj1; Douglas, Atiyekeogbebe Rita2; Reill, Phyllis3; Kelly, Michael3; Boran, Gerard3; O’Connor, Anthony1,2; Breslin, Niall1; O’Donnell, Sarah1; Ryan, Barbara1; McNamara, Deirdre1,2 Department of Gastroenterology, Tallaght University Hospital, Dublin, Ireland

1 2

TAGG Research Centre, School of Medicine, Trinity College, Dublin, Ireland

3

Department of Clinical Chemistry, Tallaght University Hospital, Dublin, Ireland

Colon capsule endoscopy (CCE) is a recommended viable alternative to colonoscopy for colonic visualization in a variety of clinical settings.1 In keeping with the evidence that patients without alarm symptoms are at low risk of colorectal neoplasia, the European Society of Gastrointestinal Endoscopy guideline of 2012 approved CCE use in average risk patients as a non-invasive option.2, 3 Several non-invasive tests have been evaluated in this setting, including the use of faecal biomarkers, fecal calprotectin (FC) and fecal immunological test (FIT) and other imaging modalities, particularly CT colonography.4, 5 Biomarkers are now widely incorporated into patient triaging and vetting procedures and are considered a useful means to priorities cases.6, 7 Biomarkers alone can rule-out significant disease in only a minority and imaging tests are still required in the majority of patients to detect both neoplastic and non-neoplastic conditions.4 As such, evaluation of symptomatic patients still represents a significant burden for colonoscopy services and viable alternatives are needed to help meet increasing demand.8 There is now an abundance of evidence to show CCE is an effective means to detect both neoplastic and non-neoplastic disease in selected patient cohorts including Inflammatory Bowel Disease patient assessment, average and low risk screening, after incomplete colonoscopy and polyp surveillance.9, 10, 11, 12, 13, 14, 15 However, the efficacy of CCE in an unselected average risk symptomatic cohort, with or without biomarker vetting is less clear. While CT Colonography is now an established alternative in symptomatic assessment, CCE could help to improve overall imaging capacity and offer additional advantages including a

simple, non-radiation communitybased alternative.

The aim of this study was to determine the feasibility of CCE imaging assessment in average risk symptomatic patients as an alternative to colonoscopy with and without additional biomarker assessment.

PATIENTS AND METHODS Population This is a prospective, singlecenter comparative study conducted in Tallaght University Hospital, Ireland. We are the only CCE center in Ireland and perform about 150 to 200 CCEs per year. Following ethical approval, patients aged 18 to 80 years, referred from primary care for investigation of lower gastrointestinal symptoms, who required a non-urgent colonoscopy based on vetting by a Consultant Gastroenterologist applying NICE criteria, were identified.6 These patients are considered intermediate or low risk. Exclusion criteria for our study were; patients unable to give informed consent or with a contraindication to either study procedure (history of dysphagia, known or suspected small or large bowel strictures, recent abdominal surgery (within 6 weeks)), a contraindication to bowel preparation or allergies to any study medication, patients with coexisting serious medical illness, pregnant subjects, and patients with an ileostomy.

Subjects on long-term nonsteroidal anti-inflammatories (NSAIDs) could participate if willing to discontinue NSAIDs for 6 weeks prior to study commencement.

As per departmental protocol, everyone on regular NSAID’s had a patency test to exclude small bowel strictures.

Suitable candidates were invited to participate by phone and a study information leaflet was posted to

all potential participants. At the first study visit informed consent was obtained, a medical history, physical examination and routine bloods performed, and study investigations scheduled.

Investigations All CCE’s were performed using PillCam COLON 2 (Medtronic, Minneapolis, United States). A low-residue diet was advised for 24 hours before the CCE. A standard split bowel preparation regimen was used prior to capsule ingestion and booster medications were employed to encourage capsule transit. The study was complete when the capsule was excreted, or the battery ran out. Experienced Capsule Endoscopists, using Rapid Reader Software Version 9, analyzed all videos. Both the first and senior author are approved CCE readers and have performed over 150 and 500 studies respectively. In keeping with our practice, all CCE’s were reviewed at our institutions weekly capsule review board. During the period of this study our bowel preparation and booster regimen changed from KleanPrep (Norgine, Middlesex, UK) with Phospho-soda, “Fleet” (Casen Recordati, Zaragoza, Spain.) and Gastrograffin (Bayer, Reading, UK) boosters to MoviPrep (Norgine, Mid Glamorgan, UK ) bowel preparation and boosters.

We changed our CCE bowel preparation and booster regimen due to a lack of availability of KleanPrep, having been substituted in our hospital pharmacy with MoviPrep during the study and safety concerns regarding the use of Phospho-soda.

Colonoscopy was scheduled for all patients on average 4 weeks after their CCE. Experienced endoscopists, meeting national quality standards, performed all colonoscopies as a day case. The endoscopist was not blinded to the result of CCE. Colonoscopy

Dr Ismail, Mohd Syafiq Assistant Prof/Specialist Registrar: LRCP & SI MB BCh NUI

reports were generated and stored on a national endoscopy database, Unisoft (HD Clinical, Hertfordshire, UK).

As per our departmental guidelines, for CCE we classified the preparation as being Good, Adequate, or Poor. This is slightly modified from the recommendation from ESGE guidelines for CCE 2012, where we combined the good and excellent rating as Good.3 For colonoscopy, we had classified prep as being good, adequate/ complete, and poor. This is based on pre-assigned prompts from the Unisoft endoscopy reporting system. This system is based on the Aronchick scale.

Significant polyps on CCE were defined, as per ESGE guidelines, as the presence of > 3 lesions or a polyp greater than > 6 mm based on polyp size estimation.3 Significant polyps on colonoscopy was defined as the presence of > 3

HOSPITALPROFESSIONALNEWS.IE | HPN • MARCH 2022

48

GI FOCUS: ENDCOSCOPY

Fig. 1 Study population

polyps, and adenomas or sessile serrated lesions > 10 mm in size.

Any histology specimens were processed and reported as normal by our institution’s pathology department.

Both FC and FIT samples were collected and delivered within 24 hours directly to the hospital laboratory and processed as standard.

Analysis Basic demographics, presenting symptoms, initial blood work, biomarker levels, all CCE and Colonoscopy findings were recorded. For analysis, clinically significant colonic findings included colorectal cancer, high risk adenoma as defined by ESGE and inflammatory bowel disease.

Clinically significant small bowel disease was defined as significant ulceration consistent with Crohn’s disease or NSAID enteritis, suspicious submucosal masses and P1 vascular lesions in subjects with a suspicion of bleeding. A FIT of > 10 ug/g and FC > 50 ug/g were considered positive.

A per protocol analysis was performed in this study. For comparisons, colonoscopy was considered the gold standard investigation. CCE findings were compared to colonoscopy and CCE sensitivity, specificity and positive and negative predictive values determined, for any and clinically significant findings.

Pearson Coefficient was also used to assess correlation between colonoscopy and CCE findings where an r value of ≥ 0.7 was considered a strong correlation.

Similarly, the accuracy of both FC and FIT was determined.

Ethics approval This study was approved by Tallaght University Hospital/St. James's Hospital Joint Research Ethics Committee (REC).

RESULTS Study population In total, 77 patients were recruited.

Of these, one withdrew consent prior to any investigation, two became pregnant after recruitment and four did not attend their CCE appointments. Of the 70 included patients, two did not have a colonoscopy after their CCE as they were not able to be contacted, one patient could not swallow the CCE capsule and in one case there was technical failure of the capsule on ingestion; all of these patients refused a colonoscopy. As a result, there were 66 patients with both CCE and colonoscopy tests available for analysis (Fig. 1). Only one patient received and passed a patency capsule for a history of chronic NSAIDS use. The mean age of our cohort was 45.8 years (range 20–79) and 42 % (n = 27) were male. The predominant symptom in 22 (34 %) patients was bleeding, 28 (44 %) diarrhea, seven (11 %) alternating constipation and diarrhea, five (8 %) abdominal pain, two (3 %) weight loss and one (1 %) chronic constipation. As expected only two patients (3 %) had anemia detected on baseline bloods defined as Hb < 11.2 g/dL in women and < 12.8 g/dL in men.

MARCH 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE

A C-reactive protein (CRP) was available in 62 patients (97 %) and 56 patients had an erythrocyte sedimentation rate (ESR). In all, 16 % (10/62) had a positive CRP (> 5 mg/L). Mean CRP was 4.1 mg/L (range 1–57.9). While, 32 % (18/56) had a positive ESR (> 20 mm/hr).

Mean ESR was 12.5 (1–47) mm/hr.

Colonoscopy performance The cecal intubation rate was 94 % (n = 62). Bowel preparation was excellent in 39 % (n = 26) adequate in 53 % (n = 35) and poor in 8 % (n = 5). In all, 64 % (n = 42) of colonoscopies had a positive finding, with clinically significant disease reported in 24 % (n = 16), including two with a histological diagnosis only (one lymphocytic, one TB colitis). Included as clinically significant disease were six cases of histologically confirmed IBD (3 UC, 3 CD), one case of radiation proctitis, seven patients with high-risk polyps (3 adenomas > 10 mm, four > 3 adenomas and one large > 10 mm sessile serrated right colon lesion) and both microscopic colitis cases (Table 1 - on page 50).

CCE performance In 66 of 68 (97 %) patients referred for CCE videos were available for review and compared to colonoscopy. The excretion rate was 76 % (n = 50). Bowel preparation quality was good in 38 % (n = 25), adequate in 55 % (n = 36) and inadequate in 8 % (n = 5). Overall, 40 (61 %) CCE’s were positive. There were no procedure related complications (Table 1). CCE abnormalities included; polyps in 23 (35 %), diverticulosis in 14 (21 %) and Colitis in n = 3 (5 %). Overall n = 8 (12 %) had significant polyps (> 3 lesions or a polyp > 6 mm). Any small bowel findings were reported in n = 15 (22 %) subjects, 3 (5 %) deemed clinically significant and was subsequently diagnosed with Crohn’s disease. In all, 14 (21 %) had clinically significant disease detected on CCE. There was one false-positive and three false-negative CCEs in 16 patients with significant disease on colonoscopy. In all, there were two patients with distal colonic inflammation overlooked. In these cases, one had very distal

RESPIRATORY OBESITY

ELDERLY

CARDIAC

WHEN CONTROL OF NMB REVERSAL IS WHAT MATTERS

BRIDION INDICATIONS • Reversal of rocuronium (ROC) or vecuronium (VEC) induced neuromuscular block (NMB) in adults.

• For routine reversal of ROC-induced block in children and adolescents aged 2 to 17 years.1 investigated in patients receiving ROC or VEC in the ICU setting. Do not use sugammadex to reverse block induced by nonsteroidal blockers such as succinylcholine or benzylisoquinolinium compounds, or steroidal blockers other than ROC or VEC. Conditions associated with prolonged circulation time such as cardiovascular disease, old age, or oedematous state may cause longer recovery times. Be prepared for possible drug hypersensitivity reactions. This medicinal product contains up to 9.7 mg sodium per ml, equivalent to 0.5 % of the WHO recommended maximum daily intake of 2 g sodium for an adult. OVERDOSE No dose related adverse events nor serious adverse events were reported. Sugammadex can be removed using haemodialysis with a high flux filter. INTERACTIONS Toremifene and fusidic acid may displace rocuronium or vecuronium from sugammadex and delay recovery (no clinically relevant capturing interactions are expected). Interaction of sugammadex with hormonal contraceptives may lead to a decrease in progesterone exposure equivalent to one missed daily dose of oral contraceptive (no displacement interactions are expected). In general sugammadex does not interfere with laboratory tests, with the possible exception of the serum progesterone assay where interference is observed at sugammadex plasma concentrations of 100 μg/ml plasma. In a study doses of 4 mg/kg and 16 mg/kg sugammadex resulted in maximum mean prolongations of the activated partial thromboplastin time by 17 and 22% respectively and prothrombin time by 11% and 22% respectively. These were of short duration (≤ 30 minutes). In in vitro experiments pharmacodynamic interaction was noted with vitamin K antagonists, unfractionated heparin, low molecular weight heparinoids, rivaroxaban and dabigatran. PREGNANCY AND LACTATION Pregnancy and Lactation: Caution in pregnant women. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from sugammadex therapy, taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman. The effects on human fertility have not been investigated. SIDE EFFECTS Refer to SmPC for complete information on side effects. Common (≥ 1/100 to < 1/10): Anaesthetic complications including movement of limbs or body or coughing during anaesthesia, grimacing, or suckling on the endotracheal tube, airway complication of anaesthesia, procedural hypertension and procedural complication. Uncommon (≥ 1/1,000 to < 1/100): Hypersensitivity reactions, including anaphylaxis, have occurred in some patients and volunteers. Other less common and rarely reported side effects are listed in the SmPC. In clinical studies with subjects treated with rocuronium or vecuronium, where sugammadex was administered using a dose labelled for the depth of neuromuscular blockade, an incidence of 0.2% was observed for recurrence of neuromuscular blockade as based on neuromuscular monitoring or clinical evidence. The use of lower than recommended doses may lead to an increased risk of recurrence of neuromuscular blockade after initial reversal and is not recommended. HANDLING See SmPC for details of compatability with infusion solutions. Physical incompatibility has been reported with verapamil, ondansetron and ranitidine. PACKAGE QUANTITIES 10 vials of 2 ml, 10 vials of 5 ml.

LEGAL CATEGORY POM. Marketing Authorisation Numbers EU/1/08/466/001-002. Marketing Authorisation Holder Merck Sharp & Dohme B.V., Waarderweg 39, 2031 BN Haarlem, The Netherlands. Date of review of prescribing information: April 2020. © Merck Sharp and Dohme B.V., 2020. All rights reserved. Further information is available on request from: MSD, Red Oak North, South County Business Park, Leopardstown, Dublin 18 or from www.medicines.ie. Date of preparation: July 2020. EMEA/H/C/000885/II/0036.

Reference: 1. Bridion SPC April 2020

PREDICTABLE. COMPLETE. RAPID.

Adverse events should be reported. Reporting forms and information can be found at www.hpra.ie.

Adverse events should also be reported to MSD (Tel: 01-299 8700)

Red Oak North, South County Business Park, Leopardstown, Dublin D18 X5K7 Ireland

IE-XBR-00032

BRIDION® 100 MG/ML SOLUTION FOR INJECTION (Sugammadex) ABRIDGED PRODUCT INFORMATION Refer to Summary of Product Characteristics (SmPC) before prescribing. PRESENTATION Vials of 200mg (2 ml) or 500mg (5 ml). INDICATIONS Reversal of rocuronium (ROC) or vecuronium (VEC) induced neuromuscular (NM) block in adults. For routine reversal of ROC-induced block in children and adolescents aged 2 to 17 years. DOSAGE AND ADMINISTRATION I.V. as a single bolus injection administered rapidly (within 10 seconds), into an existing I.V. line, by/under the supervision of an anaesthetist. Use appropriate technique to monitor recovery of NM block. Dose depends on the level of block to be reversed, not the anaesthetic regimen. Adults: Routine reversal following ROC- or VEC-induced block: • 4 mg/kg if recovery has reached at least 1-2 post-tetanic counts (PTC). Median recovery time (T4/T1 = 0.9) ≅ 3 minutes. • 2 mg/kg if recovery has occurred up to at least T2 following ROC- or VEC-induced block. Median recovery time (T4/T1 = 0.9) ≅ 2 minutes. Median recovery time (T4/T1= 0.9) is slightly faster with ROC- than VEC-induced block. Immediate reversal of ROC-induced block: 16 mg/kg. Median recovery time (T4/T1 = 0.9) ≅ 1.5 minutes when 16 mg/kg is given 3 minutes after a bolus dose of 1.2 mg/kg ROC. Not recommended for immediate reversal of VEC-induced block.

Re-administration of sugammadex: For post-operative recurrence of block after an initial dose of 2 mg/kg or 4 mg/kg, repeat dose of 4 mg/kg is recommended. Following a second dose of sugammadex, monitor the patient closely to ascertain sustained return of neuromuscular function. Re-administration of ROC or VEC after sugammadex: Up to 4 mg/kg Sugammadex a waiting time of 5 minutes for re-use of 1.2 mg/kg ROC; 4 hours waiting time for re-use of 0.6 mg/kg ROC or 0.1 mg/kg VEC. With ROC onset of NM block may be prolonged and duration of NM block may shortened. After immediate reversal, 16 mg/kg sugammadex, a waiting time of 24 hours is recommended. See SPC for patients with mild or moderate renal impairment. Special populations: Renal impairment: For mild and moderate renal impairment use adult dose. Not recommended in severe renal impairment (including patients requiring dialysis). Elderly: Use adult dose although recovery times are slower. Obese: In obese patients, including morbidly obese patients (body mass index ≥ 40 kg/m2), adult dose based on actual body weight. Hepatic impairment: Caution in patients with severe hepatic impairment, or impairment with coagulopathy. Children and adolescents (2-17 years): 2 mg/kg for routine reversal of ROC-induced block at T2. Not recommended in other routine reversal situations. Not recommended for Immediate reversal. May be diluted for accuracy of dose. Term newborn infants and infants: Not recommended. CONTRA-INDICATIONS Hypersensitivity to sugammadex or to any excipients. PRECAUTIONS AND WARNINGS Ventilatory support is mandatory for patients until adequate spontaneous respiration is restored following reversal of block. Should block reoccur following extubation, adequate ventilation should be provided. The use of lower than recommended doses may lead to an increased risk of neuromuscular blockade after an initial reversal and is not recommended. Caution should be exercised when considering the use of sugammadex in patients receiving anticoagulation for a pre-existing or co-morbid condition. An increased risk of bleeding cannot be excluded in patients with hereditary vitamin K dependent clotting factor deficiencies; with pre-existing coagulopathies; on coumarin derivatives and at an INR above 3.5; using coagulants who receive a dose of 16mg/ kg sugammadex. If re-administration of ROC or VEC is required in patients with mild or moderate renal impairment after routine sugammadex reversal a waiting time for re-use of 0.6 mg/kg ROC or 0.1 mg/kg VEC should be 24 hours. If a shorter waiting time is required, the ROC dose for a new NM blockade should be 1.2 mg/kg within 30 minutes after Sugammadex administration. For re-administration of ROC or VEC after immediate reversal a waiting time of 24 hours is recommended. If neuromuscular block is required before the recommended waiting time has passed, a nonsteroidal neuromuscular blocking agent should be used. The use in patients with severe renal impairment is not recommended including those requiring dialysis. If neuromuscular block is reversed, while anaesthesia is continued, additional doses of anaesthetic and/or opioid should be given as clinically indicated. Marked bradycardia with cardiac arrest have been observed within minutes after administration, closely monitor patients for hemodynamic changes during and after reversal. Treat with anti-cholinergic agents such as atropine if clinically significant bradycardia observed. Sugammadex has not been

50

Diagnostic yield by test.

GI FOCUS: ENDCOSCOPY

Table 1: Diagnostic yield by test

radiation proctitis and the other case the capsule was incomplete.

CCE by its nature misclassified the two patients with histologically diagnosed colitis; however, in one of these patients, they also had a significant polyp based on CCE. The only false- positive was accounted for by variation in classification of a polyp based on size. Of note, all significant polyps on colonoscopy reached the CCE threshold for excision. The sensitivity, specificity, positive and negative predictive values of CCE for significant disease were 81 %, 98 %, 93 % and 94 % respectively (Table 2 on page 51). The overall correlation between colonoscopy and CCE was moderate, Pearsons r = 0.49 but was strong for significant disease r = 0.83.

Biomarker performance In all, FIT and FC samples were available for 56 (85 %) and 59 (89 %) subjects. FIT was positive (> 10 ug/g) in 31 cases (47 %), range 1–1992 ug/g. Within this cohort there were six false-negative FITs in patients diagnosed with clinically significant disease on colonoscopy (n = 14). Overall, the sensitivity, specificity, positive and negative predictive values of FIT for CSD were 57 %, 60 %, 32 % and 81 %. FC was positive (> 50 ug/g) in 23 patients (40 %), range < 19.5 to 1250 ug/g. There were foiur false-negative FCs in 10 patients with CSD. The sensitivity, specificity, and positive and negative predictive values of FC for CSD were 40 %, 64 %, 26 %, and 88 %, respectively (Table 2).

With respect to the seven highrisk polyp cases specifically, four of six (67 %) returned a positive FIT and four of seven (57 %) a positive FC. Similarly, of the seven cases of colitis on colonoscopy FC was positive in five (71 %), unsurprisingly the FIT was also positive in five patients (71 %) with colitis. Neither CRP nor ESR were predictive of either CCE or Colonoscopy detected disease.

Diagnostic yield by test.

Parameter N (%)

Colonoscopy CCE (+) FIT (+) FC

Number

66

66

31/56

23/57

Completion rate

94 (62)

76 (50)

n/a

n/a

Inadequate preparation

5 (8 %)

5 (8 %)

n/a

n/a

Normal study

24 (36 %)

26 (39 %) n/a

n/a

Any positive finding

42 (68 %)

40 (60 %) 19/37 (49 %) 16/39 (41 %)

Clinically significant disease

16 (24 %)

14 (21 %)

Polyps

21 (32 %)

23 (35 %) n/a

n/a

Significant polyp

7 (11 %)

8 (12 %) n/a

n/a

Colitis

6 (9 %)

3 (5 %)

n/a

n/a

Diverticulosis

11 (17 %)

14 (21 %) n/a

n/a

Haemorrhoids

3 (5 %)

0

n/a

n/a

Microscopic colitis

2 (3 %)

n/a

n/a

n/a

Significant small bowel disease

3 (5 %)

3 (5 %)

n/a

n/a

8/14 (57 %)

4/10 (40 %)

CCE, colon capsule endoscopy; FIT, fecal immunochemical test; FC, fecal calprotein CCE, colon capsule endoscopy; FIT, fecal immunochemical test; FC, feca

Discussion CCE performance

could improve future detection of addition, in the real word/clinical proctitis and warrants additional scenario, the capsule report Our pilot prospective singleinvestigation. is going to be available to the center analysis of CCE efficacy endoscopist before proceeding In of 68symptomatic (97 %) patients referred for CCE videos were available for re in an66 unselected As expected, CCE was unable to colonoscopy. cohort suggests CCE is a viable to diagnose both cases of colonoscopy.

The excretion rate was 76 % (n =microscopic 50). Bowel preparation q alternative to colonoscopy. As colitis. Neither case In our cohort, CCE accurately expected only aadequate small proportionin 55 had a positive result. (n = 25), % (nall=significant 36) and inadequate in 8biomarker % (n = 5). Overa detected polyps of patients were found to Both had an established history of and had a similar diagnostic positive.

There were no procedure related complications ( [Table 1] ). CC have significant disease on watery diarrhoea. As such, clinical accuracy for benign disease with colonoscopy, (24 %).

The%), diverticulosis acumen the adherence polyps in1623 (35 14 andand Colitis in nwith = 3 (5 %) PPV’s and NPV’s of in 83 % and(21 %) majority of patients while needing biopsy protocols in suspected 65 % and 93 % and 94 % for any and often benefiting from a cases with a normal macroscopic finding and clinically significant negative test or low-risk diagnosis colon is important to prevent disease respectively. However, did not necessarily require an overlooking microscopic colitis. detection rates for colitis were invasive colonoscopy. Viable A negative CCE should not have less than optimal compared to alternatives, which offer similar prevented further referral for biopsy. colonoscopy: three of seven diagnostic accuracy and enhanced (43 %). Only three of seven with Despite the overall good capacity, would be of benefit colitis on colonoscopy ended performance of CCE in our study, to both patients and the health up with a diagnosis of UC. This the capsule excretion rate remains service alike. is difficult to explain as previous low at 76 %. Analysis is in some studies and those with modern After the CCE, colonoscopies way hampered by the required capsules have found a high rate were performed on average 4 change in bowel preparation and of diagnostic accuracy in IBD.9, 16 weeks from the CCE procedure. booster regimen during this study.

For very distal limited proctitis the The rationale for this is that Optimising capsule excretion process of excretion may affect previous blinded studies have rates remains a priority and like video interpretation, with distal assumed CCE findings not others, we continue to adapt inflammation being mis-classified detected on the colonoscopy our preparation and booster as a normal rectal cushion. Initial were a false negative, whereas regimens in line with current analysis of our cohort would recent evidence suggests that data.17 Following study conclusion, support this supposition with if the negative colonoscopy is audits of recent changes to two-thirds reclassified as showing repeated, unblinded, many polyps our bowel preparation (2 L PEG disease on repeat reading. previously overlooked were found solution) and booster regimen on the repeat procedure.11 In Enhanced awareness and training (PEG booster + Castor oil) has

MARCH 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE

Table 2: Diagnostic accuracy by test compared to colonscopy for clinically significant disease

51

Diagnostic accuracy by test compared to colonoscopy for clinically significant disease.

