935019 research-article20202020 TAN0010.1177/1756286420935019Therapeutic Advances in Neurological DisordersPS Sørensen, D Centonze Therapeutic Advances in Neurological Disorders Review Expert opinion on the use of cladribine Ther Adv Neurol Disord 2020, Vol. 13: 1–17 tablets in clinical practice DOI: 10.1177/ https://doi.org/10.1177/1756286420935019 https://doi.org/10.1177/1756286420935019 1756286420935019 © The Author(s), 2020. Article reuse guidelines: Per Soelberg Sørensen, Diego Centonze , Gavin Giovannoni, Xavier Montalban, sagepub.com/journals- permissions Daniel Selchen, Patrick Vermersch, Heinz Wiendl, Bassem Yamout, Hashem Salloukh and Peter Rieckmann Correspondence to: Per Soelberg Sørensen Abstract Department of Neurology, Danish Multiple Sclerosis Background: Gaps in current product labels and a lack of detailed clinical guidelines leaves Center, University of clinicians’ questions on the practical management of patients receiving cladribine tablets for Copenhagen, 2082, Rigshospitalet, 9, the treatment of relapsing multiple sclerosis (MS) unanswered. We describe a consensus- Blegdamsvej, Copenhagen, 2100, Denmark based programme led by international MS experts with the aim of providing recommendations pss@rh.dk to support the use of cladribine tablets in clinical practice. Diego Centonze Unit of Neurology and Methods: A steering committee (SC) of nine international MS experts led the programme and Neurorehabilitation, developed 11 clinical questions concerning the practical use of cladribine tablets. Statements IRCCS Neuromed, Pozzilli (IS), Italy to address each question were drafted using available evidence, expert experiences and Gavin Giovannoni perspectives from the SC and an extended faculty of 33 MS experts, representing 19 countries. Blizard Institute, Barts and The London School of Consensus on recommendations was achieved when ⩾75% of respondents expressed an Medicine and Dentistry, agreement score of 7–9, on a 9-point scale. Queen Mary University of London, London, UK Results: Consensus was achieved on 46 out of 47 recommendations. Expert-agreed practical Xavier Montalban recommendations are provided on topics including: the definition of highly active disease; Department of Neurology, Neuroimmunology, patterns of treatment response and suboptimal response with cladribine tablets; management Multiple Sclerosis Centre of pregnancy planning and malignancy risk, infection risk and immune function, and switching of Catalonia (Cemcat), Vall d’Hebron University to and from cladribine tablets. Hospital, Barcelona, Spain Conclusion: These expert recommendations provide up-to-date relevant guidance on the use Division of Neurology, St. Michael’s Hospital, of cladribine tablets in clinical practice. University of Toronto, Toronto, ON, Canada Daniel Selchen Keywords: cladribine tablets, consensus, disease modifying drugs, expert opinion, highly Division of Neurology, St. Michael’s Hospital, active disease, relapsing multiple sclerosis, switching, treatment response University of Toronto, Toronto, ON, Canada Patrick Vermersch Received: 26 March 2020; revised manuscript accepted: 12 May 2020. Univ. Lille, INSERM-U1172, CHU Lille, FHU Imminent, Lille, France Heinz Wiendl Department of Neurology, Introduction when to start, switch and stop treatments, and Institute of Translational A considerable number of disease modifying other important issues around pregnancy.3 Neurology, University of Münster, Münster, Germany drugs (DMDs) with different properties have Bassem Yamout been approved for the treatment of relapsing mul- Clinical guidelines and treatment labels provide a Nehme and Therese Tohme tiple sclerosis (RMS) over the two last decades framework, but rarely provide specific, detailed Multiple Sclerosis Center, American University of (recently reviewed by Cree et al.).1 This evolving information on real-life usage, and are of limited Beirut, Beirut, Lebanon treatment landscape requires physicians to have a help for individual decision making.3 This means Hashem Salloukh comprehensive understanding of the various that there are many unanswered questions about Ares Trading S.A., and affiliate of Merck Serono treatment options, including their relevant mech- the practical use of these treatments. S.A., Eysins, Switzerland anisms of action, clinical efficacy and safety, Peter Rieckmann Department of mode of administration and monitoring require- Expert consensus recommendations can be Neurology, Center for ments, in order to be able to offer optimal care.2 developed to aid treatment decision-making Clinical Neuroplasticity, Medical Park Loipl, The increasing number of treatment options also when clinical recommendations are limited and Bischofswiesen, University pose new challenges for neurologists, including there are gaps in guidance due to limited of Erlangen, Germany journals.sagepub.com/home/tan 1 Creative Commons Non Commercial CC BY-NC: This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage). Therapeutic Advances in Neurological Disorders 13 Figure 1. Overview of the modified Delphi process for achieving consensus. F2F, face to face; SC, steering committee. experience.4 Such consensus recommendations 1. The definition of highly active disease; typically summarise opinions from an expert 2. The patterns of treatment response in panel on particular, focussed topics and suggest patients treated with cladribine tablets; treatment strategies based on collective knowl- 3. Management of patients with evidence of edge and clinical experience.4 disease activity while being treated with cladribine tablets; Cladribine tablets (MAVENCLAD®) are a short- 4. Infection risk and immune function in course oral DMD for use in MS.5,6 At a cumula- patients being treated with cladribine tive dose of 3.5 mg/kg over 2 years, cladribine tablets; tablets were associated with significant improve- 5. Management of pregnancy planning and ment in clinical and imaging parameters in malignancy risk in patients being treated patients with highly active RMS in clinical trials with cladribine tablets; (CLARITY and CLARITY Extension). 6. Treatment switching to and from cladrib- Cladribine tablets were recently approved by the ine tablets and monitoring considerations. European Medicines Agency (EMA) and the United States (US) Food and Drug Administration The objective of the programme was to provide (FDA), and various other regulatory authorities consensus-based practical recommendations on throughout the world.7,8 Cladribine is a deoxy- the use of Cladribine tablets in real-life practice adenosine analogue that selectively reduces B and addressing gaps not covered in current guidelines T lymphocytes and is thought to interrupt the and labels. cascade of immune events central to the patho- genesis of MS.6 Materials and methods In order to address some of the unanswered ques- The consensus programme was based on a multi- tions relating to the use of cladribine tablets, we step modified Delphi methodology, which took describe a consensus-based programme led by place between April 2018 and June 2019. The international MS experts with the aim of provid- process is outlined in Figure 1. A steering com- ing practical recommendations to support its use mittee (SC) of nine international MS experts with in real-life