Programme

Over 152,000 Wait for Care

The Irish Hospital Consultants Association (IHCA) has warned that the ongoing shortage of hospital consultants across a large number of specialties in the Saolta University Health Care Group* is restricting patients from accessing timely, high-quality medical and surgical care and is contributing massively to growing waiting lists where now more than 152,000 people in the region are waiting for hospital treatment or an outpatient appointment with a consultant. The hospitals concerned and the respective increase in outpatient waiting lists alone include: In total, between the period of July 2015 and July 2021, there have been an additional 53,466 people added to outpatient waiting lists, an increase of 72% with a total of 127,750 across the Saolta Group now waiting to be assessed by a hospital consultant, according to the latest available figures from the National Treatment Purchase Fund.** Professor Alan Irvine, President, IHCA

Some of the longest waiting lists across the whole region are for routine, planned care particularly in Orthopaedics, ENT (Otolaryngology), Urology, General Surgery, Ophthalmology, Gynaecology and Dermatology. Patients are waiting to see a consultant and then receive treatment for procedures such as hip or knee replacements, tonsillectomies, prostate biopsies, and cataract surgery, while others face similar waits for critical gynaecological assessments and skin biopsy for possible cancers. The hospitals that have seen the greatest growth in outpatient waiting lists are Roscommon University Hospital, which has seen its list increase 3-fold (+4,307, 199%) since July 2015, and Mayo University Hospital, where there has been an additional 9,473 people added over the same period, an increase of 162%. Of the 17,222 currently waiting for inpatient or day case treatment across the Saolta Group, 5,915 are waiting more than 12 months, a third of the total number. This is two-and-a-half times (+161%) the 2,266 patients waiting for the same length of time in July 2015. A further 7,689 people are currently awaiting a gastrointestinal (GI) endoscopy in Saolta hospitals - more than a 4-fold increase (+5,942) since 2015. These waiting lists are likely to worsen in the coming months as more people who have put off seeking care during the pandemic enter the system, and as a result of the ongoing impact of the cyber-attack on the HSE. Commenting on the waiting lists, IHCA President Professor Irvine said, "The severe shortage of consultants in our public hospitals is the main contributor to the unacceptable delays in providing care to patients at our regional hospitals. These growing waiting lists demonstrate the impact of years of consultant shortages and underinvestment in capacity across public hospitals in the region. "Covid-19 and, more recently, the cyberattack have unmasked deep fundamental deficiencies in our health system which we always knew were there, but which have now been exposed in a way previously unseen. "We have a chronic recruitment and retention crisis with 1 in 5 permanent hospital consultant posts across the country and in the Saolta Group either vacant or filled on a temporary basis. "Meeting the healthcare needs of the 152,000 people in the West and North-West regions currently waiting to be assessed or treated by a consultant will only be possible by urgently filling vacant permanent hospital consultant posts and expanding the regions hospital beds, operating theatre and other essential hospital facilities. The success of the ongoing consultant contract discussions will be critical to the survival of our public health service for years to come.”

World Psoriasis Day 2021

World Psoriasis Day takes place in October annually. Each year, IFPA sets a specific theme for the upcoming World Psoriasis Day. This theme inspires members’ activities and shines a spotlight on a specific psoriasis-related issue. Several Core Communication Messages accompany the theme to explain its relevance. The theme for World Psoriasis Day 2021 is “United”. IFPA and its members in 56 countries are organizing awareness-raising and advocacy campaigns to join forces, celebrate our collective victories, and rally support for policy changes that will support people living with psoriasis. Psoriasis is a chronic, systemic, inflammatory skin disorder in which there is an increase in the rate at which skin cells are produced and shed from the skin. Psoriasis affects at least 73,000 people in Ireland. Psoriasis may seem only skin deep, but it begins inside the body within the immune system. The red, scaly, flaky, and itchy patches occur when the skin cells grow too quickly as a result of inflammation caused by the body’s immune system. Triggers for this abnormal immune reaction can include physical injuries or infections (in particular, a streptococcal throat infection), certain medicines, and emotional stress. Psoriasis varies in severity from person to person and can vary in severity in the same person at different times. Occasionally psoriasis can disappear without treatment but more usually, it is a chronic disease that requires treatment. Patches (also called plaques or lesions) can occur on various parts of the body, including the scalp, elbows, and or knees.

CONFRONT

R/R CLL VENCLYXTO® + rituximab provides superior PFS to bendamustine + rituximab with a 2-YEAR FIXED TREATMENT DURATION*2

VENCLYXTO® in combination with rituximab is NOW AVAILABLE for the treatment of adult patients with CLL who have received at least one prior therapy1

* 81% risk reduction of progression or death with VEN+R vs BR (HR=0.19;95% CI:0.15-0.26, P<0.0001) at 5 year median follow up. 2-year fixed treatment following 5-week dose titration period.2 PFS = Progression-Free Survival, R/R = relapsed/refractory VENCLYXTO®▼ (venetoclax) 10 mg/50 mg/100 mg film-coated tablets. PRESCRIBING INFORMATION. PRESENTATION: Each film-coated tablet contains 10mg, 50mg or 100mg of venetoclax. Please refer to the Summary of Product Characteristics (SmPC) before prescribing. INDICATION: 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*. DOSAGE AND ADMINISTRATION: Oral. Treatment to be initiated and monitored by a physician experienced in the use of anticancer medicinal products. See SmPC for full posology. Posology: Dose-titration schedule: the starting dose is 20 mg of venetoclax, once daily for 7 days. The dose must be gradually increased over a period of 5 weeks up to the daily dose of 400 mg. Post-titration dose for venetoclax in combination with rituximab: the recommended dose of venetoclax in combination with rituximab is 400 mg once daily. Administer Rituximab after the patient has completed the dose-titration schedule and has received the recommended daily dose of 400 mg venetoclax for 7 days. Venetoclax is taken for 24 months from Cycle 1 Day 1 of rituximab. Venetoclax in combination with obinutuzumab: Venetoclax is given for a total of 12 cycles, each cycle consisting of 28 days: 6 cycles in combination with obinutuzumab, followed by 6 cycles of venetoclax as a single agent. Administer obinutuzumab 100 mg on Cycle 1 Day 1, followed by 900 mg which may be administered on Day 1 or Day 2. Administer 1000 mg on Days 8 and 15 of Cycle 1 and on Day 1 of each subsequent 28-day cycle, for a total of 6 cycles. Start the 5-week venetoclax dose-titration schedule (see Table 1) on Cycle 1 Day 22 and continue through Cycle 2 Day 28. After completing the dose-titration schedule, the recommended dose of venetoclax is 400 mg once daily from Cycle 3 Day 1 of obinutuzumab to the last day of Cycle 12. Post-titration dose for venetoclax monotherapy: the recommended dose of venetoclax is 400 mg once daily. Treatment should be continued until disease progression or no longer tolerated by the patient. Patients should swallow the tablets whole with water at approximately the same time each day. The tablets should be taken with a meal. Prevention of tumour lysis syndrome (TLS): Prior to initiating Venclyxto, tumour burden assessment, including radiographic evaluation must be performed for all patients. The following prophylaxis measures should be followed to minimise the risk of TLS and more intensive measures should be employed as overall risk increases; adequate hydration, administration of anti-hyperuricaemic agents if necessary, blood chemistry monitoring and correction of abnormalities. Monitoring should be increased for patients at high risk of TLS. Temporary hospitalisation and close monitoring may be required in some patients, especially those at greater risk of TLS. Dose modifications for TLS or other toxicities may need to be considered during treatment. See SmPC for full details of prophylaxis measures. Special Populations: Elderly: No dose adjustment required. Renal impairment: No dose adjustment required in patients with mild or moderate renal impairment. Patients with reduced renal function may require more intensive prophylaxis to reduce the risk of TLS and closer monitoring. Safety in patients with severe renal impairment or on dialysis has not been established, and a recommended dose for these patients has not been determined. Hepatic impairment: No dose adjustment is recommended in patients with mild or moderate hepatic impairment. Patients with moderate hepatic impairment should be monitored more closely for signs of toxicity. A dose reduction of at least 50% throughout treatment is recommended for patients with severe hepatic impairment. These patients should be monitored more closely for signs of toxicity. Paediatric Population: The safety and efficacy of Venclyxto in children aged less than 18 years has not been established. CONTRAINDICATIONS: Hypersensitivity to any of the active substances or excipients. Concomitant use of strong CYP3A inhibitors at initiation and during the dose-titration phase Preparations containing St. John’s wort. SPECIAL WARNINGS AND PRECAUTIONS: Tumour lysis syndrome (TLS): Patients with high tumour burden (any lymph node with a diameter ≥5 cm) or those with a high absolute lymphocyte count (≥25 x 109/L), are at greater risk of TLS when initiating Venclyxto. Reduced renal function (CrCL < 80mL/min) further increases the risk. Patients should be assessed for risk and should receive appropriate prophylaxis for TLS, including hydration and anti-hyperuricaemics. Blood chemistries should be monitored and abnormalities managed promptly. Dosing should be interrupted if needed. More intensive measures should be employed as overall risk increases. Neutropenia and infections: Grade 3 or 4 neutropenia has been reported. Complete blood counts should be monitored throughout the treatment period. Dose interruptions or reductions are recommended for patients with severe neutropenia. Serious infections, including sepsis with fatal outcome, have been reported. Monitoring of any signs and symptoms of infection is required. Suspected infections are to receive prompt treatment, including antimicrobials and dose interruption or reduction as appropriate. Immunisation: Live vaccines should not be administered during treatment and thereafter until B-cell recovery as the safety and efficacy has not yet been established. CYP3A inducers: Co-administration of CYP3A4 inducers may lead to decreased Venclyxto exposure and consequently a risk for lack of efficacy. Concomitant use of Venclyxto with strong or moderate CYP3A4 inducers should be avoided. Women of childbearing potential: Women of childbearing potential must use a highly effective method of contraception while taking Venclyxto. INTERACTIONS: See SmPC for full details. Venetoclax is predominantly metabolised by CYP3A. CYP3A inhibitors: Concomitant use of Venclyxto with strong CYP3A inhibitors at initiation and during the dose titration phase is contraindicated due to increased risk for TLS. At initiation and during the dose-titration phase, concomitant use with moderate CYP3A inhibitors should be avoided. Alternative treatments should be considered. If a moderate CYP3A inhibitor must be used, the doses must be reduced and patients should be monitored more closely. Refer to SmPC for full details. Grapefruit, Seville oranges and starfruit should be avoided during treatment. P-gp and BCRP inhibitors: Concomitant use of Venclyxto with P-gp and BCRP inhibitors at initiation and during the dose titration phase should be avoided; if a P-gp and BCRP inhibitor must be used, patients should be monitored closely for signs of toxicities. CYP3A inducers: Concomitant use of Venclyxto with strong or moderate CYP3A inducers should be avoided. Alternative treatments with less CYP3A induction should be considered. Preparations containing St. John’s wort are contraindicated during treatment with venetoclax. Bile acid sequestrants: Co-administration of bile acid sequestrants with Venclyxto is not recommended as this may reduce the absorption of venetoclax. If a bile acid sequestrant is to be co-administered with Venclyxto, the SmPC for the bile acid sequestrant should be followed to reduce the risk for an interaction, and Venclyxto should be administered at least 4-6 hours after the sequestrant. Warfarin: It is recommended that the international normalised ratio be monitored closely in patients receiving warfarin. Substrates of P-gp, BCRP, and OATP1B1; Co-administration of narrow therapeutic index P-gp, or BCRP substrates with Venclyxto should be avoided. If a narrow therapeutic index P-gp or BCRP substrate must be used, it should be used with caution. For an orally administered P-gp or BCRP substrate sensitive to inhibition in the gastrointestinal tract its administration should be separated from Venclyxto administration as much as possible to minimise a potential interaction. If a statin is used concomitantly with Venclyxto, close monitoring of statin related toxicity is recommended. FERTILITY PREGNANCY AND LACTATION: Women of childbearing potential/Contraception in females: Women should avoid becoming pregnant while taking Venclyxto and for at least 30 days after ending treatment. Pregnancy: Venclyxto is not recommended during pregnancy and in women of childbearing potential not using highly effective contraception. Breast-feeding: Breast-feeding should be discontinued during treatment with Venclyxto. Fertility: Before starting treatment, counselling on sperm storage may be considered in some male patients. SIDE EFFECTS: See SmPC for full details on side effects. Very common side effects (≥1/10): Pneumonia, upper respiratory tract infection, neutropenia, anaemia, lymphopenia, hyperphosphataemia, hyperkalaemia, hypocalcaemia, diarrhoea, vomiting, nausea, constipation and fatigue. Common side effects (≥1/100 to <1/10): Sepsis, urinary tract infection, febrile neutropenia, tumour lysis syndrome, hyperuricaemia and blood creatinine increased. Tumour lysis syndrome (TLS): TLS is an important identified risk when initiating Venclyxto. ▼ 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. † This indication is not reimbursed. * Indications are reimbursed. DATE OF REVISION: June 2020. PI/1138/008. References: 1. VENCLYXTO® Summary of Product Characteristics, available at www.medicines.ie. 2. Kater AP, Kipps TJ, Eichhorst B, et al. Five-year analysis of MURANO study demonstrates enduring undetectable minimal residual disease (uMRD) in a subset of relapsed/refractory chronic lymphocytic leukemia patients following fixed-duration venetoclax-rituximab therapy. Oral presentation (125) presented at: 62nd American Society of Hematology Annual Meeting and Exposition; December 5-8, 2020; Virtual meeting IE-VNCLY-210002 Date of Preparation: January 2021

