Long-term management of multiple sclerosis patients treated with cladribine tablets beyond year 4

Introduction Oral cladribine is a highly effective pulsed selective immune reconstitution therapy licensed for relapsing multiple sclerosis (RMS) since 2017. A full treatment course comprises two treatment cycles given 1 year apart, followed by two treatment-free years. The management of cladribine-treated patients beyond year 4 needs to be addressed as patients have now passed the initial 4 years since European Medical Agency approval. Areas covered A panel of neurologists and a neuroradiologist experienced in MS treatment/monitoring evaluated clinical trial data and real-world evidence and proposed recommendations for the management of cladribine-treated patients beyond year 4. Expert opinion Continuous monitoring of disease activity during the treatment-free period is important. Subsequent management depends on the presence or absence of inflammatory disease activity, determined in the absence of consistent guidelines via practice-driven neurological decision criteria. Persisting or newly occurring inflammatory disease activity is an indication for further treatment, i.e. either re-initiation of cladribine or switching to another highly effective disease-modifying therapy. The decision to retreat or switch should be based on clinical and radiological evaluation considering disease course, treatment history, and safety aspects. In the absence of disease activity, either retreatment can be offered, or the treatment-free period can be extended under structured monitoring

Multiple Sklerose Therapie Konsensus Gruppe (MSTKG): Positionspapier zur verlaufsmodifizierenden Therapie der Multiplen Sklerose 2021 (White Paper)

Multiple sclerosis is a complex, autoimmune-mediated disease of the central nervous system characterized by inflammatory demyelination and axonal/neuronal damage. The approval of various disease-modifying therapies and our increased understanding of disease mechanisms and evolution in recent years have significantly changed the prognosis and course of the disease. This update of the Multiple Sclerosis Therapy Consensus Group treatment recommendation focuses on the most important recommendations for disease-modifying therapies of multiple sclerosis in 2021. Our recommendations are based on current scientific evidence and apply to those medications approved in wide parts of Europe, particularly German-speaking countries (Germany, Austria, Switzerland)

Teriflunomide in relapsing-remitting multiple sclerosis: outcomes by age and pre-treatment status.

Background and aims To investigate effectiveness and safety of teriflunomide (14 mg once daily) in association with age and pre-treatment in unselected MS patients. Methods Prespecified analysis of a non-interventional, prospective, real-world study in Germany. Results A total of 558 (49.5%) patients were above 45 years old, and 593 patients (52.6%) had been pre-treated within 6 months prior to teriflunomide. Baseline Expanded Disability Status Scale (EDSS) was higher with older age, with lower number of relapses. Relapse rate decreased in all age groups, and in both treatment-naïve (0.82 ± 0.73 at baseline; 0.25 ± 0.55 under teriflunomide) and pre-treated (from 0.48 ± 0.76; 0.22 ± 0.50) patients after 12 months compared with the year before teriflunomide initiation. EDSS remained stable in patients of all age groups as well as in therapy-naïve and pre-treated patients over 24 months. The percentage of patients with adverse events (AEs) ranged between 29.2% (age group >25-35) and 38.9% (age group >55-65), with an increased discontinuation rate (most commonly due to diarrhoea, alopecia and nausea) in the higher age groups. AE rates were lower in pre-treated compared with treatment-naïve patients. Conclusion Overall, patients of all age groups including older patients, and irrespective of pre-treatment, benefit from teriflunomide treatment in routine clinical practice. Registration BfArM public study database number 2075

An epidemiological study on the course of disease and therapeutic considerations in relapsing–remitting multiple sclerosis patients receiving injectable first-line disease-modifying therapies in Germany (EPIDEM)