clinical practice. The questions focussed well-documented experience with cladribine tab- on six topics: lets led the programme, co-chaired by P.S.S. and 2 journals.sagepub.com/home/tan PS Sørensen, D Centonze et al. P.R. The SC in turn was supported by the identi- this did not affect the overall strength of the rec- fication of an extended faculty (EF) through the ommendations. A summary of the available evi- nomination of additional internationally recog- dence for each topic is provided in the following, nised practicing neurologists with experience of and the recommendations for each question pro- caring for people with MS. A total of 76 interna- vided in Tables 1–6. tional experts were invited to participate in the EF, with 33 taking part. A total of 19 countries were represented in the programme. The role of Definition of highly active disease the EF was to review the available evidence, com- Currently, there is no universally accepted defini- plete a questionnaire and finally vote on draft tion of highly active MS, yet many MS treatments recommendations. include this in their labelled indication. Clinical trials lack consistent definitions for ‘highly active’ The SC outlined the areas of clinical focus and MS in subgroup analyses (reviewed by drafted 21 clinical questions to be addressed. Fernandez).15 In general, patients with highly These were ranked using a web-based platform, active MS will have frequent relapses and/or an resulting in 11 prioritised questions, categorised increasing burden of brain magnetic resonance into six topics. The questions included both con- imaging (MRI) lesions.16 Other features that may textual questions, relating to the definition of be taken into consideration include severity and highly active RMS, and practical questions, relat- localization of relapses, clinical or MRI disease ing to the use of cladribine tablets in different activity on treatment, burden of T2 lesions and clinical scenarios. A comprehensive literature presence of gadolinium (Gd+) enhancing lesions. review was performed using the PICO (popula- tion, intervention, comparison, outcome) frame- The consensus recommendation for the defini- work for each of the 11 questions. The level of tion of highly active MS is provided in Table 1 evidence was assessed and agreed by the SC using for both treatment naïve patients (Question 1a), the GRADE (grading of recommendations assess- and those who have received an appropriate ment, development, and evaluation) level of evi- course of a DMD (Question 1b). Additional fac- dence ratings scale.9 tors associated with poor prognosis may also be taken into consideration, alongside activity met- A questionnaire was developed by the SC with rics, when deciding whether to initiate a high- draft answers based on the available evidence efficacy therapy in treatment naïve patients with from the literature review, combined with their MS including those with ⩾1 spinal cord lesions, expert opinion, where evidence was lacking. The incomplete recovery from relapses, accrual of questionnaire was completed remotely via the on- physical or cognitive impairment and a short line platform by the EF, following a review of the inter-attack interval.16,17 available evidence. The results from the question- naire were used to develop draft clinical recom- mendations, which were then voted on by the SC Patterns of treatment response in patients and EF members. Consensus was achieved when treated with cladribine tablets ⩾75% of respondents agreed in the range 7–9 (on Clinical judgement about response to treatment a 9-point scale). Each statement/recommenda- and acceptance of any on-treatment disease activ- tion was assigned a strength score (i.e. the median ity is often subjective and can vary between indi- score) and a level of consensus, defined as the vidual physicians. There is no consensus on the percentage of votes with a score of 7–9.10–14 definition of treatment failure, or suboptimal treatment response in MS, nor indeed specifically for patients receiving cladribine tablets. Results In total, 47 recommendations were drafted by the There are published decision models that may SC and voted on. Consensus was achieved on 46 support the identification of patients failing on of these recommendations. Not all EF members current treatment including the Canadian MS voted on all questions. The exact reasons for the Working Group model20 and the multifactorial few abstentions were unclear but could have been MS decision model.21 Both of these use a traffic due to time constraints and the length of the on- light-based system to flag whether a change of line questionnaire and voting procedure. However, therapy should be considered for a given patient. journals.sagepub.com/home/tan 3 Therapeutic Advances in Neurological Disorders 13 Table 1. Defining highly active disease. Consensus recommendation Strength of Level of recommendation‡ consensus¶ Q1a. What patient baseline characteristics and activity metrics indicate highly active disease: • If patients are treatment naïve? (Level of evidence: moderate) Clinicians should consider the following activity metrics that may indicate highly active 8 (7.8) 88.2% disease in a treatment naïve patient: (30/34) • 1 prior clinical relapse in the last year AND evidence of subclinical MRI activity (Gd+ or new or enlarging T2 lesions) in a patient with poor prognostic factors (clinical, MRI or biomarker) OR • 2 or more clinical relapses in the last year, with or without MRI activity Q1b. What patient activity metrics indicate highly active disease and suitability for high-efficacy treatment or escalation therapy: • If patients have had an appropriate course of a DMD? (Level of evidence: moderate) Clinicians should consider the following activity metrics that may indicate highly active 8 (7.8) 88.2% disease, and suitability for high-efficacy treatment or escalation therapy, in a patient who (30/34) has had an appropriate course of another DMD:* • 1 prior clinical relapse in the last year with subclinical MRI activity (Gd+ or new or enlarging T2 lesions) OR • 2 prior clinical relapses in the last year without MRI activity OR • ⩾1 Gd+ lesions or ⩾ 2 new or enlarging T2 lesions in the last 12 months *A new baseline MRI scan should be taken into consideration. The timing of the re-baseline scan may vary depending on the treatment.18,19 ‡Median score on a 1–9 scale (mean score in brackets). ¶Percentage of votes with 7–9 on a 9-point scale. DMD, disease modifying drug; Gd+, presence of gadolinium; MRI, magnetic resonance imaging. However, there has been no wide implementation (Question 2b) treatment responses with cladrib- of these models across the MS community. ine tablets are provided in Table 2. The European Academy of Neurology/European Committee of Treatment and Research in Management of patients with evidence of Multiple Sclerosis (EAN/ECTRIMS) recom- disease activity while being treated with mendation suggests ‘combining MRI with clinical cladribine tablets measures to evaluate disease evolution’.18 The American Academy of Neurology (AAN) recom- Disease activity in the first 2 years mends including ⩾1 relapses, ⩾2 MRI lesions or The full recommended dose of cladribine tablets increased disability when assessing suboptimal is 3.5 mg/kg given as two