For adults. Not actual patients.

SLOW DOWN SPMS WITH ACTIVE DISEASE.1

IT’S TIME FOR MAYZENT®

MAYZENT® is the first and only oral treatment specifically indicated for SPMS with active disease1,2*†

Mayzent ▼ (Siponimod) 0.25mg and 2mg film-coated tablets ▼ 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. See section 4.8 of the SmPC for how to report adverse reactions.Important note: Before prescribing, consult Summary of Product Characteristics (SmPC). Presentation: Tablets: 0.25 mg film-coated tablets corresponding to 0.25 mg siponimod. 2 mg filmcoated tablets corresponding to 2 mg siponimod. ♦Excipient with known effect: Each tablet of 0.25 mg contains 59.1 mg lactose (as monohydrate) and 0.092 mg soya lecithin. Each tablet of 2 mg contains 57.3 mg lactose (as monohydrate) and 0.092 mg soya lecithin. Indications: Treatment of adult patients with secondary progressive multiple sclerosis (SPMS) with active disease evidenced by relapses or imaging features of inflammatory activity. Dosage and administration (D&A): Treatment with Mayzent should be initiated and supervised by a physician experienced in the management of multiple sclerosis. CYP2C9 genotype should be determined before initiation of treatment. Mayzent should not be used in patients with a CYP2C9*3*3 genotype. Treatment initiation with a titration pack that lasts for 5 days. Once daily intake in the morning. On day 1 and 2: 0.25 mg. On day 3: 0.5 mg. On day 4: 0.75 mg. On day 5: 1.25 mg. Maintenance dose starts on day 6. Adults: Maintenance dose: 2 mg once daily. Maintenance dose for CYP2C9 *2*3 or *1*3 genotype: 1 mg once daily. No dose adjustments are needed in patients with renal impairment. Caution should be exercised when initiating treatment in patients with mild or moderate hepatic impairment (see section CI). Mayzent should be used with caution in the elderly patients (65 years or above) due to insufficient data on safety and efficacy. ♦Missed dose and re-initiation:If a dose is missed on one day in the first 6 days of treatment or if 4 or more consecutive daily doses are missed during maintenance therapy, the same initial dose titration and monitoring recommendations should apply. Contraindications (CI): Hypersensitivity to the active substance, or to peanut, soya or any of the excipients listed. ♦Immunodeficiency syndrome. ♦History of progressive multifocal leukoencephalopathy (PML) or cryptococcal meningitis (CM). ♦Active malignancies. ♦Severe liver impairment (Child Pugh class C). ♦Patients who in the previous 6 months had a myocardial infarction (MI), unstable angina pectoris, stroke/transient ischaemic attack (TIA), decompensated heart failure (requiring inpatient treatment), or New York Heart Association (NYHA) class III/IV heart failure. ♦Patients with a history of second degree Mobitz type II atrioventricular (AV) block, third degree AV block, sino atrial heart block or sick sinus syndrome, if they do not wear a pacemaker. ♦Patients homozygous for CYP2C9*3 (CYP2C9*3*3) genotype (poor metaboliser). ♦During pregnancy and in women of childbearing potential not using effective contraception. Warnings and precautions (W&P): ♦Infections: Before initiating treatment with Mayzent, a recent complete blood count (CBC) (i.e. within last 6 months or after discontinuation of prior therapy) should be available. Assessments of CBC are also recommended periodically during treatment. Absolute lymphocyte counts <0.2 x 109/l, if confirmed, should lead to dose reduction to 1 mg. Confirmed absolute lymphocyte counts <0.2 x 109/l in such a patient (already receiving 1 mg) should lead to interruption of Mayzent until the level reaches 0.6 x 109/l when re initiation of Mayzent can be considered. In patients with severe active infection, wait for resolution before initiating treatment. Patients should be instructed to report symptoms of infection to their physician promptly. Effective diagnostic and therapeutic strategies should be used in patients with symptoms of infection while on therapy and up to 3 to 4 weeks after discontinuation. Consider discontinuing therapy if a serious infection develops. Vigilance is advised for clinical symptoms or magnetic resonance imaging (MRI) findings suggestive of PML or for clinical symptoms of CM and, if suspected, Mayzent treatment should be suspended until PML or CM can be excluded. If diagnosed, appropriate treatment should be initiated. Patients without a healthcare professional confirmed history of varicella or without vaccination against varicella zoster virus (VZV) should be tested for antibodies to VZV prior to treatment initiation. ♦Vaccination: VZV vaccination is recommended in antibody-negative patients and initiation of treatment should be postponed for 1 month to allow the full effect of vaccination to occur. Concomitant use is not recommended with live attenuated vaccines and for 4 weeks after stopping Mayzent therapy. Vaccines may be less effective if administered during Mayzent treatment. Treatment discontinuation 1 week prior to planned vaccination until 4 weeks after is recommended. ♦Anti-neoplastic, immune-modulating or immunosuppressive therapies (including corticosteroids): Caution is required when used concomitantly with Mayzent and in the weeks after administration of any of these medicinal products is stopped. ♦Macular edema: Siponimod therapy should not be initiated in patients with macular oedema until resolution. An ophthalmic examination is recommended 3 to 4 months after Mayzent therapy initiation in all patients. In patients with history of diabetes mellitus, uveitis or underlying/co-existing retinal disease Mayzent should be used with caution due to potential increase of risk of macular oedema and an opthalmic examination is recommended prior to and regularly during therapy. Discontinuing therapy is recommended if macular edema develops. After resolution, reinitiation of treatment after discontinuation should be based on the potential benefits and risks for the individual patient. ♦Bradyarrhythmia and Treatment initiation with certain pre existing cardiac conditions: See section CI. ♦Patients with the following cardiac conditions should be observed for a period of 6 hours after the first dose of Mayzent for signs and symptoms of bradycardia: sinus bradycardia (heart rate <55 bpm), history of first- or second- degree (Mobitz type I) AV block, history of myocardial infarction, or history of heart failure (patients with NYHA class I and II). In these patients, it is recommended that an electrocardiogram (ECG) is obtained prior to dosing and at the end of the observation period. If post dose bradyarrhythmia or conduction related symptoms occur or if ECG 6 hours post dose shows new onset second degree or higher AV block or QTc ≥500 msec, appropriate management should be initiated and observation continued until the symptoms/findings have resolved. If pharmacological treatment is required, monitoring should be continued overnight and 6 hour monitoring should be repeated after the second dose. ♦Due to the risk of serious cardiac rhythm disturbances or significant bradycardia Mayzent should not be used in patients with: history of symptomatic bradycardia or recurrent syncope, uncontrolled hypertension, or severe untreated sleep apnoea. In such patients, treatment with siponimod should be considered only if the anticipated benefits outweigh the potential risks, and advice from a cardiologist should be sought prior to initiation of treatment in order to determine the most appropriate monitoring strategy. ♦Mayzent should not be used in patients with significant QT prolongation (QTc >500 msec) or who were treated with QT prolonging medicinal products with known arrhythmogenic properties. ♦Mayzent should not be used in patients with arrhythmias requiring treatment with class Ia (e.g. quinidine, procainamide) or class III (e.g. amiodarone, sotalol) antiarrhythmic medicinal products (risk of torsades de pointes). ♦Mayzent should not be used in patients receiving concurrent therapy with heart-rate-lowering calcium channel blockers (such as verapamil or diltiazem) or other substances that may decrease heart rate (e.g. ivabradine or digoxin) (risk of severe bradycardia and heart block). ♦If concomitant treatment with one of the above substances is being considered during initiation of treatment with Mayzent, advice from a cardiologist should be sought regarding the switch to a nonheart-rate-lowering medicinal product or appropriate monitoring for treatment initiation. ♦At treatment initiation, use with caution in patients receiving stable dose of beta-blocker if resting heart rate is ≤50 bpm. In this case, beta-blocker should be interrupted until the baseline heart rate is >50 bpm. Mayzent treatment can then be started and treatment with beta blocker can be re-initiated after up-titration to Mayzent maintenance dose. ♦Initiation of Mayzent treatment results in a transient decrease in heart rate and has been associated with transient atrioventricular conduction delays; therefore a titration scheme to reach the maintenance dose on day 6 is applied. After the first dose, the heart rate decrease starts within one hour and the day 1 decline is maximal at approximately 3 to 4 hours. With continued up titration, further heart rate decreases are seen on subsequent days, with maximal decrease reached on day 5 to 6. The highest daily post-dose decrease in absolute hourly mean