Making Information About Cladribine Tablets Accessible to People with Multiple Sclerosis: A Patient-Survey-Led Narrative Review for Healthcare Professionals.

Cladribine tablets have been granted marketing authorization in Europe and approved by the Food and Drug Administration (FDA) in the USA to treat relapsing forms of multiple sclerosis (MS). However, people with MS (PwMS) may be more familiar, and therefore more confident, with treatments requiring long-term and frequent dosing. Differences in such treatment strategies can lead to questions relating to how short-course non-continuous treatments, such as cladribine tablets, can work and how well they are tolerated. In response to this, we aimed to create an evidence-based report on patient-focused aspects of treatment with cladribine. To inform development, MS experts, including healthcare professionals (HCPs) and PwMS, proposed topics that PwMS and their families and caregivers would most like to discuss with HCPs during consultations to help them better understand cladribine treatment. The statements regarding each topic were then ranked by PwMS and used to inform the topics covered in this report. We explain here the use of cladribine tablets, which includes explanations of how cladribine tablets work, how to take cladribine tablets, and considerations required prior to and while taking cladribine tablets. We also describe how cladribine tablets affect relapse rate and quality of life and detail side effects, when they are likely to happen, and for how long. We also discuss how cladribine tablets affect family planning, fertility, and the use of vaccines. Alongside each section is a brief, plain language description of what is covered and an accompanying visual to aid conversations between HCPs and PwMS. Improved understanding by PwMS of treatments, such as cladribine, can empower them to play a bigger role in shared decision-making regarding their treatment. Additionally, the open dialogue we aim to promote with this type of report could lead to treatment choices being better tailored for individuals with chronic diseases on the basis of personal experiences, preferences, and circumstances.

Expert opinion on the long-term use of cladribine tablets for multiple sclerosis: Systematic literature review of real-world evidence.

BACKGROUND: Treatment with cladribine tablets (CladT), an immune reconstitution therapy for relapsing multiple sclerosis (RMS), involves two short courses of treatment in Year 1 and Year 2. Most patients achieve sustained efficacy with CladT, but a small proportion may experience new disease activity (DA). Following completion of the indicated dose, physicians may have questions relating to the long-term management of these patients. Since the EU approval of CladT over 5 years ago, real-world evidence (RWE) is increasing and may provide some insights and guidance for clinical practice. We describe a systematic literature review (SLR) of RWE and provide expert opinions relating to six questions regarding the long-term use of CladT. METHODS: Pertinent clinical questions were developed by a steering committee (SC) of 14 international multiple sclerosis (MS) experts regarding breakthrough DA in Year 1, new DA after 2 years or more of treatment, long-term management of stable patients, and whether additional courses of CladT may be required or safe. An SLR was performed in EMBASE and PubMed using the population, intervention, comparators, outcomes, study design (PICOS) framework to identify relevant studies within the last 15 years. Searches of key congress proceedings for the last 2-3 years were also performed. Following review of the results and RWE, the SC drafted and agreed on expert opinion statements for each question. RESULTS: A total of 35 publications reporting RWE for CladT were included in this review. In the real world, breakthrough DA in Year 1 is of low incidence (1.1-21.9%) but can occur, particularly in patients switching from anti-lymphocyte trafficking agents. In most patients, this DA did not lead to treatment discontinuation. Reported rates of DA after the full therapeutic effect of CladT has been achieved (end of Year 2, 3 or 4) range from 12.0 to 18.7% in the few studies identified. No RWE was identified to support management decisions for stable patients in Year 5 or later. Views among the group were also diverse on this question and voting on expert opinion statements was required. Only two studies reported the administration of additional courses of CladT, but detailed safety outcomes were not provided. CONCLUSIONS: RWE for the long-term use of CladT in the treatment of RMS is increasing, however, gaps in knowledge remain. Where possible, the RWE identified through the SLR informed expert statements, but, where RWE is still lacking, these were based solely on experiences and opinion, providing some guidance on topics and questions that occur in daily clinical practice. More real-world studies with longer-term follow-up periods are needed and highly anticipated.

Expert opinion on COVID-19 vaccines and cladribine tablets in MS: A plain language summary.