Background: In relapsing–remitting multiple sclerosis (RRMS), ‘no evidence of disease activity’ (NEDA) is regarded as a key treatment goal. The increasing number of treatments allows for individualized treatment optimization in patients with suboptimal response to first-line disease-modifying therapies (DMTs). Therefore, monitoring of clinical and subclinical disease activity on DMTs has been recognized as an important component of long-term patient management. Methods: EPIDEM was a multicenter non-interventional retrospective study in a large cohort of RRMS patients receiving injectable DMTs for at least 2 years in outpatient centers throughout Germany. It documented measures and ratings of disease activity on DMTs to characterize the factors that made the treating neurologists consider to switch therapy towards potentially more effective or better-tolerated drugs. Results: The cohort included predominantly female patients with a mean age of 45 years and a mean disease duration of 9.6 years, who had been continuously treated with an injectable DMT for a median duration of 54 months. Overall, 34.0% of the patients had experienced ⩾1 relapse on any DMT in the previous 2 years; 21.0% exhibited magnetic resonance imaging (MRI) activity, and the Kurtzke Expanded Disability Status Scale (EDSS) score increased by at least 0.5 points in 20.1%. Overall, 50.3% of the patients with EDSS progression and 70.6% of the patients with relapses were assessed as clinically stable by the neurologists. A change of treatment was considered in a fraction of patients with disease activity: in 22.8% of those with relapse activity, in 37.8% of those with MRI activity and in 20.1% of those with EDSS progression. Conclusion: The results of EPIDEM underline the importance of standardized evaluation and documentation of ongoing disease activity and disability deterioration. Judged from the present data, the current paradigm of low tolerance for disease activity and recommendations for early treatment optimization have not been turned fully into action as yet. More widespread implementation of current guideline recommendations may allow patients to more benefit from the growing panel of effective treatment options

REBISTART: Adherence of Patients with Multiple Sclerosis to Treatment with Subcutaneous Interferon Beta in the Context of a Patient Support Program.

INTRODUCTION Treatment adherence is a critical success factor in the disease-modifying therapy (DMT) of multiple sclerosis (MS). The REBISTART study prospectively evaluated adherence in patients using components of a patient support program (PSP). METHODS The 12-month non-interventional multicenter study examined the real-world adherence to subcutaneously (sc) injected interferon beta-1a (Rebif®). Patient-assessed adherence was measured by a visual analog scale (VAS) and the Morisky Medication Adherence Scale (MMAS). Objective adherence data were obtained by readouts from the RebiSmart® injection device. RESULTS Of 333 patients, 70.9% used the nursing service as the core component of the PSP. Self-assessed VAS-based adherence was stable over time at 94.0-96.3%. Similarly, MMAS score (maximum 4) was 3.8-3.9 at all visits, also reflecting high self-assessed adherence. In 269 patients using the RebiSmart® injection device, mean readout-based objective adherence was similarly high (93.0-98.4% throughout visits). At last available visit, VAS-based adherence was independent of participation in the PSP nursing service (93.1% with participation versus 91.7% without it). Adherence was also independent of injection method or disease-related measures, including fatigue, depression, cognition, and quality of life. The most frequent reason for the premature discontinuations (38.7% of patients) was "change of treatment" (10.0%). DISCUSSION We suggest that subgroups that may specifically benefit from PSP include patients who live alone, use multiple comedications, and are affected by cognitive impairment, depression, and/or fatigue. Further studies should investigate the potential usefulness of PSPs in these populations. CONCLUSIONS Very high adherence rates independent of the PSP nursing service over 1 year of treatment indicate that IFN beta-1a sc is an easy-to-use and well-tolerated disease-modifying drug. TRIAL REGISTRATION NUMBER Vfa.de: No. 892. https://www.vfa.de/de/arzneimittel-forschung/datenbanken-zu-arzneimitteln/nisdb/nis-details/_892

Real-life outcomes of teriflunomide treatment in patients with relapsing multiple sclerosis: TAURUS-MS observational study