heart rate is observed on day 1, post-dose declines on the following days are less pronounced. Heart rate returns to placebo levels within 10 days after treatment initiation. ♦Liver function: Recent (i.e. within last 6 months) transaminase and bilirubin levels should be available before initiation of treatment with Mayzent. A liver function test is recommended in patients who develop symptoms suggestive of hepatic dysfunction during treatment and therapy should be discontinued if significant liver injury is confirmed. After resolution, reinitiation of treatment should be based on the potential benefits and risks for the individual patient. Caution should be exercised in patients with a history of significant liver disease. See section CI. ♦Cutaneous neoplasms: Mayzent should not be used in patients receiving concomitant phototherapy with UV-B radiation or PUVA photochemotherapy. Skin examination is recommended for all patients at treatment initiation, and then every 6 to12 months taking into consideration clinical judgement. Patients should be advised to promptly report any suspicious skin lesions to their physician. Caution is required against exposure to sunlight without protection in patients treated with Mayzent. ♦Unexpected neurological signs: Vigilance is warranted for any unexpected neurological or psychiatric symptoms/signs or accelerated neurological deterioration (posterior reversible encephalopathy syndrome). ♦Prior treatment with immunosuppressive or immune modulating therapies: Caution is required when switching patients from other disease modifying therapies (the half-life and mode of action of the other therapy must be considered). A CBC is recommended prior to initiating Mayzent to ensure that immune effects of the previous therapy (i.e. cytopenia) have resolved. Initiating treatment with Mayzent after alemtuzumab is not recommended. ♦Blood pressure: Special care is indicated if patients with uncontrolled hypertension are treated with Mayzent. Blood pressure should be regularly monitored during treatment. ♦Pharmacogenomics: See section CI for patients with CYP2C9*3*3 genotype (approximately 0.3 to 0.4% of population). See section D&A for CYP2C9 *2*3 or *1*3 genotype. ♦Women of childbearing potential: See section CI. Before initiation of treatment, women of childbearing potential must be informed of the risk to the foetus, must have a negative pregnancy test and must use effective contraception during treatment and for at least 10 days after treatment discontinuation.♦Stopping therapy: Patients should be observed for relevant signs of possible severe exacerbation or return of high disease activity upon Mayzent discontinuation and appropriate treatment should be instituted as required. In vast majority of SPMS patients, lymphocyte counts return to the normal range within 10 days of stopping therapy. However, residual pharmacodynamic effects, such as lowering effects on peripheral lymphocyte count, may persist for up to 3 to 4 weeks after the last dose. ♦Interference with haematological testing: Peripheral blood lymphocyte counts cannot be utilised to evaluate the lymphocyte subset status of a patient treated with Mayzent. ♦Excipients: Peanut or soya: see section CI. Lactose: patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose galactose malabsorption should not take Mayzent. Interactions: ♦Anti-neoplastic, immune-modulating or immunosuppressive therapies (including corticosteroids): See section W&P.♦Anti-arrhythmic drugs, QT prolonging drugs, drugs that may decrease heart rate: See section W&P.♦Betablockers: See section W&P. ♦Vaccination: see W&P. ♦CYP2C9 and CYP3A4 inhibitors: Concomitant use with Mayzent is not recommended with moderate CYP2C9 inhibitors and moderate or strong CYP3A4 inhibitors (can consist of a moderate CYP2C9/CYP3A4 dual inhibitor e.g. fluconazole or a moderate CYP2C9 inhibitor in combination with a separate moderate or strong CYP3A4 inhibitor).♦CYP2C9 and CYP3A4 inducers: Caution is required with strong CYP3A4/moderate CYP2C9 inducers (e.g. carbamazepine) in all patients and with moderate inducers of CYP3A4 (e.g. modafinil) in patients with CYP2C9*1*3 and*2*3 genotype (a reduction in siponimod exposure is expected). Fertility, Pregnancy and Lactation: Pregnancy, women of childbearing potential, contraception in females: see section CI. Before initiation of treatment in women of childbearing potential a negative pregnancy test result must be available and counselling should be provided regarding serious risk to the foetus. Women of childbearing potential must use effective contraception during treatment with Mayzent and for at least 10 days after stopping treatment. Mayzent should be stopped at least 10 days before a pregnancy is planned. If a woman becomes pregnant while on treatment, Mayzent must be discontinued. Medical advice should be given regarding the risk of harmful effects to the foetus associated with treatment and ultrasonography examinations should be performed. Embryotoxicity, fetotoxicity and teratogenicity were demonstrated in animal studies. Breast-feeding: Mayzent should not be used during breast feeding (no data in human lactation are available and siponimod is excreted into animal milk). Fertility: The effect of siponimod on human fertility has not been evaluated. Siponimod had no effect on male reproductive organs in rats and monkeys or on fertility parameters in rats. Driving and using machines: Mayzent has no or negligible influence on the ability to drive and use machines. However, dizziness may occasionally occur when initiating therapy. Therefore, patients should not drive or use machines during the first day of treatment initiation with Mayzent. Undesirable effects: Very common (≥10%): Headache, hypertension, liver function test increased. Common (≥1 to <10%): Herpes zoster, melanocytic naevus, Basal cell carcinoma, lymphopenia, dizziness, seizure, tremor, macular oedema, bradycardia, atrioventricular block (first & second degree), nausea, diarrhoea, pain in extremity, oedema peripheral, asthenia, pulmonary function test decreased. Please see Summary of Product Characteristics for further information on undesirable effects. Frequency not known: In the extension part of the phase 3 study, a case of cryptococcal meningitis has been reported. Marketing Authorisation Holder: Novartis Europharm Ltd, Vista Building, Elm Park, Merrion Road, Dublin 4, Ireland. Marketing Authorisation Numbers, Mayzent 0.25 mg film coated tablets: EU/1/19/1414/001 002. Marketing Authorisation Numbers, Mayzent 2 mg film coated tablets: EU/1/19/1414/003. Prescribing information last revised: Feb 2021.

▼ 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.

CDP=confirmed disability progression; CI=confidence interval; Gd+=gadolinium-enhancing; HR=hazard ratio; MOA=mechanism of action; SPMS=secondary progressive multiple sclerosis. * EXPAND was a randomized, double-blind, placebo-controlled, Phase III study with a broad range of 1651 patients with SPMS over 24 months, followed by an optional open-label extension.2 † In a subgroup analysis in EXPAND, SPMS with active disease was defined as patients with relapse in the 2 years prior to the study and/or presence of T1 Gd+ lesions at baseline.1

References: 1. MAYZENT [Summary of Product Characteristics]. Novartis Ireland, available from Novartis Ireland Limited, Vista Building, Elm Park Business Campus Merrion Road, Dublin 4. 2. Kappos L, Bar-Or A, Cree BAC, et al; for the EXPAND Clinical Investigators. Siponimod versus placebo in secondary progressive multiple sclerosis (EXPAND): a double-blind, randomised, phase 3 study. Lancet. 2018;391(10127):1263-1273.

Continuing Professional Development CPD CPD

AUTHOR: Heinz Wiendl, Ralf Gold & Frauke Zipp for the Multiple Sclerosis Therapy Consensus Group

60 Second Summary

MS as a chronic, heterogeneous disease with a pathogenesis that derives from the complexities of both the immune and central nervous system lends its self to evidence based treatment guidelines and consensus statements to guide therapeutic decisions. This is even more the case in view of the rapidly increasing number of available compounds and therapeutic strategies that are now available for the different stages of the disease. Guidelines and consensus statements aim to provide orientation to the less specialized health care professional, inform patients and help in defining common standards of care and harmonizing treatment policies, often with implications for reimbursement. With such a wide range of implications, including important financial interests, the value and acceptance of guidelines depends on the transparency of the development process and the scientific and professional authority and recognition of those involved, particularly when it comes to “softer” recommendations that are not derived from unequivocal evidence. An explicit goal of multiple sclerosis (MS) therapy is the “best possible disease control”, including the “best possible quality of life” of the patient, with the option to use highly effective therapeutics early or as early as possible in response to disease activity. Presently, two treatment approaches dominate the selection of optimal therapy for (highly) active MS. Both strategies are based on evaluating the individual patient’s risk of further MS progression and considering the risk versus efficacy of the specific diseasemodifying therapies.