courses 12 months treatment response.19 There is a strong debate in apart.24 Following completion of the two treat- the MS community whether physicians should ment courses in years 1 and 2, The patient is treat to ‘no evidence of disease activity’ (NEDA), observed in years 3 and 4 without any additional defined as an absence of relapses, disability wors- planned treatment with cladribine tablets. Any ening and MRI activity.17,22,23 However, NEDA patient with residual activity in the first 12 months can be difficult to sustain in the long term, and should receive the full dose of cladribine tablets, can depend on the mechanism of action of the since a lower cumulative dose appears to result in DMD and timing of the re-baseline scan.22,23 significantly lowered efficacy.5 In CLARITY, 56.1% of patients receiving cladribine tablets Consensus recommendations for the definitions were disease activity-free during year 1 (defined of optimal (Question 2a) and suboptimal as having no relapses, no 6-month sustained 4 journals.sagepub.com/home/tan PS Sørensen, D Centonze et al. Table 2. Patterns of treatment response in patients treated with cladribine tablets. Consensus recommendations Strength of Level of recommendation‡ consensus¶ Q2a. What are the patterns of treatment response with cladribine tablets? (Level of evidence: low) A complete or durable treatment responder to cladribine tablets is a patient with 8 (8.0) 93.9% no evidence of significant clinical or radiological activity after completion of the full (31/33) recommended cumulative dose.* In the absence of new disease activity in year 3, 4, or beyond, a patient is not a candidate for 9 (8.5) 97.0% treatment switch to another DMD. (32/33) *A new baseline MRI scan should be taken into consideration. • Refer to Question 1b for the threshold of clinical or radiological activity in a patient following an appropriate course of a DMD that indicates a suboptimal responder Q2b. What are the patterns of suboptimal response with cladribine tablets? (Level of evidence: low) A patient with worsening or unchanged disease activity during the first 2 years of treatment 8 (7.6) 84.8% with cladribine tablets, should be considered as a putative non- or suboptimal responder (28/33) and is a candidate for treatment with a high-efficacy DMD. •  efer to Question 1b for the threshold of clinical or radiological activity in a patient following an appropriate course of a DMD R that indicates a suboptimal responder • Refer to Question 10 for ‘How to switch from cladribine tablets’ ‡Median score on a 1–9 scale (mean score in brackets). ¶Percentage of votes with 7–9 on a 9-point scale. DMD, disease modifying drug. change in EDSS score, no new T1 gadolinium- Disease activity in years 3, 4 or beyond enhancing lesions and no active T2 lesions).25 Cladribine tablets are efficacious in patients with MS for up to 4 years after the initial dose in clini- When considering disease activity in the first year, cal trials; re-initiation of therapy after year 4 has the timing of the maximal effect of cladribine tab- not been investigated.24 The CLARITY exten- lets on B and T cells may need to be considered.24 sion study (CLARITY EXT) was a safety study This is recognised in the AAN guidelines, which in which 867 patients from the original CLARITY state that relapses or new MRI lesions may trial were enrolled. Of these, 98 patients who develop after initiation of a disease-modifying received cladribine tablets during CLARITY, therapy but before it becomes effective.19 Across received placebo in CLARITY EXT (CP group), clinical studies, the largest proportion of patients and no further doses of cladribine tablets, and with grade 3 or 4 lymphopenia was seen 2 months 186 patients received an additional two treatment after the first cladribine dose in each year. The courses of cladribine tablets, 12 months apart in greatest reduction in lymphocyte count is reached years 3 and 4 (CC group; 7 mg/kg cumulative at 4 months after the first dose.7,24 It is a possibil- dose). All efficacy analyses were exploratory. The ity that residual disease activity at less than incidence of lymphopenia events during 6 months may indicate that the maximum effect CLARITY EXT increased in the CC group com- on lymphocytes has not been reached. pared with the CP group (36.6% versus 9.2%, respectively).8 Furthermore, there was an increase The CLARITY study protocol allowed relapses in lymphopenia leading to discontinuation in years 1–2 to be treated as per clinical practice (11.8% versus 0%, respectively). However, these with short-term systemic corticosteroid therapy. findings occurred in the absence of the require- This occurred in 23% of patients receiving clad- ment to achieve a lymphocyte count of at least ribine tablets versus 46% of patients receiving pla- 800 cells/mm3 before initiation of cladribine tab- cebo [odds ratio (OR) 95% confidence interval lets in year 2, as per current practice.24 In patients (CI): 0.34 (0.26, 0.46) p < 0.001].7,26,27 with ⩾800 cells/mm3 prior to administration of journals.sagepub.com/home/tan 5 Therapeutic Advances in Neurological Disorders 13 subsequent courses in years 2, 3 and 4, the inci- be considered in patients with grade 4 lymphopenia. dence of lymphopenia dropped to 11% and 12% Reasons provided for this included ‘a lack of indica- in years 3 and 4, respectively.28 During the exten- tion for prophylaxis with anti-viral treatments in sion period, 75.6% of patients in the CP group patients with lymphopenia’, ‘no scientific evidence’, stayed relapse free, compared with 81.2% of ‘more evidenced on risk/benefit ratio is needed for patients in the CC group.8 Additional exploratory “continuous” antiviral therapy’, ‘lack of evidence MRI analyses demonstrated that cladribine tab- based documentation for efficacy and duration of lets had a durable effect on MRI outcomes in the anti-viral prophylaxis’ and ‘lack of sufficient evi- majority of patients, an effect that was sustained dence that prophylactic antivirals significantly up to the end of the extension period. reduces the risk of shingles to justify routine use’. Consensus recommendations for the manage- ment of patients with evidence of disease activity Vaccinations during: Year 1 (Question 3a); the first 2 years There are no comprehensive studies available on (Question 3b); in years 3 or 4 (Question 4a); or vaccines and cladribine tablets, and the effects of beyond year 4 (Question 4b) while being treated cladribine tablets on the immunological memory with cladribine tablets are provided in Table 3. acquired by previous vaccinations have not been Consensus was not achieved for one recommen- studied. Certain vaccines may be recommended by dation in answer to Question 4a. The reasons physicians to their patients before initiation of clad- provided by the EF for this was that they would ribine tablets as part of a de-risking strategy; how- consider re-treatment with cladribine tablets in ever, this may vary by physician and by country. this instance. Re-treatment in year 3 or 4 has not been formally investigated in a clinical trial set- Guidance on vaccinations is provided in the ting, in addition to an increased incidence of lym- Mavenclad SmPC and in the German Competence phopenia and other adverse events following Network