Test

Sensitivity % Specificity% PPV% NPV%

Clinically significant disease CCE

Any positive finding

81

98

93

94

FIT > 10 ug/g 57

60

32

81

FC > 50 ug/g

40

64

26

88

CCE

79

71

83

65

FIT > 10 ug/g 49

63

72

61

FC > 50 ug/g

37

70

66

41

Table 2: Diagnostic accuracy by test compared to colonscopy for clinically significant disease

CCE, colon capsule endoscopy; FIT, fecal immunochemical test; FC, fecal calprotein.

CCE, colon capsule endoscopy; FIT, fecal immunochemical test; FC, fecal calprotein. shown an 87 % capsule excretion polyp detection of 21/66 (32 %) direct comparison of CCE with neoplasia and inflammatory rate and also improved image colonoscopy. This study design bowel disease, they are not a was enhanced in our study Biomarker performance improving quality.18, 19 Similarly, does hamper recruitment. We feel replacement for direct colonic by prior CCE. The CCE polyp and standardising reporting of that in the setting of a pilot study visualisation. Our study supports detection rate was 35 %. Apart preparation quality in CCE is assessing a novel aspect of CCEFIT was their role in selecting outpatients from positive polyp detection, all cases In all, FIT and FC samples were available for 56 (85 %) and 59 (89 %) subjects. an area of ongoing research.20 in investigating the symptomatic with a higher risk of clinically of terminal ileal Crohn’s disease (> 10 ug/g) insuboptimal/ 31 cases (47 %), range 1–1992 ug/g. Within this cohort there were six false-negative However, rates of patient, where patients had significant disease, with five of were initially picked up on CCE, if FITs in patients diagnosed with clinically significant disease on colonoscopy the does not routinely inadequate bowel preparation to undergo both CCE and (n = 14). Overall, seven cases of colitis and four of an endoscopist were similar for specificity, both CCE and positive sensitivity, and predictive values of FIT for CSD were 57perform %, 60 terminal %, colonoscopy including two sets seven withnegative high-risk adenomas ileal intubation, colonoscopy, five%. of 66 (8 %), bowel preparation, the19.5 sample having a 50 positive biomarker these casesThere would have been 32 % and 81 FC was positive (> ug/g) in 23 study. patientsof (40 %), range < to 1250 ug/g. highlighting the importance of this sizesensitivity, is adequate tospecificity, draw some low patients positive predictive value The If borne were foiur false-negative FCsTheir in 10 with CSD. andmissed. positive andout in additional issue for both tests. form of a conclusion as a proof for clinically significant disease, studies this would represent negative predictive values ofFIT FC32for CSD were 40 %, 64 %, 26 %, and 88 %, respectively ( [Table 2] of concept. We welcome bigger % and FC 26 %, suggests another advantage for CCE As with CT colonography, CCE ).

With respect to the seven referring high-risk polypbiomarker cases specifically, four studies of six in(67 returned multi-centred the%) future all positive patientaselection. has the potential to visualise more positive and four (57 %) positive FC. ofthis the seven cases of colitis on following initial pilot study. patients for aacolonoscopy may Similarly, than just theFIT colon, which mayof beseven warranted andunsurprisingly alternatives colonoscopy FC was positive not in be five (71 %), the FIT was also positive inConclusion five patients particularly advantages in patients A strength, however, is that such as CCE or CT colonography with chronic gastrointestinal CCE is a safe and effective (71 %) with colitis. Neither CRP nor ESR were predictive of either CCE or Colonoscopy detected endoscopists were unblinded remain options. For biomarker symptoms. In this study, while small alternative to colonoscopy in disease. to the CCE result, which may negative individuals, based on our bowel abnormalities were detected symptomatic average risk patients account for the relatively low data, noninvasive imaging may be in 15 (22%) only three (4.5%) with or without the addition of discrepancy rate in all polyp preferred. Both algorithms warrant were significant, all with enteritis, biomarker screening. detection. Previous studies further consideration. resulting in changed management. have suggested CCE accurately References available on request detects more polyps than The small size of our study is a The use of biomarkers is now This article first appeared in colonoscopy, which can later drawback, but we feltof theCCE lack efficacy commonplace in the assessment Our pilot prospective single-center analysis in an unselected symptomatic cohort Endoscopy International Open be found on a targeted repeat of available evidence for CCE of patients presenting to hospital suggests CCE is a viable alternative to colonoscopy. As expected only a small proportion of 2021; 09(06): 965-970 colonoscopy.11 As such, it remains use in a symptomatic unselected or community clinics. While they patients were found to have cohort significant disease 16that (24 The majority a possibility our%). colonoscopy DOI: of 10.1055/a-1401-9528 warranted a furtheron colonoscopy, are helpful indicators of significant

Discussion

patients while needing and often benefiting from a negative test or low-risk diagnosis did not necessarily require an invasive colonoscopy. Viable alternatives, which offer similar diagnostic accuracy and enhanced capacity, would be of benefit to both patients and the health service alike.

GI News

Specialised IBS Diet Plan Less Important A new study has shown that a specialised IBS diet plan that avoids certain types of food and often excludes gluten is not as necessary as previously believed.

Researchers from Chalmers University of Technology and Uppsala University in Sweden have found no correlation between high gluten intake and increased IBS symptoms. The researchers did find that a certain type of carbohydrate called ‘fodmaps’ that can aggravate intestinal problems; however, the overall results indicate that this also has less influence than previously thought.

In this new study reseachers used rice pudding prepared in different

ways in order to mimic IBS triggers on group of 110 people with IBS problems.. The first rice pudding variety was rich in gluten, and the other one contained large amounts of the carbohydrate of the fodmap variety, which is fermentable carbohydrates.

Many foods are rich in fodmaps, including dairy products, types of bread and certain fruits and vegetables. Additionally, the researchers created a neutral rice pudding as a placebo that would be suitable for an IBS diet plan.

Participants ate the rice puddings rich in fodmaps, gluten, and the IBS diet plan friendly version

with no aggravating ingredients, in a random order, for one week per category. The study was double-blind, meaning neither the participants nor researchers knew who ate which pudding and when.

“Diet studies are difficult to conduct double-blind, as it can often be obvious to the participants what they are eating.

This is a big obstacle, as the knowledge that something has been added to or removed from the diet can affect the result. The fact that we succeeded in creating diets that were completely blind, together with a large number of participants, makes our study unique,” explained Elise Nordin,

PhD student in Food Science at Chalmers and lead author of the scientific article, published in the American Journal of Clinical Nutrition.

The subjects’ gastrointestinal systems were provoked through high doses (1.5 times daily intake in a normal population) of fodmaps and gluten. The fodmaps aggravated the symptoms, but not to the extent that the researchers had expected based on results from previous studies. Gluten, on the other hand, was found to have no measurable negative effect on the subjects’ perceived symptoms.

HOSPITALPROFESSIONALNEWS.IE | HPN • MARCH 2022

52

GI FOCUS: HELICOBACTER PYLORI

Association of Helicobacter Pylori With Development of Peptic Ulcer Disease Among Cirrhotic Patients: An Evidence From Population-Based Study Written by Tsu Jung Yang, Krithika Dhanasekar, Renu Bhandari, Divya Muraleedharan, Swathy S. Chirindoth, Harpreet Kaur, Ruchir Goswami, Prakash Maiyani, Maheshkumar Desai, Dharmeshkumar V. Moradiya, Hiteshkumar Devani, Achint A. Patel

Dr Tsu-jung Yang

Introduction Chronic liver disease and its complications are major health problems. There is evidence to suggest higher bleeding complications, delayed healing, and a greater ulcer recurrence rate in patients with liver cirrhosis compared with the general population.1 In a study by Kamalaporn et al., the prevalence of peptic ulcer disease (PUD) in cirrhotic patients reported by endoscopy screening studies was approximately 5% to 20% when compared with 2% to 4% in the general population.2 The reasons for the increased ulcer rate in cirrhotic patients are unknown.

Oxidative stress that causes gastric tissue damage in cirrhosis may be one of the components causing gastric lesions and hemorrhage.3 Studies have shown that PUD has been the cause of upper GI bleeding in almost 10% of cirrhotic patients4 An episode of upper GI bleeding can actually worsen the prognosis of cirrhotic patients.5 Eradication therapy may be beneficial because it diminishes the risk of recurrent PUD.6 Helicobacter pylori (H. pylori) are a non-invasive gram-negative bacterium that colonizes gastric mucosa and causes PUD.7 Although several virulence factors of H. pylori have been identified but the precise mechanism by which it causes mucosal damage is yet to be understood.3,8 H. pylori play an important role in causing PUD in the general

population. However, its role in cirrhosis remains obscure. There are various studies on H. pyloriassociated with PUD in cirrhotic patients, but the results have been non-conclusive regarding the association of H. pylori with PUD in patients with liver cirrhosis.9-11 Therefore, there is a need for further study in this area. In the present study, we aim to find an association of H. pylori with PUD in patients with liver cirrhosis by using the largest nationally representative database.

MATERIALS & METHODS Data sources We derived a study cohort from the National (Nationwide) Inpatient Sample (NIS) of the Healthcare Cost and Utilization Project (HCUP), Agency for Healthcare Research and Quality (AHRQ).

NIS is one of the largest all-payer publicly available databases on inpatient discharges from U.S. hospitals maintained by the AHRQ. The NIS approximates a 20-percent stratified sample of discharges from U.S. community hospitals, excluding rehabilitation, and long-term acute care hospitals, and contains more than 7 million hospitalizations annually.12 With the established weights in NIS, this data could be weighted to represent the standardized U.S. population and obtain national estimates with high accuracy.13 The NIS contains data from 1000 hospitals and includes information on about eight million

MARCH 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE

hospitalizations each year. The database represents a random, 20% stratified sample of all inpatient discharges from 46 states (representing >97% of discharges from all the US hospitals). Variable “DISCWT” (Discharge-level weight) is provided by HCUP to generate national estimates.13 The sample sizes and the proportions presented in this study are the weighted estimates obtained by applying the discharge level weights. Each individual hospitalization in this database is de-identified and maintained as a unique entry with one primary discharge diagnosis.

Study population and design We used data of 2017 for analysis purposes based on complete data availability during this time period. We restricted analyses to only adult hospitalizations. We identified various diagnoses of interest by using the International Classification of Diseases, 10th Revision, Clinical Modification (ICD-10-CM) diagnosis codes.

Hospitalization with Peptic Ulcer Disease (PUD) was identified with the presence of ICD-10-CM codes of K25xx-K28xx in any diagnostic field that is available in the dataset.

These codes have been used by previously published articles from administrative databases such as NIS [14]. Similarly, cirrhosis by previously validated ICD-10-CM diagnosis codes K74.60 and H. pylori infection by using B96.81.15 Definition of variables We extracted demographics, hospital-level characteristics (geographical region, size, and teaching status), and patientlevel characteristics as supplied as part of NIS. We estimated comorbidities using Elixhauser comorbidity software, which is also supplied by HCUP tools and software [16]. Specific concurrent medical conditions and procedures of interest were identified by ICD-10-CM diagnosis and procedure codes.

End point The primary objective of the

study was to estimate the association of H. pylori to PUD in cirrhotic patients. The secondary objective was to determine the baseline characteristics and factors associated with H. pylori infections in patients with PUD and concurrent cirrhosis.

Statistical analysis Descriptive statistics were used to compare and present the baseline population. Categorical variables were compared with the chi-square test, and continuous variables were compared with Student's t-test or Wilcoxon rank-sum test based on the distribution of data variables. To estimate the association of H. pylori to PUD in cirrhotic patients, we formulated logistic regression models and adjusted them for potential confounders. First, we formulated a regression model by inserting hospitalization due to PUD as an outcome variable and the presence of cirrhosis and H. pylori as independent variables. Then we inserted interaction between cirrhosis and H. pylori in a regression model in order to estimate the association of H. pylori to PUD in cirrhotic patients. In a final regression model to calculate adjusted estimates, we included patient demographics, comorbidities, and other concurrent factors such as NSAIDs, steroids use, alcoholism, and smoking.

We utilized Statistical Analysis System (SAS) 9.3 (SAS Institute, Cary, NC, USA) for all analyses and included designated weight values to produce nationally representative estimates.13 For regression models, we used survey procedures to account for the inherent survey design of NIS to produce more robust estimates.17 We considered a two-tailed p-value <0.05 as statistically significant.

RESULTS Association of H. pylori with PUD in cirrhotic patients In 2017, there were 30,421,825 adult hospitalizations in the USA,

53 out of which 956,020 had cirrhosis, and 431,825 had PUD present in their diagnoses. Prevalence of H. pylori was 2.2% in cirrhotic patients with PUD and 2.8% in non-cirrhotic patients with PUD. In regression analysis, H. pylori was associated with PUD in cirrhotic patients (OR 15.1; 95% CI: 13.9-16.4; p <0.001) and non-cirrhotic patients (OR 48.8; 95% CI: 47.5-50.1; p <0.001).

Baseline characteristics of patients with PUD and concurrent cirrhosis

by H. pylori status Demographic characteristics of patients admitted due to PUD with underlying cirrhosis and having H. pylori were more likely to be 50-64 years old (49.4% vs 44.1%; p <0.0001), male (63.4% vs 59.9%; p <0.0413), African American (16.3% vs 10.6%; p <0.0001), and Hispanic (26.2% vs 14.9%; p <0.0001). H. pylori are more likely to be associated with complicated PUD hospitalizations (51.2% vs 44.2%; p <0.0067). Alcoholism and smoking were more common in the H. pylori group compared to those without H. pylori infection (43.6% vs 35.8%; p <0.0001 and 33.7% vs 24.8% p <0.0001, respectively).

Moreover, low median household income (39% vs 31.8%; p <0.0001) and uninsured/self-pay (18.6% vs 10.1%; p <0.0001) were more prevalent in patients with H. pylori infection.

Factors associated with H. pylori infection in patients with PUD and concurrent cirrhosis Several predictors associated with H. pylori infection among patients with PUD and concurrent cirrhosis are African American (OR 2.3, 95% CI: 1.5-3.6), Hispanic (OR 2.6, 95% CI: 1.7-4.0), and smoking (OR 1.5, 95% CI: 1.1-2.2).

prevalence of H. pylori infection in cirrhotic patients compared to the general population.

However, the results varied with the method of diagnosis (serological versus endoscopic diagnosis).20,21 A meta-analysis

by Vergara in 2002 suggested a high prevalence of H. pylori infection without PUD in cirrhotic populations.22 Asymptomatic H. pylori infection might contribute to low prevalence in the present study because the majority of H. pylori infections could have been underdiagnosed. This postulate is supported by a Greek study of asymptomatic patients with cirrhosis undergoing screening endoscopy. The study did not find an association between H. pylori infection and PUD in cirrhotic patient.5 Congestive gastropathy from portal hypertension in liver cirrhosis resulting in a hostile environment for H. pylori might be contributory.23,24 Furthermore, a study by Kim et al. suggested that the severity of liver cirrhosis is inversely related to the presence of H. pylori infection.25 H. pylori are well known to cause PUD, chronic gastritis, gastric cancer, and gastric mucosaassociated lymphoid tissue lymphoma. Their pathogenic role in liver cirrhosis is not exactly clear. Nonetheless, our results suggested that their presence is more likely to be associated with complicated hospitalizations in the studied population (51.2% vs 44.2%; p <0.0067). This finding is contradictory to previous

studies, which suggested that H. pylori may not play a role in cirrhotic patients with PUD.23,24,26 Although the prevalence may be low especially in decompensated cirrhotic patients, the infection is more likely to be associated with follicular gastritis and gastric variceal bleeding. Different types of gastritis from H. pylori infection, such as atrophic versus follicular types, can explain the inconsistency in our results.

Atrophic type causes low gastric acid secretions due to atrophied parietal cells, whereas follicular type causes increased gastric acid secretions by stimulating gastrin secretion from G cells. H. pyloriinduced follicular gastritis can be considered as an independent risk factor for gastric variceal bleeding, which can result in complicated hospital admissions.27 However, it is not exactly clear which type is predominant in PUD patients with cirrhosis.

H. pylori infection was more common in middle-aged, African American, or Hispanic, male patients compared to those without the infection according to our study. According to our literature search, we did not notice a similar epidemiologic study in the US population that evaluated the association of H. pylori infection with PUD in cirrhotic patients. However, a large histo-epidemiological study by Sonnenberg et al. suggested that H. pylori infection is more common

in males and low socioeconomic populations.28 A serological study of H. pylori in low-income individuals in the southeastern United States by Epplein et al. suggested that African Americans had two- to six-fold increased odds of H. pylori seropositivity after adjusting socioeconomic status.29 In addition, a singlecenter histopathological study

by Nguyen et al. mentioned the highest risk of H. pylori infection among African American and Hispanic populations.30 In line with previous studies, the present study suggested that being African American or Hispanic increases the odds of H. pylori infection by 2.3- and 2.6-folds, respectively.

Risk factors contributing to H. pylori infection in the studied population could have been similar to the general population hence explaining our results.

It is well known that alcohol and smoking are related to PUD, whereas their relationship to H. pylori infection is not exactly clear.

In the present study, smoking increases the odds of H. pylori infection by one-and-half folds (OR 1.5, 95% CI: 1.1-2.2, p <0.001).

This is in contrast to one Chinese and two Japanese studies that reported a negative association between smoking and H. pylori infection.31-33 On the contrary,

Discussion Several significant findings of the present study include the following: (1) H. pylori were significantly associated with PUD in cirrhotic patients, (2) the prevalence of H. pylori among patients admitted with PUD and concurrent cirrhosis was lower than the general population, (3) African American, Hispanic, and smoking were significant factors associated with increased odds of H. pylori infection.

The prevalence of H. pylori infection varies with different geographic locations around the world. It ranges from 50%-70% in Asian countries to 15.5% in an Australian study of mainly white population.18 In a meta-analysis

by Hooi et al., the pooled H. pylori prevalence estimate for the United States (US) general population was 35.6%.19 Compared to our findings, previous studies have suggested a higher HOSPITALPROFESSIONALNEWS.IE | HPN • MARCH 2022

54

GI FOCUS: HELICOBACTER PYLORI

a study from Northern Ireland reported a positive correlation, whereas other studies reported no association between smoking and H. pylori infection.34-36 The only Asian study that suggested a positive correlation was a singer center Japanese study that included outpatient male smoking patients.37 The genetics, racial, and lifestyle differences may explain the discrepancy because the majority of our studied population was white and more closely resembled the Northern Ireland study. Unfortunately, our study was not designed to evaluate the difference in those results. Several studies in different parts of the world have mentioned a negative correlation between alcohol and H. pylori infection.31,34,38-41 Alcohol may exert antimicrobial effects on H. pylori, inhibit growth by lowering gastric pH, and affect gastric acid secretion, gastric mucosa, and gastric emptying both directly and indirectly thereby creating a hostile environment for H. pylori colonization.42-47 We did not find a statistically significant association between alcohol and H. pylori infection in our studied population (OR 1, 95% CI: 0.7-1.5), so conclusions cannot be made.

Low socioeconomic status is an independent risk factor for H. pylori infection, and this probably remains the same for PUD and

cirrhotic patients. As mentioned in our results, factors associated with low socioeconomic status such as low median household income, uninsured/self-pay were significantly associated with H. pylori infection. Other risk factors include dietary habits and lifestyle behaviors. Underlying medical comorbidities such as obesity, hypertension, congestive heart failure, and chronic pulmonary disease, etc., cannot predict H. pylori infection in the studied population. H. pylori are supposedly acquired in the early phase of life; hence its prevalence is likely not affected by medical comorbidities.48

Our study is the first nationwide study looking at H. pylori epidemiology in hospitalized patients with PUD and cirrhosis.

Since our results relied on accurate coding practices across the nation, the acquired data could have been confounded and will need to be interpreted with caution. We only studied hospitalized patients, so our results will not be applicable to the general outpatient population.

We did not evaluate causation and explanation of our findings, owing to the retrospective nature of our study. Despite the limitations, strengths of our study include a large sample size representative of the general US population and

the first nationwide study on this particular subject.

Conclusions Finally, we concluded that H. pylori are associated with PUD and concurrent cirrhosis. However, it is less prevalent than other studies done in the general population.

African American, Hispanic, and smoking were significant factors that increased the odds of H. pylori infecti on. Our results suggested that future large-scale studies are required to further understand the epidemiology and confirm our findings.

References available on request

GI News Gas-Related Intestinal Symptoms Gas-related symptoms are associated with poorer quality of life, and higher stress, anxiety, and depression, with breaking wind being the most frequently reported gas issue, affecting eight out of 10 adults in the general population (81.3 %) in a 24-hour period, according to a new survey which was presented at UEG Week Virtual 2021.

Other gas-related symptoms included stomach rumbling, which affected 60.5% of respondents, closely followed by belching (58%), and bad breath (48.1%).

Trapped wind (47.2%), abdominal distension/swollen tummy (39.6%) and bloating/abdominal pressure (38.5%) also had a noticeable impact, while only 11.1% of respondents reported having no gas symptoms. On average survey participants had been affected

by three different gas symptoms within the previous 24-hour period.

The findings from the study, which surveyed nearly 6,000 people across the United States, United Kingdom, and Mexico, were based on a representative sample of people aged 18 to 99 years asked to fill out validated Intestinal Gas Questionnaires (IGQs) via the internet, to measure the presence and severity of 7 gas-related symptoms in the last 24 hours.

Researchers also collected information on body mass index, exercise, emotional wellbeing, and quality of life in the past 7 days.

The survey, conducted by scientists from the Rome Foundation Research Institute in the US in collaboration with Danone Nutricia Research in France, revealed that higher IGQ

MARCH 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE

scores correlated with lower mental health and quality of life scores on the PROMIS Global-10 questionnaire, higher stress, anxiety, and depression, and more non-gastrointestinal (GI) symptoms. However, IGC scores did not correlate with weight/BMI and only had a modest negative association with the amount of exercise taken.

Lead author, Professor Olafur Palsson from the University of North Carolina Department of Medicine, said: “I think the most remarkable and surprising finding in our study is that almost all adults in the general population experience some daily gas-related symptoms. This is important given the data also clearly reveals that these symptoms affect people’s general wellbeing. Having a

high amount of these common intestinal symptoms is associated with higher levels of depression, anxiety and stress, as well as impaired general quality of life.”

He added, “The reasons for the marked differences in the amount of gas-related symptoms between Mexico and the other countries we surveyed are unknown, and need to be investigated further. Cultural, linguistic, diet or public health factors might affect population levels of gas-related symptoms.”

The survey methods used included the IGQ, the Patient Health Questionnaire non-GI physical symptoms (PHQ-12) and anxiety and depression (PHQ-4) scales, the PROMIS Global-10 QoL questionnaire and questions on exercises amount, height, weight, and life stress.

A feel good result Entocort®CR Capsules are indicated for the induction of remission in patients with mild-to-moderate Crohn’s disease affecting the ileum and/or the ascending colon, and for the induction of remission in patients with active microscopic colitis.

Entocort® CR 3 mg Gastro-Resistant Hard Capsules.

Hard gelatin capsules with an opaque, light grey body and opaque, pink cap, marked CIR 3 mg each containing budesonide 3 mg.

INDICATIONS: Crohn’s disease: Induction of remission in mild to moderate Crohn’s disease affecting the ileum and/or the ascending colon. Induction of remission in active microscopic colitis.

DOSAGE AND ADMINISTRATION: Oral use. Swallow whole with water, do not chew.

Adults: Active Crohn’s disease: 9 mg once daily in the morning, for up to eight weeks.

Effect is usually achieved within 2 to 4 weeks. When discontinuing, reduce dose over the last 2 to 4 weeks. Entocort can be used for up to 3 months: 6 mg, once daily in the morning. Long-term use is not recommended. To replace prednisolone in steroid-dependent patients, 6 mg once daily in the morning. Prednisolone dose should be tapered. To prevent recurrence after surgery in patients with high disease activity: 6 mg once daily in the morning. No benefit shown in post surgical patients with obstructive fibrostenotic Crohn’s disease.

Active microscopic colitis: 9 mg once daily in the morning for up to 8 weeks. Reduce dose for last 2 to 4 weeks. Use lowest effective dose.

Elderly: As for adults. Experience is limited. Children: Not recommended.

CONTRAINDICATIONS: Hypersensitivity to active or excipients.

PRECAUTIONS AND WARNINGS: Systemic corticosteroid effects may occur, including glaucoma. Monitor for visual disturbance caused by e.g. cataract, glaucoma or rare diseases such as central serous chorioretinopathy (CSCR).

Monitor for infections.