1. REFLECT - Before reading this module, consider the following: Will this clinical area be relevant to my practice? 2. IDENTIFY - If the answer is no, I may still be interested in the area but the article may not contribute towards my continuing professional development (CPD). If the answer is yes, I should identify any knowledge gaps in the clinical area. 3. PLAN - If I have identified a knowledge gap - will this article satisfy those needs - or will more reading be required? 4. EVALUATE - Did this article meet my learning needs - and how has my practise changed as a result?Have I identified further learning needs? 5. WHAT NEXT - At this time you may like to record your learning for future use or assessment. Follow the 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.

Multiple sclerosis therapy consensus group (MSTCG): answers to the discussion questions

Question 1: when should disease-modifying immunotherapy be initiated? Before or after the onset of disability? Already with CIS (e.g., isolated optic neuritis)?

An explicit goal of multiple sclerosis (MS) therapy is the “best possible disease control”, including the “best possible quality of life” of the patient, with the option to use highly effective therapeutics early or as early as possible in response to disease activity. Specifically, the appropriate disease-modifying therapy (DMT) is selected based on the individual patient, and incorporates a situation and prognostic analysis that includes disease activity, disease severity, balancing therapy safety and risks, and considering the patient’s age, gender, and living situation. From the perspective of the MSTCG (Multiple Sclerosis Therapy Consensus Group) and supported by several large observational and registry studies, modern MS therapy can and should prevent the accumulation of disability and, thus, possible neurodegeneration. The MSTCG recommends classifying MS as mild/moderate or active/highly active (see Fig. 1). The classification is based on i) relapse frequency, ii) MRI findings (lesion load, lesion localization), and iii) regression of relapse(s), disease activity, and disease severity (measured by clinical as well as radiological parameters); also, the patient’s age and comorbidities have to be considered. Activity is determined based on clinical relapses (severity of clinical symptoms/duration/tendency to regress) and/or MRI activity (contrast-enhancing lesions; new or enlarged T2 lesions). Progression is determined by an annual or more frequent examination, including a careful clinical assessment. In addition to the EDSS, standardized instruments for assessing clinical function in patients with MS include the Multiple Sclerosis Functional Composite (MSFC), the Brief International Cognitive Assessment for MS (BICAMS), the 6- and 2-min walk tests, or the timed 25-ft walk test. Notably, the MS classifications are not categorical and rigid: they require continuous review and close follow-up. It is generally agreed that DMTs have a better effect early in the course of MS. Recent registry data indicate that later initiation of DMT leads to more extensive disability in the longer term.1,2,3 In addition to preventing acute episodes of the disease, prophylactic therapy may reduce the risk of long-term neurologic deterioration or secondary progression.4 The long-term therapeutic benefits strongly depend on how early DMT is started. Due to the great heterogeneity of the clinical MS course, the further individual patient’s course is extremely difficult to predict. Although the term “benign MS” has been abandoned eventually, there may be courses that do not lead to any (significant) disability after 30 years – even without therapy. While in overall analyses up to 15–20% of patients may not accumulate measurable disability in the longer term, there are no reliable or accepted predictors for a course without substantial disability. Hence, DMT in MS must be started as early as possible after diagnosis to avoid further/future disability. In individual cases, a waitand-see approach with regular neurological and imaging checks may also be considered in patients with very low lesion burden and complete remission of mild clinical symptoms.

In the context of a clinically isolated syndrome (CIS) suggestive of central nervous system demyelination, defined as a monofocal or multifocal clinical event, e.g., optic neuritis or a spinal cord, brain stem, or hemispheric syndrome, the MSTCG takes a proactive position on the management of these patients. Currently, three licensed medical treatments are available for CIS patients (Interferon-b-1a i.m., Interferonb-1a s.c., Interferon-b-1b s.c.). (Interestingly, in the USA, siponimod is a recently approved additional option). Furthermore, it is of utmost importance that in this early phase of the disease, the affected patients become aware of and compliant to the need to monitor the situation to ensure the best possible treatment and management in the long term to prevent disease activity and neurodegeneration. This includes clinical and MRI follow-up and patient education in this specific phase of the disease. In persons with isolated optic neuritis without further evidence of CNS pathology on MRI, there is the possibility of no further progression to MS. Hence, here disease monitoring without treatment can be an option to consider in discussion with the patient.5 In patients with further evidence of CNS lesions or oligoclonal bands that do not fulfill the MRI criteria for a full MS diagnosis, medical therapy needs to be clearly favored and advised over a pure monitoring approach. Any decision-making is a joint process requiring a responsible choice by the affected patient. In case of no immediate medical treatment, disease monitoring will be continued to uphold the opportunity for an effective early therapeutic intervention. Generally, under exclusion of other differential diagnostic causes, CIS patients (regardless of whether the criteria for DIT and DIS are met) must be offered immunotherapy. The choice of immunotherapy should be based on predictive parameters; primarily i) MRI findings (number and localization of lesions) but also ii) extent of relapse regression, iii) multifocal presentation, and iv) CSF-specific OCB or chronic inflammatory CSF changes. For CIS patients with a high lesion burden and/or infratentorial lesions on diagnostic MRI, immunotherapy should be actively recommended given the presumed unfavorable prognosis. Here, depending on the individual circumstances, high-efficacy therapy can be considered already for initial treatment. Importantly, the treatment of CIS should not be unnecessarily delayed and should not follow an escalation approach in the individual (highly-active) case. Last but not least, already CIS can be considered as MS in several colleagues’ opinions. The latest revision of the McDonald criteria allows the diagnosis of MS in many cases previously considered as CIS.6, 7

Question 2: which diseasemodifying therapy should be selected when? Should a less potent and low-risk therapy initially be selected for all patients, or should some patients immediately receive a high-efficacy therapy with a higher risk profile and requiring more complex monitoring? To be considered in this context: escalation in three stages versus individually adjusted escalation

Presently, two treatment approaches dominate the selection of optimal therapy for (highly) active MS. Both strategies are based on evaluating the individual patient’s risk of further MS progression and considering the risk versus efficacy of the specific disease-modifying therapies. According to the escalation approach, lowerefficacy therapies with a known and relatively safe risk profile are selected for initial treatment. Figure 1

If – despite sufficiently long and regular treatment – disease activity persists/recurs, treatment is escalated to a more potent therapy option. In the alternative approach, treatment is initiated with a high-efficacy diseasemodifying therapy already at the time of diagnosis; for example, with alemtuzumab, cladribine, natalizumab, ocrelizumab, ofatumumab, or S1P receptor modulators (fingolimod, ozanimod, ponesimod). Limiting current treatment recommendations to the escalation approach is insufficient regarding the current data situation and diminishes the possibilities to start treatment with a higher-efficacy medication. The DGN guideline attempts to grade disease-modifying therapies according to potency and thus divides medications into three groups. In the view of the MSTCG, this is scientifically unsound as any minimal differences in the percentage of relapse reduction cannot be formally compared between the drugs due to different study collectives. Problematically, this

scientifically not well-founded approach ultimately results in a “three-part division” of the therapy algorithm – consisting of first a low-potent, then a medium-potent, and finally a highpotent therapy. This stepwise escalation, which is described as the preferential approach, does not correspond to established consensus recommendations, new study findings, or European/ international therapy concepts – according to which not only the time of therapy (earliest possible) but also the potency of the therapy influences the long-term outcome. Thus the meanwhile more proactive therapy concepts and the freedom of therapy are ultimately restricted with a threepart escalation. Choosing the first DMT in MS patients is challenging. The choice must occur on an individual patient level and take into account several factors: clinical symptoms, MRI activity, the efficacy of the therapeutic agent, side effects of the therapeutic agent, handling, route of administration, and the patient’s life circumstances and family situation.8, 9 A general rule applies: the more potent the DMT, the higher the potential risk of severe side effects. The escalation regimen, in which therapy is always started with a less effective drug and switched to a high-efficacy DMT if disease activity persists, was initially advocated when only a few DMTs were available. With the availability of multiple highefficacy DMTs, including depleting therapies, the hit-hard-andearly concept was postulated, recommending the use of high-efficacy DMT at disease onset, in analogy to, for example, rheumatology. Controlled trials that might demonstrate the superiority of one of these therapeutic approaches have now been initiated, but results will not be available for several years. Retrospective registry studies already suggest that in patients with disease activity, early use of high-efficacy DMT compared to lower-efficacy DMT may delay subsequent disability progression or transition to SPMS.2, 4 The underlying reason may be in concordance with delaying therapy initiation early in the disease: persistent clinical or subclinical disease activity under less effective therapy may cause irreversible neurological deficits and allow the activation of signaling pathways associated with progressive disease that could have been otherwise prevented. High-efficacy therapies are not suitable for every patient and require an individual risk-benefit assessment. Depleting or immune reconstitution therapies (IRTs), including autologous hematopoietic stem cell transplantation, have a special position in this regard. They cause profound changes in the immune system. Thus, on the one hand, they show a higher risk of severe side effects and notably increased risk of infection in the first months after a therapy pulse. On the other hand, a proportion of patients profit from disease stabilization and therapeutic effects persisting years beyond the end of therapy, inducing long-lasting therapy-free disease stability.10,11,12 Substance-specific risk reduction strategies need to be applied. In comparison, conventional immunotherapies require continuous therapy with cumulative risks over time, counting towards the individual risk-benefit balance. Considering the disease course in the long term, there is an advantage of using high-efficacy versus lower-efficacy DMTs from the beginning. This treatment strategy is supported by registry data, although prospective studies are lacking. Due to a likely increased risk for severe side effects and in consideration of individual life circumstances, the use of high-efficacy DMTs at the beginning of the disease should be decided individually, following the neurologist’s recommendations and the patient’s wishes. Different therapy concepts exist within the group of highefficacy DMTs. I) Sustained therapy: efficacy relatively

immediate with application and accompanied by reversibility after discontinuation: natalizumab and S1P receptor modulators (as well as ocrelizumab and ofatumumab with limitation due to the mechanism of action), versus II) pulsed therapy: efficacy due to immune depletion and repopulation significantly beyond the half-life of the drug, possibly also permanent therapy-free disease stability: alemtuzumab and cladribine (and possibly ocrelizumab, with severe limitation due to mechanism of action). Although the DGN guideline mentions chronic/continuous versus pulsed therapy approaches, it clearly prefers the chronic therapy approach. This is justified by pointing towards the lack of long-term data for pulsed therapies, which, however, is not correct. Ultimately, education about both therapy concepts must be provided, especially since the patient must be informed about the possibility of disease stabilization without continuous therapy.10