WHAT IS THIS SUMMARY ABOUT?: People with multiple sclerosis (shortened to MS) who are taking cladribine tablets may have concerns about whether they can be vaccinated against COVID-19. This summary details the findings from a previously published article, in which an international committee of 10 MS experts developed recommendations to answer some important questions about COVID-19 vaccines in people with MS (including relapsing-remitting or active secondary progressive disease) taking cladribine tablets. WHAT WERE THE RESULTS?: The committee identified 13 recommendations, which were all agreed upon by at least three-quarters (75%) of the 38 voting MS experts. Generally, they recommended that people with MS taking cladribine tablets should be vaccinated for COVID-19 as soon as possible, because the vaccine is thought to be both safe and effective, and vaccine responses were not likely to be affected by cladribine tablets. WHAT DO THE RESULTS MEAN?: Overall, people with MS taking cladribine tablets should receive the COVID-19 vaccine to protect themselves, unless advised differently by their healthcare provider.

Expert opinion on COVID-19 vaccination and the use of cladribine tablets in clinical practice.

BACKGROUND: Gaps in current evidence and guidance leave clinicians with unanswered questions on the use of cladribine tablets for the treatment of multiple sclerosis (MS) in the era of the COVID-19 pandemic, in particular relating to COVID-19 vaccination. OBJECTIVE: We describe a consensus-based program led by international MS experts with the aim of supplementing current guidelines and treatment labels by providing timely recommendations relating to COVID-19 vaccination and the use of cladribine tablets in clinical practice. METHODS: A steering committee (SC) of 10 international MS experts identified 7 clinical questions to answer concerning the use of cladribine tablets and COVID-19 vaccination, which addressed issues relating to patient selection, timing and efficacy, and safety. Clinical recommendations to address each question were drafted using available evidence combined with expert opinion from the SC. An extended faculty of 28 MS experts, representing 19 countries, in addition to the 10 SC members, voted on the recommendations. Consensus on recommendations was achieved when ⩾75% of respondents expressed an agreement score of 7-9, on a 9-point scale. RESULTS: Consensus was achieved on all 13 recommendations. Clinical recommendations are provided on whether all patients with MS receiving cladribine tablets should be vaccinated against COVID-19, and whether they should be prioritized; the timing of vaccination around dosing of cladribine tablets (i.e. before and after a treatment course); and the safety of COVID-19 vaccination for these patients. CONCLUSION: These expert recommendations provide timely guidance on COVID-19 vaccination in patients receiving cladribine tablets, which is relevant to everyday clinical practice.

Expert opinion on the use of cladribine tablets in clinical practice.

BACKGROUND: Gaps in current product labels and a lack of detailed clinical guidelines leaves clinicians' questions on the practical management of patients receiving cladribine tablets for the treatment of relapsing multiple sclerosis (MS) unanswered. We describe a consensus-based programme led by international MS experts with the aim of providing recommendations to support the use of cladribine tablets in clinical practice. METHODS: A steering committee (SC) of nine international MS experts led the programme and developed 11 clinical questions concerning the practical use of cladribine tablets. Statements to address each question were drafted using available evidence, expert experiences and perspectives from the SC and an extended faculty of 33 MS experts, representing 19 countries. Consensus on recommendations was achieved when ⩾75% of respondents expressed an agreement score of 7-9, on a 9-point scale. RESULTS: Consensus was achieved on 46 out of 47 recommendations. Expert-agreed practical recommendations are provided on topics including: the definition of highly active disease; patterns of treatment response and suboptimal response with cladribine tablets; management of pregnancy planning and malignancy risk, infection risk and immune function, and switching to and from cladribine tablets. CONCLUSION: These expert recommendations provide up-to-date relevant guidance on the use of cladribine tablets in clinical practice.

Role of endothelin in fibrosis and anti-fibrotic potential of bosentan.

Recent data demonstrate the fundamental role of endothelin in the pathogenesis of fibrosis, and the anti-fibrotic potential of dual endothelin receptor antagonists such as bosentan. Although transforming growth factor-beta, aldosterone and connective tissue growth factor, have already been established as contributors to the process of fibrosis, endothelin now emerges as a key player, which may have a role both in the initiation and in maintenance of fibrosis, and may mediate the pro-fibrotic effects of the other agents. Bosentan is an orally active, dual endothelin receptor antagonist, which competitively antagonizes the binding of endothelin to both endothelin receptors ETA and ETB. Bosentan prevents endothelin-induced fibroblast proliferation and extracellular matrix deposition and contraction, and reduces cardiac, hepatic, pulmonary and renal fibrosis in different disease models characterized by the activation of the endothelin system. Bosentan even reverses existing fibrosis, possibly by its effect of stimulating matrix metalloproteinase type 1 (collagenase) expression. The anti-fibrotic effects of bosentan extend to fibrosis induced by mediators other than endothelin such as transforming growth factor-beta, angiotensin II and aldosterone, indicating a central role of endothelin and endothelin receptors in fibrotic processes.