Caution in: patients with reduced liver function; patients with infections, hypertension, diabetes mellitus, osteoporosis, peptic ulcer, glaucoma or cataracts or family history of diabetes or glaucoma or any condition where glucocorticosteroids may have unwanted effects; patients with severe affective disorders (or family history), including depressive or manic-depressive illness and previous steroid psychosis; patients not immune to chicken pox and measles. If exposed, consider immunoglobulin therapy, or antiviral agents.

Contains sucrose. Caution when transferring from another glucocorticosteroid to Entocort CR Capsules, monitor adrenocortical function and unmasked allergies. During surgery or other stress situations, supplementary glucocorticoid treatment is recommended. On dis

continuation, reduce dose over 2 to 4 weeks, monitor for withdrawal effects, adjust dose if necessary. Coadministration of CYP3A inhibitors is expected to increase side effects: avoid/monitor (see interactions). With chronic high doses, systemic glucocorticosteroid effects such as hypercorticism and adrenal suppression may occur, and very rarely psychiatric/behavioural effects. Children: not recommended. If used monitor child’s growth, evaluate risk-benefit. Long-term studies have not been performed.

INTERACTIONS: CYP3A4 inhibitors (e.g. ketoconazole, itraconazole), HIV protease inhibitors and grapefruit juice can increase systemic budesonide, CYP3A4 inducers (e.g. carbamazepine) may reduce budesonide levels; adjust dose. Colestyramine may reduce Entocort uptake. Raised levels/effects of corticosteroids reported with oestrogens and contraceptive steroids. At recommended doses, omeprazole does not affect the pharmacokinetics of oral budesonide whereas cimetidine has a slight but clinically insignificant effect.

USE DURING PREGNANCY AND LACTATION: Pregnancy: Associated with foetal abnormalities in animals; consider risk-benefit. Breast-feeding: Budesonide is excreted in breast milk; at therapeutic doses, exposure to breast-fed infants anticipated to be low.

UNDESIRABLE EFFECTS: Common (≥1/100 to < 1/10): Cushingoid features, hypokalemia, behavioural changes such as nervousness, insomnia, mood swings, and depression, palpitations, dyspepsia, skin reactions (urticaria, exanthema), muscle cramps, menstrual disorders; Uncommon (≥ 1/1,000 to < 1/100): Anxiety, tremor; psychomotor hyperactivity.

Rare (≥1/10,000 to <1/1,000): Aggression, blurred vision, glaucoma, cataract, ecchymosis.

Very rare (< 1/10,000): Anaphylactic reaction, growth retardation. Systemic corticosteroid effects may occur depending on dose, duration and individual.

LEGAL CATEGORY: POM. MA No: 2018/003/001.

MA HOLDER: TILLOTTS PHARMA GmbH, Warmbacher Strasse 80, 79618 Rheinfelden, Germany DATE OF PREPARATION: May 2020. CODE: 2020/21 Full prescribing information available on request from the Marketing Authorisation holder or from Tillotts Pharma Ltd., 25 Sandyford Office Park, Dublin 18. Tel:(00 353 1) 294 2015. Entocort® is a trademark.

56

GI FOCUS: RECTAL CANCER

Multidisciplinary management of early rectal cancer – The role of surgical local excision in current and future clinical practice Written by Lisanne J.H.Smitsa,Annabel S.van Lieshouta, Alexander A.J.Grütera, KarinHorsthuisb, Jurriaan B.Tuynmana Department of Surgery, Amsterdam UMC, Vrije Universiteit Amsterdam, Cancer Center Amsterdam, the Netherlands a

Department of Radiology, Amsterdam UMC, Vrije Universiteit Amsterdam, Cancer Center Amsterdam, the Netherlands b

Since the implementation of bowel screening programs there has been a shift towards the detection of rectal cancer in earlier stages.1,2 Even though the standard treatment for most patients with rectal cancer remains to be total mesorectal excision (TME), the increasing incidence of early rectal cancer has led to an important position of local excision techniques and organ preservation in the treatment of patients with early rectal cancer.3

patients, but data are still scarce.

Nevertheless, in patients who undergo a local excision definitive treatment can be tailored, which may lead to a higher percentage of patients in which the rectum can be preserved. This review focusses on the role of local excision in the treatment of early rectal cancer, and aims to discuss its position in current and future clinical practice.

Radical TME surgery is associated with morbidity, stoma rates, faecal incontinence, and urinary- and sexual dysfunction, whereas local excision techniques provide less morbidity and a minimal chance of transient functional impairment, which may lead to better outcomes in terms of quality of life.4, 5, 6, 7 Over the past decades local techniques to excise rectal lesions have become widely available and consist of a broad spectrum of options, ranging from snare polypectomies to full thickness surgical local excisions.

The optical assessment of polyps during endoscopy provides the first step in clinical staging and decision-making. Based on optical assessment endoscopists decide on the chance of a curative endoscopic resection of the lesion.

Morphologic characteristics such as size, bleeding, granularity and the non-lifting sign, combined with the Paris classification system add to the evaluation of polyps.24 However, a metaanalysis by Backes and colleagues showed that the sensitivity of morphologic features as an indicator for T1 tumours varies between 0.21 and 0.46.25 Several tools are available to enhance the endoscopic assessment of nonpedunculated polyps. Advanced imaging techniques as magnifying endoscopy, chromoendoscopy and narrow band imaging (NBI) have been developed to diagnose T1 tumours and T1 tumours with deep submucosal invasion. Magnifying endoscopy allows a more detailed evaluation of the mucosal structure.

In magnifying chromoendoscopy methylene blue or indigo carmine dyes are used to assess the mucosal architecture, which can be classified by the Kudo pit pattern criteria.26,27 The utilization of narrow bandwidth filters by NBI helps to visualise and assess mucosal microcapillaries and surface patterns.28, 29, 30, 31 Overall, metaanalyses have demonstrated that both magnifying chromoendoscopy and NBI contribute to diagnosing T1 tumours and deep submucosal

Prior to the introduction of transanal minimally invasive surgery (TAMIS), surgical local excision techniques, such as Parks’ transanal excision and transanal endoscopic microsurgery (TEM), resulted in inferior oncological outcomes or were associated with high investment costs and relatively long learning curves.8,9 The introduction of TAMIS in 2009 has contributed to the expanded availability of surgical local excision techniques worldwide.10 Since preoperative staging has limitations, the histopathological assessment of the locally excised specimen is crucial. Local excision is therapeutic in case of low-risk tumours, but only diagnostic in high-risk tumours and additional completion surgery is recommended. Alternatively, (neo) adjuvant chemoradiotherapy might offer a reduction in the risk of local recurrence for pT1-2 rectal cancer

CLINICAL STAGING Endoscopy

MARCH 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE

invasion.25,32 In spite of the advancements in endoscopic staging, several studies have shown that invasive growth can be missed during endoscopy.33, 34, 35 To estimate the chance of malignancy prediction models have been developed, these models support the optical diagnosis of carcinomas.34,36 Future developments to reduce the risk of piecemeal resections in T1 tumours and unnecessary radical surgery may lie in artificial intelligence and new advanced imaging techniques.

Magnetic resonance imaging To determine the optimal treatment for each rectal cancer patient, clinical staging using magnetic resonance imaging (MRI) is essential. The outcomes of MRI determine treatment allocation.

MRI has proven its value for advanced stages of rectal cancer.37 Through evaluation of cT substage, extramural vascular invasion, relation of the tumour to the mesorectal fascia, and enlarged lymph nodes, MRI helps to predict the risk of recurrence and distant metastases.3 For early rectal cancer MRI seems less accurate; studies have shown that MRI may lead to overstaging of the cT substage.38,39 Detering and colleagues39 showed that overstaging of pT1 tumours by MRI occurred in 54.7% of the patients. Of the patients that were potential candidates for local excision as a sole treatment (i.e. pT1N0), MRI staged 30.3% of the patients correctly. In addition to this shortcoming, other studies showed limited accuracy in the assessment of nodal disease on MRI.37,39,40 However in contrast to these outcomes, Balyasnikova and colleagues41,42 suggested that high-resolution MRI is able to accurately distinguish tumours in which the submucosa is partly preserved, from tumours involving the muscularis propria, and tumours breaching the muscularis propria. Utilization of this staging strategy has potential implications

for treatment of early rectal cancer patients, the possibility of organ preservation, and the subsequent excision technique (e.g. endoscopic submucosal dissection (ESD), TAMIS, or TME). Nevertheless, this strategy is still reserved for radiologists specialized in early rectal cancer and clinicians often face clinical staging reports that poorly reflect the histopathological outcome of T1-2 rectal cancers. Consequently, patients who could have been treated sufficiently by local excision may undergo radical surgery.

Endorectal ultrasound Endorectal ultrasound (ERUS) provides another option to clinically stage rectal cancer. If performed by an experienced physician, ERUS may help to differentiate T1 from T2 tumours.43 Moreover, Chan and co-workers44 reported that ERUS outperformed MRI in more advanced T3 tumours, presumably due to a higher sensitivity of smaller lesions and ability to differentiate thin layers such as the serosa. However, it is difficult to determine the distance to the mesorectal fascia in posterior tumours. In these patients the value of ERUS may be limited and MRI might be necessary. The recent study of Detering et al.39 that was based on population data showed that the addition of ERUS to MRI in clinical staging leads to a lower percentage of overstaging in early rectal cancer, although this percentage remained as high as 31%. Therefore, in some patients the combination of both diagnostic tools may be beneficial, especially if overstaging by MRI is suspected based on endoscopic findings, ERUS can contribute to clinical decision-making.

LOCAL EXCISION TECHNIQUES Endoscopic techniques Endoscopic resection techniques for rectal lesions are widely available. An indisputable advantage of endoscopic

57

resections compared with surgical excisions is that general anaesthesia is not required.

Consequently, endoscopic resections may be less harmful in patients with substantial comorbidity. Endoscopic mucosal resection is a common technique to excise rectal lesions, but is limited by piecemeal resections and does not allow adequate assessment of resection margins or depth of tumour infiltration. An increasingly popular technique is ESD, during this en-bloc resection the tumour is dissected through the submucosa, just above the muscular layer. Therefore, this approach can be therapeutic in the earliest cases of rectal cancer.45 ESD has potential downsides as well; the technique is associated with relatively high rates of perforation, is technically demanding, time consuming, and only performed by relatively few endoscopists.46 Nonetheless, it may provide a good alternative for surgical local excision in T1 cancers. To compare ESD to TAMIS and to assess clinical outcomes in non-pedunculated adenomas and early cancers, the results of a randomized controlled trial are awaited.47 Surgical techniques Early methods of transanal excision, such as the excision according to Parks, showed high local recurrence rates.48 The

introduction of TEM as described

by Buess49 led to an improved visualization and consequently to a more precise resection of rectal lesions. TEM is associated with a lower percentage of positive resection margins and lower rates of local recurrence compared to conventional transanal excisions.8 For quite some time TEM was the preferred technique to excise rectal lesions. However, the trend of natural orifice transluminal endoscopic surgery (NOTES) induced the implementation of TAMIS. Since TEM requires additional costs of the platform and instruments (investment of approximately $80.000), TAMIS introduced a system that uses conventional laparoscopic instruments and less expensive platforms (costs $350–500), thereby increasing the availability of surgical local excision techniques.9 In lesions that will be excised surgically, location influences the surgical approach. It is of great importance that the surgeon incorporates the possibility of future completion surgery in the decision to locally excise cancerous lesions. If the location cannot be determined based on imaging, endoscopic findings can support to determine the location of the tumour. During endoscopy it might be hard to orient and detect the location of the lesion.

However, by obtaining an air-fluid

level the location of the lesion can be determined. A benefit of both TEM and TAMIS over endoscopic techniques is that resections can be performed in different resections planes. Different levels of resections can be obtained by these techniques, varying from a submucosal resection to a locoregional resection involving a small part of the mesorectum.56 Lesions located in specific areas need to be excised with care.

Posterior lesions can be treated efficiently by a full thickness resection, whereas anterior lesions should be approached with caution and a partial thickness resection is recommended. Anteriorly, an intramuscular resection does not compromise a possible completion TME and may lead to reduced complication rates, such as injuries to the vaginal wall or peritoneal entry.57 In particular, anterior lesions located in the proximal one third of the rectum are more likely to lead to peritoneal entry.57 In addition, similar attention should be paid to lesions close to the anorectal junction. As in anterior lesions, a full thickness excision of lesions close to the anorectal junction may jeopardize the TME resection plane. Moreover, it could influence the possibility of an anastomosis in completion surgery.

For these reasons, tumour location and thoughtful surgical planning are essential in the outcomes of surgical local excision.

TAMIS operative technique TAMIS is generally performed during general anaesthesia. In frail patients spinal anaesthesia may be considered. Prior to the procedure patients are administered proper bowel preparation and prophylactic antibiotics. Since the SILS platform provides a 360° overview, patients can be placed in lithotomy position.

After a pudendal nerve block and dilatation of the anal canal, the SILS port is positioned and can be sutured to secure its position.

In low tumours that require repositioning of the port during the procedure suturing can be omitted.

Pneumorectum is established

by CO2 insufflation using an insufflation system such as AirSeal® (ConMed Inc., Largo, FL, USA) or the AP 50/30 Insufflator (LEXION Medical, St. Paul, MN, USA). Alternatively, the insufflation stabilization bag (Applied Medical, Rancho Santa Margarita, CA, USA) can be used to reduce billowing.

First, the lesion is circumferentially marked with a margin of 1 cm to define the dissection plane. The dissection is performed using standard laparoscopic equipment and is started at 6 o'clock until the correct resection plane is developed. During the dissection, manipulation of the tumour by the instruments should be avoided to reduce the chance of seeding vital tumour cells into the rectal wall. It is highly recommended to stay very close to the muscular layer, since

HOSPITALPROFESSIONALNEWS.IE | HPN • MARCH 2022

58

GI FOCUS: RECTAL CANCER

distortion of the mesorectum should be avoided. Potential bleeding can be managed by suction and bipolar or unipolar electrocautery. When the excision is completed, the specimen is retrieved, oriented, pinned on cork and send for histopathological assessment. After thorough washing the rectal wall is closed using a continuous V-lock™ (Covidien, Mansfield, MA) suture, or may be left open in posterior mid- and upper rectum lesions.

Therapeutic options and oncological outcomes The flaws of the current imaging techniques in clinical staging of early rectal cancer, create the opportunity for local excision as a diagnostic and potentially curative tool. Local excision of lesions up to 3–5 cm could be treated with upfront radical local excision. In this strategy, local excision can be used to definitively diagnose the tumour stage, and by the evaluation of histopathological risk factors the necessity of additional treatment options can be weighed. This approach offers the potential of organ preservation for the majority of patients, since only a small proportion will need completion surgery.

Surveillance Due to the minimally invasive approach and low morbidity rates in comparison to radical surgery, local excision provides an appealing treatment option in early rectal cancer.53,63 However, local excisions are only considered oncologically safe in low-risk pT1 tumours.11 Whether local excision can be performed as a definitive treatment depends on the histopathological assessment of the specimen. Solely local excision is justified in low-risk pT1 tumours, but in high-risk pT1 tumours or pT2 tumours additional therapy is recommended. In patients that are unfit for surgery or patients that waive radical completion surgery, local excision as definitive treatment may be considered.

The oncological outcomes of a surveillance strategy after local excision, also referred to as watchful waiting, are largely based on observational cohort studies.

Local recurrence rates in these studies vary. A nationwide cohort study that combined surgical local excisions reported a local recurrence rate of 12.5% for pT1 tumours and a recurrence rate of 22.2% in pT2 tumours.64 Bach et al.65 described a large series of patients treated with TEM and showed local recurrence rates of

19% for pT1 lesions and 29% for pT2 lesions. A recent meta-analysis

by Van Oostendorp et al.13 reported local recurrence of patients with high-risk pT1 and pT2 tumours, and revealed rates of 13.6% and 28.9%, respectively.

The proportion of salvageable recurrences is varies between 73% and 92%.66, 67, 68, 69, 70 However, overall survival in case of local recurrence seems poor and is estimated on 50%.71 If treatment of high-risk tumours consists of local excision only, close surveillance should aim for early detection of local recurrence and the subsequent opportunity of salvage surgery. This strategy requires extensive follow-up that includes frequent local evaluation

by MRI and endoscopy every three to six months for the first two years and every six months or annually thereafter up until five years after local excision.

Adjuvant chemoradiotherapy An alternative treatment strategy after local excision of high-risk pT1 and pT2 rectal cancer is adjuvant chemoradiotherapy.

In this strategy, radiotherapy of the rectum and mesorectum accompanied by chemotherapy is considered to reduce the risk of local recurrence. This rectum preserving treatment option seems promising due to the avoidance of TME related morbidity. Even though adjuvant chemoradiotherapy is associated with morbidity as well, serious complications occur within acceptable margins.72, 73, 74 Nonetheless, randomised controlled trials, as the TESAR trial, proving high-quality data and longterm outcomes of adjuvant chemoradiotherapy are to be awaited.75 Currently, the available evidence consists of cohort studies with small sample sizes.

One of the largest studies of Jeong et al.76 comprised 83 patients and showed a local recurrence rate of 3.6% in pT1 tumours. A systematic review of Cutting et al.77 reported a 5.8% local recurrence rate for pT1 tumours and 13.8% for pT2 tumours. In addition, a metaanalysis described similar results but determined a local recurrence rate of 3.9% for high-risk pT1 tumours specifically, which is comparable to outcomes of completion TME surgery.13 Overall, adjuvant chemoradiotherapy seems an attractive option to preserve the rectum and yet reduce the risk of local recurrence compared to a surveillance strategy. However, more highquality data and

MARCH 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE

long-term oncological outcomes are needed to prove its oncological safety.

Completion surgery The standard approach for highrisk pT1 and pT2 rectal cancers that have been locally excised, is completion TME surgery. This approach is the treatment option associated with the lowest local recurrence rates. A meta-analysis included fourteen studies that evaluated local recurrence rates for completion TME after local excision of pT1-2 rectal cancer and showed a local recurrence rate of 4.1% for high-risk pT1 tumours and 4.3% for pT2 tumours.13 Besides oncological outcomes the feasibility of a completion TME after local excision is important. Although completion TME procedures are considered to be more difficult due to the compromised resection plane and fibrosis, the postoperative complication rate is acceptable and leakage rates seem to be comparable to primary TME resections.78, 79, 80 Some studies suggested that the pathology specimen of completion TME may be of lower quality, but evidence is conflicting and it does not seem to influence local recurrence rates.78, 80, 81 Besides, transanal total mesorectal excision (TaTME) instead of conventional TME surgery may reduce the risk of perforation and lead to better specimen quality.82 Altogether, completion TME remains the treatment option with the best oncological outcomes, but is associated with treatment related morbidity and functional impairment.4, 5, 6, 7 Neoadjuvant chemoradiotherapy Finally, upfront chemoradiotherapy followed by clinical restaging and possible local excision may be a fourth treatment strategy.

One should be aware that this treatment option potentially causes overtreatment since the clinical staging is not accurate in early rectal cancer. Nevertheless, in more advanced rectal cancers this strategy has shown to result in organ preservation. In cases of a complete clinical response a watch and wait strategy may be utilized.

For this strategy local regrowth of 15.7% has been reported.83 The international watch and wait database revealed a 2-year local regrowth rate of 25.2%.84 However, the watch and wait strategy can only be performed in patients with a clinical complete response. If small pT1-2 tumours remain after neoadjuvant treatment, additional treatment may consist of local excision. This method has been evaluated in several trials.

Even though the neoadjuvant treatment strategy is associated with good oncological outcomes, it has potential downsides. First, local excision after neoadjuvant treatment impacts anorectal function and shows high rates of short-term morbidity, mostly due to pain, blood loss and impaired wound healing.88, 89, 90, 91 Nevertheless, a recent post-hoc analysis of GRECCAR 2 data showed that both short- and long-term surgical morbidity was significantly lower in patients who underwent local excision compared to TME or cTME after neoadjuvant treatment. Second, in about 50% of the patients, neoadjuvant treatment has shown to downstage tumours or lead to a complete response.72,86 This implicates that a large share of patients require additional radical surgery, which might be associated with higher morbidity rates due to the neoadjuvant chemoradiotherapy.

Therefore, this treatment strategy may be more promising in locally advanced tumours or in patients who might be eligible for sphincter-saving surgery after neoadjuvant treatment.

Conclusions In the treatment of early rectal cancer, local excision seems an attractive option that can be incorporated in several treatment strategies. However, effective treatment of these patients requires a multidisciplinary approach and cooperation of radiologists, gastroenterologists, pathologists, radiotherapists, oncologists and surgeons. Since accurate clinical staging remains challenging the approach of local excision as a diagnostic and potentially curative tool will lead to a patient tailored treatment and will lower the percentage of patients who undergo avoidable radical surgery.33, 39 If preoperative imaging shows no risk factors, local excision as a definitive treatment can be achieved in a large share of patients, which leads to low morbidity and good functional results.61,62 If histopathological examination reveals risk factors for local recurrence, additional treatment should be recommended.

Currently, completion surgery remains the standard of care in high-risk pT1 and pT2 tumours, but organ preservation strategies of (neo)adjuvant treatment regimens show promising results. In the near future the role of local excision in clinical practice may grow due to the implementation of combined surgical local excision and (neo) adjuvant chemoradiotherapy treatment strategies.

References available on request

59

GI FOCUS: COELIAC DISEASE

Coeliac Disease - pitfalls in monitoring adherence to a gluten free diet I want you to consider that everything we’re doing is wrong. This was the opening statement made by a Professor of Gastroenterology presenting at a UK symposium last year. The topic of discussion was how we monitor coeliac disease. With adherence rates reported to be between 42 and 92%, it is true that many coeliacs are at risk of developing complications such as lymphoma, ulcerative jejunitis, osteoporosis, infertility, and nutritional deficiencies. In children signs of non-adherence include faltering growth and delayed puberty. To reduce the incidence of comorbidity we must have the right tools to detect gluten exposure. There are a variety of methods used in practice to assess adherence to a gluten free diet validated scores, questionnaires, ask the patient, request a dietitian review and of course serology.

Healthcare professionals like numbers, and biomarkers give us quick reassurance; until they don’t.

Long term follow-up in coeliac disease remains controversial.

Currently there are no effective non-invasive markers of gluten free diet adherence, with point-of-care testing, dietary adherence questionnaires and serology all having poor sensitivity for the detection of villous atrophy. Serological response is often used as a surrogate for histological recovery however. A recent survey reported 65% of Gastroenterologists in Canada used bloods including serology as a monitoring tool. Overall however serology was performed less frequently in adults than children in favour of routine intestinal biopsy, showing a trend towards the use of the gold standard assessment.

There are inherent difficulties in using coeliac serology as a

monitoring tool. In order to obtain clinically meaningful endpoints, it is essential that patients are eating a certain amount of gluten prior to testing. Guidelines vary on the amounts and duration with one institution saying gluten in more than one meal daily for 6 weeks, and another recommending 1-3 slices of bread daily for 1-3months before testing. Once you can be sure the patient is adequately prepared for a test there are a few other serological anomalies to consider. It is reported that 1.7%–5% of coeliacs are affected by seronegative coeliac disease (SNCD). This is a rare and still poorly defined form of coeliac disease, presenting with negative serology, villous atrophy, genetic compatibility, with or without symptoms of malabsorption and who demonstrate clinical and histological response to a gluten free diet. A further 2% of coeliacs have IgA deficiency. This is a separate entity to seronegativity. In this case, if not done automatically by the lab, you need to order IgG antibodies as an alternative to IgA antibodies. According to a recent meta analysis, sensitivity of the anti-tissue transglutaminase (tTg) antibody for ongoing villous atrophy was only 43.6%. So even if well considered and accurately prepared there appears to be a limit to how much serological testing can tell us about mucosal healing. It is like flipping a coin. There is a 50% chance of persistent villous atrophy with a negative IgA tTg result.

If you decide to pursue biopsy as a method of assessment and find persistent villous atrophy there are caveats here too. There are many mimics of villous atrophy including NSAIDs or olmesartan use, Helicobacter pylori gastritis, giardiasis, collagenous or microcytic colitis to name but a

few. The timeframe for biopsy must also be selected carefully.

Villous atrophy improves on a gluten free diet but it may take 2-3 years so be careful not to repeat the biopsy too early. It has been suggested that immune tolerance is possible over time. A recent study showed that neither occasional nor voluntary dietary gluten intake was associated with the onset of clinical, serological, histologic, or endoscopic changes in a group of coeliac patients.

Interestingly no association was found between histological alterations and the amount of gluten intake following diagnosis.

This means the traditional advice of a strict gluten free diet for all warrants further investigation and review. The tolerable amount of gluten is still contended and this casts a shadow over current dietary advice. Perhaps there is a subset of patients where a more relaxed approach can be considered but we need the monitoring tools to allow that to happen in a safe way.