Background: Teriflunomide is a once-daily oral immunomodulatory agent approved for the treatment of relapsing–remitting multiple sclerosis (MS). We aimed to obtain data on the effectiveness, tolerability, and subject satisfaction with teriflunomide (Aubagio®) under clinical practice conditions in unselected MS patients. Methods: This work was a non-interventional, prospective, longitudinal, observational study in 307 sites in Germany. Results: A total of 1128 patients were eligible for the efficacy analysis [67.5% female; mean age (± standard deviation) 44.9 ± 9.7 years, range 20–73 years]. Time since first MS symptoms was 10.6 ± 8.2 years, and time since MS diagnosis was 8.9 ± 7.6 years. Expanded Disability Status Scale (EDSS) score at inclusion was 2.3 ± 1.5 (70.4% with score < 3.5). The mean observation period was 16.3 ± 9.1 months. A total of 75.2% had received previous disease-modifying therapies (DMTs) at any time. Of these patients, 504 (44.7%) received no DMT within 6 months of study entry, 593 patients (52.6%) had DMT discontinued prior to study entry [glatiramer acetate in 10.6%, subcutaneous interferon-beta 1a (IFNβ-1a) in 9.3%, intramuscular IFNβ-1a or IFNβ-1b in 6.6% each, azathioprine oral in 0.4%, other in 7.3%, last medication not known in 12.0%]. The mean annualized relapse rate decreased from 0.87 in the 24 months prior to study entry to 0.35 in the 24 months after study entry ( n = 468; p ⩽ 0.001). EDSS and Fatigue Severity Scale remained stable. In patients who received previous MS treatments, Treatment Satisfaction Questionnaire (TSQM-9) values (maximum = 100), for the observation at 24 months improved by 8.1 points for effectiveness, 17.0 points for convenience, and 15.3 points for global satisfaction ( p ⩽ 0.001 each, compared with study entry). In the safety cohort ( n = 1139), the proportion of patients with adverse events (AEs) of any severity was 35.8%, and with serious events 13.0%. The most frequently reported AEs were diarrhea ( n = 55), followed by MS relapse ( n = 48), hair thinning ( n = 38), and viral upper respiratory tract infection ( n = 31). Conclusions: Relapse rate was halved during the observation period in comparison with the same time period before study entry. Patient satisfaction with teriflunomide was high in this real-world observation of patients, the majority of whom switched from other DMTs. The safety and tolerability profile of teriflunomide was similar to that reported in previous clinical trials

Towards the implementation of ‘no evidence of disease activity’ in multiple sclerosis treatment: the multiple sclerosis decision model

Objective: The introduction of new and potent therapies for the treatment of relapsing remitting multiple sclerosis (MS) has increased the desire for therapeutic success. There is growing doubt that the mere reduction of relapse rate, Expanded Disability Status Scale (EDSS) progression and magnetic resonance imaging (MRI) markers are exclusive and appropriate factors to monitor the new aim of ‘no evidence of disease activity’ (NEDA). However, there is no generally accepted definition so far. Methods: To achieve the therapeutic aim of NEDA, a panel of MS experts searched the available literature on clinical and paraclinical outcomes to propose a test battery that is sensitive to detect disease activity in an everyday clinical setting. Results: The panel proposed to include, besides relapse rate, disability progression and MRI, neuropsychological outcome measures such as cognitive status, fatigue, depression and quality of life. To standardize the examinations in an economic and schematic way, a multifactorial model [multiple sclerosis decision model (MSDM)] that includes the domains ‘relapse’, ‘disability progression’, ‘MRI’, and ‘neuropsychology’ is proposed. The scheme reflects the complexity of the disease even in the early stages when scales such as the EDSS are not able to distinguish low levels of progression. Conclusion: The MSDM aims to support early treatment decisions and uncover timely treatment failure. Prospective investigations are required to prove that such a disease-monitoring concept leads to an early and effective silencing of disease activity

Long-term management of multiple sclerosis patients treated with cladribine tablets: an expert opinion

Introduction Oral cladribine is a highly effective pulsed selective immune reconstitution therapy licensed for relapsing multiple sclerosis. A full treatment course comprises two treatment cycles given with 1 year of intermission. Further dosing is not routinely recommended in years 3 and 4. Areas covered The long-term management of patients treated with oral cladribine has not been fully defined on the basis of clinical studies as of yet. The authors provide their expert opinion on this. Expert opinion Based on available evidence and experience from routine clinical use, the authors suggest a structured approach to the long-term management of patients treated with cladribine tablets according to their responder type, i. e. the degree and timing of disease activity, if any, after treatment initiation. Informed treatment decisions require structured patient monitoring by established clinical and imaging parameters. In patients with relevant disease activity in year 3 or 4 and beyond, the use of additional cycle(s) of oral cladribine might become an option. For patients requiring a treatment switch, the choice of therapies primarily includes moderately to highly effective MS drugs