guidance.24,31 Consensus recommenda- additional cladribine tablets treatment in year 3 tions on vaccinations for patients receiving cladribine or 4 in the CLARITY EXT study was observed. tables are provided in Table 4 (Questions 6 and 7). Infection risk and immune function in Management of latent or active infections patients being treated with cladribine Active infection with HIV, tuberculosis or hepati- tablets tis must be excluded before initiation of cladrib- ine tablets.24 Latent infections may be activated Lymphopenia and infection risk (including upon treatment with cladribine tablets, therefore herpes zoster) screening must be performed.24 A pooled safety analysis showed the incidence of infection was similar between cladribine tablet- Guidance on the management of latent and active exposed cohort and placebo groups, except for infections is provided in the Mavenclad SmPC and herpes zoster.30 Infections or infestations, includ- in the German Competence Network guide- ing herpes zoster were more common in patients lines.24,31 Guidance on John Cunningham virus receiving cladribine tablets during periods with activation and screening for progressive multifocal Grade 3 or 4 lymphopenia.30 leukoencephalopathy is also provided in EAN/ ECTRIMS recommendations.18 Consensus recom- Guidance on the management of lymphopenia and mendations for the management of latent or active herpes zoster is provided in the Mavenclad Summery infections are provided in Table 4 (Question 8). of Product Characteristics (SmPC) and in the German Competence Network guidance.24,31 Consensus recommendations on the management Management of pregnancy planning and of lymphopenia and infections in patients on cladrib- malignancy risk in patients being treated ine tables are provided in Table 4 (Question 5). with cladribine tablets Whereas consensus was reached on recommenda- tions regarding use of antiviral prophylaxis in patients Management of pregnancy planning with lymphopenia (Question 5b), five EF members There are no clinical studies that have investi- (16%) did not agree that antiviral treatment should gated the effect of cladribine tablets on pregnancy 6 journals.sagepub.com/home/tan PS Sørensen, D Centonze et al. Table 3. Managing patients with evidence of disease activity while being treated with cladribine tablets. Consensus recommendations Strength of Level of recommendation‡ consensus¶ Q3a. How would you manage a patient who has taken the first course of cladribine tablets but has evidence of new disease activity in year 1? (Level of evidence: moderate) After the first treatment course of cladribine tablets in year 1, a patient with disease 8 (8.3) 97.0% activity less than pre-treatment levels, might not necessarily be an indication for treatment (32/33) discontinuation.*19,29 Corticosteroids should be used to treat the relapse according to local guidelines. Clinicians may 9 (8.4) 97.0% wait and monitor the patient and provide cladribine tablets at the beginning of year 2 in order to (32/33) allow the patient to receive the recommended cumulative dose. *Disease activity in the first 3–6 months of treatment with cladribine tablets may be a carry-over from a patient’s prior treatment, especially for those switching from lymphocyte trafficking agents (fingolimod or natalizumab). Q3b. How would you manage a patient who has worsening disease activity during the first two years of treatment with cladribine tablets? (Level of evidence: very low) During the first two years of treatment with cladribine tablets, a patient with increasing disease 8 (8.0) 87.9% activity above pre-treatment levels, may be a candidate for a treatment switch to another (29/33) high-efficacy DMD.* Corticosteroids should be used to treat relapses according to local guidelines. 9 (8.7) 97.0% (32/33) *Disease activity in the first 3–6 months of treatment with cladribine tablets may be a carry-over from a patient’s prior treatment, especially for those switching from lymphocyte trafficking agents (fingolimod or natalizumab). • Refer to Question 1b for the threshold of clinical or radiological activity in a patient following an appropriate course of a DMD that indicates a suboptimal responder • Refer to Question 10 for ‘How to switch from cladribine tablets’. Q4a. How would you manage a patient who has taken the indicated two courses of cladribine tablets but has evidence of new/reappearing disease activity only in year 3–4? (Level of evidence: low) Clinicians should consider a switch to another high-efficacy DMD in a patient with a complete 7 (6.7) 60.6% but non-durable response to cladribine tablets with evidence of new/reappearing disease NOT activity in year 3–4 ACHIEVED Clinicians should consider treatment options and associated risks and discuss with the patient. 9 (8.6) 100% (33/33) • R efer to Question 1b for the threshold of clinical or radiological activity in a patient following an appropriate course of a DMD that indicates a suboptimal responder • Refer to Question 10 for ‘How to switch from cladribine tablets’ Q4b. How would you manage a patient who has taken the indicated two courses of cladribine tablets but has evidence of new/reappearing disease activity only beyond year 4? (Level of evidence: low) Treatment options for a patient with a complete but non-durable response to cladribine tablets 8 (8.3) 97.0% with evidence of new/reappearing disease activity beyond year 4 could include: (32/33) • Consideration of a switch to another high-efficacy DMD after thorough risk/benefit analysis. • Consideration of re-initiation with cladribine tablets, after thorough risk/benefit analysis. • Benefit of additional treatment with cladribine tablets in response to disease activity beyond year 2 has not been investigated. The incidence of lymphopenia and other adverse events is increased with additional treatment in years 3 or 4. Re-initiation of therapy after year 4 has also not been investigated. • Clinicians should consider treatment options and associated risks and discuss with the patient. ‡Median score on a 1–9 scale (mean score in brackets). ¶Percentage of votes with 7–9 on a 9-point scale. DMD, disease modifying drug. journals.sagepub.com/home/tan 7 8 Table 4. Infection risk and immune function in patients being treated with cladribine tablets. Consensus recommendations Strength of Level of recommendation‡ consensus¶ Q5a. How are patients with severe lymphopenia on cladribine tablets managed? (Level of evidence: moderate/low) A patient with grade 3 or 4 lymphopenia on cladribine tablets may be at an increased risk of infection and should be actively monitored for 8 (8.2) 93.8% signs and symptoms of infections. Clinicians should consider appropriate prophylactic treatment based on the individual patient’s risk. (30/32) A patient with grade 3 or 4 lymphopenia should be actively monitored for signs and symptoms particularly suggestive of herpes zoster. A 9 (8.6) 96.9% patient should also be informed about the signs and symptoms of herpes zoster. If such signs and symptoms occur, anti-viral treatment should (31/32) be initiated immediately. Q5b. Do patients with severe lymphopenia on cladribine tablets need anti-viral prophylaxis against herpes zoster? Which anti-herpes therapy should be used prophylactically? (Level of evidence: moderate/low) Initiation of anti-viral prophylaxis with a licenced anti-viral drug should be recommended in a patient with grade 4 lymphopenia.