Dietetic assessment of adherence also has limitations. Targeted dietetic intervention through removal of identified gluten sources or avoidance of trace amounts of gluten led to resolution of persistent villous atrophy in only 50% of patients studied.

In summary, serology appears to be a poor surrogate marker for mucosal recovery and dietary assessment may fail to uncover a potential gluten source in some patients with ongoing villous atrophy. This could be explained by non-disclosure or under reporting of dietary intake but warrants further investigation Although current clinical guidelines do not recommend routine repeat biopsy, it appears to be the surest way to monitor mucosal healing and response. Although such a change in clinical practice would have

Written by Elaine Neary RD, Clinical Specialist Dietitian Gastroenterology, Tallaght University Hospital

financial implications, the cost of non-adherence has a clear impact on the health of individuals. Equally an overly strict gluten free diet can affect quality of life. In the meantime we need more accurate non-invasive markers of mucosal damage in children and adults with coeliac disease who are following a gluten free diet.

Perhaps novel biomarkers such as Gluten Immunogenic Peptide (GIP) might have the ability to increase detection rates of non-adherence.

This convenient urine test checks for gluten exposure. There has been criticism of false negatives but researchers say testing over a number of days is a pragmatic approach. According to one study, 3 negative urine tests from three different days revealed a 97% possibility of no villous atrophy.

New biomarkers are promising and will add to our understanding of gluten metabolism and, with additional studies, could be used as a supplemental tool in the future management of our patients.

In conclusion, current methods fall short in detecting rates of non-adherence in coeliac disease leading to comorbidities that are largely preventable. Long term monitoring is not as straightforward as we once thought and requires more thorough consultation.

Do not rely on serology alone.

Serology, dietary adherence and mucosal remission do not have a perfect relationship. The only way to know for sure if your patient is responding to diet therapy is to repeat biopsy. So back to my opening line, please consider everything you’re doing is wrong.

References available on request

HOSPITALPROFESSIONALNEWS.IE | HPN • MARCH 2022

60

GI FOCUS: OSTEOPOROSIS

Fracture Rates and Economic Outcomes Fracture rates and economic outcomes in patients with osteoporosis prescribed risedronate gastro-resistant versus other oral bisphosphonates: a claims data analysis Written by Friederike Thomasius, Frankfurter Hormon Und Osteoporosezentrum, Frankfurt, Germany, Santiago Palacios, Palacios’ Institute of Women’s Health, Madrid, Spain, Asif Alam, Theramex, London, UK, Mitra Boolell, Theramex, London, UK, Francis Vekeman, STATLOG, Montreal, Canada & Geneviève Gauthier, STATLOG, Montreal, Canada

In Europe, in 2010, it was estimated that 22 million women and 5.5 million men aged between 50 and 84 years old were living with osteoporosis.1 In the USA, approximately 12.3 million individuals older than 50 years were estimated to have osteoporosis in 2020.2 These numbers are expected to continue to increase over the next decades with the aging of the population.1 Men and women with osteoporosis have an increased risk of fractures or bone breaks which can substantially impact their quality of life.3 Osteoporosis fracture may lead to chronic pain and disability and higher risk of early mortality and pose a substantial financial burden on patients, their family, and the health care systems.4,5,6,7 Oral bisphosphonates are the recommended first-line treatment for patients with osteoporosis in the USA and in Europe.8, 9 Acting as antiresorptive agents, the use of oral bisphosphonate treatments has been associated with a significant reduction of the risk of fractures in patients with osteoporosis.7, 8, 10 However, oral bisphosphonates are poorly absorbed, and lack of adherence to complex dosing instructions involving fasting and not lying down after taking the medication can further limit its absorption.11 Real-world evidence indicates that more than 50% of patients do not follow all dosing instructions of the immediaterelease formulation.12 A poor absorption of bisphosphonates can result in suboptimal effectiveness and increased risk of fractures,13,14,15 leading to significant utilization of health care resources and costs.4, 16, 17 Risedronate gastro-resistant (GR) was developed with the goal of providing more convenient dosing instructions and reducing the

risk of gastrointestinal (GI) side effects by eliminating the need for fasting, without impacting the overall bioavailability and efficacy of the treatment.11, 18 The GR formulation has the advantages of a better absorption independent of food intake, which is expected to translate into improved efficacy and a reduction in fracture rates compared to other immediaterelease oral bisphosphonates, including alendronate sodium, ibandronate sodium, and risedronate sodium. However, there is limited real-world data comparing fracture rates between patients treated with risedronate GR versus other oral bisphosphonates.

The main objective of the study was to quantify and compare fracture rates among women with osteoporosis treated with risedronate GR versus other oral bisphosphonates. Health care resource utilization (HCRU), health care costs (HCC), and medication persistence and adherence were also compared between the two treatment groups.

METHODS Data source This study used data from the IBM® MarketScan® Commercial and Medicare Supplemental Databases (Q1 2009 to Q4 2019).

The MarketScan Commercial and Medicare Supplemental Databases represent health services (both pharmacy and medical) of approximately 130 million employees, dependents, and retirees in the USA with primary or Medicare supplemental coverage through privately insured fee-for-service, pointof-service, or capitated health plans. The databases include de-identified patient-level claims and are compliant with the Health Insurance Portability and Accountability Act (HIPAA).

MARCH 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE

Study design The study used a retrospective observational design. Outcomes were compared between women with osteoporosis treated with risedronate GR (GR cohort) versus other oral bisphosphonates (other bisphosphonates cohort).

For each patient, the date of the first observed prescription fill for an oral bisphosphonate was defined as the index date and the treatment initiated on that date as the index treatment. The 6-month period prior to the index date was defined as the baseline period.

The observation period of patients spanned the period from the index date to the earliest of the data cut-off date or end of continuous eligibility.

Sample selection and construction of study cohorts Adult women with at least one medical claim associated with a diagnosis for osteoporosis (ICD-9 codes, 733.0x; ICD-10 codes, M80.xx, M81.xx) were identified. Patients were included in the study if they had at least one prescription fill for an oral bisphosphonate (alendronate sodium, ibandronate sodium, and risedronate sodium).

Selected women were also required to have continuous eligibility (both pharmacy and medical benefits) for at least 6 months prior to the index date and for at least 2 years following the index date to allow sufficient time to observe fracture events.

Furthermore, no treatment switch (i.e., from risedronate GR to other oral bisphosphonates or from other oral bisphosphonates to risedronate GR) were allowed during the minimum 2-year period.

As bisphosphonates can also be used to treat Paget’s disease and bone damages from some types of cancer, patients with a

diagnosis for Paget’s disease or malignant neoplasm recorded during the 6-month baseline period were excluded.

Patients were classified into two mutually exclusive study cohorts based on the treatment initiated on the index date, i.e., risedronate GR cohort and other oral bisphosphonates cohort (including immediate-release risedronate).

Matching To balance the patients’ profile between cohorts, each woman in the risedronate GR cohort was matched to one woman in the other bisphosphonates cohort with similar demographic and clinical characteristics. Matching factors, evaluated on the index date or at baseline as appropriate, included age, year of the index date, insurance plan type (e.g., comprehensive, preferred provider organization, exclusive provider organization/point-of-service, health maintenance organization), region, Charlson Comorbidity Index19 categories (≤ 2 and > 2), selected comorbid conditions20 with statistically significant differences between cohorts, presence of a fracture, and the use of selected drugs affecting bone density (abaloparatide, aromatase inhibitors, estrogens, denosumab, gonadotropinreleasing hormone agonists, injectable bisphosphonates, romosozumab, systemic corticosteroids, and teriparatide).

Definition of outcomes and statistical analyses Outcomes were compared between the risedronate GR cohort and the other oral bisphosphonates cohort. For fracture rates, a subgroup analysis was performed among patients initiated on alendronate on the index date—the majority of patients in the other oral bisphosphonates cohort.

61 Figure 1

Fracture rates Fracture events were identified based on the presence of medical claims associated with a diagnosis code of fracture during the observation period (see Online Resource 1 for list of diagnosis codes). The incidence of fractures was assessed overall as well as stratified by the main skeletal sites (i.e., hip, pelvis, spine, wrist/arm).

To ensure capturing new fracture as opposed to follow-up care, a definitional algorithm was applied for patients who had more than one medical claim associated with a diagnosis of fracture over the observation period.21, 22 For two claims indicative of fractures occurring at the same skeletal site, to be considered a new fracture, the date of the second medical claim was required to occur ≥ 90 days after the first claim. Subsequent medical claims occurring < 90 days apart were considered follow-up care/ fracture aftercare. For two claims indicative of fractures occurring at distinct skeletal sites, to be considered a new fracture, the date of the second medical claim was required to occur ≥ 30 days after the date of the initial medical claim. Subsequent medical

claims occurring < 30 days apart were considered a single event involving multiple skeletal sites.

For each cohort, the incidence rate (IR) of fractures was calculated as the number of fracture events divided by the total patient-years of observation to account for the different lengths of observation.

The IR was compared between cohorts using generalized linear models (GLMs) with a log link and negative binomial distribution, adjusting for matched pairs.

Results were reported as incidence rate ratios (IRRs) along with their respective confidence intervals (CIs) and p-values.

Time from initiation of the index treatment to the date of the first fracture event was also described using Kaplan–Meier (KM) curves and compared between the two cohorts using the log-rank test.

HCRU and HCC All-cause HCRU and HCC during the observation period were assessed and compared between the two cohorts. Health resources components and associated costs evaluated included inpatient stays, emergency department (ED) visits, outpatient visits, and other

ambulatory encounters. Total medical costs (i.e., inpatient, ED, outpatient, and other ambulatory encounters costs) as well as all-cause and bisphosphonate-related pharmacy costs were also assessed.

To account for the varying observational time across patients, HCRU were reported as IRs per 1,000 patient-years of observation, and HCC were calculated as weighted average costs and reported per patient per year (PPPY).

HCRU were compared between cohorts using GLMs with a log link and negative binomial distribution, adjusting for matched pairs. Results were reported as IRRs along with their respective CIs and p-values.

For HCC, to account for the nonnormality of the cost distribution as well as matched pairs, p-values and 95% CIs were estimated using non-parametric bootstrap resampling techniques. Results were reported as incremental HCC with their corresponding p-values and CIs. All costs were standardized and reported in 2019 US dollars using the medical care component of the Consumer Price Index.23

Persistence and adherence to the index medication Treatment persistence with the index medication was defined as the time from the date of initiation of the index treatment to the date of discontinuation of the index treatment. Treatment discontinuation was defined as a treatment gap of ≥ 90 consecutive days—measured between the end of the days of supply of a filled prescription and the date of the subsequent filled prescription for the index treatment, if any. Patients who did not discontinue the index treatment were censored on the date of the first switch to another oral bisphosphonate, the data cut-off date, or the end of insurance eligibility, whichever occurred first. Results were presented graphically using KM curves and compared between the two cohorts using the log-rank test.

Adherence to the index treatment was measured with the medication possession ratio (MPR), calculated as the number of days covered by the treatment over the period of interest divided by the numbers of days during the period. Adherence while on treatment (i.e., from the first to

HOSPITALPROFESSIONALNEWS.IE | HPN • MARCH 2022

62

the last dispensing of the index treatment plus the days of supply of the last dispensing) and over fixed periods of 6 months, 1 year, and 2 years was considered.

RESULTS Patient characteristics Out of the 1,364,890 women with ≥ 1 dispensing for an oral bisphosphonate in the database (risedronate GR, 16,737; other oral bisphosphonates, 1,348,153), 2,726 women prescribed risedronate GR and 2,726 matched women prescribed other oral bisphosphonates were selected after applying the inclusion and exclusion criteria. Among patients in the other bisphosphonates cohort, the majority were initiated on alendronate (66.3%) followed by ibandronate (20.2%) and risedronate immediate release (13.5%). Median age was 60.0 years old in both cohorts, and most patients were from the South region (45.2%) or Northeast region (29.5%) of the USA. Overall, 1.7% of patients in both cohorts had a diagnosis of fracture recorded during the baseline period. The proportion of patients with a wrist/arm fracture at baseline was slightly higher among GR patients (0.9% vs.

0.5%, p = 0.031).

Fracture rates During the observation period, regardless of the site, patients in the GR cohort had a lower incidence of fractures compared to patients in the other bisphosphonates cohort.

Statistically significant differences were observed for any site of fractures and spine fractures— patients in the GR cohort were associated with a 17% reduction in overall risk of fracture (IR per 1,000 patient-years: GR, 34.65 vs. other, 42.13; p < 0.05) and 29% reduction in the risk of spine fractures (IR per 1,000 patient-years: GR, 10.84 vs. other, 15.13; p < 0.05). A stratification by age group showed that the incidence of fractures, including hip fractures, more than doubled when comparing patients < 65 to those ≥ 65 years old as of the index date. At each time point considered over the observation period, the rate of incident fractures was lower in the GR cohort compared to the other bisphosphonates cohort, reaching statistical significance at 36

GI FOCUS: OSTEOPOROSIS

months (GR, 7.08%; other, 8.67%; p = 0.037) (Fig. 1 on page 61).

Results remained consistent and numerically similar when comparing fracture rates between patients treated with risedronate GR versus alendronate. When compared to patients initiated on alendronate, patients initiated on risedronate GR were associated with a 19% reduction in the overall risk of fracture (IR per 1,000 patient-years: GR, 33.97 vs. other, 42.53; p < 0.05) and 31% reduction in the risk of spine fracture (IR per 1,000 patientyears: GR, 10.76 vs. other, 15.86; p < 0.05).

HCRU and HCC Compared to patients who were prescribed other bisphosphonates, those who were prescribed risedronate GR had fewer inpatient stays during the observation period (106.74 inpatient stays per 1,000 patientyears for GR vs. 124.20 inpatient stays per 1,000 patient-years for other, IRR = 0.86 [0.76–097]). The incidence of ED, outpatient, and other ambulatory encounter visits was not statistically significantly different between the two cohorts.

Consistent with their lower utilization of inpatient services, inpatient costs were $993 per patient per year lower in the GR cohort compared to the other bisphosphonates cohort (GR = $3,611 vs. other = $4,603, p < 0.05). No statistically significant differences were observed for costs associated with ED, outpatient, and other ambulatory encounter visits.

When compared to patients in the other bisphosphonates cohort, patients in the GR cohort incurred incremental total pharmacy costs of $680 per patient per year— partly driven by higher dispensing costs for oral bisphosphonates.

(Fig. 2 on page 63). Average MPR while on treatment at 6 months, 1 year, and 2 years was not statistically significantly different between the two cohorts (Fig. 2).

Discussion Results from the current study indicate that over an average observation period of more than 50 months, patients prescribed risedronate GR had lower rates of fracture and in particular a lower rate of spine fractures compared to patients prescribed other bisphosphonates. Of note, although the proportion of patients who had experienced a fracture at any site during the 6-month baseline period was the same in the two treatment cohorts, a slightly higher proportion of patients prescribed risedronate GR experienced a wrist/arm fracture, perhaps indicative of a higher risk of subsequent fractures.

As expected, the incidence of hip fracture, the most expensive fracture type,17 was the lowest among patients under 65 years old and increased sharply in older patients. Overall, the incidence of fractures more than doubled in patients ≥ 65 versus < 65 years old. In general, the lower rates of fractures observed in the present study compared to previously published results from observational studies are consistent with the relatively young age of the studied population.24,25,26

Persistence on the index treatment

Indeed, in a study using claims data from commercially insured patients (all patients < 65 years old; mean age: 56.0 years old), the authors estimated incidence rates of fractures at any site between 15.4 and 16.1 per 1,000 patient-years for bisphosphonates.25 In a similar study using claims from Medicare insured patients (all patients ≥ 65 years old; mean age, 78.2 years old), the authors estimated at 56.3 per 1,000 patient-years the incidence rate of fractures at any site.24

Overall, in both cohorts, most patients discontinued their index treatment within the first 2 years from its initiation. At 2 years after the index date, the rate of discontinuation of the index medication was 80.5% in the GR cohort and 74.4% in the other bisphosphonates cohort. The persistence on the index treatment was overall statistically significantly lower for patients in the GR cohort, mainly driven by a higher discontinuation rate within the first few months of treatment initiation

Compared to patients prescribed other bisphosphonates, those who were prescribed risedronate GR were associated with a higher rate of treatment discontinuation, especially during the first few months after the index date. A potential explanation for this observation could be the 4 to 6 times higher out-of-pocket costs observed for risedronate GR than that for other bisphosphonates (mean [median] out-of-pocket costs per dispensing, 28–30-day supply, GR, $42.39 [$37.95] vs.

MARCH 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE

other, $10.72 [$6.10]; 84–90day supply, GR, $83.69 [$69.71] vs. other, $21.13 [$11.88]). This observation is further supported by a well-documented body of literature on the detrimental impact of increased out-of-pocket costs on medication compliance and persistence, in particular for chronic conditions.27,28,29,30,31,32 This study offers a unique perspective on the fracture rates of patients prescribed risedronate GR versus other oral bisphosphonates in real-world settings. Several randomized clinical trials have assessed the efficacy of bisphosphonates, and the body of evidence from these studies suggests no differential effect on fracture rates between bisphosphonates.33 However, in real-world settings, patients’ behavior towards their medication may impact the ability of bisphosphonates to prevent fractures.

Lack of persistence and poor compliance are known challenges with bisphosphonates, all of which may impact the overall efficacy of bisphosphonates.14, 33,34,35 A systematic literature review of 89 prospective and retrospective observational studies examining patient adherence and persistence to oral bisphosphonates in adults with osteoporosis found that mean persistence rates ranged from 17.7 to 74.8% at 1 year and from 12.9 to 60.6% at 2 years. Similarly, compliance rates ranged from 31.7 to 72.0% at 1 year and from 34.5 to 47.9% at 2 years across studies.33 Although reasons for the lack of persistence and compliance are likely multifactorial, complex dosing instructions as well as GI side effects have been reported as potential reasons.15, 33,34,35 Adding to the detrimental impact on bisphosphonates effectiveness of poor medication persistence and compliance is the poor compliance with dosing instructions. Absorption of oral bisphosphonate by the system is poor—usually less than 1% on average—and may be further limited by concurrent intake of food and beverage.11 As such, to derive the full benefits of immediate-release formulations of oral bisphosphonates, patients are required to follow a strict dosing schedule—the drug is typically required to be taken on an empty stomach ≥ 30 to 60 min before the first food, drink, or other medications of the day.

Furthermore, patients must not lie down for 30 min after taking the medication.36,37,38

63 Figure 2

Real-world evidence indicates that a significant fraction of patients do not follow the complex dosing instructions of the immediate-release formulation of bisphosphonates.12 In a survey of 363 women with osteoporosis aged ≥ 55 years old, 40.5% reported not being compliant with dosing instructions ensuring adequate absorption, 34.7% were not compliant with dosing instructions preventing adverse events, and as many as 56.5% were not compliant with all dosing instructions.12 Other external factors, such as the calcium content in tap water, may also interfere with the absorption of bisphosphonates.39 The lower rates of fractures observed among patients in the risedronate GR cohort, despite their lower persistence on the medication, could be explained by its more convenient dosing administration. Indeed, among patients remaining on bisphosphonates, those on risedronate GR are more likely to receive an improved medication benefit because of its absorption irrespective of fasting compared to the complex and,

hence often not followed, dosing administration of immediaterelease bisphosphonates.

Likely reflecting their lower incidence of fractures, patients prescribed risedronate GR were associated with a lower utilization of inpatient services, which translated into lower inpatient costs. The amount of health care resources and the associated costs diverted by osteoporotic fractures are substantial.4, 16, 17, 40 For instance, using claims data from the USA, Tran et al. found that the all-cause incremental yearly health care costs of commercially insured women with versus without incident osteoporotic fracture over a period of 5 years following the fracture were $77,370, $28,737, $23,155, $21,478, and $18,835, respectively.40 Even a small decrease in the risk of fracture has thus the potential for significant health care resources and health care costs saving on the long term.

Results from this study should be interpreted in light of some limitations. First, given the retrospective nature of the data used, this study did not attempt

to establish causal inference.

Instead, findings should be interpreted as association-level results. Second, because the databases used include patients with a commercial health plan or a Medicare Supplemental health plan, the study sample may not be representative of the general osteoporosis population. This is underscored by the relatively young age of studied patients.

Third, the higher out-of-pocket cost associated with risedronate GR compared to that of other bisphosphonates may be the source of a selection bias.

Another potential source of confounding comes from the fact that the database used does not include the necessary clinical information to identify patients at a higher risk of fracture. Fourth, osteoporosis and other conditions considered in this study were identified based on diagnostic codes recorded on administrative claims used for billing purposes, which in some instance could reflect suspected rather than confirmed clinical diagnoses.

It is also possible that not all diagnoses are systematically recorded on claims; thus, underreporting of certain

conditions is also a possibility.

Similarly, the incidence of spine fracture may be underestimated as most cases do not come to medical attention. Fifth, claims data only provide information on filled prescriptions, not on how medications are actually consumed. Finally, the HCC reported are likely to be an underestimation of the total costs resulting from fractures as they do not capture administrative costs of third-party payers for claims processing, out-of-pocket costs, indirect costs (e.g., productivity loss), or other intangible costs.

Despite their lower persistence, patients prescribed risedronate GR were associated with a lower incidence of fractures compared to those prescribed other oral bisphosphonates, leading to lower utilization of inpatient services which translated into lower inpatient costs. These results are consistent with the hypothesis that the more convenient dosing administration of risedronate GR could improve the absorption of bisphosphonate and help patients with osteoporosis get an improved benefit of treatment.

References available on request

HOSPITALPROFESSIONALNEWS.IE | HPN • MARCH 2022

64

GI FOCUS: CROHN’S DISEASE

Crohn’s Disease: Presentation to Management Interview with Theresa Lowry Lehnen (GPN, RNP, PhD) Clinical Nurse Specialist and Associate Lecturer Institute of Technology Carlow

Inflammatory Bowel Disease (IBD) describes a group of conditions in which the intestines become inflamed. The two most common inflammatory bowel diseases are Crohn’s disease and ulcerative colitis. Another form of IBD is microscopic colitis.

There is no official database which gives accurate figures, but it is thought that at least 40,000 people are living with IBD in Ireland. There were 5.9 new cases of Crohn’s disease in Ireland per 100,000 population in 2011 and 14.9 new cases of ulcerative colitis. The incidence of Crohn's disease is higher than ulcerative colitis in children. Males and females are affected equally and patients can be diagnosed at any age, including babies and children. The peak age of incidence is between the ages of 15 and 35, with a second (smaller) peak from the 50s to 70s. IBD diagnosed in children can behave differently and can be treated differently to that diagnosed in adults.

and Colitis who have been diagnosed with COVID-19 has already been analysed and the results to date provide some initial reassurance – with little evidence to show that patients with IBD are at greater risk of contracting COVID-19.

Professor Glen Doherty, Consultant Gastroenterologist at St. Vincent’s University Hospital said: “The initial results of this study are really promising as they show that people living with Crohn’s and Colitis are mostly not at greater risk of complications of COVID-19 and may not be as vulnerable a group as we initially feared.

“Crohn’s and Colitis are becoming much more common in our population. The number of new cases diagnosed each year has tripled in the last 10 years. It is estimated that currently 0.5% of the population suffer with Ulcerative Colitis (UC) and 0.3% of people with Crohn’s. This translates to 40,000 patients in Ireland living with these diseases but most don’t like to talk about it because of the embarrassing nature of the symptoms.” Doherty said “Continued research and ongoing clinical trials are essential so we can find new treatments for the increasing number of people living with this disease.”

Crohn’s Disease Development According to Theresa Lowry Lehnen, Clinical Nurse Specialist and Associate Lecturer Institute of Technology Carlow, Crohn’s disease (CD) is a chronic idiopathic inflammatory bowel disease characterized by transmural inflammation and lesions that can affect the entire gastrointestinal tract, but most commonly occurs at the terminal

Heredity

MARCH 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE

There is both direct and indirect evidence to suggest that genetics plays a role in the development of Crohn's disease.

Theresa told Hospital Professional News, “Direct evidence is provided as 32 different specific genetic alterations have been identified which are more common in people with Crohn's disease than in the population at large, and indirect evidence seen because Crohn's disease appears to run in families. The immune system also becomes disrupted in Crohn's disease and sends tumour necrosis factor (TNF) antibodies to kill all bacteria, regardless of whether they are friendly or not. TNF antibodies

The Immune System Crohn's Disease

Crohn’s Disease Latest Research Efforts are underway to better understand if commonly used medications for Crohn’s and Colitis alter the risk of complications of COVID-19. Irish investigators from St. Vincent’s University Hospital are working as part of a global research study called SECURE-IBD (https:// covidibd.org/) to understand how the disease impacts Crohn’s and Colitis patients. Information on over 1,000 patients with Crohn’s

ileum and colon. The prevalence of CD has an incidence of 3 to 20 cases per 100,000. The exact pathogenesis of CD is unknown, although a number of genetic, immune system and environmental factors have been shown to increase the risk of the illness and lead to the aberrant gut immune response characteristic of the disease.