Question 3: when should the immunotherapy be terminated? Should the therapy generally be terminated after a few5 years, or is long-term and sometimes permanent therapy feasible? To be considered in this context: the problem of disease reactivation/rebound

The scientific data on this clinically highly relevant question is scarce. The only available data result from retrospective observational studies mostly on older injectable MS therapeutics and comprising relatively small cohorts. A prospective paper from the Global MS Database describes that while relapse rates remain stable after discontinuation of injectable MS therapies, disease progression is significantly accelerated.13 These results are consistent with smaller retrospective observations. So if treatment is well tolerated and safe, patients should be motivated to continue. Special consideration must be given to agents inhibiting leukocyte migration (natalizumab and the S1P receptor modulators fingolimod, ozanimod, ponesimod, siponimod). Here, discontinuation without a concept for follow-up treatment should be the exception due to possible recurrence or even rebound of disease activity (challenging situations arise, for example, in the context of pregnancy, lactation, or surgery). IRTs (alemtuzumab, cladribine, and within limitation maybe also ocrelizumab) are special cases, in the sense that disease stability without further or follow-up treatment is part of the therapeutic concept. Available data indicate that about 50% of patients can be stable for many years after alemtuzumab without a need for follow-up treatment, including the possibility of treating recurrent disease activity again with CD52 depletion (with the prospect of achieving re-stabilization). Only a few controlled studies currently exist for the discontinuation of B-cell depleting drugs. However, a reversible mechanism of action, and therefore ultimately a return of disease activity, can be expected due to the B-cell dominance of the depletion principle. Established prognostic or diagnostic markers (such as the dynamics of depleting vs. repopulating immune cell types) that would indicate durable remission for a specified group do not exist for MS. Hence, also IRTs require established guidelines for monitoring and appropriate action plans for recurring disease activity. More attention is now being paid to disease activity in relation to age, effects of therapy relating to age, and phenomena of immune senescence versus immunocompetence in old age. Roughly, the inflammatory activity and the effect of immunotherapy, especially the influence on progression, decrease with age. When weighing the therapeutic goals and benefit-risk profile, considering disease activity becomes more important, especially at a higher age (> 50). We generally recommend that MS patients who are stable on a given DMT, receive clinical and/or radiological monitoring, and are without any safety or tolerability issues, should continue therapy. Discontinuing or pausing treatment is associated with the risk of recurrence of disease activity and/or progression, depending on the mechanism of action. Discontinuing or pausing treatment at a patient’s explicit request (without planned follow-up therapy) may be done if adhering to clear guidelines for clinical and imaging monitoring. The DGN guideline positions itself very clearly towards the discontinuation of diseasemodifying therapy in the long term and strongly recommends this possibility after 5 years. From the point of view of the MSTCG, this recommendation is not feasible considering the available data and can even create risks for some patients. Discontinuation or pausing of therapy at the explicit request of the patient (without a planned follow-up therapy) can take place under clear conditions for clinical and imaging monitoring but is by no means the rule. Corresponding discontinuation studies have only just been initiated internationally. On the other hand, there are clear epidemiological data on a possible “re-activation” in the sense of disease progression at any time, as well as data on a re-activation or rebound after discontinuation of immunomodulatory drugs. In addition, increased disease activity (rebound) may occur after discontinuation of natalizumab or S1P receptor modulators. In this line of critique, from the point of view of the MSTCG, the DGN guideline balances medication safety for the patient higher than modern options for long-term disease stabilization. Several studies and reports describe the further development of MS and clinical and paraclinical disease activity after discontinuing DMT. The course after discontinuation depends on various factors such as disease severity in the individual patient, disease duration, comorbidities, and the type of DMT. While pulsed immunotherapies tend to stabilize disease over the longer term, maintenance therapies suggest a more rapid return of disease activity after cessation. The therapy sequence is also essential.14, 15 In addition, there are immunopathogenic factors (genetics, environment, lifestyle). Another factor to consider is differences in wash-out periods, i.e., the times between discontinuation of a substance and initiation of follow-up treatment (typically from one to six months). Special consideration in this context is given to drugs that affect leukocyte migration.16, 17 For them, in addition to the expected recurrence of disease activity due to discontinuation, various reports describe a rebound, meaning a return of disease activity to a level exceeding that before the start of therapy. Although numerous studies describe this effect for fingolimod and natalizumab, rebound does not occur in every individual after discontinuing these therapies. However, an appropriate follow-up treatment should always be administered after fingolimod and natalizumab to prevent the potential recurrence of disease activity. Hence, discontinuation or suspension of a medication for the therapy of (highly) active MS, either based on suboptimal efficacy or safety concerns, must be accompanied by a clear follow-up concept. The following factors should be considered when selecting a follow-up medication: 1.) disease activity (clinical and MRI): the higher the disease activity, the larger the need for immediate initiation of a new therapy; 2.) disease severity; 3.) half-life as well as biological activity of the previous medication (differentiation between socalled maintenance therapies (natalizumab, S1P receptor modulators, partly ocrelizumab) and pulsed therapies, (alemtuzumab, cladribine, partly ocrelizumab)); 4.) the risk of “carry-over” PML should be reduced as much as possible, and clinical, MRI, and liquid diagnostic parameters (detection of HPyV-2 [JCV] DNA by PCR) should be used to determine the baseline or pre-conversion status. The risk of recurrence of disease activity or rebound (especially after leukocyte migration therapies such as natalizumab or S1P receptor modulators) should be considered and can be expected 2–6 months after discontinuation of these agents. For SPMS, uncertainties may arise further down the line when patients with initially active disease have been treated and no longer have relapses. Various experts, including the authors of the North American guideline, recommend discontinuing therapy when there is pure progression without relapse. However, it is unclear whether the DMT suppresses relapse activity despite not affecting progression, meaning that patients would continue to benefit from the relapse rate reduction provided by DMT. If therapy is discontinued in SPMS patients, close monitoring of subsequential inflammatory activity is essential. Article Citation: Wiendl, H., Gold, R., Zipp, F. et al. Multiple sclerosis therapy consensus group (MSTCG): answers to the discussion questions. Neurol. Res. Pract. 3, 44 (2021). https://doi.org/10.1186/s42466021-00140-1

References available on request

Lead your patients to

stronger bones with Prolia®1-4

10 YEARS DATA5

Osteoporosis is a serious ongoing condition and ongoing treatment is required.6,7,8,9*

* Prolia® should not be stopped without considering alternative treatment in order to prevent rapid bone mineral density loss and a potential rebound in vertebral fracture risk.6