* 8 (7.7) 84.4% (27/32) Initiation of anti-viral prophylaxis with a licenced anti-viral drug may be considered in a patient with grade 3 lymphopenia. Special 8 (7.4) 75% consideration should be given to any patient at risk of herpes zoster infection such as elderly patients.*,** (24/32) Anti-viral prophylaxis should be maintained until severity of lymphopenia is reduced. 8 (7.7) 83.9% Therapeutic Advances in Neurological Disorders 13 (26/31) Vaccination with Shingrix may be considered for any patient at increased risk of herpes zoster infection (for example those with age ⩾50, 8 (7.4) 81.3% previous herpetic exacerbations) (26/32) *Anti-viral prophylaxis could include: 200 mg acyclovir/day, 400 mg acyclovir/day, or 500 mg valaciclovir/day **Grade 3 lymphopenia was more common in year 2 of the CLARITY study, and duration of lymphopenia was longer. Zoster infection is more common in older patients. The history of the patient should be taken into consideration including the patient age, prior duration of lymphopenia and previous infection with varicella zoster virus. • Refer to Questions 6 and 7 for recommendations on vaccinations Q6. What vaccinations are recommended as part of the de-risking strategy before patients are initiated with cladribine tablets? (Level of evidence: very low) Clinicians should review a patient’s vaccination status before initiation with cladribine tablets and consult their local vaccination guidelines.* 9 (8.4) 93.8% (30/32) Vaccination for varicella zoster virus is recommended in any antibody-negative patient prior to initiation of cladribine therapy. 9 (8.7) 96.9% (31/32) *A review of a patient’s vaccination status includes the patient history and may also include a check of antibody titres. Q7. How do you manage vaccinations after treatment with cladribine tablets; inactivated component vaccines versus live attenuated vaccines? (Level of evidence: low) Cladribine tablets should not be initiated within 4–6 weeks after vaccination with live or attenuated live vaccines. 9 (8.6) 100% (31/31) Any use of live attenuated vaccines should be avoided during treatment with cladribine tablets. Users should wait for the leukocytes/ 9 (8.4) 96.8% lymphocytes to return to normal wherever possible. (30/31) (Continued) journals.sagepub.com/home/tan Table 4. (Continued) Consensus recommendations Strength of Level of recommendation‡ consensus¶ If an inactivated component vaccination is essential for a patient, clinicians should wait for the lymphocyte levels to return to within the normal 8 (7.3) 77.4% range. (24/31) For certain multi-dose vaccinations,* clinicians may consider giving the first dose of the vaccine 4–6 weeks before treatment initiation with 8 (8.1) 93.5% journals.sagepub.com/home/tan cladribine tablets. Subsequent vaccine dose(s) should be given at a later date, after initiation with cladribine tablets, once lymphocyte counts (29/31) have recovered *Relevant multi-dose vaccinations include those for HBV, HPV, VZV, measles, pneumococcus Q8. How should latent or active infections be managed before initiation of cladribine tablets? [e.g. positive PPD/Quantiferon test for TB, HPV (cervical screening), HBV/HCV test, PML] (Level of evidence: low) Cladribine tablets are contraindicated in a patient with HIV or an active chronic infection (e.g. HBV, HCV, VZV, Syphilis, TB, PML etc.), and a 9 (8.5) 96.8% delay in initiation of cladribine tablets should be considered in a patient with an acute infection until the infection is fully controlled.* (30/31) • In any case of infection (latent or active), a relevant specialist should be contacted (e.g. infectious disease, pulmonologist, hepatologist etc.). • The infection should be diagnosed, managed, and treated according to local guidelines. Screening for PML is recommended in any patient previously treated with natalizumab, particularly those who are JCV antibody positive, and a 9 (7.7) 83.3% baseline MRI (within 3 months) should be performed before initiation of cladribine tablets. Additional CSF analysis should be considered (26/31) *Clinicians should consider a patient’s prior treatment since those switching from a DMD associated with lymphopenia, may be at an increased risk from latent infections. ‡Median score on a 1–9 scale (mean score in brackets). ¶Percentage of votes with 7–9 on a 9-point scale. CSF, cerebrospinal fluid; DMD, disease modifying drug; HBV, hepatitis B virus; HCV, hepatitis C virus; HPV, human papillomavirus; JCV, John Cunningham virus; MRI, magnetic resonance imaging; PML, progressive multifocal leukoencephalopathy; PPD, purified protein derivative; TB, tuberculosis; VZV, varicella-zoster virus. 9 PS Sørensen, D Centonze et al. Therapeutic Advances in Neurological Disorders 13 outcomes. There are limited data from the clad- vote in the range 7–9 regarding contraindicated ribine clinical programme on outcomes from use of cladribine tablets in active malignancy. Two women exposed to cladribine (n = 44) and from of these EF members provided a score of 5 (nei- women whose partners had been exposed to clad- ther agree nor disagree) and one gave a score of 3. ribine (n = 10); however, the numbers are too Reasons for this included ‘there is no evidence small to draw conclusions.32 that cladribine tablets are contraindicated in active malignancy – it should be at clinician’s discretion Guidance on the management of pregnancy plan- depending upon the malignancy’ and ‘I would ning is provided in the Mavenclad SmPC and in think it would depend on the type of malignancy’. the German Competence Network guidelines.24,31 One voting expert gave no reason for their allo- Consensus recommendations on the manage- cated score. ment of pregnancy planning are provided in Table 5 (Question 9a). Two EF members did not strongly agree with the recommendation on breast Treatment switching to and from cladribine feeding, both giving a score of 6. The reason pro- tablets and monitoring considerations vided for not scoring in the range 7–9 was the duration of abstaining from breast feeding; 7 days Switching to cladribine tablets was seen to be sufficient. There are no randomised clinical studies investi- gating a switch in DMD to cladribine tablets. However, there are currently a number of treat- Risk of malignancy with cladribine tablets ments for RMS with different mechanisms of In a pooled analysis of clinical studies and long- action that are candidates for treatment sequenc- term follow up of patients treated with cladribine ing with cladribine tablets; therefore, advice on tablets 3.5 mg/kg, events of malignancies were switching is necessary and important. observed more frequently in cladribine tablets- treated patients compared with patients who Specific guidance on switching to cladribine tab- received placebo (0.29 versus 0.15 events per lets is limited. The German Competence Network 100PY, respectively) (included all studies that provide the most comprehensive guidance to date, used cladribine tablets monotherapy, matching detailing individual treatments and suggested the recommended dose: CLARITY, CLARITY washout/safety interval times.31 This has been EXT and ORACLE-MS, plus follow-up in used as a basis for