Environmental Factors

65 cause most of the inflammation associated with Crohn's disease.”

One of the most notable risk factors for developing Crohn's disease is smoking, aside from family history and ethnic background.

Diagnosis of Disease There are 3 main phenotypes ofCrohn’s CD: inflammatory, stricturing, and penetrating. Presenting Theresa notes that the diagnosis bowel syndrome (IBS). IBS is ayears before the diagnosis symptoms are variable and some patients may have symptoms for of Crohn’s disease can be quite disorder that affects the muscle difficult given that presenting Prednisolone is used in cases of Crohn’s Patients with inflammatory with abdominal contractionsdisease of the boweloften and is present Theresa explains disease why saying, is made. symptoms can be insidious where budesonide proves not characterized by intestinal “Smokers are twice as likely to and nonspecific. ineffective.

It has the same type of pain and may develop more systemic symptoms including weight loss, lowinflammation, nor is it a chronic develop Crohn'sdiarrhoea, compared with and short and long-term side effects disease, she adds. non-smokers and those who “Symptoms that require further grade fevers, and fatigue.

Patients with stricturing disease may develop bowel obstructions as budesonide, and has also been smoke usually experience more investigation include weight loss, Treatments known to cause mental health severe symptoms compared with bloody diarrhoea, irondevelop deficiency, fistula or abscesses. When an abscess is present, while those with penetrating CD can problems in an estimated 5% those with the condition who While there are several medications and night-time awakenings,” of people. do not smoke.

While there is available to treat Crohn's disease, in addition to abdominalshepain, patients can have systemic symptoms such as fever and chills says. “Similarly, significant no evidence that diet causes, or there is no cure. Here Theresa gives family history of IBD, unexplained Aminosalicylates plays role in Crohn's disease, andamay also present with signs ofC acute peritonitis. an overview of some of the more elevations in the - reactive protein certain types of food and drink have been associated with worsening symptoms including milk, dairy products, alcohol, spicy, fatty and high-fibre foods.

There is no single diet or eating plan that will work for everyone with Crohn’s disease and dietary recommendations must be tailored individually. Although flares are sometimes associated with stressful events, there is no evidence to prove that stress causes or contributes to Crohn’s disease.”

level, sedimentation rates, or other acute phase reactants such as ferritin and platelets, or low B12 should prompt further investigation.

Diagnosis of Crohn’s Disease

“There is no single test that can

common treatments.

Steroids

Steroids are used to induce remission but are not an effective maintenance agent. Steroids are usually only used to treat the active disease because their long-term use is associated with a range of adverse side effects.

Budesonide and prednisolone are two steroids that are often used to treat Crohn's disease.

Sulfasalazine belongs to a group of medicines called aminosalicylates, known to reduce inflammation inside the colon.

Sulfasalazine can be used as an alternative to steroids to treat mild cases of Crohn's disease.

Common side effects include headache, nausea, abdominal pain and diarrhoea.

be used to confirm or disprove Theresa notes that the diagnosis of Crohn’s disease can be quite difficult given that presenting a diagnosis of Crohn's disease.

The diagnosis of CD is made symptoms can be insidious and nonspecific. on the basis of symptoms, endoscopic and investigation radiologic “Symptoms that require further include weight loss, bloody diarrhoea, iron Immunosuppressants findings. (Colonoscopy, Biopsy, deficiency, and night-time she says. “Similarly, significantImmunosuppressants family historyareof IBD, SBE,awakenings,” CT, MRI, Wireless Capsule Endoscopy) Pathology can also used in maintenance therapy unexplained elevations be inconfirmatory. the C - reactive protein level,is sedimentation rates, or other acute Budesonide usually the first and in combination with choice of steroid prescribed to steroids wheninvestigation. a person has conditions mimic phase such ferritin andcan platelets, orhelp lowcontrol B12theshould further There are 3reactants main phenotypes of as “Other symptomsprompt of a relapse of symptoms. Two symptoms of CD so it is important CD: inflammatory, stricturing, Crohn's disease. Taken on a immunosuppressants widely used “There is no single test that be used to confirm or disprove a diagnosis of Crohn's disease. to rulecan out infection and other and penetrating.

Presenting short-term basis of less than 12 for treating Crohn's disease are causes even when patients with symptoms are variable and some weeks budesonide may cause The diagnosis of CD is made on of symptoms, endoscopic and radiologic findings. azathioprine and mercaptopurine. known CD are the havingbasis flare-ups. patients may have symptoms acne, oedema of the face, Patients with diarrhoea should be for years before the diagnosis of arms, feet and legs, Common side effects (Colonoscopy, Biopsy, SBE, CT, MRI, Wireless hands, Capsule Endoscopy) Pathology can ofalso be assessed for infection, IBD, and Crohn’s disease is made. Patients mood changes, insomnia and azathioprine include increased in certain cases coeliac disease. with inflammatory disease often indigestion. If taken for more confirmatory. vulnerability to infection, bleeding Other conditions that may present with abdominal pain than 12 weeks, budesonide may and bruising. Less common present similar to CD include and diarrhoea, and may develop “Other conditions can mimic symptoms of CD socause it isosteoporosis, important to rule out other increased sideinfection effects includeand headaches, appendicitis, Behcet disease, and more systemic symptoms vulnerability to infection, shortness of breath, dizziness, Ulcerative Colitis.”known CD are causesweight even with having Patients with diarrhoea including loss,when low-gradepatients cataracts, muscleflare-ups. cramps and nausea and vomiting. fevers, and fatigue. Patients with stiffness, and vitamin D and Both Crohn’s Disease shoulddisease be assessed infection, IBD,and and in certain cases coeliac Otheroriginally conditions Mercaptopurine stricturing may develop for Ulcerative calcium supplements will be disease.

Colitis (UC) are developed to treat leukaemia ” bowel obstructions while those required to help protect against bowel diseases that may present similarinflammatory to CD include appendicitis, Behcet disease, andhasUlcerative Colitis. since proved effective in the with penetrating CD can develop the effects of osteoporosis. Due fistula or abscesses. When an abscess is present, in addition to abdominal pain, patients can have systemic symptoms such as fever and chills and may also present with signs of acute peritonitis.

(IBDs), but there are some key differences.

It is important not to confuse

to increased vulnerability to infections, close contact with people who are known to have infections, particularly those with chickenpox, measles and shingles should be avoided.

treatment of Crohn's disease.

Given in tablet form, its side effects are not as severe as those associated with other forms of chemotherapy treatment.

Common side effects include

inflammatory bowel disease Both Crohn’s Disease and Ulcerative Colitis (UC) are inflammatory bowel diseases (IBDs), (IBD) like Crohn’s disease or but there are some key ulcerative differences. colitis with irritable

Crohn’s disease

Ulcerative Colitis

Inflammation may develop anywhere in the GI tract from the mouth to the anus Most commonly occurs at the end of the small intestine May appear in patches May extend through entire thickness of bowel wall About 67% of people in remission will have at least 1 relapse over the next 5 years

Limited to the large intestine (colon and rectum) Occurs in the rectum and colon, involving a part or the entire colon Appears in a continuous pattern Inflammation occurs in innermost lining of the intestine About 30% of people in remission will experience a relapse in the next year

HOSPITALPROFESSIONALNEWS.IE | HPN • MARCH 2022 It is important not to confuse inflammatory bowel disease (IBD) like Crohn’s disease or

66

nausea and vomiting while less common side effects include loss of appetite, fatigue, and breathlessness and weakness caused by anaemia. Effective contraception if sexually active is important while taking mercaptopurine, as it temporarily affects both ova and sperm and can increase the risk of birth defects.

GI FOCUS: CROHN’S DISEASE

curative and patients still require ongoing therapy even after surgery for disease recurrence.

Surgery

Biological therapies are a new type of medication created using naturally occurring biological substances, such as antibodies and enzymes. Two main biological therapies are infliximab and adalimumab. Infliximab is usually only recommended in severe cases of Crohn's disease that have not responded to steroid and immunosuppressant treatments, and where the person is unsuitable for surgery.

Surgery is required when the symptoms of Crohn's disease cannot be controlled using medication alone. During surgery, the inflamed section of the digestive system is removed and the remaining part is reattached.

An estimated 80% of people with Crohn's disease require surgery at some point in their life. Surgery does not cure Crohn's disease, but it can provide long periods of remission, often lasting several years. A stoma may be required if the disease or inflammation is so severe that an immediate anastomosis is not safe. In some in¬stances, the stoma may be temporary and can be closed once the severe inflammation and infection is controlled. A colostomy is also required if the rectum is removed.

The goal of medication management is to control the inflammation and induce a clinical remission with pharmacological therapy, however, most patients will eventually require surgery.

Unfortunately surgery is not

Over 40,000 people in Ireland are living with inflammatory bowel disease (IBD), most of whom are diagnosed between the ages of 15 and 30. Of these approximately 20,000 people suffer from colitis and Crohn’s Disease.

Biological Therapies

Theresa notes that most Irish patients are hospitalised within two years of diagnosis and more than half will eventually need surgery. “A report by the Irish Society for Colitis and Crohn’s Disease in 2015, showed that 49% of sufferers lost or had to leave a job because of their condition. The report also showed that Crohn’s alone cost the health service ¤185 million a year and that paediatric cases of IBD have increased three-fold in Ireland since 2003,” she says.

“A survey of service providers treating patients with IBD, conducted by the Irish Society of Gastroenterology (ISG), found that the lack of dedicated specialist nurses in Ireland was the greatest barrier to delivering patient care. The Irish Society for Colitis and Crohn’s Disease campaign for the 2018 World IBD Day (#DoubleUp) proved very successful. The campaign called for the number of specialist Inflammatory Bowel Disease (IBD) nurses to be increased from 14 to at least 28, to bring Ireland in line with international best practice.

As of May 2019 the number of specialist nurses in Ireland has increased to 26.

“A holistic person-centred approach is required in the management of patients with Crohn’s Disease, who face a lifelong condition that can be emotionally and physically debilitating. The role of the clinician is to provide ongoing assessment, management, support and education. Key roles are to establish a therapeutic relationship with the patient, assess their understanding of the condition, establish goals and expectations for successful management of their condition and evaluate their physical, emotional, and psychological well-being. “Common concerns for patients are adherence to their therapeutic regimen, pain and discomfort. Many patients experience anxiety, anger, frustration, stress and depression.

Assessment, monitoring, audit and evaluation for disease activity, progression, and effects of the therapeutic regime on a patient with Crohn’s disease is a continuous process. By implementing person-centred care, monitoring and evaluating symptoms, outcomes and responses to therapy, clinicians play a pivotal role in managing the illness and improving the patient’s quality of life.”

References available on request

GI News New study reveals potential target for alcohol-associated liver disease Shelly C. Lu, MD, director of the Karsh Division of Gastroenterology and Hepatology in the Department of Medicine and senior study author

The discovery, published in the peer-reviewed journal Nature Communications, can also help lead to a new treatment approach for people suffering from the disease.

Investigators at Cedars-Sinai have uncovered a new pathway that helps explain how consuming too much alcohol causes damage to the liver, specifically mitochondrial dysfunction in alcohol-associated liver disease.

Cases of alcohol-associated liver disease continue to rise and is one of the leading causes of alcoholrelated deaths. The spectrum of the disease includes hepatitis, fibrosis to cirrhosis and liver cancer.

Cirrhosis alone causes 1.6 million deaths worldwide and over 50% of cases are due to alcohol abuse.

Besides abstinence, there currently are no effective therapies for treating people with the disease.

MARCH 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE

"Alcohol-associated liver disease is a major problem in the world," said Shelly C. Lu, MD, director of the Karsh Division of Gastroenterology and Hepatology in the Department of Medicine and senior author of the study. "We've known for a long time that alcohol somehow damages mitochondria, but until now, it's not been clear as to what the mechanisms are for this damage to occur."

To better understand the mechanisms for mitochondrial damage in alcohol-associated liver disease, Lu and her team looked at the role of an enzyme called MATα1 that's responsible for providing the liver vital nutrients for survival.

Using liver tissues from patients with alcohol-associated liver disease and preclinical models, the team found levels of this enzyme were selectively reduced in the mitochondria.

"Once we saw the depletion of MATα1, we needed to figure out

what was making that happen," said Lucia Barbier-Torres, PhD, a postdoctoral scientist in the Lu Laboratory and first author of the study.

The team found alcohol activates the casein kinase 2 (CK2) protein, which triggers a process called phosphorylation of MATα1 at a specific amino acid residue.

In their experiments, the team found this process facilitates an interaction between MATα1 with another protein called PIN1 and prevents MATα1 from transporting into the mitochondria.

"Once this interaction happens, MATα1 cannot get into the mitochondria to provide the essential nutrient and instead gets degraded," Barbier-Torres said.

"Our results support a novel and targetable mechanism to help treat alcohol-associated liver disease," said Lu, who is also a professor of Medicine and the Women's Guild Chair in Gastroenterology.

®

THIS IS FEWER MIGRAINE DAYS. THIS IS LONG-TERM EVIDENCE.

▼

2,3

4

THIS IS

PREVENTION

1,2

AIMOVIG® IS REIMBURSED FOR CHRONIC MIGRAINE PATIENTS WITH THREE OR MORE PREVIOUS PROPHYLACTIC TREATMENT FAILURES

ABBREVIATED PRESCRIBING INFORMATION ▼ Aimovig® (erenumab) 70 mg and 140 mg solution for injection in pre-filled pen Important note: Before prescribing, consult full prescribing information.

Presentation: Aimovig 70 mg solution for injection in pre-filled pen. Each pre-filled pen contains 70 mg erenumab. Aimovig 140 mg solution for injection in pre-filled pen. Each pre-filled pen contains 140 mg erenumab. Indications: Aimovig is indicated for prophylaxis of migraine in adults who have at least 4 migraine days per month. Dosage and administration: Adults: The recommended dose of Aimovig is 70 mg administered subcutaneously every 4 weeks.

Some patients may benefit from a dosage of 140 mg once every 4 weeks. Each 140 mg dose is given either as one subcutaneous injection of 140 mg or as two subcutaneous injections of 70 mg. Aimovig is intended for patient self-administration in the abdomen, thigh, or, if someone else is giving the injection, also into the outer area of the upper arm. Administration should be performed by an individual who has been trained to administer the product. The needle cover of Aimovig prefilled pen contains dry natural rubber, which may cause allergic reactions in individuals sensitive to latex. Special populations: Paediatric patients: The safety and effectiveness of Aimovig has not been studied in paediatric patients. Elderly (aged 65 years and over): The safety and effectiveness of Aimovig has not been studied in elderly patients. No dose adjustment is necessary as the pharmacokinetics of erenumab are not affected by age. Renal impairment: No dose adjustment is necessary in patients with mild to moderate renal impairment. Hepatic impairment: No studies have been performed in patients with hepatic impairment. Hepatic clearance is not a major clearance pathway for erenumab. Contraindications: Hypersensitivity to the active substance or to any of the excipients. Warnings and precautions: Hypersensitivity reactions: Serious hypersensitivity reactions, including rash, angioedema, and anaphylactic reactions, have been reported with erenumab in post-marketing experience. These reactions may occur within minutes, although some may occur more than one week after treatment. In that context, patients should be warned about the symptoms associated with hypersensitivity reactions. If a serious or severe hypersensitivity reaction occurs, initiate appropriate therapy and do not continue treatment with erenumab. Constipation: Constipation is a common undesirable effect of Aimovig and is usually mild or moderate in intensity. In a majority of the cases, the onset was reported after the first dose of Aimovig; however patients have also experienced constipation later on in the treatment. In most cases constipation resolved within three months. In the post marketing setting, constipation with serious complications has been reported with erenumab. In some of these cases hospitalisation was required, including cases where surgery was necessary. History of constipation or the concurrent use of medicinal products associated with decreased gastrointestinal motility may increase the risk for more severe constipation and the potential for constipation related

complications. Patients should be warned about the risk of constipation and advised to seek medical attention in case constipation does not resolve or worsens. Patients should seek medical attention immediately if they develop severe constipation. Constipation should be managed promptly as clinically appropriate. For severe constipation, discontinuation of treatment should be considered.

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. Latex sensitive individuals: The removable cap of the Aimovig pre-filled pen contains dry natural rubber latex, which may cause Allergic reactions in individuals sensitive to latex Pregnancy, lactation, fertility: Pregnancy: There are a limited amount of data from the use of erenumab in pregnant women. As a precautionary measure it is preferable to avoid the use of Aimovig during pregnancy. Lactation: It is not known whether erenumab is present in human milk. The use of Aimovig could be considered during breastfeeding only if clinically needed. Fertility: There is no data available on the impact of Aimovig on male and female fertility.

Animal studies showed no impact on female and male fertility. Adverse drug reactions: Common (≥1/100 to <1/10): Hypersensitivity reactions including anaphylaxis, angioedema, rash, swelling/ oedema and urticaria. Injection site reactions, constipation, muscle spasm, pruritus. Interactions: No effect on exposure of co-administered medicinal products is expected based on the metabolic pathway of monoclonal antibodies. No interactions with oral contraceptives (ethinyl estradiol and norgestimate) or sumatriptan were observed in studies with healthy volunteers. Legal Category: POM. Marketing Authorisation Holder: Novartis Europharm Ltd, Vista Building, Elm Park, Merrion Road, Dublin 4, Ireland. Marketing Authorisation Numbers: EU/1/18/1293/001 006. Date of last revision of Abbreviated Prescribing Information: September 2020. Full prescribing information is available upon request from: Novartis Ireland Limited, Vista Building, Elm Park Business Campus, Merrion Road, Dublin 4, Ireland, Tel: + 353 1 220 4100 or at www.medicines.ie. Detailed information on this product is also available on the website of the European Medicines Agency http://www.ema.europa.eu. ▼ This medicinal product is subject to additional monitoring. Reporting suspected adverse reactions of the medicinal product is important to Novartis and the HPRA. It allows continued monitoring of the benefit/risk profile of the medicinal product.

All suspected adverse reactions should be reported via HPRA Pharmacovigilance, website: www.hpra.ie. Adverse events could also be reported to Novartis preferably via www.report.novartis.com or by email: drugsafety.dublin@novartis.com or by calling 01 2080 612.

References: 1. Aimovig SmPC available at medicines.ie 2. Tepper S, et al. Safety and efficacy of erenumab for preventive treatment of chronic migraine: a randomised, double-blind, placebocontrolled phase 2 trial. Lancet Neurol 2017; 16: 425-434. 3. Goadsby PJ, et al. A controlled trial of erenumab for episodic migraine. N Engl J Med 2017; 377: 2123-2132. 4. Ashina M, et al. Eur J Neurol. 2021 in Press Long-term efficacy and safety of erenumab in migraine prevention: Results from a 5-year, open-label treatment phase of a randomized clinical trial - PubMed (nih.gov) *Image used is not an actual Aimovig® patient IE145414 | August 2021

68

GI FOCUS: RESEARCH

New Approaches to Crohn’s and Ulcerative Colitis Professor Abhay Pandit, Scientific Director of CÚRAM

A team of researchers at CÚRAM, the SFI Research Centre for Medical Devices at NUI Galway, have discovered a radically new approach to the treatment of Crohn’s disease and ulcerative colitis.

The study, published in Advanced Science, identified a groundbreaking therapeutic strategy for restoring the lining of the intestine of patients with the condition and other inflammatory bowel diseases.

The treatment could also help prevent further inflammation, which is how the disease progresses and worsens over time.

The NUI Galway CÚRAM researchers have designed a hyaluronan (HA) enema, which has shown significant potential in protecting against damage to the intestinal lining by decreasing inflammation and aiding in the maintenance of the health of the intestinal lining.

Crohn's disease and ulcerative colitis, or IBD, is characterised by chronic inflammation of the gastrointestinal tract and effects over 3.2 million people in Europe.

Professor Abhay Pandit, Scientific Director of CÚRAM, said, “The team strongly believes that the developed system can be delivered as an HA enema to act as a barrier-protecting system on the damaged colon barrier, reducing intestinal inflammation in the treatment of colonic inflammatory diseases.

“This will result in reduced inflammation and protection of the intestinal lining.”

The research represents a significant leap forward from the standard therapeutic interventions for colitis, which have focused mainly on maintaining remission levels, and do not address the root cause of the condition, especially damage to the intestinal lining and intestinal function.

The study authors state, “Our findings illustrate the efficacy and protection of HA-enema in colitis and indicate that both HA-based systems play an essential protecting role against DSS-induced colitis. The current research demonstrates the rectal HA-enema used as an amending mucoadhesive coat on the damaged colon barrier, modulating intestinal barrier inflammation and permeability.

However, testing the system effect in a single acute colitis model, unavailability of rectal region-sitespecific colitis mice models are the key limitation of the study. In addition, testing in chronic and large animal models, investigating further on the possible mechanistic aspects (including receptor level mechanistic effects, understanding the barrier protective/epithelial repair processes, effect on the colon microbiome) are essential.

Besides, the potential benefits with the current HA-enema system are the possibility to encapsulate any model therapeutic drugs (especially corticosteroids, immunosuppressants, or

MARCH 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE

for Crohn’s and colitis, CÚRAM researchers have also identified inflammation-specific targeted carriers for local drug delivery to inflammatory bowel disease.

“The team strongly believes that the developed system can be delivered as an HA enema to act as a barrierprotecting system on the damaged colon barrier, reducing intestinal inflammation in the treatment of colonic inflammatory diseases”

The findings have been published in Biomaterials.

disease modifying drugs) in the particles, which may help in effective combinatorial therapies in distal colitis. Due to the close association of dysregulated intestinal barrier functions with systemic diseases, the current biophysical protecting barrier strategy with HA-enema holds promise and may help in restoring the dysregulated intestinal barrier functions and help in the distal colitis management.”

The study authors conclude, “In conclusion, our work elucidates an inflammation-targeted drug delivery platform for localised therapeutics delivery in the inflamed colon (colitis) conditions.

Furthermore, investigations are required particularly into surface charge measurements of the colitis mucosa, establishing pharmacokinetic/dynamic assessments, therapeutic effectiveness in longer-term (chronic conditions), larger animal models, and assays involving intestinal barrier functions before assessing such technologies' clinical effects in humans.”

Dr Niranjan Kotla, conducted the principal research of the study at CÚRAM in collaboration with Dr Venkatakrishna R Jala, from the Department of Microbiology and Immunology, James Graham Brown Cancer Centre, University of Louisville, in the US. Dr Yury Rochev, co-lead on the publication added, "This research demonstrates the efficacy of a unique therapeutic strategy able to induce a positive effect on damaged colonic tissue. The reduction in inflammation will be of great benefit to patients and highlights the potential use of this treatment."

Alongside the research into a specific therapeutic treatment

The study looked at the highly challenging but potentially effective practice of delivering drugs directly to inflamed intestinal sites to treat inflammatory bowel disease, particularly Crohn's and ulcerative colitis.

The research team, led by Professor Abhay Pandit and Dr Yury Rochev in collaboration with Prof Larry Egan, Professor of Clinical Pharmacology at NUI Galway, developed strong anionic charged inflammation targeted nanocarriers (IT-NCs) loaded with an immunosuppressant model drug.

“Our results suggest that ITNCs have promising therapeutic potential as delivery carriers' in colitis management,” said Professor Pandit.

This research was funded by the European Union's Horizon 2020 the EU Framework Programme for Research and Innovation.

The first study has been published in Advanced Science and is available here https://onlinelibrary. wiley.com/doi/full/10.1002/ advs.202103189 The second study has been published in Biomaterials and is available here, https://www.sciencedirect. com/science/article/pii/ S0142961222000035?via%3Dihub

70

GI FOCUS: OESOPHAGEAL CANCER Distance from incisors

Oesophageal Cancer Interview with Theresa Lowry Lehnen (GPN, RNP, PhD) Clinical Nurse Specialist and Associate Lecturer Institute of Technology Carlow

Cervical esophagus

UES Trachea

when the tumour has reached a relatively locally advanced or even metastatic stage.”

Symptoms of oesophageal cancer include:

Oesophageal cancer (OC) is the eighth most common cancer and sixth most common cause of cancer mortality worldwide.

Oesophageal cancer is more common in people aged over 60.

It affects more men than women.

More than 500 people are diagnosed with it in Ireland every year.