PROLIA® (denosumab) Brief Prescribing Information

Please refer to the Summary of Product Characteristics (SmPC) before prescribing Prolia. Pharmaceutical Form: Pre-filled syringe with automatic needle guard containing 60 mg of denosumab in 1 ml solution for injection for single use only. Contains sorbitol (E420). Indication: Treatment of osteoporosis in postmenopausal women at increased risk of fractures. Dosage and Administration: 60 mg Prolia administered as a subcutaneous injection once every 6 months. Patients must be supplemented with calcium and vitamin D. No dosage adjustment required in patients with renal impairment. Not recommended in paediatric patients under 18 years of age. Give Prolia patients the package leaflet and patient reminder card. Re-evaluate the need for continued treatment periodically based on the benefits and potential risks of denosumab on an individual patient basis, particularly after 5 or more years of use. Contraindications: Hypocalcaemia or hypersensitivity to the active substance or to any of the product excipients. Special Warnings and Precautions: Traceability: Clearly record the name and batch number of administered product to improve traceability of biological products. Hypocalcaemia: Identify patients at risk for hypocalcaemia. Hypocalcaemia must be corrected by adequate intake of calcium and vitamin D before initiation of therapy. Clinical monitoring of calcium levels is recommended before each dose and, in patients predisposed to hypocalcaemia, within 2 weeks after the initial dose. Measure calcium levels if suspected symptoms of hypocalcaemia occur. Renal Impairment: Patients with severe renal impairment (creatinine clearance < 30 ml/min) or receiving dialysis are at greater risk of developing hypocalcaemia. Skin infections: Patients receiving Prolia may develop skin infections (predominantly cellulitis) requiring hospitalisation and if symptoms develop then they should contact a health care professional immediately. Osteonecrosis of the jaw (ONJ): ONJ has been reported rarely with Prolia 60 mg every 6 months. Delay treatment in patients with unhealed open soft tissue lesions in the mouth. A dental examination with preventative dentistry and an individual benefit:risk assessment is recommended prior to treatment with Prolia in patients with concomitant risk factors. Refer to the SmPC for risk factors for ONJ. Patients should be encouraged to maintain good oral hygiene, receive routine dental check-ups and immediately report oral symptoms during treatment with Prolia. While on treatment, invasive dental procedures should be performed only after careful consideration and avoided in close proximity to Prolia administration. The management plan of patients who develop ONJ should be set up in close collaboration between the treating physician and a dentist or oral surgeon with expertise in ONJ. Osteonecrosis of the external auditory canal: Osteonecrosis of the external auditory canal has been reported with Prolia. Refer to the SmPC for risk factors. Atypical femoral fracture (AFF): AFF has been reported in patients receiving Prolia. Discontinuation of Prolia therapy in patients suspected to have AFF should be considered pending evaluation of the patient based on an individual benefit risk assessment. Long-term antiresorptive treatment: Longterm antiresorptive treatment may contribute to an increased risk for adverse outcomes such as ONJ and AFF due to significant suppression of bone remodelling. Concomitant medication: Patients being treated with Prolia should not be treated concomitantly with other denosumab containing medicinal products. Warnings for Excipients: Patients with rare hereditary problems of fructose intolerance should not use Prolia. Dry natural rubber: The needle cover of the pre-filled syringe contains dry natural rubber (a derivative of latex) which may cause allergic reactions. Interactions: Prolia did not affect the pharmacokinetics of midazolam, which is metabolized by cytochrome P450 3A4 (CYP3A4). There are no clinical data on the co-administration of denosumab and hormone replacement therapy (HRT), however the potential for pharmacodynamic interactions would be considered low. Pharmacokinetics and pharmacodynamics of Prolia were not altered by previous alendronate therapy. Fertility, pregnancy and lactation: There are no adequate data on the use of Prolia in pregnant women and it is not recommended for use in these patients. It is unknown whether denosumab is excreted in human milk. A risk/benefit decision should be made in patients who are breast feeding. Animal studies have indicated that the absence of RANKL during pregnancy may interfere with maturation of the mammary gland leading to impaired lactation post-partum. No data are available on the effect of Prolia on human fertility. Undesirable Effects: The following adverse reactions have been reported: Very common (≥ 1/10) pain in extremity, musculoskeletal pain (including severe cases). Common (≥ 1/100 to < 1/10) urinary tract infection, upper respiratory tract infection, sciatica, constipation, abdominal discomfort, rash, alopecia and eczema. Uncommon (≥ 1/1000 to < 1/100): Cellulitis, ear infection and lichenoid drug eruptions. Rare (≥ 1/10,000 to < 1/1,000): Osteonecrosis of the jaw, hypocalcaemia (including severe symptomatic hypocalcaemia and fatal cases), atypical femoral fractures, and hypersensitivity (including rash, urticaria, facial swelling, erythema and anaphylactic reactions). Very rare (< 1/10,000): Hypersensitivity vasculitis. Please consult the Summary of Product Characteristics for a full description of undesirable effects. Pharmaceutical Precautions: Prolia must not be mixed with other medicinal products. Store at 2°C to 8°C (in a refrigerator). Proliamay be exposed to room temperature (up to 25°C) for a maximum single period of up to 30 days in its original container. Once removed from the refrigerator Prolia must be used within this 30 day period. Do not freeze. Keep in outer carton to protect from light. Legal Category: POM. Presentation and Marketing Authorisation Number: Prolia 60 mg: Pack of 1 pre-filled syringe with automatic needle guard; EU/1/10/618/003. Price in Republic of Ireland is available on request. Marketing Authorisation Holder: Amgen Europe B.V., Minervum 7061, NL-4817 ZK Breda, The Netherlands. Further information is available from Amgen Ireland Limited, 21 Northwood Court, Santry, Dublin DO9 TX31. Prolia is a registered trademark of Amgen Inc. Date of PI preparation: October 2020 (Ref: IE-PRO-0920-00003)

Adverse reactions/events should be reported to the Health Products Regulatory Authority (HPRA) using the available methods via www.hpra.ie. Adverse reactions/events should also be reported to Amgen

Limited on +44 (0)1223 436441 or Freephone 1800 535 160. References:

1. Prolia® [denosumab], Summary of Product Characteristics. 2. Cummings SR et al, N. Eng. J Med 2009;361:756-765. 3. Holzer G et al, J Bone Miner Res 2009;24(3):468-74. 4. Poole K et al; J Bone Miner Res 012; 27 (suppl1):S44 abstract 1122. 5. Bone HG, et al; Lancet Diabetes Endocrinol. 2017;5:513-23;3-23. 6. Tsourdi E, et al. Bone. 2017;105:11–7. 7. Hernlund E, et al. Arch Osteoporos. 2013;8:136; 8. Kanis JA, et al. Osteoporos Int. 2019;30:3–44; 9. Brown JBMR 2013 Vol28 pp746-752.

The need for a Model of Care for Osteoarthritis in Primary Care in Ireland

Written by Dr Helen French, Senior Lecturer, School of Physiotherapy, RCSI & Dr Joice Cunningham, Postdoctoral Research Fellow, School of Physiotherapy, RCSI

Synopsis - Osteoarthritis (OA) places a substantial burden on individuals and societies, and represents a global challenge to healthcare services. International guidelines recommend education, exercise and weight management as first-line treatments for OA. However, in practice, uptake of guidelinebased non-surgical care is suboptimal. While clinical guidelines provide recommendations regarding best practice, for the most part they fail to address how to operationalise these recommendations into clinical practice. A Model of Care (MoC) is a framework, pathway or strategy that drives the translation of evidence into clinical practice by outlining the optimal manner in which condition specific care should be delivered to consumers within a local health system. The ENACt (ManagemENt of OsteoArthritis in primary Care in Ireland) project aims to develop a primary care-based MoC for OA in Ireland, which will be informed by best evidence and iterative consultation with key stakeholders including service users and service providers. This Health Research Board funded project is being conducted by a research team based in RCSI led by principal investigator Dr. Helen French. This article will describe the stages of the ENACt project and the planned development process for the MoC.

Dr Helen French, Senior Lecturer, School of Physiotherapy, RCSI Dr Joice Cunningham, Postdoctoral Research Fellow, School of Physiotherapy, RCSI

Osteoarthritis (OA) is the most common joint disease in Ireland, affecting approximately 400,000 people. It is one of the leading causes of pain and physical disability. The number of people with OA in Ireland and internationally is growing, with an estimated half of those aged over 65 years diagnosed with OA. An aging population leads to higher prevalence of agerelated chronic conditions, which results in a greater burden on healthcare services1. Long-term pain and disability associated with age-related musculoskeletal conditions such as OA can result in restricted activities of daily living, reduced physical activity, decreased active involvement in society and healthy working life expectancy, and increased risk of other non-communicable diseases2-5. Whilst aging is an important contributing factor to the development of OA, it should not be considered a disease of “wear and tear”. OA is now seen as a low-grade inflammation disease6 , affecting all tissues of the joint, involving cartilage degradation, bone remodelling, osteophytes, and synovitis7. While the mechanisms responsible for OA are multifactorial, the age-related shift in the immune response to a more pro-inflammatory state, also referred to as ‘inflammaging’, is thought to play a role in the development and progression of OA8. Furthermore, increasing levels of obesity superimposed on aging increases chronic lowgrade inflammation. The demand for joint replacement surgery is projected to continue to grow, quadrupling by 20309, leading to concerns regarding capacity to meet future demands10. Therefore, the personal and economic burden of OA is substantial and set to continue to increase. With increasing healthcare utilisation and costs, the global health and socioeconomic impact of OA is currently unsustainable and constitutes a major worldwide challenge11, 12. At present, there is an over-emphasis on surgical and pharmacological interventions, despite evidence supporting conservative treatments such as exercise, weight loss and education. Public health interventions are required to address the existing overuse of inappropriate and low-value care and provide equitable access to cost-effective, evidence-based, management (high-value care)13 . The GP is generally the first port of call for people seeking care for OA in Ireland and acts as a "gatekeeper" to the wider health system, such as hospitals and specialist clinics. Sláintecare, which is the first largescale attempt to reform the health service, recognises that the Irish health service is currently over hospital-centric and sets out a vision to move services into community and primary care. The ENACt project aligns with this vision. Currently there is no Model of Care (MoC) for OA in primary care in Ireland. Despite the already considerable and escalating societal, economic and personal burden of OA, it is frequently overlooked in national and global strategic plans for chronic disease management, with prioritisation given to other non-communicable diseases such as heart disease, diabetes, chronic obstructive pulmonary disease and mental health problems13. OA does not feature alongside other chronic diseases such as asthma and diabetes in chronic disease management programmes or strategies https:// www.hse.ie/eng/about/who/ gmscontracts/2019agreement/ chronic-disease-managementprogramme/. Therefore, the aim of the ENACt project is to develop a MoC for OA in primary care in Ireland to deliver best practice care nationwide. This research, to be conducted in three work packages, aims to determine current primary care management of OA in Ireland, and to develop a MoC focusing on core interventions (education, exercise and weight loss) over a 4-year period (October 2020-October 2024). The project will comprise three phases: • Work Package 1 will involve identifying current management of OA. This will include i) a scoping review to establish evidence for primary care-based MoCs for OA internationally ii) a qualitative systematic review to establish the barriers and facilitators to implementation of

OA management programmes (OAMPs) iii) qualitative interviews to investigate current management of OA in Ireland.

Interviews will involve service providers including; general practitioners (GPs) and other primary care clinicians such as physiotherapists and nurses, as well as service users, i.e., individuals with OA and iv) secondary analysis of data from the Irish Longitudinal Study of Aging (TILDA) to investigate the utilisation of drugs for OA over an 8-year period. • Work Package 2 will involve the development of the primary care-based MoC for OA in Ireland by triangulating Work Package 1 findings, using behaviour change frameworks to identify the most appropriate components of the MoC. Key constructs will be mapped onto theoretical construct domains, to further map to behaviour change techniques (BCTs), which will be used to further develop components of the MoC. The affordability, practicability, effectiveness, acceptability, side-effects/safety and equity (APEASE) criteria will be used to ensure it can be realistically delivered. • Work Package 3 will involve the MoC being delivered to individuals with OA at three GP practices, followed by acceptability testing of the model. This will be done through qualitative interviews with service providers (i.e.,

GPs and other primary care clinicians) and service users (i.e., individuals with OA) involved in this process to ascertain its acceptability.