the development of the consen- PREMIERE).30 However, in an independent sus recommendations on switching to cladribine analysis of key MS clinical trials, there was no tablets as provided in Table 6 (Question 10), observed increased incidence of malignancy asso- which may act as a guide to support switching ciated with cladribine tablets, and the incidence decisions; however, individual patients may vary rate was similar to that reported for other and decisions should be made on the specific case. DMDs.30,33 Furthermore, the incidence of malig- nancies observed with cladribine tablets 3.5 mg/kg was almost identical to the expected rate of malig- Switching from cladribine tablets nancies from the GLOBOCAN matched refer- There are no Class 1 clinical trials specifically ence population (0.97, 95% CI 0.44–1.85).30 investigating a treatment switch from cladribine There was no increase in malignancies over time tablets to other DMDs. In patients treated with in patients treated with cladribine tablets, and no cladribine 3.5 mg/kg in CLARITY, approximately increase in the types of malignancies known to be 75% remained relapse-free when given placebo associated with severe immunosuppression (e.g. during CLARITY Extension.8 Indeed, in one non melanoma skin cancer, virally associated study, 4 years after the last dose of cladribine tab- tumours and haematological malignancies).30 lets 3.5 mg/kg, approximately 25% of patients had switched to another DMD.34 Across the clinical Consensus recommendations regarding the risk of development programme, 21.5% (124/576) of malignancy with cladribine tablets are provided in patients had a record of using another DMD Table 5 (Question 9b). Consensus was achieved post-treatment with cladribine tablets; the major- on all three recommendations around the risk of ity of these (56%) received treatment with inter- malignancy. Three EF members (10%) did not feron β-1a.34 10 journals.sagepub.com/home/tan PS Sørensen, D Centonze et al. Table 5. Pregnancy planning management and malignancy risk in patients being treated with cladribine tablets. Consensus recommendations Strength of Level of recommendation‡ consensus¶ Q9a. How should pregnancy planning be managed in patients on cladribine tablets? (Level of evidence: very low) Based on human experience with other substances inhibiting DNA synthesis, cladribine 8.5 (8.3) 96.9% tablets could cause congenital malformations when administered during pregnancy. (31/32) Studies in animals have shown reproductive toxicity. There is very limited pregnancy data from the clinical trial programme. Cladribine tablets are contraindicated and should not be administered during pregnancy. 9 (8.8) 100% Subsequent courses of cladribine tablets may be delayed during this time. (32/32) Breast-feeding is contraindicated during dosing with cladribine tablets and for 10 days 9 (8.5) 93.8% after the last dose. (30/32) Before initiation of treatment both in year 1 and year 2, women of childbearing potential 8 (8.4) 100% and males who could potentially father a child should be counselled regarding the potential (32/32) for risk to the foetus and the need for effective contraception for at least 6 months after the last dose of cladribine tablets.* Any unforeseen pregnancy within 6 months after the last dose of cladribine tablets is not 9 (8.5) 96.9% necessarily an indication for a termination of the pregnancy. Any further administrations of (31/32) cladribine tablets should, however, be discontinued immediately or delayed in this event. Patients should be counselled about potential risks to the foetus and referred to a high- risk pregnancy clinic. *It is currently unknown whether cladribine may reduce the effectiveness of systemically acting hormonal contraceptives. Therefore, women using systemically acting hormonal contraceptives should add a barrier method during cladribine treatment and for at least 4 weeks after the last dose in each treatment year.24 Q9b. Do cladribine tablets result in an increased risk of malignancy? (Level of evidence: moderate) Cladribine tablets may increase the risk of malignancies, as seen with other high-efficacy 8 (7.7) 86.7% DMDs. (26/30) • There was a higher incidence of malignancies in clinical studies and long-term follow up of patients treated with a cumulative dose of 3.5 mg/kg cladribine tablets compared with placebo*; however, when compared with a matched reference population, there was no evidence for an increased risk.** Clinicians should instruct patients to observe the standard guidelines for cancer 9 (8.5) 100% screening.*** (30/30) Cladribine tablets are contraindicated in patients with an active malignancy. 9 (8.2) 90.0% (27/30) *Included all studies that used cladribine tablets monotherapy, matching the recommended dose: CLARITY, CLARITY EXT and ORACLE-MS + follow-up in PREMIERE. **The rate of malignancies observed with cladribine tablets during the clinical development programme in MS was similar to the expected rate in the GLOBOCAN reference population [8.00 observed events in the monotherapy oral cohort versus 8.27 expected events, respectively; SIR: 0.97 (95% CI 0.44, 1.85)]. Non-melanoma skin cancer was excluded due to inconsistent reporting in GLOBOCAN. Data is adjusted for country of origin, age and gender.30 ***Physicians should direct patients to country-specific screening regimens, which may be found on cancer society or local health authority web sites. ‡median score on a 1–9 scale (mean score in brackets). ¶percentage of votes with 7–9 on a 9-point scale. CI, confidence interval; DMD, disease modifying drug; MS, multiple sclerosis; SIR, standardised incidence ratio. journals.sagepub.com/home/tan 11 Therapeutic Advances in Neurological Disorders 13 Table 6. Treatment switching to and from cladribine tablets and monitoring considerations. Consensus recommendations Strength of Level of recommendation‡ consensus¶ Q10. When switching to cladribine tablets, what are the washout periods/baseline requirements for different DMDs? Are there any specific treatment classes that preclude cladribine tablets as a next switch?* (Level of evidence: very low) Switch decisions should be made after a thorough risk/benefit analysis.19,29 9 (8.8) 100% (31/31) Due to a lack of clinical evidence for treatment switches in MS, caution should be taken in a patient who is 9 (8.1) 90% switching from a prior treatment due to adverse events that may also occur with cladribine tablets. (28/31) *Due to a lack of clinical evidence for treatment switches in MS, recommendations are based on individual treatment risks or carry-over risks. Glatiramer acetate/Interferon-beta 9 (8.7) 100% • Possible treatment effects on blood (e.g. lymphopenia, leukopenia, thrombopenia), and/or liver and (31/31) kidney parameters should have subsided • Recommended safety interval: none generally required Dimethyl fumarate 9 (8.4) 93.5% • Possible treatment effects on the differential blood count, should have subsided following the last dose (29/31) of dimethyl fumarate • Possible additional treatment effects on blood (e.g. severe lymphopenia), liver/kidney parameters should have subsided • Recommended safety interval: none generally required Teriflunomide 8 (7.9) 90.3% • Possible treatment effects on the immune system and liver values should have subsided (28/31) • Washout necessary – it must be documented that teriflunomide is no longer detectable in the blood • Recommended safety interval: normally around 4 weeks Fingolimod 8 (7.7) 80% • Possible treatment effects on the differential blood count, should have subsided following the last dose (25/31) of fingolimod. There should be no cytopenia. • Possible treatment effects on other blood parameters and liver values, as well as vital signs, should have subsided • Recommended safety interval: normally around 4 weeks Natalizumab 8 (7.8) 90.3% • Possible effects on the immune system (e.g. lymphocytosis, cytopenia) should have subsided (28/31) • PML should be excluded (e.g. MRI including FLAIR sequence immediately before start of treatment). A CSF examination including a JCV-PCR should be considered beforehand in patients with positive JCV antibody status and a treatment duration of >12 months) • Recommended safety interval: normally around 4–8 weeks Alemtuzumab 8 (8.3) 96.8% • Possible treatment effects on the immune system (e.g. cytopenia) should have subsided (lymphocyte (30/31) typing is optional e.g. T and B cells) • Clinical and laboratory monitoring (including platelets, creatinine, TSH and urine sediment) must be continued for 4 years following the last alemtuzumab infusion • Recommended safety interval: normally around 6–12 months Ocrelizumab 8 (8.0) 93.1% • Differential blood count must be ascertained before treatment initiation (lymphocyte typing is optional e.g. (27/29) • CD19+ B cells) • Any treatment effects on the immune system (e.g. cytopenia) should have subsided • Recommended safety interval: normally around 6–12 months Q11. How do you switch from cladribine tablets? What DMDs can patients use after cladribine tablets? If the patient’s lymphocyte counts have not recovered to LLN but a treatment switch is required, what is the recommended course of action? (Level of evidence: very low) (Continued) 12 journals.sagepub.com/home/tan PS Sørensen, D Centonze et al. Table 6. (Continued) Consensus recommendations Strength of Level of recommendation‡ consensus¶ Potential additive effects on the immune system should be considered when choosing subsequent DMDs 9 (8.5) 93.5% following treatment with cladribine tablets. (29/31) Treatment-specific effects on lymphocyte counts should have ideally subsided before switching from 8 (8.4) 100% cladribine tablets. (31/31) The waiting time is defined by the clinical need to switch. Cases of treatment non-response should be 9 (8.6) 100% decided on an individual risk/benefit analysis. (31/31) Caution is recommended in switching from cladribine tablets to natalizumab in any patient who is JCV 9 (8.4) 93.5% antibody positive. (29/31) ‡Median score on a 1–9 scale (mean score in brackets). ¶percentage of votes with 7–9 on a 9-point scale. CSF, cerebrospinal fluid; DMD, disease modifying drug; FLAIR, fluid-attenuated inversion recovery; JCV, John Cunningham virus; LLN, lower limit of normal; MRI, magnetic resonance imagining; MS, multiple sclerosis; PCR, polymerase chain reaction; PML, progressive multifocal leukoencephalopathy; TSH, thyroid stimulating hormone. There are very few data on the outcomes of involved (both SC and EF) and the breadth of patients who have switched from cladribine tab- geographical representation. Limitations include lets to other DMDs, coming only from real-world the lack of available class 1 evidence to support observations, therefore guidance on the manage- the development of many recommendations. ment of this switch is lacking. The PREMIERE long-term follow-up registry includes some The recommendations reflect status of knowl- patients that have been treated with other DMDs edge in 2019 and will be updated in a timely fash- following treatment with cladribine tablets ion when new evidence and/or novel data emerges. (n = 941).5 In a snapshot analysis before the study The consensus recommendations should provide end, the highest proportion of patients switched practical, specific advice to all health-care provid- to IFN β: 23.0%, followed by glatiramer acetate: ers (involved in the treatment and management of 9.7%.5 No specific pattern in the reported serious patients with MS, address gaps in existing guid- adverse events and no unexpected safety findings ance and ultimately improve care. were observed. Consensus recommendations for switching from Acknowledgements cladribine tablets to another DMD are provided Emma East of Vivid Medical Communications in Table 6 (Question 11). provided editorial assistance, funded by Merck KGaA, Darmstadt, Germany. The SC would like to thank all the experts who contributed their knowledge to this programme by completing the Conclusion questionnaire and voting on the draft recommen- The recommendations described here are the col- dations. Listed below are 29 EF members who lective opinions of an international group of MS are happy to be cited in this document: experts. The SC identified and prioritised a num- ber of essential questions concerning the practical Mohammed Al Jumah1, Thomas Berger2, Alexey use of cladribine tablets in real-life clinical situa- Boyko3, Helmut Butzkuven4, Marinella Clerico5, tions. Recommendations were drafted based on a Joao Correia de Sa6, Sara Eichau7, Juha-Pekka review of the literature and expert opinion and Erälinna8, Oscar Fernández9, Mark Freedman10, were voted on through a rigorous and transparent Claudio Gasperini11, Joachim Havla12, Eva process. Havrdová13, Dana Horáková14, Gunnar Juliusson15, Juerg Kesselring16, Natalia Khachanova17, Joanna The strengths of the recommendations provided Kitley18, Myhr Kjell-Morten19, Marcello Moccia20, here are the result of the large number of experts Ester Moral21, Thomas Mueller22, Jiwon Oh23, journals.sagepub.com/home/tan 13 Therapeutic Advances in Neurological Disorders 13 David Paling24, Tobias Ruck25, Johann Sellner26, 15Department of Hematolog, Skåne University Aksel Siva27, Natalia Totolyan28, Tjalf Ziemssen29. Hospital, Lund University, Lund, Sweden 1National Neuroscience Institute, King Fahad 16Department of Neurology & Neurorehabilitation, Medical City (KFMC), Riyadh, Kingdom of Kliniken Valens, Taminaplatz 1, CH-7317 Saudi Arabia Valens, Switzerland 2Department of Neurology, Medical University 17RussianNational Research Medical University, of Vienna, Waehringer Guertel 18-20, 1090 Department of Neurology, Neurosurgery and Vienna, Austria Medical Genetics, Moscow, Russia 3Department of Neurology, Neurosurgery & 18Wessex Neurological Centre, Southampton Medical Genetics of the Pirogov Russian National General Hospital, Southampton, SO16 6YD, Research Medical University (RNRMU), UK Department of Neuroimmunology of the Federal 19Department of Neurology, Haukeland Center of Cerebrovascular Pathology and Stroke, University Hospital, and the Department of Moscow, Russia Clinical Medicine, University of Bergen, Bergen, 4MS and Neuroimmunology Unit, Department Norway of Neuroscience, Alfred Centre, Monash 20Department of Neurosciences, Federico II University, Melbourne, Australia University of Naples, Italy 5Department of Clinical and Biological Sciences, 21Department of Neurology, Hospital de Sant University of Torino, Torino, Italy Joan Despí Moises Broggi, Sant Joan Despí, Spain 6CHLN Hospital de Santa Maria, Faculdade 22Department of Neurology, St. Joseph Hospital Medicina, Lisboa, Portugal Berlin-Weißensee, Gartenstr. 