The oesophagus is the neuromuscular tube that connects the pharynx with the stomach and lies in the posterior mediastinum within the thorax near the lung pleura, peritoneum, pericardium, and diaphragm. The upper and lower oesophagus are controlled by the sphincter function of the cricopharyngeus muscle and gastro-oesophageal sphincter, respectively. The functions of the oesophagus and its sphincters are to transport swallowed materials from the pharynx to the stomach, and to defend the airways and itself from the reflux of gastric contents.

Speaking about how oesophageal cancer develops, Theresa Lowry Lehnen, Clinical Nurse Specialist and Associate Lecturer Institute of Technology Carlow says, “Oesophageal cancer occurs when cells in the oesophagus develop mutations in their DNA and the cells grow and divide out of control. The accumulating abnormal cells form a tumour in the oesophagus that can grow to invade nearby structures and spread to other parts of the body. The tumour does not cause symptoms at first, but as it grows causes difficulty with swallowing. As oesophageal cancer expands, the lumen of the oesophagus narrows, and dysphagia occurs due to mechanical obstruction. Due to the muscular and expansive nature of the oesophagus, symptoms from an obstructing or stricturing lesion may only become apparent

Dysphagia Acid reflux pain in the sternum, back or throat Weight loss Anorexia Cough Risk factors for developing oesophageal cancer include increasing age, gender (OC is two to three times more common in males than females), gastroesophageal reflux disease (GORD), Barrett's oesophagus, achalasia, obesity, smoking, alcohol, drinking very hot liquids, poor diet and undergoing radiation treatment to the chest or upper abdomen.

The main risk factors associated with development of oesophageal adenocarcinoma are gastrooesophageal reflux, obesity, high intake of red meat and low intake of fruits and vegetables.

Oesophageal squamous cell carcinoma develops from squamous epithelial cells and is typically localised to the upper two-thirds of the oesophagus.

Tobacco consumption and alcohol intake are the most notable risk factors, although their relative risk varies by region.

Theresa says, “The increase in the incidence of oesophageal adenocarcinoma has paralleled with the rise of obesity in the western world. A variety of observational studies, systemic reviews and meta-analyses have shown and confirmed association between obesity and OAC. The risk of OAC in patients with a BMI of 30 or above is approximately 16 times greater compared to those with a normal BMI.” Furthermore, patients with Barrett’s oesophagus have been shown to have a 30 to 60-fold increase in the incidence of oesophageal adenocarcinoma, although the annual absolute risk of developing OAC is 0.12%. The

MARCH 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE

40cm

Aorta Thoracic esophagus

Right crus of diaphragm LES

Abdominal esophagus

incidence of Barrett’s oesophagus is two to three times higher in men than women, and male sex is an independent risk factor for malignant transformation.

“The role of HPV infection in the development of oesophageal cancer has long been suspected,” she adds. “Although HPV has been widely studied, the overall rate of HPV infection in oesophageal squamous cell carcinoma remains controversial and there is a lack of robust evidence for a definitive etiological role.

“The association between HPV and oropharyngeal SCC, and the histologic similarities between the squamous epithelium of the oral mucosa and upper oesophagus could suggest a similar association. HPV16 and HPV18 are the most frequently detected types in HPV-associated cancers.

Studies have shown a significant association between HPV16 and OSCC, but not HPV18.”

Diagnosis, Staging and Treatment In 2019, new national clinical guidelines, ‘Diagnosis, staging

71 and treatment of patients with oesophageal or oesophagogastric junction cancer National Clinical Guideline No. 19’ developed by multidisciplinary groups supported by the HSE’s National Cancer Control Programme (NCCP) and quality assured by the Department of Health’s National Clinical Effectiveness Committee (NCEC) were launched to help with the diagnosis, staging and treatment of patients with oesophageal or oesophagogastric junction (OGJ) cancer. It details advances in staging, diagnosis, and treatment that define and underpin a modern standard of care across all designated centres in Ireland.

Theresa adds, “Patients with oesophageal cancer usually present with dysphagia, prompting endoscopy and biopsy.

Diagnosis incudes clinical history, examination, barium swallow, endoscopy, endoscopic ultrasound (EUS), liver ultrasound scan, biopsy.

Endoscopy is the traditional gold standard for detecting oesophageal cancer, but less invasive screening methods are being developed such as Cytosponge, a cell collection device that is swallowed and retrieved with a string, followed by analysis of cells for trefoil factor 3 protein. This method aims to identify patients who warrant an endoscopy for suspected Barrett's oesophagus.

“Tumour characteristics documented at endoscopy should include the exact site relative to the gastro-oesophageal junction, extension into the stomach and distance from the teeth, length of the lesion, circumferential involvement and presence of obstruction. Any adjacent pre-malignant lesions, i.e. squamous dysplasia or Barrett’s oesophagus should be documented and measured.

Tumours of the oesophagus are conventionally described in terms of distance of the upper border of the tumour to the incisors.

When measured from the incisors via endoscopy, the oesophagus extends approximately 30 to 40 cm. The oesophagus is divided into four main segments: Cervical oesophagus (15–20 cm from the incisors); upper thoracic oesophagus (20–25 cm from the incisors); middle thoracic oesophagus (25–30 cm from the incisors) and lower thoracic oesophagus and gastroesophageal junction (30–40 cm from the incisors).

Once the diagnosis is confirmed, clinical staging is the next step for which computed tomography (CT) and positron-emission tomography (PET) are the two most useful imaging tools.”

Treatment for oesophageal cancer includes surgery, radiotherapy and chemotherapy. Management is dependent on the patient’s

characteristics and the tumour, mainly the TNM-stage.

She adds, “Tumour, node and metastasis (TNM) staging is the most common way to stage oesophageal cancer although the number staging system can also be used. A higher number, such as stage 4, means a more advanced cancer. Early tumours may be suitable for endoscopic removal, whereas more locally advanced cancers are treated with chemotherapy, chemoradiotherapy, surgical resection or combinations of these.”

There are 4 stages of tumour size in oesophageal cancer - T1 to T4.

Tumour (T) T1: the cancer has grown no further than the submucosa. T1 is divided into T1a and T1b.

T1a: the cancer is in the inner layer (mucosa) or thin muscle layer of the oesophagus wall.

T1b: the cancer has grown into the supportive tissue (submucosa).

T2: the cancer has grown into the muscle layer of the wall of the oesophagus.

T3: the tumour has grown into the adventitia, the membrane covering the outside of the oesophagus.

T4: tumour has grown into other organs or body structures. T4 is divided into T4a and T4b.

T4a: the cancer has grown into the pleura, pericardium, diaphragm, or peritoneum.

T4b: the cancer has spread into nearby structures such as the trachea, vertebra or the aorta.

Node (N)12 Node (N) describes whether the cancer has spread to the lymph nodes. There are 4 possible stages - N0 to N3.

N0: no lymph nodes containing cancer cells.

N1: there are cancer cells in 1 or 2 nearby lymph nodes.

N2: there are cancer cells in 3 to 6 nearby lymph nodes.

N3: there are cancer cells in 7 or more nearby lymph nodes.

Metastasis (M)12 Metastasis (M) describes whether the cancer has spread to a different part of the body. There are 2 stages of metastasis.

M0 means the cancer has not spread to other organs.

M1 means the cancer has spread to other parts of the body.

Treatment According to Theresa, treatment requires a multidisciplinary team approach and optimal therapy

is still debated. Endoscopic therapies, including radiofrequency ablation, endoscopic mucosal resection and endoscopic sub mucosal dissection, have become the standard treatment modality for Barrett’s oesophagus and early carcinoma.

“Advances in the understanding of the role of genomic instability in Barrett’s oesophagus will facilitate identifying patients at risk for malignant transformation who would benefit from early intervention,” she adds.

Multimodal treatment, which includes chemotherapy, radiation therapy followed by surgical resection or without surgical resection, in varying orders remains the main mode of treatment for most patients.

“Chemotherapy can be given before surgery to shrink the tumour and make it easier to remove or after surgery, to lower the risk of the cancer coming back. Chemotherapy may also be required both before and after surgery. This is common with adenocarcinoma. Many oesophageal cancer patients receive a combination of two or three chemotherapy drugs.

“External radiotherapy uses highenergy rays to kill or shrink cancer cells. The rays are aimed directly at the tumour. It can be given before surgery to shrink the tumour or after surgery to kill any cancer cells left behind to prevent the cancer coming back.15 During Internal radiotherapy (brachytherapy), the radiation source is placed into the oesophagus for several minutes.

Released radiation aims to kill the cancer cells but causes little or no damage to the nearby healthy tissue.

“In some patients with partial oesophageal obstruction, dysphagia may be relieved by placement of an expandable metallic stent or by radiation therapy if the patient has disseminated disease or is not a candidate for surgery.

“Surgery is the most common treatment for cancer that has not spread outside the oesophagus.

Minimally invasive surgical approaches have become the standard for oesophagectomy and current literature has demonstrated similar oncological outcomes with reduced morbidity.7 As oesophageal cancer surgery is associated with considerable morbidity and changes in postoperative quality of life, careful attention to patient selection for resection is essential in order to

minimise the risk of futile surgery in patients with incurable disease.”

St James’s Hospital, Dublin is the National Centre for Oesophageal and Gastric Cancer and the National Centre for Management of Early Upper Gastrointestinal Mucosal Neoplasia. The hospital manages approximately 65% of oesophageal surgical resections nationally. Cure rates are improving, with overall survival at 35%, 65% for node negative disease, and 75% for Stage I/II disease. Outcomes are consistent with best international benchmarks.

Theresa notes, “Patients with oesophageal cancer face several challenges during the course of their illness and treatment because of the uncertainty in their prognoses and complexity and side effects of the treatment.

Symptoms affect patients’ quality of life on a physical, social, and emotional level.

“Oesophageal cancer patients’ quality of life is first negatively affected by the obstructing tumour and later by complex treatment.

Before a diagnosis of oesophageal cancer is established a majority of patients have experienced dysphagia and appetite loss, resulting in considerable weight loss and fatigue, which influence the patients’ daily living and quality of life. Patients with advanced tumour stage may experience additional problems, e.g. odynophagia, hoarseness and coughing due to tumour overgrowth or metastatic disease.

“Health professionals establish strategies and play an important role in preparing, supporting and educating patients and their families about what to expect during and after treatment and ensure that patients’ vulnerability is addressed throughout the treatment pathway. Given the poor prognosis of OC and impact of surgery, it is important to address patients’ support needs to help them regain control, reduce their anxiety, improve compliance, create realistic expectations, promote self-care, and generate feelings of security.

“In most cases, oesophageal cancer is a treatable disease, but it is rarely curable. The 5-year relative survival rate is 19.9%. As a new approach, targeted therapies and novel drugs play an important role in the current and future treatment of cancer.”

References available on request

HOSPITALPROFESSIONALNEWS.IE | HPN • MARCH 2022

72

GI FOCUS: THYROID FUNCTION

Management of Disorders of Thyroid Function Written by Dr Julie Martin-Grace, Research Registrar in Endocrinology, Beaumont Hospital & RCSI/ Beacon Hospital StAR MD Programme and Dr Carla Moran, Consultant Endocrinologist & Associate Professor, UCD School of Medicine

concentration of thyroid hormone rises, TSH secretion is suppressed by negative feedback to the anterior pituitary gland. thereby ensuring T4/T3 levels remain within a controlled range.3

Dr Julie Martin-Grace

Dr Carla Moran

Overview

The regulation of thyroid function is tightly controlled by the hypothalamic-pituitary-thyroid axis due to a classical endocrine negative feedback loop. Thyroid stimulating hormone (TSH, or thyrotropin) is released by the anterior pituitary in response to thyrotropin-releasing hormone (TRH) and stimulates thyroid hormone production, thyroxine (T4) & triiodothyronine (T3), in the thyroid gland. As the circulating

Diseases of the thyroid gland are common and affect up to 10% of people over their lifetime.1 The most common problem is reduced thyroid hormone production (hypothyroidism), which is often due to an autoimmune disease called Hashimoto’s Thyroiditis. Graves’ disease is the most common cause of increased thyroid hormone production (hyperthyroidism) and is also autoimmune in nature. 42 Thyroid disease predominantly affects females and often arises 43 during child-bearing years.

Both conditions are treated with medication (Thyroxine in the case of hypothyroidism and anti-thyroid drugs such as carbimazole or propylthiouracil for most causes of hyperthyroidism), but some patients with hyperthyroidism will require more definitive treatments such as surgery or radio-iodine treatment.

Spectrum of Thyroid Dysfunction Disorders of thyroid function are classified as either primary or secondary, depending on whether the problem lies in the thyroid gland itself (primary) or the hypothalamus or pituitary gland (central or secondary).

This distinction helps to explain the different patterns of thyroid function tests seen in different clinical scenarios (Table 2). For example, in primary hypothyroidism, the thyroid gland fails to produce sufficient thyroid hormone, so circulating

Table 1. Symptoms and signs associated with hypothyroidism and thyrotoxicosis

Table 1. Symptoms and signs associated with hypothyroidism and thyrotoxicosis.

Symptoms

Introduction The thyroid gland consists of two lobes which lie below the strap muscles in the anterior neck, joined in the midline by a band of tissue known as the thyroid isthmus. In healthy adults, the thyroid weighs between 10-20 g.2 The thyroid is made up of follicles, which consist of a single layer of epithelial cells that surround a central lumen filled with clear colloid, surrounded by a network of capillaries.3

Iodine is an important component of thyroid hormone (TH) production. Iodide is transported into the thyroid follicular cells, where it undergoes oxidation and organification in the colloid lumen to produce T4 and a small amount of T3. T4 and T3 are then secreted into the circulation, where the majority of TH is bound to plasma proteins.3 T4 is made only in the thyroid gland itself, but the majority of T3, the active form of the hormone, is converted from T4 to T3 outside the thyroid gland, predominantly in the liver and kidney. T3 then binds to thyroid hormone receptors present in cell nuclei, which in turn bind to specific regulatory sequences in DNA and mediate the actions of thyroid hormone by affecting the transcriptions of these TH target genes.3 Thyroid hormone affects almost every organ in the

body; it is essential for normal brain development and growth in childhood, and in adulthood maintains healthy brain function, regulates the metabolic rate, affects cardiac chronotropic and inotropic drive, and regulates cholesterol metabolism and skeletal muscle health. Therefore, disorders of thyroid function can affect multiple organ systems, producing a wide range of symptoms and clinical signs4 (Table 1).

Signs

44

MARCH 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE 45 Spectrum of Thyroid Dysfunction

Hypothyroidism Fatigue/lethargy Cold intolerance Menorrhagia Constipation Weight gain Dry skin and hair Myalgia Often none Goitre may be present If severe: Pale, cool skin Periorbital oedema Slow relaxing reflexes Loss of hair at eyebrows

Thyrotoxicosis Palpitations Hyperactivity/irritability Emotional lability Heat Intolerance Amenorrhoea or lighter menstrual bleeding Increased appetite Weight loss Increased bowel frequency Fine tremor Tachycardia/Atrial Fibrillation Warm, sweaty palms Proximal muscle weakness Eyelid retraction/lag Brisk reflexes Goitre may be present

73

levels of T4/T3 fall, however the hypothalamus and anterior pituitary will function normally, and increase secretion of TSH to boost thyroid hormone production.

Therefore, in severe primary hypothyroidism, TSH level will be elevated, and T4/T3 levels low. If the problem is the pituitary gland itself (central hypothyroidism), both TSH and T4/T3 will be low. In primary hyperthyroidism, excess thyroid hormone is secreted by the thyroid gland, switching off TSH secretion, and therefore TSH levels will be undetectable.

Hypothyroidism Primary hypothyroidism is a relatively common condition, particularly amongst women.5 While the exact prevalence of hypothyroidism in Ireland is not known, thyroid hormone replacement therapy (levothyroxine) was the third most commonly prescribed drug on both the GMS and DPS schemes in Ireland in 2020.6 Central hypothyroidism is rare, and almost always occurs in conjunction with anterior pituitary hormone

57

58

57

deficiency.7 Both primary and central hypothyroidism are treated with thyroid hormone replacement, predominantly levothyroxine.8 Subclinical Hypothyroidism Subclinical hypothyroidism (SHypo) is a biochemical diagnosis, which over time can progress to overt hypothyroidism, particularly in individuals with positive antithyroid antibodies.9 TSH levels are elevated, but thyroid hormone levels (T4/T3) remain in the normal reference range, and therefore SHypo does not always require treatment. Both European and US guidelines advise treating SHypo in patients under 70 years of age only if TSH >10 mIU/l (a typical reference range for TSH is 0.27-4.2mU/L). If symptoms suggestive of hypothyroidism are present, a trial of thyroid hormone replacement can be considered.10, 11 SHypo should be treated with thyroid hormone replacement in pregnant women and women considering a pregnancy.12 Treatment of Hypothyroidism The first-line treatment for both primary hypothyroidism, central hypothyroidism, and subclinical hypothyroidism

(where appropriate) is thyroxine (T4) monotherapy, in the form of levothyroxine.8, 13, 14 T4 is then converted to active T3 in peripheral tissues under the normal physiological pathway.3 The goal of therapy is three-fold; to improve symptoms, normalise serum TSH in the case of primary and subclinical hypothyroidism (or achieve a free T4 concentration within the upper reference interval for central hypothyroidism7, 8) and avoid overtreatment.14 A dose of 1.6µg/kg/day is generally sufficient to treat primary hypothyroidism, however in elderly patients or those with known ischaemic heart disease, thyroid hormone replacement should be commenced at a low dose, and up-titrated over several months to avoid adverse effects.3 Pregnant women require higher doses of thyroxine and close monitoring of thyroid function and should increase their daily dose by 20-30% as soon as pregnancy is confirmed. This can be achieved by doubling their regular dose on two days per week.12, 15 Levothyroxine should be taken on an empty stomach, and patients should not eat, or drink any fluids other than water (including caffeinated beverages) for at least 30 minutes. They should also avoid taking medications such as calcium supplements or iron at the same time, to avoid interfering with absorption.14 Thyroxine has a half-life of approximately 7 days, therefore clinicians should ideally wait for 6-12 weeks between dose adjustments and rechecking thyroid function testing.14, 16 Overtreatment with thyroid replacement therapy carries a risk of atrial fibrillation and osteoporosis17, and therefore it is important to monitor serum TSH annually once a patient is established on replacement therapy.16 There is little evidence to suggest that treatment with combination

therapy of T4/T3 offers an advantage over T4 monotherapy 18, and therefore is not recommended routinely by either the British Thyroid Association (BTA), American Thyroid Association (ATA) or the European Thyroid Association (ETA) guidelines. However, combination therapy may be considered as a trial approach in patients on a case-by-case basis. Such patients should be adherent to T4 therapy and have consistently achieved target TSH measurements but experience persistent symptoms that may be due to hypothyroidism, without any other cause for symptoms identified.13, 14, 19 Combination therapy is not recommended in women who are pregnant or seeking fertility in the short to medium term. The use of thyroid hormone extract is not recommended in any setting, and especially not in pregnancy.14, 19, 20 Thyrotoxicosis Thyrotoxicosis is the term used to describe the clinical findings that arise when bodily tissues are exposed to excess amounts of thyroid hormone (Table 1 & 2). Hyperthyroidism is used to describe thyrotoxicosis which occurs due to overproduction of thyroid hormone by the thyroid gland itself (e.g. Graves’ disease, toxic multinodular goitre, toxic adenoma), however thyrotoxicosis can also occur due to inflammation or destruction of the gland (thyroiditis, which causes the release of large amounts of pre-formed thyroid hormone into the circulation), or exogenous use of thyroid hormone in excessive doses. It is important to identify the underlying cause of thyrotoxicosis, as the treatment and long-term outcomes will differ.

Graves’ disease is caused by the production of anti-TSH receptor antibodies (TRAb).

These antibodies bind to the TSH

Table 2. Patterns of thyroid function tests in primary and central thyroid disorders

58 1.Table 1. Patterns of thyroid in primary and central disorders.

Table Patterns of thyroid functionfunction tests in tests primary and central thyroid thyroid disorders.

Subclinical Central Central Subclinical Central Central PrimaryPrimary Subclinical PrimaryPrimary Subclinical Hypothyroidism Hypothyroidism Hypothyroidism* Hyperthyroidism Hyperthyroidism Hyperthyroidism Hypothyroidism Hypothyroidism Hypothyroidism* Hyperthyroidism Hyperthyroidism Hyperthyroidism

TSH ↑ TSH fT4/fT3 fT4/fT3 ↓

↑ ↓

↑ ↔

↑ ↔

↓/ ↔ ↓/ ↔ ↓ ↓

↓↓ ↑

↓↓ ↑

↓/↓↓ ↓/↓↓ ↔ ↔

↑/↔ ↑/↔ ↑ ↑

59 60 61

59 Legend: TSH stimulating thyroid stimulating hormone, freefree T4, fT3 free T 3, ↑above upper end of reference Legend: TSH thyroid hormone, fT4 free fT4 T4, fT3 T 3, ↑above upper end of reference range, range, 60 ↔within reference range, ↓below lower reference limit ↓↓ Undetectable. * Pattern also seen with non↔within reference range, ↓below lower reference limit ↓↓ Undetectable. * Pattern also seen with non61 thyroidal illness. thyroidal illness.

62

62

63

63 Hypothyroidism Hypothyroidism

HOSPITALPROFESSIONALNEWS.IE | HPN • MARCH 2022

74

receptor on the surface of thyroid follicular cells and activate the receptor, causing excessive TH production. The level of TRAb usually falls with time and ATD therapy, and so thyrotoxicosis due to Graves’ Disease remits in up to 40% following 12-18 months of medical therapy. If remission does not occur, or the patient experiences a relapse, definitive management is required, which may entail radioactive iodine therapy, total thyroidectomy or long-term medical management with ATD.21 Toxic multinodular goitre (many thyroid nodules with autonomous TH production) or toxic adenoma (a single adenoma with autonomous TH production) can also cause thyrotoxicosis, however in such patients spontaneous remission does not occur, and therefore ATD therapy is used to normalise thyroid function as a bridge to definitive management.

Thyroiditis is usually managed symptomatically, with antiinflammatory treatment, if required, for neck pain, and betablockade for palpitations during the thyrotoxic phase. Although thyroiditis is self-limiting, many patients experience hypothyroidism following the thyrotoxic phase, which is usually, but not always, transient. Importantly, antithyroid drugs should be avoided, since they are ineffective (the thyrotoxicosis is due to the release of stored TH, not production of new TH) and any ensuing hypothyroidism will be worsened by using such medications.

Subclinical Hyperthyroidism Subclinical hyperthyroidism (SHyper) is a biochemical diagnosis. It is usually due to toxic adenoma or toxic multinodular goitre. TSH is low or suppressed but thyroid hormone concentrations (both T4 and T3) remain within the reference range and can be divided into grade 1 (TSH is below the lower reference limit but remains detectable)

GI FOCUS: THYROID FUNCTION

or grade 2 (TSH is fully suppressed). Grade 2 SHyper is associated with increased risk of fractures, atrial fibrillation, heart failure and increased mortality in older adults, and therefore should be treated in patients over 65 years. Treatment should also be considered in patients <65 years with persistent grade 2 SHyper and symptoms or known heart disease22. Of note, patients with suppressed TSH, normal FT4 and raised T3 have a condition called T3 toxicosis, which is often also caused by toxic adenoma or toxic multinodular goitre, but notably these patients are treated as having thyrotoxicosis, not SHyper.

Treatment of Thyrotoxicosis and Subclinical Hyperthyroidism There are two main components of the medical management of thyrotoxicosis; β-adrenergic blockade for symptomatic relief, particularly for patients with a resting tachycardia, and the use of anti-thyroid drugs to block the production of thyroid hormone.

Non-selective β-adrenergic blockers are useful to control the adrenergic symptoms associated with thyrotoxicosis (palpitations, tremor etc). When used in high doses, non-selective β-adrenergic blockers such as propranolol (3040mg three times daily) can also inhibit the peripheral conversion of T4 to active T3.21, 23 Anti-thyroid drugs (ATD) such as thionamides (propylthiouracil, carbimazole and methimazole) are used to normalise thyroid function in hyperthyroidism, by inhibiting the synthesis of thyroid hormone within the thyroid. There are two different approaches to their use, a dose-titration approach or block and replace approach. The dose-titration approach, whereby a patient is commenced on a high dose of ATD, and the dose gradually reduced depending on thyroid function tests every 4-8 weeks, until a steady state is achieved, has the advantage of using the

MARCH 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE

lowest possible ATD dose but requires frequent monitoring to guide dose modification. The block and replace approach, whereby a patient receives a high ATD dose daily, with replacement thyroxine being added once the FT4 level is normal, requires less frequent monitoring but requires higher cumulative doses of ATD, increasing the potential risk of adverse events.24 There is little difference in efficacy between the two regimes, however during the Covid-19 pandemic, the block and replace regime was recommended for newly diagnosed patients.25 Carbimazole, which is decarboxylated to the active drug methimazole in the liver, and propylthiouracil, both inhibit the de novo synthesis of thyroid hormone, and at high doses propylthiouracil can also inhibit the peripheral activation of T4 to T3. Up to 5% of patients treated with thionamides will experience a mild skin rash, which can be managed with antihistamine therapy alone and usually subsides.