The profound effect of impaired musculoskeletal health on healthy aging, characterised by morbidity and mortality, has been recognized by the World Health Organisation. ‘Care as usual’ traditional OA management approaches often result in varying treatments, evidencepractice gaps and fragmented and delayed treatment due to waiting lists and over-demand. Therefore, a ‘paradigm shift’ in OA management is urgently required to promote evidence-informed OA management, which addresses the underutilisation of core recommended treatments and over-reliance on pharmacological agents and surgery. The ENACt project will develop a MoC tailored specifically to the Irish healthcare system, with the ultimate goal of implementing and evaluating this MoC on a largescale national level.

References available on request

News Representing Patients with Axial Spondyloarthritis

Arthritis Ireland has joined the Axial Spondyloarthritis International Federation (ASIF), an international membership organisation representing 50 patient associations around the world. ASIF works to increase awareness and knowledge of axial spondyloarthritis (axSpA), a range of chronic inflammatory conditions that primarily affect the spine and sacroiliac joints. A report published by ASIF last month highlights that there is on average a seven-year delay in achieving a confirmed diagnosis, which can result in irreversible damage. The Delay to Diagnosis report sets out for the first time a global perspective of the impact of diagnostic delay and the factors that contribute to it. It also identifies opportunities for overcoming the delay, drawing on different examples of best practice from around the world. Arthritis Ireland is the national patient organisation and health research charity representing the one million people living with arthritis in Ireland. According to Gráinne O’Leary, Chief Executive of Arthritis Ireland, “Axial spondyloarthritis is a very challenging condition in terms of its impact on people’s lives. However, the situation is exacerbated by low levels of awareness and understanding of the condition, with early symptoms frequently attributed to general back pain. “Becoming a member of ASIF will benefit people living with axSpA in this country and is a positive step for Arthritis Ireland. We look forward to working together with international colleagues to raise awareness of the condition and to address the many difficulties that exist around achieving a timely diagnosis,” Ms O’Leary stated. AxSpA places a huge physical impact and psychological stress on patients, which can disrupt every aspect of their life and its quality, including mobility, sleep, work and relationships. Symptoms frequently begin when the person is in their twenties. AxSpA encompasses radiographic (ankylosing spondylitis or AS) and non-radiographic (nr-axSpA) forms. It is also associated with a wide range of comorbidities, including cardiovascular disease, diabetes, renal disease, inflammatory bowel disease, enthesitis and uveitis. Two-thirds (64%) of people with axSpA experience depression. It is estimated that axial spondylorarthritis affects 3 to 7 people per 1,000 – although international estimates vary considerably. This translates to potentially 15,000-33,000 people living with axSpA in Ireland.

New ‘one-stop-shop’ Gynaecological Cancer Platform

A new first-of-its-kind platform for Ireland providing relevant, reliable and evidence-based information for people affected by cervical cancer was launched to mark World Gynaecological Oncology Awareness Day (GO Day) on Monday September 20. The ThisIsGo.ie platform offers a one-stop-shop for helpful resources and advice on cervical cancer as part of the first phase of its development, including over 130 different articles, videos and audio content covering every stage of cancer diagnosis, treatment, and life with and after cancer. The platform has been codeveloped by the Irish Cancer Society through its Women’s Health Initiative and support researchers and clinicians in UCD, in close collaboration with women and families directly affected by cervical cancer, and supported by Pfizer. ThisIsGo.ie offers a personalised experience tailored to the stage and needs of individual users, including a specific section for partners of women who have or have had cervical cancer. It contains evidence-based information on everything from the stages of cervical cancer and a step-by-step guide for what to expect from treatment, to important parts of the journey that may often be overlooked including simple tips on preparing for hospital, and talking to children about cancer. Gynaecological Oncologist Professor Donal Brennan

Gynaecological Oncologist Prof Donal Brennan, whose team developed the platform, said, “Over the last three years Irish people have become aware of the terrible impact a cervical cancer diagnosis can have on women and their families. We hope that ThisIsGo. ie will provide a safe and accurate repository of information that will empower women with cervical cancer to understand the disease and complications associated with treatment. “This platform provides a very necessary resource for women who often struggle to access all the supports they need during what can be short and intermittent hospital visits. By taking a holistic approach it provides access to information on a wide range of subjects ranging from cancer diagnosis and treatment to emotional and physical wellbeing, practical and financial advice as well as dealing with long term side-effects of treatment such as lymphoedema, bowel, bladder and sexual dysfunction.” “In Ireland, in our #DareToAsk campaign we are encouraging patients to ask their doctors those questions they have been too shy or afraid to ask,” says Sharon O’Toole, Trinity College Dublin and co-ordinator of the World GO Day activities on behalf of the Irish Network for Gynaecological Oncology, which will be launching a special podcast in conjunction with the “the Answers for Cancers podcast” team on World GO Day to answer many of these questions that have been collated from patients, and it will also be featured on the ThisIsGo.ie platform. Over 1400 gynaecological cancers are diagnosed in Ireland annually (NCRI 2020 Annual Report), representing over 12% of female cancers. This year's message for World GO Day is simple: Information is power, but

communication is the solution!

ESMO 2021 Multiple Myeloma Study

Among patients with multiple myeloma (MM), higher amylase levels are linked with more advanced disease as well as inferior survival, according to research presented at the European Society of Medical Oncology (ESMO) Congress 2021. Elevated amylase in Multiple myeloma (MM) was first described in 1988. It has been postulated that translocation of chromosome 1, where the amylase gene is situated is responsible for the ectopic production from the malignant plasma cells. Previous case reports have shown that patients with hyperamylasemia in MM are associated with extensive bone disease, rapid progression and shorter survival. The study was conducted to ascertain the degree of elevated amylase in MM patients.

Methods

It was conducted as a single institutional study. In newly diagnosed or relapsed cases of MM, serum amylase levels were determined. The study included patients with normal lipase and creatine clearance and without any evidence of intestinal obstruction or perforation. Patients with amylase value > 100 U/L were designated to have “elevated amylase level” in the study. Statistical analysis done using SPSS version 20.

Results

serum amylase levels and the mean value was 130±69 U/L. The median age of patients was 65 years. The male to female ratio was 1.9: 1. There was no statistically significant association between age, gender, type of heavy chain class, light chain or high-risk cytogenetics. Among the patients with ISS stage I, II and III, 20.8%, 31.3%, and 41.2% were noted to have elevated amylase levels. A statistically significant association was noted between the presence of extramedullary disease (EMD) and elevated amylase level (p-value 0.028). Higher mortality at 29.4% and shorter mean survival of 30.2±3.3 months was noted in those patients with elevated amylase level in comparison to 17% mortality and mean survival of 51.7±4.9 months in those with normal amylase level. The study authors state, “Patients with MM associated with elevated amylase levels were more likely to be diagnosed with advanced ISS stage, higher mortality and shorter survival. A significant association was noted between elevated amylase level and EMD. The limitations of the study were small sample size.”

Reference

Panthula C, Jose WM, Krishnan S. The utility of serum amylase as a clinical marker in patients with multiple myeloma. Paper presented at: European Society for Medical Oncology (ESMO) 2021 Congress; September 16-21, 2021. Abstract 847P.

Chronic Pain: A Neuroimmune Phenomenon

Chronic adult pain is a common problem affecting about 19% of the European population with 61% of these people being unable to work normally resulting in absenteeism, decrease productivity and early retirement with associated negative social and economic impacts and increased demands on healthcare provision. Whilst acute pain is adaptive and protective and usually attributable to a precipitating event chronic pain is not and there is as yet no physiological benefits attributable to chronic pain. Acute pain is generally responsive to anti-inflammatory medication supplemented if necessary with a short courseof opioid medication. This is not however the case with chronic pain. Chronic neuropathic pain (CNP) in particular is notoriously difficult to treat and is the main reason for attendance at pain clinics. The factors which affect the transition from acute adaptive pain to chronic maladaptive pain are poorly understood and are an area of investigation because of the high prevalence of chronic pain in society. It has been noted that patient suffering from chronic pain express symptoms and demonstrate signs of sickness behavior. Sickness or pain related behavior relates to the interaction between the patient and environment, similar to what is seen in patients who have an acute infection on board. This observation has led to the realization that pain chronicity is probably a central immunemediated phenomenon. Ongoing research has further identified