1, 13088 Berlin, 7MultipleSclerosis Unit (UEMAC), Virgen Germany Macarena Hospital, Seville, Spain 23St. Michael’s Hospital, Keenan Research 8Universityof Helsinki, Finland and University of Centre of the Li Ka Shing Knowledge Institute, Turku, Finland Division of Neurology, University of Toronto, 9Instituto Canada de Investigación Biomédica de Málaga (IBIMA), Hospital Regional Universitario de 24Royal Hallamshire Hospital, Sheffield and Málaga, Málaga 29010, Spain NIHR Sheffield Biomedical Research Centre 10Multiple (BRC), University of Sheffield, Sheffield, UK Sclerosis Research Unit, Professor of Neurology, Division of Neurology, Department 25Department of Neurology with Institute of of Medicine, The Ottawa Hospital, Canada Translational Neurology, University Hospital 11Department Muenster, Albert-Schweitzer-Campus 1, 48149 of Neuroscience, San Camillo Muenster, Germany Forlanini Hospital, 00152 Rome, Italy 26Neurology and Multiple Sclerosis Center, 12Institute of Clinical Neuroimmunology, Landeskrankenhaus Mistelbach-Gänserndorf, Ludwig-Maximilians University, Marchioninistr. Liechtensteinstr. 67, 3120 Mistelbach, Austria 15, 81377, Munich, Germany 27IstanbulUniversity Cerrahpaşa School of 13Department of Neurology and Center of Medicine, Department of Neurology, Clinical Clinical Neuroscience, First Faculty of Medicine Neuroimmunology Unit and MS Clinic, Istanbul, Charles University and General University Turkey Hospital, Katerinska 30, Prague 2, 12000, Czech Republic 281st Saint Petersburg Pavlov State Medical 14Department University, Neurology Department, 6-8 Lva of Neurology and Center of Tolstogo Street, St Petersburg, 197022, Russia Clinical Neuroscience, First Faculty of Medicine Charles University and General University 29Center of Clinical Neuroscience, University Hospital, Katerinska 30, Prague 2, 12000, Czech Hospital Carl Gustav Carus, Dresden University Republic of Technology, Germany 14 journals.sagepub.com/home/tan PS Sørensen, D Centonze et al. Conflict of interest statement KGaA, Celgene, Roche, MedDay and Almirall; PSS has served on advisory boards for Biogen, and research support from Biogen, Sanofi- Merck Healthcare KGaA, Novartis, Teva, Genzyme, Bayer and Merck KGaA. MedDay Pharmaceuticals and GSK; on steering HW is a member of Scientific Advisory Boards/ committees or independent data monitoring Steering Committees for Bayer Healthcare, Biogen boards in trials sponsored by Merck Healthcare Idec, Sanofi Genzyme, Merck Serono, Novartis, KGaA, Teva, GSK and Novartis; has received Roche and Teva. He received speaker honoraria speaker honoraria from Biogen Idec, Merck and travel support from Bayer Vital GmbH, Bayer Healthcare KGaA, Teva, Sanofi-Aventis, Schering AG, Biogen, CSL Behring, EMD Serono, Genzyme, Celgene and Novartis. His department Fresenius Medical Care, Genzyme, Merck Serono, has received research support from Biogen, Omniamed, Novartis, and Sanofi Aventis and Merck Healthcare KGaA, Teva, Novartis, Roche Teva. He received compensation as a consultant and Genzyme. from Biogen Idec, Merck Serono, Novartis, DC is an Advisory Board member of Almirall, Omniamed, Roche and Sanofi Genzyme. He has Bayer Schering, Biogen, GW Pharmaceuticals, received research supports from Bayer Healthcare, Merck Serono, Novartis, Roche, Sanofi-Genzyme Bayer Vital, Biogen Idec, Merck Serono, Novartis, and Teva and received honoraria for speaking or Sanofi Genzyme, Sanofi US, and Teva Pharma as consultation fees from Almirall, Bayer Schering, well as German Ministry for Education and Biogen, GW Pharmaceuticals, Merck Serono, Research (BMBF), German Research Foundation Novartis, Roche, Sanofi-Genzyme and Teva. He (DFG), Else Kröner Fresenius Foundation, is also the principal investigator in clinical trials Fresenius Foundation, Hertie Foundation, Merck for Bayer Schering, Biogen, Merck Serono, Serono, Novartis, NRW Ministry of Education Mitsubishi, Novartis, Roche, Sanofi-Genzyme and Research, Interdisciplinary Center for Clinical and Teva. His preclinical and clinical research Studies (ISKF) Muenster and RE Children’s was supported by grants from Bayer Schering, Foundation. Biogen Idec, Celgene, Merck Serono, Novartis, BY has received honoraria for lectures and advi- Roche, Sanofi-Genzyme and Teva. sory boards from Bayer, Biogen, Genpharm, GG has received speaker honoraria and consult- Genzyme, Merck-Serono and Novartis; and has ing fees from Abbvie, Actelion, Atara Bio, received research grants from Bayer, Biogen, Almirall, Bayer Schering Pharma, Biogen Idec, Merck-Serono, Novartis and Pfizer. FivePrime, GlaxoSmithKline, GW Pharma, HS is an employee of Ares Trading S.A., and affil- Merck & Co., Merck Healthcare KGaA, Pfizer iate of Merck Serono S.A., Eysins, Switzerland. Inc, Protein Discovery Laboratories, Teva Pharmaceutical Industries Ltd, Sanofi-Genzyme, PR has received honoraria for lectures/steering UCB, Vertex Pharmaceuticals, Ironwood and committee meetings from Merck, Biogen Idec, Novartis; and has received research support unre- Bayer Schering Pharma, Boehringer-Ingelheim, lated to this study from Biogen Idec, Merck & Sanofi-Aventis, Genzyme, Novartis, Teva Pharmaceutical Industries, and Serono Symposia Co., Novartis and Ironwood. International Foundation. XM has received speaking honoraria and travel expenses for participation in scientific meetings, Funding has been a steering committee member of clinical The authors disclosed receipt of the following trials or participated in advisory boards of clinical financial support for the research, authorship, trials in the past years with Actelion, Bayer, and/or publication of this article: This work was Biogen, Celgene, Genzyme, Merck, Novartis, supported by Merck KGaA, Darmstadt, Germany Roche, Sanofi-Genzyme, Teva Pharmaceutical, who provided funding for the project. The SC Excemed, MSIF and NMSS members received financial compensation for attendance at two advisory board meetings as part DS has received grants and/or personal fees from of this programme. No payments were made to Teva, Merck Serono, Novartis, Roche, Genzyme, the authors for the writing of this manuscript. Sanofi-Genzyme, Biogen Inc. and Bayer HealthCare. The Extended Faculty received no financial com- PV has received honoraria or consulting fees from pensation for the completion of the on-line ques- Biogen, Sanofi-Genzyme, Servier, Novartis, Merck tionnaire, or the consensus voting. journals.sagepub.com/home/tan 15 Therapeutic Advances in Neurological Disorders 13 ORCID iD in the use of conventional therapy in Crohn’s Diego Centonze https://orcid.org/0000-0002- disease: results from an international survey and 8390-8545 discussion programme. J Crohns Colitis 2012; 6: 116–131. 13. Mrowietz U, de Jong EM, Kragballe K, et al. A consensus report on appropriate treatment optimization and transitioning in the management References of moderate-to-severe plaque psoriasis. J Eur 1. Cree BAC, Mares J and Hartung HP. Current Acad Dermatol Venereol 2014; 28: 438–453. therapeutic landscape in multiple sclerosis: an evolving treatment paradigm. Curr Opin Neurol 14. Papay P, Ignjatovic A, Karmiris K, et al. 2019; 32: 365–377. 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