If the reaction is severe, the patient can be changed to an alternative ATD. Agranulocytosis is a rare (1-3/1000) but potentially serious side effect of both carbimazole and propylthiouracil. All patients commenced on thionamides should be counselled regarding this risk and given written advice regarding possible symptoms of agranulocytosis (severe sore throat, mouth ulcers, fever, flu-like illness). If these symptoms occur, patients are advised to stop taking the medication immediately and present within 24 hours for a full blood count. If the white cell count is normal, the patient can restart the ATD. As the onset of agranulocytosis is often abrupt and unpredictable, monitoring using full blood count is not recommended.21 Hepatotoxicity is reported in association with both carbimazole and propylthiouracil.26 Carbimazole is associated with a cholestatic pattern however propylthiouracil has been reported to cause

fulminant hepatic failure, which is often fatal.27 Carbimazole is therefore recommended as first line ATD therapy in non-pregnant adults by both the ATA and ETA. Patients commenced on ATD therapy are recommended to have thyroid function testing performed every 4-6 weeks while the dose is being titrated, and every three months once a maintenance dose has been achieved.16 Women of childbearing age should be counselled regarding the risks of conceiving while being treated for thyrotoxicosis.

Thyrotoxicosis in pregnancy increases the risk of complications for both mother and fetus, and ATD cross the placenta and are associated with an increased risk of birth defects.28 Women who conceive during treatment for hyperthyroidism should be treated with propylthiouracil in the first trimester (due to the risk of methimazole embryopathy during fetal organogenesis) and may be switched back to carbimazole in the second and third trimester to attempt to reduce the risk of hepatotoxicity.21, 28 Conclusion Disorders of thyroid dysfunction are common in the community and cover a broad spectrum of presentations ranging from overt hypothyroidism to thyrotoxicosis.

Correct administration of thyroxine is essential to optimise absorption and pharmacists have a role in conveying this message to patients. Anti-thyroid drugs are generally safe and well tolerated, however patients should be counselled regarding the rare, but serious potential risk of agranulocytosis. Pre-pregnancy counselling is an important component of the care of women of child-bearing age treated for all disorders of thyroid function, to optimise pregnancy outcomes for both the mother and infant.

References available on request

Tuberculosis 75

Role of the TB Clinical Nurse Specialist in Tuberculosis Care and Treatment St James’s Hospital TB referral centre has a team which consists of Consultants, Registrar, TB Clinical Nurse Specialist (CNS), senior pharmacist and secretary.

The TB CNS is an integral part of this team. The role is wide-ranging and involves been an advocate for the patient, maintaining continuity of care, supporting and educating the patients and also educating those involved in the patient’s care.

A holistic approach is important as each patient differs in the level of support/needs required therefore care and support must be patient centred. Most patients diagnosed with active TB are treated in the ambulatory care setting. The TB CNS is the link for the patient between community care and the hospital TB team.

may result in onward transmission, ill health, preventable death and drug resistance. Therefore, it is important that any issues are resolved promptly in order that the patient continues taking their medications. Our TB service offers patients urgent reviews outside of routine clinic times to facilitate this.

The TB team works in conjunction with other MDT members and hold’s twice weekly MDT meetings.

Our MDT members consist of Microbiology colleagues from the Irish Microbiology Reference Laboratory (IMRL) and Public Health. The IMRL updates the team on the identification type of TB and sensitivities so that treatment is tailored accordingly.

Our TB MDT offers clinicians from around the country the opportunity to discuss their patients also when they are seeking our expert input and advice. All MDT outcomes are documented on our Electronic Patient Record (EPR) system by the TB CNS. The TB service holds weekly outpatient clinics, twice weekly ward rounds and a fortnightly Nurse Led Latent TB clinic. We also offer urgent walk in reviews outside of clinic times.

Patient Monitoring and Follow up

Adherence Building strong relationships with the patient is vital in order to promote adherence to treatment. Adherence to TB medication is paramount to a successful treatment outcome.

Non-adherence can occur for many reasons e.g. stigma, side effects of medications, chaotic lifestyle, denial of the TB diagnosis and lengthy treatment course.

Treatment duration for active TB can be for a minimum of 6 months but in the case of Multi Drug Resistance TB can be 18 months. Having a point of contact for each patient ensures that there is always someone available to answer questions/concerns. Each patient is given contact details of the TB CNS and are encouraged make contact if issues arise.

Non-adherence to TB treatment

To ensure adherence some patients (as per Health Protection Surveillance Centre Guidelines 2010) require Directly Observed Therapy (DOTS). This involves the TB CNS referring the patient to the Public Health Nurse (PHN) who will observe the patient taking their TB medication each day. In this instance the TB CNS in collaboration with the PHN promote adherence.

Due to the potential hepatotoxicity of TB medications, patients require frequent blood monitoring. This is done at baseline and 4-6 weekly intervals. TB CNS monitors these results and decisions are made if patient’s need to temporarily hold TB medications or requires a change in medications. As hepatotoxicity can occur at any time point of the treatment course, close blood monitoring is continued for duration of treatment. Some patients require therapeutic drug monitoring (TDM). This involves taking numerous blood tests at certain time interval’s throughout the day, which the TB CNS carriers out.

TBM is important if a patient fails to improve as expected (and nonadherence is not an issue) or there is a question of malabsorption.

Other side effects such as nausea/ vomiting, peripheral neuropathy, rash can also occur which require prompt evaluation.

Patients are encouraged to not miss any of their clinic appointments as our TB medications are dispensed from clinic. Any patient who fails to attend will get a phone call from the TB CNS and another appointment is facilitated as soon as possible. This ensures adherence to treatment.

Education All patients with a new diagnosis of active TB/Latent TB meet the TB CNS and receive education on their diagnosis and treatment plan. Often, they request that family members are spoken with, which is beneficial

Written by Lorraine Dolan, TB Clinical Nurse Specialist, Respiratory Assessement Unit, St James’s Hospital

to the patient as family members are an important support network.

Patients are encouraged to contact the TB CNS with any questions.

Lectures and education session are also given by the TB CNS to other health care professionals who may be involved in the care of pts with TB. This includes other hospitals, community colleagues and also University’s. Stigma is still evident in relation to a TB diagnosis in Ireland and many of our patients have reported been ostracized from family and friends. Only through awareness and continued education will this be eliminated. One positive to arise from the Covid pandemic is that the wearing of face masks has been normalized. Prior to this our patients would have felt very vulnerable and self-conscious with wearing masks when there was potential of onward transmission of TB. Advocacy There is a requirement for the TB CNS to regularly advocate on patients behalf. This can arise due to issues with employment

and sick leave, accommodation or financial issues. The TB CNS has close links with social work department, Inclusion health, safety net and other agencies in order to advocate on behalf of the patients if required.

Research Audit and research is an integral part of the TB CNS role to ensure that we provide the best possible service to our patients.

Currently the TB CNS is principal investigator on a research study into Video Observed Therapy (VOT) and comparing it to DOTS. VOT is the use of a mobile app for patients to record themselves taking their medication to ensure treatment compliance. This research study will be conducted over two years.

TB is a complex disease and requires expert input in order to have a successful outcome. The TB CNS along with MDT colleagues play a vital role in ensuring that only the highest standard of care is afforded to the patient and that all patients receive the most appropriate TB investigation’s, treatment and support.

HOSPITALPROFESSIONALNEWS.IE | HPN • MARCH 2022

76

Vitamin D

What is our Understanding of Vitamin D Written by Dr Kevin McCarroll, Consultant Physician, St James’s Hospital, Dublin

MARCH 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE

Vitamin D has become the focus of huge interest in recent years, with an increasing number of studies identifying a high prevalence of deficiency. Vitamin D is widely regarded as being important for a healthy immune system and is implicated in the pathogenesis of cancer, autoimmune, cardiovascular and respiratory diseases as well as depression and cognitive impairment. More recently a large body of circumstantial evidence supports a role for vitamin D in ameliorating the symptoms or severity of Covid-19. In fact, to date there are nearly 1000 peer-reviewed studies published on the topic of ‘Vitamin D and

Covid-19’. Vitamin D is not a nutrient in the traditional sense as it is a hormone that is largely derived from cutaneous synthesis after UVB exposure. Furthermore, dietary sources are limited and make a small contribution to overall intake but include fortified foods (milks, breakfast cereals), oily fish and eggs.

What constitutes vitamin D deficiency?

This has only been defined in relation to optimal bone health. A 25-hydroxyvitamin D level of less than 30 nmol/L is generally considered to represent deficiency and can cause rickets in children, osteomalacia in adults and result in secondary hyperparathyroidism. A level between 30-50 nmol/L represents possible deficiency and may be deleterious to bone health though other factors such as calcium and phosphate intake interact with vitamin D and play a role. For this reason, levels in the 30-50 nmol/L range are generally categorised as “insufficient". Despite this, higher calcium intake appears to partially compensate for lower vitamin D status by reducing secondary hyperparathyroidism. To ensure that one is vitamin D replete, it is prudent to maintain a level of ≥50 nmol/L. Vitamin D levels

77 up to 75 nmol/L have been associated with more optimal suppression of serum parathyroid hormone (PTH), bone turnover markers and bone density in several studies though evidence is mainly observational and definitive data is lacking. The Endocrine Society defines vitamin D insufficiency as a level between 50-75 mol/L but this is not widely accepted. Vitamin D levels of up to 60 nmol/l may reduce falls risk in some adults and levels up to 75 nmol/L are associated with better performance in tests of physical function including gait speed. For this reason, a target level of 75 nmol/L is recommended for older adults by some bodies including the American Geriatric Society, particularly for those who are frail and at risk of falls and fractures.

Several studies report positive associations between higher levels of 25(OH)D and other health outcomes but definitive data is lacking. Levels above 125 nmol/l may be deleterious though toxicity is rare and generally only found with levels above 300 nmol/l.

How common is deficiency?

Deficiency is common in Ireland and countries above above 37° N latitude, where little or no vitamin D synthesis occurs between the months of November to March giving rise to the so-called “vitamin D winter”. In fact, vitamin D levels are typically highest in August/ September at the end of the summer and lowest in February/March. Indeed, the level usually drops by about 30 per cent between seasons.

In Ireland, overall, 13.1 per cent of the population older than 50 are vitamin D deficient (<30 nmol/L) based on findings from The Irish Longitudinal Study of Ageing (TILDA). In the same study, deficiency affected nearly one in four (24.1%) in the winter with the greatest prevalence (37%) in those aged over 80. Furthermore, more than half (59.2%) had levels below 50 nmol/l in the Winter. There were also regional variations with higher rates of deficiency in the north and west of the country. Using TILDA data, it is also estimated that 27 per cent of over-70s that were cocooning may be deficient.

Several other Irish studies report similar rates of deficiency.

For example, In in the West of Ireland the overall prevalence of deficiency using a lower cut-off (<25 nmol/l) in a large cohort (n=24,302) was 17%. More specifically, deficiency affected 42% in nursing homes, 37% of

outpatient attendees and 13% of community dwellers. More than half (54%) also had vitamin D levels below 50 nmol/l. Similarily, in a study of frail, older Irish adults (n=1,316) attending geriatric outpatient clinics in Dublin, 33% were found to be deficient (<30 nmol/L) with 75 per cent of non supplemented patients having levels below 50 nmol/L. One of the the largest Irish studies of vitamin D status to date included 36,466 people aged 1890+ in the Leinster area who had vitamin D checked by request of their GP. It identified an on overall rate of deficiency of 13% rising to 23% in the Winter. Furthermore, up to half of adults had levels below 50 nmol/L. Unlike many studies which included older adults, it identified the highest rate of deficiency (21%) in those who were younger (18-39 years) with the lowest rate of 10-11% in those aged 60-79 but rising to 17% in the 80+ age group. A similar 'U" shaped relationship has been identified in the West of Ireland. The highest prevalence of deficiency in a population group in Ireland was found in those of South East Asian ethnicity living in Dublin (n=186) where 66.7% were found to be deficient all year round and with only 6.7% having a level above 50 nmol/l .

Factors affecting vitamin D status Vitamin D status varies by geographical area in Ireland.

For example, those living in Leinster have the the lowest rate of deficiency while a higher prevalence is found in all other provinces. In the largest study to geomap vitamin D status in Europe (n=34,466) based on vitamin D samples from Irish adults mainly in Dublin, there was a striking difference in vitamin D status between postal codes areas. Notably, in winter, areas in South Dublin (Dublin 4, Dublin 6/6W, Dublin 14/16) were found to have greater levels when compared to west, central and north Dublin. In Dublin city centre (Dublin 1 and Dublin 2) there were also greater levels of deficiency (34- 37%) versus nearby areas of Dublin 4 and Dublin 6 where prevalence was nearly half this at 19%.

Several factors may account for these study findings including area differences in levels of UVB irradation, dietary vitamin D intake, sun exposure, ethnicity and lifestyle factors such as smoking. In particular, lower socioeconomic status (SES) is

linked with lower vitamin D status in several studies including in the Irish TILDA sample, where lower asset wealth was associated with a 50% increased risk of deficiency. Lower consumption of vitamin D rich or fortified foods which are more expensive, less use of supplements and sun holiday travel in poorer socioecomic areas are factors.

Lower SES is also associated with higher rates of obesity which probably lowers vitamin D levels as a result of sequestration in fat tissue. Smoking is also a factor, as it has been independently associated with lower vitamin D in most studies, though the mechanism is not understood.

UVB irradiation also varies significantly by latitude even within Ireland (51 -55 N) but is also reduced by cloud cover which is greater in certain parts of the country. In those of nonEuropean ethnicity who have more pigmented skin, there is a greater risk of deficiency as longer sun exposure is required for vitamin D synthesis due to increased UV absorption by cutaneous melanin. In younger adults, a rise in veganism, vegetarian and reduced animal products in the diet may be a factor as meat, vitamin D-fortified dairy and fish consumption account for a significant proportion of overall dietary vitamin D intake.

Additionally, younger adults who are shiftworkers may lose out on the opportunity for sun exposure and are found to have a higher prevalence of deficiency. In older adults, the higher prevalence of deficiency is due in part to increasing frailty and less sun exposure. However, the capacity of the skin to synthesise vitamin D may decline by as much as 75 per cent with age, possibly due to reduced levels of cutaneous 7-dehydrocholesterol, the precursor of pre-vitamin D. Vitamin D testing Vitamin D deficiency is often picked up on blood tests in those who either have no or nonspecific symptoms. However, severe deficiency can give rise to generalised aches and pains and osteomalacia, which can be exacerbated by low calcium intake. So who should be tested?

Guidelines vary though ‘at-risk’ groups should be considered for testing. These include frail older adults, those with minimal sun exposure, malabsorption syndromes, unexplained musculoskeletal symptoms and low bone density. Consider rechecking levels to ensure

adequate response to treatment, especially if compliance with supplements is in question or in those with osteomalacia or metabolic bone disease. However, there is no need for routine testing or retesting. If using daily supplements, levels should not be checked for at least three months — the time taken to reach steady state. Its also important to factor in the season of testing when interpreting results. For example, vitamin D levels can typically vary by up to 15 nmol/l between seasons. A recent study in Dublin (n=36,458) found that nearly one in four patients were retested though 12.2% were done too early (within 3 months) or too frequent (29% had two or more retests annually) and 57% were in those who were initially vitamin D replete (≥50 nmol/l).

Prevention and Treatment Whilst dietary sources of vitamin D are limited they account for a small but significant contribution to overall status, especially in the winter. Rich sources include oily fish, sundried mushrooms, vitamin D-fortified milk and breakfast cereals. Some fortified foods also have the added advantage of containing additional calcium, which along with vitamin D is important for bone health.

However, diet alone is not enough to maintain adequate vitamin D status in the Irish population.

In most cases, oral supplementation with 8001,000 IU vitamin D3 daily will be sufficient to maintain a level of 50 nmol/L, though higher doses may be required if there is poor gut absorption, obesity or liver disease. A variety of vitamin D tablets are licensed to treat or prevent deficiency and include daily (800 IU or 1,000 IU), onceweekly (7,000 IU) or once-monthly (25,000 IU). Therapy with 50,000 IU once weekly for about six weeks can be used for more rapid correction of deficiency followed by maintenance supplements. The dose response to supplements ranges from about 2.0 -2.5+ nmol/L per 100 IU, so 800 IU daily should result in a minimum increase of about 20 nmol/L. If additional calcium is required, combined vitamin D / calcium supplements can be used, aiming for total calcium intake (dietary and supplemental) of 1000 mg daily. While there are different recommendations for daily or equivalent daily vitamin D intakes, the National Academy of Medicine advises 600 IU/day for those aged between 1–70 and 800 IU/ day if older than 70.

HOSPITALPROFESSIONALNEWS.IE | HPN • MARCH 2022

78 Cancer Research

Record ¤450K funding for Emerging Clinician Research Leaders Professor Karen Cadoo, Cancer Geneticist and Ovarian Cancer Specialist, St James’s Hospital/ Trinity College Dublin

already a national referral centre for adults with a genetic risk of cancer, providing services to over 2,000 people from all around the country who match this criteria.

for instance, but such projects are essential to creating the intelligence that can improve cancer survival and save lives in future in her opinion.

Professor Cadoo points to a very useful Covid-19 registry that the hospital has developed as evidence that a similar registry for cancer genetic risk is possible.

Rapid access clinic

‘Biobanking’

Emerging Irish clinician researchers will be supported in pursuing exciting projects across areas including lung cancer, breast cancer and cancer genetics as part of a record ¤450K investment by the Irish Cancer Society over the next two years.

The funding is provided as part of the Society’s Clinician Research Leadership Award. The award ‘buys out’ the time of hospitalbased clinicians who are at the forefront of patient care so they can devote time to forward-looking research projects, with the aim of attracting and retaining worldclass oncology consultants for Ireland who will drive evidencebased advances for patients.

On the following pages we take a look at the research work this funding will assist with.

Clinician Research Leadership Award: Professor Karen Cadoo For some people their risk of cancer may be higher due to genes that are passed down through their family.

Professor Karen Cadoo of St James’s Hospital has dedicated her research to helping people understand this risk and the steps they can take to reduce this, or catch the signs of cancer early.

It is estimated that somewhere between 5-10% of cancer cases are linked to faults in the genes or ‘mutations’ that people inherit, and Prof Cadoo’s vision is to give more people better access to the kinds of insights that can indicate their level of risk and what should be done in relation to it.

“If we can improve information, if we can improve acceptability and accessibility so that doing genetic testing is more routine, as in the way people do other things in their life, then that would be brilliant,” she says.

Genetic screening When talking to Professor Cadoo about the work that she will undertake through the award, a key word that comes through is ‘ambition’.

She references a recent report from the Irish Cancer Society, in association with researchers from University College Cork, in which patients express their frustrations at the availability of services in Ireland for determining something so crucial as their genetic risk of developing cancer, and access to counselling to help explain what this means.

Ireland currently lags behind other countries according to Professor Cadoo, like the UK whose very effective cancer genetic screening system she feels we can realistically strive towards here.

The ovarian cancer specialist is conscious that this will not be possible in one leap - important foundations must first be put in place to enable this grand ambition to be realised.

For a start, it’s a big help that her base at St James’s Hospital is

Using available expertise on biobanking - the storing of patients’ biological samples for future investigation - at the site will help to ensure that those involved can benefit from scientific breakthroughs in genetic testing in years to come

MARCH 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE

Using available expertise on biobanking - the storing of patients’ biological samples for future investigation - at the site will help to ensure that those involved can benefit from scientific breakthroughs in genetic testing in years to come, she says.

“Things change into the future.

If you have samples from people who you know have mutations or those who don’t have mutations but have a risk in their family, then maybe over time you can progress things; for instance when new genetic discoveries are made internationally.

“For example, it can be a case that someone comes in with a family history of colon cancer and we don’t find anything. It’s not necessarily that there is no genetic risk present, we just mightn’t have the means at our disposal to find it at that point in time… but technology advances in the future may be able to provide the answer, so if you have banked samples for research there’s a lot of great things you can do with it.”

Professor Cadoo is accepting of the fact that registries and biobanks do not sound terribly exciting compared to new breakthroughs in treatments,

Alongside the registry and biobank at St James’s, Prof Cadoo wants to pilot a range of initiatives including a rapid access clinic for those concerned about their genetic risk of cancer, and a nurse phone line that people can get in touch with to ask questions, with a view to proving their value on a national scale in future.

“People’s heads can be spinning when they discover a genetic risk, so they may not ask their doctor about questions that may eventually become apparent to them. If they could pick up the phone and ask all their questions then hopefully that will be an improvement.

“Even the people who won’t necessarily use such a resource might benefit from the fact that they know it exists, that it’s an option that’s there for them as a kind of safety net,” says Professor Cadoo, who feels that making such services available for patients can help empower them to navigate their own way through their care and to look after their health.

On the importance of the Irish Cancer Society’s Clinician Research Leadership Award, Professor Cadoo says it will provide her with much-needed “headspace” to take her research to the next level and help make a difference for patients.

Confidence starts with clearance...1

can your patients with moderate to severe plaque psoriasis live life confidently?

Brodalumab

Kyntheum® is the first therapy for moderate to severe plaque psoriasis that selectively targets the IL-17 receptor subunit A2 • Rapid onset of action: By Week 2, 1 in 4 Kyntheum® patients achieved PASI 753* • Sustained response: At 2 years, 61% of Kyntheum® patients had sustained clearance rates, in an observed data analysis of PASI 75, 90 and 100 (n=90 at 120 weeks, no p values calculated)4 PASI, Psoriasis Area and Severity Index. *Time for 25% of patients to achieve PASI 75 was 2.1 weeks (one study, 95% CI 2.01-2.26) in a large sample population (n=1,236).3

Kyntheum® (brodalumab) is indicated for the treatment of moderate to severe plaque psoriasis in adult patients who are candidates for systemic therapy5

To learn more about Kyntheum® visit uk.dermaworld.eu Prescribing Information for Kyntheum® (brodalumab) 210 mg solution for injection in pre-filled syringe Please refer to the full Summary of Product Characteristics (SmPC) (www.medicines.ie) before prescribing.

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.

Indication: Treatment of moderate to severe plaque psoriasis in adult patients who are candidates for systemic therapy. Active ingredient: Each pre-filled syringe contains 210 mg brodalumab in 1.5 ml solution. 1 ml solution contains 140 mg brodalumab. Dosage and administration: Posology: Adults: The recommended dose is 210 mg administered by subcutaneous injection at weeks 0, 1, and 2 followed by 210 mg every 2 weeks. Consideration should be given to discontinuing treatment in patients who have shown no response after 12-16 weeks of treatment. Some patients with initial partial response may subsequently improve with continued treatment beyond 16 weeks.

Administer by subcutaneous (SC) injection. Each pre-filled syringe is for single use only. Elderly: No dose adjustment recommended.

Hepatic and renal impairment: No dose recommendations can be made. Children and adolescents below the age of 18 years: Safety and efficacy of Kyntheum have not been established. Method of administration: Kyntheum should not be injected into areas where the skin is tender, bruised, red, hard, thick, scaly, or affected by psoriasis.

The pre-filled syringe must not be shaken. After proper training in SC injection technique, patients may self-inject Kyntheum when deemed appropriate by a physician. Patients should be instructed to inject the full amount of Kyntheum according to the instructions provided in the package leaflet. Contraindications: Hypersensitivity to the active substance or to any of the excipients. Active Crohn’s disease. Clinically important active infections (e.g. active tuberculosis). Precautions and warnings: Inflammatory bowel disease (including Crohn’s disease and ulcerative colitis): Cases of new or exacerbations of inflammatory bowel disease have been reported with IL-17 inhibitors. Therefore Kyntheum is not recommended in patients with inflammatory bowel disease. If a patient develops signs and symptoms of inflammatory bowel disease, or experiences an exacerbation of pre-existing inflammatory bowel disease, Kyntheum should be discontinued and appropriate medical

management should be initiated. Suicidal ideation and behaviour: A causal association between treatment with Kyntheum and increased risk of suicidal ideation and behaviour has not been established.

Carefully weigh the risk and benefit of treatment with Kyntheum for patients with a history of depression and/or suicidal ideation or behaviour, or patients who develop such symptoms. Patients, caregivers and families should be advised of the need to be alert for the emergence or worsening of depression, suicidal ideation, anxiety, or other mood changes, and they should contact their healthcare provider if such events occur. If a patient suffers from new or worsening symptoms of depression and/or suicidal ideation or behaviour is identified, it is recommended to discontinue treatment with Kyntheum.