Written by Professor Connail McCrory MB BCH BAO LRCP&SI FCAI FIPP FPMCAI MD

Clinical Professor, School of Medicine, Trinity College Dublin Honorary Consultant, St. James Hospital, Dublin

the relationship between pain and the immune system and pain is one of the four cardinal signs of inflammation. Depression, anxiety, sleep disturbance and hyperalgesia are commonly problematic in patients with chronic pain. It is now believed that the neuronal interface which results in these responses includes T cells, macrophages, glial cells and secreted neuropeptides. The nervous system and immune system share a common language mediated at least in part by neuropeptides, (cytokines, chemokines and neurotrophins). Bidirectional communication becomes maladaptive leading to enhanced pain signaling and chronicity. Whilst there has always been a debate about whether pain chronicity is driven by peripheral stimulation or is solely a central effect it is now quite clear that activation of the dorsal root ganglion and dorsal horn of the spinal cord are central to the development of pain chronicity. Chronic pain occurs when automatic spontaneous nonstimulated sensory unpleasant phenomenon are experience by the patient.1 Neuropathic pain may be caused by lesion of the somatosensory system and is estimated to be a chronic problem in 7-8% of the general population in Europe. Access to the central nervous system in humans for the purposes of research is ethically challenging and traditionally difficult to perform. There has been much development in the field of neuroimaging however this has its limitations in terms of regular clinical application. Chronic neuropathic pain (CNP) remains the greatest clinical challenge. Diagnosis is still heavily dependent on clinical assessment. A multitude of questionnaires are available to help clinicians diagnose CNP but many of these are quite labour-intensive to apply. The DN4 and LANNS Questionnaires are probably the simplest and easiest to use. Laboratory testing such as nerve conduction studies and sensory evoked potentials, laser evoked potentials, punch biopsy, which can quantify Aδ and C fibres, measuring density of intraepidermal nerve fibres and quantitative sensory testing are time-consuming and expensive. The search for an easy to measure inexpensive biomarker continues. The management of CNP relates to both interventional / surgical therapies such as pulsing the dorsal root ganglion and spinal cord stimulation which require

hospital attendance including a visit to the operating theatre with anaesthesia and are expensive to carry out. With the high number of patients suffering from CNP it is simply not practical or within the healthcare budget to provide these expensive therapies to all patients. Doctors are left with medication as the easiest to obtain therapeutic option however effectiveness is limited by relatively poor efficacy and deleterious side-effects. Number needed to treat (NNT) versus number needed to harm (NNH) ratios are humbling. Two of the most commonly used drug classes are the tricyclic antidepressants and opioids.2 As these drugs do seem to have benefit in patients with CNP their mode of action centrally must explain at least in part the pathophysiology of CNP. Chronic post-surgical pain (CPSP) is disabling and can result in significant physical and economic morbidity for the patient. CNP is the commonest cause of CPSP and may affect up to 40% of patients having surgery depending upon the site and type of surgery. Thoracic surgery in particular is associated with CPSP. Poor acute pain control in the immediate postoperative setting has been associated with the development of chronic pain but the aetiology is more complex than this. We investigated the effect of thoracic surgery on human cerebrospinal fluid (CSF) neuropeptides and found that despite adequate acute pain control significant central CSF pro-inflammatory neuropeptide biosynthesis occurred in vivo in patients having a thoracotomy.3 This was associated with the development of CPSP. Amitriptyline is probably seen as the most effective drug in the management of neuropathic pain. We examined the effect of amitriptyline on T-cell phenotype and function on human peripheral blood mononuclear cells. This was achieved by Annexin V / propidium staining, flow cytometry and Elisa examination. Levels of secreted cytokines, chemokines and neurotrophins were measured. The results showed that there was no increase in T-cell death however the type of T-cell present was altered by amitriptyline. The frequency of naïve T cells was significantly lowered after amitriptyline and nortriptyline therapy. The effect of interferongamma on CD AT cells was also reduced. Interestingly natural killer T cells are significantly higher following treatment with nortriptyline. Amitriptyline lowered the levels of interleukin 16 and tumour necrosis factor.4 Amitriptyline is a modulator of both phenotype and function of T cells. Further examination of cerebrospinal fluid (CSF) in patients who responded well to amitriptyline demonstrated a reduction in pro inflammatory pathways of neuronal glial communication and evidence of a neurotrophic effects.5 Opioid medication has been used extensively to treat acute, chronic and cancer pain. It is effective in the management of acute and cancer pain however opioid medication in the management of chronic pain is a very contentious issue. This is well delineated in the CDC report 2016. Opioid related phenomena include sedation, tolerance, euphoria, reward, addiction, analgesia, depression, hyperalgesia and death. There is growing evidence that central signaling maybe responsible at least in part for these phenomenon. Crosstalk between glia, immune cells and neurons, which we refer to as the neurommune interface, occurs by messengers which include cytokines, chemokines, neurotrophins and neuropeptides. Changes in the dynamic of these messengers may be caused by opioid therapy. There remains debate about whether opioids are truly immunosuppressive. In vivo human opioid mural uniform ecology has remained largely unexplored. The effect of opioid therapy on expression of proteomic and neuropeptide constituents of (CSF) will provide greater insight into the pure mechanisms of action in vivo. We examined human CSF in patients with CNP medication with opioid (predominantly oxycodone) versus patients with CNP not medicated with opioids using mass spectrometry. 432 proteins were found to be increased in baseline CSF in the patients receiving opioids versus those not receiving opioids. The 10 most differentially increased proteins included somatostatin. In addition 47 neuropeptides demonstrated decreased expression in the group receiving opioids versus the group which were not medicated with opioids.6 The quoted studies are referenced at the end of this article for those who wish to explore this topic further. Amitriptyline and opioids are commonly employed therapies which have significant neuroimmune effects. The amitriptyline work demonstrates the effect is not just related to neuropeptide metabolism but also has a direct effect on T-cell expression and the receptors on the surface of T cells and the neuropeptide secreted from these cells. The opioid study demonstrates that opioid prescription has a major effect on central neuropeptide and protein biosynthesis in humans. The fact that both these drugs have an effect on immune function supports the concept that CNP is a neuroimmune phenomenon. Again constant surveillance must be provided by both the prescribing doctor and dispensing pharmacist when these therapies are employed because affects on human central peptide and protein biosynthesis in vivo are quite extensive.

References

(1) Neuroimmunity and Chronic Pain

British Journal of Anaesthesia Education 2018 (12): 377-383 J Royds, CMcCrory (2) European Journal of Neurology 2010 17 1113-1123

European Federation of neuroscience guidelines on the pharmacological treatment of neuropathic pain: 2010 revision Attal et al

(3) Central and systemic inflammatory response to thoracotomy – potential implications for acute and chronic postsurgical pain.

Journal of Neuroimmunology 2015;285:147-49 RM Talbot, KF McCarthy, C McCrory (4) An investigation into the modulation of T-cell phenotypes by amitriptyline and nortriptyline

European Neuropsychopharmacology 2020,31,131-144 Royds J, Conroy MJ,Dunne MR, McCrory C, Lysaght J (5) Examination and characterization of the effect of amitriptyline therapy for chronic neuropathic pain on your peptide and propionic constituents of human cerebrospinal fluid. Brain Behaviour & Immunity – Health 10 (2021) 100184 J Royds,H Cassidy, M Conroy, M Dunne, J Lysaght, C McCrory (6) An investigation into Proteomic Constituents of Cerbrospinal Fluid in patients with chronic neuropathic pain medicated with opioids-a pilot study.

J Neuroimmune Pharmacology 2021;16(3): 634-650 Royds J, Conroy MJ, Dunne MR, Cassidy H, Matallanas D, Lysaght J, McCrory C

Value Added Medicines Report

Medicines for Ireland have recently published a new report, “Value

Added Medicines Report: Discussion document on the contribution of Value Added

Medicines in Ireland”, which has been produced in conjunction with their sister organisation, Medicines for Europe. The report outlines a range of important national and European policy recommendations that illustrate the important role that Value Added Medicines (VAMs) play in a wide range of benefits for patients and Healthcare Professionals – from ensuring better adherence and compliance, to keeping healthcare costs down by reducing the need for patients to be moved to expensive next line therapies. The current Irish environment, and structure of reimbursement, does not allow the Irish government to harness these benefits, potentially saving costs and increasing patient care. Says the organisation, “We need a shift in mindset – from one that focuses purely on cost to an outlook that is centred around better outcomes for patients that takes a holistic look at the whole patient journey. Perhaps even more importantly, we need a new and simplified regulatory pathway for VAMs in Ireland. “That’s why all of us at Medicines for Ireland and within the Value Added Medicines Committee, welcome the opportunity to engage with key stakeholders on this important topic, and to begin the discussions around what a fitfor-purpose regulatory framework for VAMs may look like for Ireland. What’s clear is that we need a system that rewards innovation with appropriate incentives, whilst recognising the potential long-term value and savings that VAMs can bring to the State.” The November issue of Hospital Professional News will carry details of the report in full.

Fundraising For You at University Hospitals Limerick

Pictured are some of the staff at University Hospitals Limerick who recently bid farewell and best wishes to frontline workers before they headed off on a two-day cycle to Dublin, as part of a fundraiser, icu4u.ie Frontline medical staff throughout the Republic of Ireland and Northern Ireland cycled to the Memorial Gardens at Islandbridge in Dublin in September, to remember those who have lost their lives to Covid-19. They aim to raise ¤150,000 for those impacted by the secondary challenges of the pandemic through 4 chosen charity partners:

• ALONE (supporting older people)

• Aware (mental health supports)

• Aware NI (depression supports in Northern Ireland)

• Breakthrough Cancer

Research (new treatments for poor prognosis and difficult to treat cancers). The ICU4U event saw small teams of ICU doctors, nurses, paramedics, ambulance drivers, other healthcare staff and Gardai depart from each of the six nationwide University Hospitals in Cork, Belfast, Galway, Limerick, Sligo and Waterford on 2-3 September, with midway points in Dundalk, Athlone, Portlaoise and Kilkenny.

Interoperability is Key says Pharmacy Federation

Digital transformation of health care may allow for more inclusive, equitable and ethical use of healthcare resources, can improve health outcomes and reduce healthcare costs, and is often more environmentally friendly, the International Pharmaceutical Federation (FIP) said in a new Statement of Policy, which was adopted by the FIP Council. However, the full potential of digital and technology-enabled solutions cannot be achieved without the implementation of interoperability, which must be a prerequisite for any digital technology development, and this includes the use of internationally recognised interoperability standards, terminology and taxonomy, the federation has stated. “We expect the impact of digital advances, such as predictive and personalised medicine, facial recognition, natural language processing and augmented reality, to gain even greater significance. We must be prepared to tackle the challenges to usher pharmacy into its digitally supported future,” said Jacqueline Surugue, chair, FIP Technology Forum. Furthermore, in order to leverage the potential of digital health into a sustainable pharmacy ecosystem, the world needs a confident, capable, agile and digitally enabled pharmaceutical workforce, the federation said.

Its new policy statement makes a number of specific recommendations to academic institutions, government and policymakers, FIP member organisations and pharmacists in order to support digital transformation.