Hypersensitivity reactions: In the event of an anaphylactic reaction, or any other serious allergic reaction, administration of Kyntheum should be discontinued and appropriate therapy initiated. Infections: Kyntheum may increase the risk of infections. Caution should be exercised when considering the use of Kyntheum in patients with a chronic infection or a history of recurrent infection. Patients should be instructed to seek medical advice if signs or symptoms suggestive of an infection occur. If a patient develops a serious infection, they should be closely monitored and Kyntheum should not be administered until the infection resolves. Kyntheum should not be given to patients with active tuberculosis. Anti-tuberculosis therapy should be considered prior to initiation of Kyntheum in patients with latent tuberculosis.

Reduced absolute neutrophil count: A decrease in absolute neutrophil count, generally transient and reversible, has been observed in 5.6% of patients receiving Kyntheum. Vaccinations: It is recommended that patients be brought up-to-date with all immunisations in accordance with local immunisation guidelines prior to initiation of treatment with Kyntheum. Live vaccines should not be given concurrently with Kyntheum. The safety and efficacy of Kyntheum in combination with immunosuppressants, including biologics, or phototherapy have not been evaluated. Drug interactions: Live vaccines should not be given concurrently with Kyntheum. Fertility, pregnancy and lactation: Women of childbearing potential: Use an effective method of contraception during treatment and for at least 12 weeks after treatment. Pregnancy: There are no or limited amount of data from the use of brodalumab in pregnant women. As a precautionary measure, it is preferable to avoid

the use of Kyntheum in pregnancy. Benefit risk for exposure of the infant to live vaccines following third trimester exposure to Kyntheum should be discussed with a physician. Breast-feeding: It is unknown whether brodalumab is excreted in human milk. A risk to the newborns/ infants cannot be excluded. Whether to discontinue breast-feeding or discontinue Kyntheum therapy should be decided, taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman. Fertility: No data are available on the effect of brodalumab on human fertility. Side effects: Common (≥1/100 to <1/10): Influenza, tinea infections (including tinea pedis, tinea versicolor, tinea cruris), headache, oropharyngeal pain, diarrhoea, nausea, arthralgia, myalgia, fatigue, injection site reactions (including injection site erythema, pain, pruritus, bruising, haemorrhage). Uncommon (≥1/1,000 to <1/100): Candida infections (including oral, genital and oesophageal infections), conjunctivitis, neutropenia. Rare (≥1/10,000 to <1/1,000): Anaphylactic reaction. Precautions for storage: Store in a refrigerator (2°C-8°C). Do not freeze. Keep the pre-filled syringe in the outer carton in order to protect from light. Kyntheum may be stored at room temperature (up to 25°C) once, in the outer carton, for a maximum single period of 14 days. Once Kyntheum has been removed from the refrigerator and has reached room temperature (up to 25°C) it must either be used within 14 days or discarded. Legal category: POM. Marketing authorisation number and holder: EU/1/16/1155/001, LEO Pharma A/S, Ballerup, Denmark. Last revised: July 2020.

REF- 05353 (3) 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, website: www.hpra.ie Adverse events should also be reported to Drug Safety at LEO Pharma by calling +353 1 4908924 or e-mail medical-info.ie@leo-pharma.com

References: 1. Warren RB, et al. JEADV 2021;35:450–457. 2. Brembilla NC, et al. Front Immunol 2018;9:1682. 3. Yao CJ, et al. J Drugs Dermatol 2019;18(3):229–233. 4. Puig L, et al. J Am Acad Dermatol 2020;82(2):352–9.

5. Kyntheum® SPC, IE: www.medicines.ie. Last accessed: February 2022.

Further information can be found in the Summary of Product Characteristics or from: LEO Pharma, Cashel Road, Dublin 12, Ireland. e-mail: medical-info.ie@leo-pharma.com ® Registered trademark

Date of preparation: February 2022 IE/MAT-51818 V2

80 Cancer Research

Clinician Research Leadership Award: Professor Aoife Lowery Professor Aoife Lowery, Consultant Surgeon, Galway University Hospital and Associate Professor in the Discipline of Surgery, NUI Galway

“We’re trying to look at how the cancer cells respond to heat, and specifically in the dynamic environment of the lung. The lung is particularly complicated because it is continually inflating and deflating, there’s blood running through it and all of these things can affect the microwave heat and how it works on the cancer cells, so we’re currently looking at what’s known as the thermotolerance, or heat tolerance, of cancer cells in pre-clinical models with the aim of ultimately translating it to the clinical setting,” Professor Lowery said of the project.

Preventing treatment-related cardiac dysfunction

All too often, cancer surgeon Professor Aoife Lowery sees the underappreciated impact that the side effects from treatment can have on patients.

As the outcomes and survival for patients with breast cancer continue to improve, she feels that survivorship issues such as the side effects of cancer treatment are becoming increasingly recognised.

“From a clinician’s perspective we are very focused on treating the cancer and improving survival, and may consider things like hair loss to be an unfortunate side effect of effective cancer treatment,” says Professor Lowery, a recent recipient of the Irish Cancer Society’s Clinician Research Leadership Award that will allow her to dedicate more time to forward-looking cancer research projects.

Reducing hair loss This includes her work with bioengineers at the Translational Medical Device Laboratory in NUIG and Luminate Medical (www.luminatemed.com) on a device aimed at helping patients going through chemotherapy to reduce hair loss. It will improve on currently available approaches such as cold caps by reducing pain and discomfort, and improving ease of use for patients.

Translational research refers to the process of translating lab-based research breakthroughs into realworld benefits for patients, and the intention is to run the first clinical trial of this device with patients at University Hospital Galway.

The ‘Lily Device’ works by applying a tolerable amount of pressure to a person’s scalp to reduce the bloodflow, thereby reducing the toxic effects of chemotherapy at the hair follicle.

“The idea is to develop something that’s smart, wearable and portable. The patient will have personalised settings to control the pressure, they can wear it during chemotherapy but can also leave the hospital with this on,” Professor Lowery says of the device, which is at the advanced prototype development stage prior to hopefully being made available to future patients.

Breast reconstruction Another example of a project that Professor Lowery is working on with her bioengineering colleagues, and that she will be able to dedicate more time to through the Irish Cancer Society award, is a novel and improved way of reconstructing the breast after a patient has surgery for breast cancer.

“What we’re looking at is a tissue engineering approach using stem cells from the patient’s own fat which are very easy to access via liposuction, and combining them with a biocompatible scaffold to grow more fat cells. This would then be injected into the defect left after a lumpectomy, or in a larger volume to recreate the breast after mastectomy, and the hydrogel scaffold that we are using will keep the cells in place to develop mature fat.”

Professor Lowery is hopeful that this approach will improve on

MARCH 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE

currently available procedures such as fat-grafting and implants, which can lose shape and volume over time as well as other related complications.

Minimally Invasive Cancer Treatment At the moment many people with lung cancer tumours must rely on surgery to remove the cancerous growths, which is currently the cornerstone of curative treatment for lung cancer.

This major surgery can have a “really significant impact on quality of life” for patients, many of whom may have other health issues according to Professor Lowery, and can leave them with postoperative difficulties including pain and shortness of breath.

Professor Lowery predicts that increased use of lung cancer screening in future years will lead to earlier detection of smaller tumours, but there are still limited effective treatment options for patients who cannot have surgery.

The Galway-based researcher is working on another project supported through the Enterprise Ireland Disruptive Technology Innovation Fund that aims to harness a technology known as microwave ablation, which involves applying microwave heat through a small probe to burn the tumour and kill the cancer cells within and around it.

“To be able to offer a treatment option to someone for whom there are very few options available would make a real difference.

Professor Lowery will also be using the time made available through the Irish Cancer Society award to examine how breast cancer treatments like chemotherapy, radiotherapy and hormone-based therapies affect the function of the heart.

She will be working with a group of cardiologists, medical oncologists and surgeons from NUIG to find out the magnitude and severity of this issue for patients.

“At the moment, particularly with the backlog caused by the cancellations during Covid surges, the clinical workload is very busy and tends to expand to fill all of your time. The funding from this award will be used to provide part-time cover for another doctor to undertake some of my hospital sessions allowing me to then dedicate that time to research - so the clinical work will still carry on, and I’ll have the time to focus on patient-centred cancer research,” she says.

“Research has transformed cancer care – this is particularly evident with breast cancer where improvements in diagnosis and treatment have changed this from a disease where survival was quite poor, to those diagnosed early now having over 95% 5-year survival.

“We want to continue that progress and also focus on ensuring that those living through and after cancer treatment have a good quality of life which is not negatively impacted by the side effects of cancer treatment - that is what motivates me.”

Cancer Research 81

Clinician Research Leadership Award: Professor Jarushka Naidoo The notion of producing a brand new ‘wonder treatment’ for cancer is something that is often talked about. However, less discussed is a promising stream of therapies being developed based on the premise that beneficial effects may come from within our very own bodies.

Immunotherapy seeks to use a person’s own immune system against cancer, as consultant oncologist at Beaumont RCSI Cancer Centre (Beaumont Hospital and RCSI University of Health Sciences), Professor Jarushka Naidoo explains: “We know that immunotherapy with immune checkpoint inhibitors is an effective treatment that can benefit over 15 different cancer types, including lung cancer. The promise of immunotherapy is that if we generate an immune response against cancer, we may also create immunologic ‘memory’ that results in long-term benefit,” says Professor Naidoo, whose two main areas of expertise are lung cancer and immunotherapy.

“The next wave in immunotherapy will be to try to understand which patients benefit and why, and to understand why some patients develop rare but occasionally serious side effects from immunotherapy - which we understand very little about.”

IR-TOX One particular area of focus for Professor Naidoo will be to develop an Irish Immune-related Toxicity Team, or ‘IR-TOX’ team for short, which seeks to improve understanding of why some patients experience side-effects from immunotherapy and streamline their diagnosis and management.

“Around 10-30% of patients will unfortunately experience side-effects related to their immunotherapy. Some of these can be very difficult to diagnose and manage, because we don’t know why they happened or in some cases, what might be the best treatments.

“IR-TOX was inspired by a similar group I setup at Johns Hopkins University in the USA, where I was an Assistant Professor for several years, before returning to Ireland. This will be a dynamic group of experts interested in immunotherapy toxicities from around Ireland, who will come together to discuss immune toxicity

Professor Jarushka Naidoo Consultant Medical Oncologist at Beaumont Hospital and The Royal College of Surgeons in Ireland. She is Lung Cancer Lead at Cancer Trials Ireland and Adjunct Assistant Professor of Oncology, at Johns Hopkins University USA

cases in a Multi-Disciplinary Team or ‘MDT’ - format.

“We will set this up virtually, to help support patients who develop these side effects around the country. The goal will be to improve access to specialists when it gets up and running in the coming months,” says Professor Naidoo, who is leading the initiative alongside Beaumont Hospital and RCSI endocrinologist Prof Mark Sherlock.

The ‘microbiome’ Also in the area of immunotherapy, Professor Naidoo will be working with collaborators in APC Microbiome and UCC to examine the role of a patient’s ‘microbiome’ - a collective term for microorganisms such as bacteria that inhabit the human body - and how it affects immunotherapy.

The project will involve a ‘biomarker protocol’ whereby samples will be collected from patients to hopefully help answer the question of why some are more susceptible to side-effects or to respond to immunotherapy.

In the field of lung cancer, Professor Naidoo serves as the Lung Cancer Disease-specific subgroup Chair for Cancer Trials Ireland, the national clinical trials group. To facilitate the growth of clinical trials for lung cancer in Ireland, Prof Naidoo has set up a collaborative group called the Irish Lung Cancer Alliance (@IrishLungCancer).

ADEPPT trial One of these trials has already been developed through this group is called the ADEPPT trial

– a groundbreaking first-ever investigator-initiated trial for lung cancer in Ireland.

“It’s a clinical trial that investigates the effect of a new drug for a historically difficult-to-treat type of lung cancer, called KRAS-mutant lung cancer,” she reveals.

“In the last one to two years, two new treatments have emerged that appear potentially effective for this type of lung cancer. My trial will examine the role of one of these medicines in patients who are elderly (over 70 years old) or functionally frail. This trial offers a unique opportunity for Ireland to obtain access to a new and exciting drug, for a population that is usually excluded from clinical trials, but that still deserves the best of treatments,” says Prof Naidoo.

The trial will be open across Ireland, the UK and Spain through a European clinical trials network called ETOP, and Prof Naidoo will serve as overall study chair.

Professor Naidoo intends to utilise strong connections in Europe and those she retains at the renowned Johns Hopkins University in the US from her time working there, to help further opportunities for Irish patients and the medical community in the areas of immunotherapy and lung cancer.

“The Irish medical community punches above its weight in terms of depth of expertise, and contribution to advancements in medicine. To fully realise the potential of this expertise and advancements, partnership with others is a crucial step, especially in a small country.

“Collaboration in research allows us to benefit from the input of others while also developing our abilities, altogether bringing progress forward. So it’s incredibly important in to foster the connections that allow this to happen.”

Asked about the difference the extra research time made possible through the Society’s Clinician Research Leadership Award will make for her, Professor Naidoo enthuses that: “An award like this is truly transformative. It allows those with an interest and commitment to research to set out their stall in an Irish context, and to take the first steps that will lead to long-term benefits for patients.

“Developing clinical trials and creating collaborative networks takes time. This time and team building is needed to lay the foundation for progress for our patients, now and into the future.”

HOSPITALPROFESSIONALNEWS.IE | HPN • MARCH 2022

82 Clinical R&D ¤5.6 MILLION SFI PROFESSORSHIP AWARD

40,000 people in Ireland and ten million people globally every year.

¤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.

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 will lead the new AUGMENT project at UCC’s APC Microbiome Ireland SFI Research Centre, to investigate precision medicine in relation to gut inflammation and the microbiome.

This will contribute to furthering research in IBD, Crohn’s Disease and Ulcerative Colitis, which affect

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 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, Professor 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.

He continues, “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.”

THE HUNT FOR A GROUNDBREAKING BIOMARKER TEST FOR PARKINSON'S DISEASE CONTINUES

¤5.6 million in funding has been awarded to Prof Subrata Ghosh, through the prestigious Science Foundation Ireland Research Professorship Award, Prof Ghosh Deputy Director of APC Microbi

MARCH 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE

Lundbeck is combining its biomarker discoveries with leading microfluidic experts at the Danish Technical University (DTU) to develop a state-of-the-art biomarker assay. The project aims to not only facilitate early diagnosis of neurodegenerative diseases,

such as Parkinson's disease and Multiple System Atrophy (MSA), but also enable improved monitoring of disease progression and effects of disease-modifying therapies.

Three years ago, Lundbeck embarked on a journey to develop a validated biomarker test for Parkinson's disease focused on the detection of minute amounts of pathological aggregates formed by the protein alpha-synuclein. In collaboration with expert academic groups, Lundbeck scientists developed a test that determined with 90% accuracy (https://doi. org/10.1186/s40478-021-01282-8) whether a person had misfolded alpha-synuclein aggregates indicative of Parkinson's disease in the cerebrospinal fluid (CSF).

This objective biomarker enables a fast, early and more precise diagnosis, facilitating early intervention and allowing for more meaningful treatment outcomes.

However, challenges related to scaling and robustness of the assay to achieve high precision remain.

Lundbeck is now ready to take our biomarker assay to the next level. Together with DTU professor Alexander K. Büell, PhD, an expert in protein aggregation and microfluidics, Lundbeck scientists aim to push the boundaries of neuroscience once again and go from a test providing binary answers to an assay that may also determine the progression of Parkinson's disease.

Through an improved assay setup utilizing microdroplets and big data tools, Lundbeck aims to quantify, through amplification, minute

83 amounts of pathological aggregates in tissue and biofluids, such as CSF. This innovative work is supported by a research grant from The Michael J. Fox Foundation for Parkinson’s Research (MJFF).

A robust, accurate and quantitative assay would aid early diagnosis and serve as a disease-progression marker, which, in turn, could be used to further the clinical research into disease modifying treatments for Parkinson’s. The project is pre-competitive, meaning that the results derived from the research will be shared with the pharmaceutical industry, academia and made public by MJFF. The funding will support a postdoctoral researcher for two years under joint supervision from DTU and Lundbeck.

A well-established partnership within Parkinson's research This is the sixth time in 13 years that MJFF is funding a research program driven by Lundbeck.

ABBVIE EXPANDS IMMUNOLOGY PORTFOLIO IN THE EUROPEAN UNION AbbVie (NYSE: ABBV) has announced that the European Commission (EC) has approved SKYRIZI® (risankizumab, 150 mg, subcutaneous injection at week 0, week 4 and every 12 weeks thereafter) alone or in combination with methotrexate (MTX), 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 anti-rheumatic drugs (DMARDs). Marking the second indication for risankizumab, the Marketing Authorization will be valid in all member states of the European Union, as well as Iceland, Liechtenstein, Norway and Northern Ireland.

Professor Brian Kirby speaking about the European Commission Approval of risankizumab for the Treatment of Adults with Active Psoriatic Arthritis said, “We know that almost 30% of Psoriasis patients will develop Psoriatic Arthritis. As a Dermatologist having treatments available that are effective both on skin and the joints provide reassurance when treating Psoriasis patients. It is positive to see an additional treatment available for the treatment of PsA.” “Discovering, developing, and delivering medicines that have a remarkable impact on patients’ lives is a complex endeavour that takes time, expertise, and unwavering innovation,” said Andres Rodrigo, General Manager, AbbVie Ireland. “This approval is a significant milestone for AbbVie in our pursuit to continually raise standards of care, helping alleviate

the burden experienced by patients with psoriatic disease.”

Risankizumab received EC approval based on data from two Phase 3 clinical studies, KEEPsAKE-1 and KEEPsAKE-2.1-6 In these studies, risankizumab met the primary endpoint of ACR20 response at week 24 versus placebo, and ranked secondary endpoints including, but not limited to, improvements in several clinical manifestations of psoriatic arthritis such as physical function (as measured by the Health Assessment Questionnaire Disability Index [HAQ-DI]) and minimal disease activity (MDA) at week 24.

The safety profile of risankizumab in psoriatic arthritis was consistent with the safety profile of risankizumab in plaque psoriasis, with no new safety risks observed.

Through week 24, serious adverse events occurred in 2.5 percent and 4.0 percent of patients treated with risankizumab in KEEPsAKE-1 and KEEPsAKE-2, respectively, compared with 3.7 percent and 5.5 percent on placebo. Rates of serious infections were 1.0 and 0.9 percent in risankizumab-treated patients in KEEPsAKE-1 and KEEPsAKE-2, respectively, and 1.2 and 2.3 percent in patients who received placebo. The rates of adverse events leading to discontinuation of the study drug were 0.8 percent and 0.9 percent of patients treated with risankizumab in KEEPsAKE-1 and KEEPsAKE-2, respectively, compared with 0.8 percent and 2.3 percent on placebo. In KEEPsAKE-1, there was one death in the risankizumab group not related to the study drug per investigator. There were no deaths reported in KEEPsAKE-2.

Risankizumab is part of a collaboration between Boehringer Ingelheim and AbbVie, with AbbVie leading development and commercialization globally.

Xevudy (sotrovimab) for the early treatment of COVID-19 by the EC, member states participating in the JPA, including Ireland, were able to proceed with ordering sotrovimab to support their pandemic response. Sotrovimab is now available in Ireland.

The grant of the marketing authorisation in the EU is based on data from the COMET-ICE phase III trial, demonstrating that intravenous treatment with sotrovimab resulted in a 79% reduction (adjusted relative risk reduction) (p<0.001) in all-cause hospitalisations for more than 24 hours or death due to any cause

by Day 29 compared to placebo, meeting the primary endpoint of the trial. In absolute numbers, 30 (6%) of the 529 patients in the placebo arm progressed, compared to six (1%) of the 528 patients receiving sotrovimab. Interim data were published in The New England Journal of Medicine on October 27, 2021 and final data were prepublished on November 8, 2021 on medRxiv.

UPADACITINIB ACHIEVED PRIMARY AND KEY SECONDARY ENDPOINTS IN FIRST PHASE 3 INDUCTION STUDY IN PATIENTS WITH CROHN’S DISEASE AbbVie has announced positive top-line results from U-EXCEED, a Phase 3 induction study, showing upadacitinib (45 mg once daily) achieved both primary endpoints of clinical remissiona,b and endoscopic responsec at week 12.1 The U-EXCEED study enrolled patients with moderate to severe Crohn’s disease who had an inadequate response or were intolerant to biologic therapy, with over 60 percent having previously failed two or more biologics.1 U-EXCEED is the first of two Phase 3 induction studies to evaluate the safety and efficacy of upadacitinib in adults with moderate to severe Crohn’s disease.1

GSK has announced that agreement has been reached with the Irish Government for the supply of COVID-19 treatment Xevudy (sotrovimab), developed in partnership with Vir Biotechnology.

“The data from this first Phase 3 induction study in Crohn’s disease suggest upadacitinib may help address the needs of patients suffering from this disease, as demonstrated in stringent endpoints such as endoscopic response,” said Michael Severino, M.D., vice chairman and president, AbbVie. “We continue to leverage our expertise in IBD by driving research and development that help shape the IBD landscape and elevate standards of care for patients.”

The contract is enabled by the 2021 Joint Procurement Agreement (JPA) between GSK, Vir and the European Commission (EC) for the supply of up to 220,000 doses of sotrovimab to EU member states.

Following the December 2021 grant of marketing authorisation to

In U-EXCEED, clinical remission was measured by the Crohn's Disease Activity Index (CDAI) and by the patient-reported symptoms of stool frequency/abdominal pain (SF/AP).1 A significantly greater proportion of patients treated with a 12-week induction regimen of

References on request SUPPLY AGREEMENT BETWEEN GSK AND IRISH GOVERNMENT WILL ENABLE ACCESS TO COVID-19 TREATMENT XEVUDY (SOTROVIMAB) FOR PATIENTS IN IRELAND



upadacitinib 45 mg daily achieved clinical remission per CDAI at week 12 compared to placebo (39 percent, versus 21 percent; p<0.0001).1 Similar results were seen with clinical remission per SF/ AP (40 percent in upadacitinibtreated patients versus 14 percent in placebo-treated patients; p<0.0001).1 In this study, all patients were also evaluated for improvement in the intestinal mucosa by endoscopy.1 At week 12, a significantly greater proportion of patients treated with upadacitinib 45 mg achieved endoscopic response compared to the placebo group (35 percent versus 4 percent; p<0.0001).1 Among patients taking corticosteroids at baseline, a significantly higher proportion of patients receiving upadacitinib 45 mg achieved steroid-free clinical remissiond per CDAI and per SF/AP compared to placebo at week 12.1 A significantly higher proportion of patients receiving upadacitinib compared to placebo also achieved early symptom improvement measured by CR-100 (defined as reduction of CDAI ≥100 points from baseline) at week 2 as well as clinical remission at week 4.1 During the 12-week, doubleblind, placebo-controlled period, the safety profile of upadacitinib 45 mg was consistent with the safety profile observed in previous studies across indications, with no new safety risks observed.1 The most common adverse event was nasopharyngitis for upadacitinib and exacerbation of Crohn’s disease for placebo.1 Serious adverse events occurred in 9.3 percent of patients in the upadacitinib 45 mg group compared to 9.9 percent of patients in the placebo group.1 Rates of serious infections were 2.8 percent in those treated with upadacitinib 45 mg and 1.8 percent in patients who received placebo.1 All events of herpes zoster (1.5 percent of patients) were nonserious and reported in the upadacitinib group only.1 There was one case of adjudicated gastrointestinal perforation in the upadacitinib group.1 An additional 207 patients at week 12 received an upadacitinib 45 mg daily induction regimen (including non-responders to placebo or from an open-label arm).1 Among these patients, there were two additional cases of adjudicated gastrointestinal perforation reported. Overall, the safety results in these patients were consistent with what was observed in the upadacitinib 45 mg group during the placebo-controlled period.1 References on request

HOSPITALPROFESSIONALNEWS.IE | HPN • MARCH 2022

When it comes to your patients’ psoriasis treatment goals

What means everything to the patient?

The potential for nothing left on their skin.* High skin clearance matters to patients: Patients who achieve and maintain high levels of skin clearance (PASI 9099 or PASI 100) have significantly better HRQoL than those with lower levels of skin clearance (PASI 75-89). 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

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 pre-filled 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: For treatment of moderate to severe plaque psoriasis in adults 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 psoriasis. Dosage: The recommended dose of Skyrizi is 150 mg by subcutaneous injection at weeks 0, 4, and every 12 weeks thereafter.

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 pre-filled 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. DATE OF REVISION: May 2021 PI/1361/003 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: August 2021 | IE-RISN-210075