Current recommendations and guidelines for use of disease modifying drugs (DMDs) in relapsing-remitting multiple sclerosis refer to interferon β (IFNβ) and glatiramer acetate as injectables as well as the new orals teriflunomide, dimethyl fumarate (DMF) and also fingolimod, natalizumab and alemtuzumab. Several pivotal studies have demonstrated a short-term benefit for earlier treatment with DMDs on clinical and MRI activity but there are only limited data available from controlled studies on long-term clinical outcome including sustained accumulation of disability and conversion to secondary progression. Therapeutic decision-making in clinical practice is at risk to be influenced by patients’ needs for high tolerability and convenience of DMDs. Recently, reports on unexpected side effects of the new orals including single case reports of progressive multifocal leucoencephalopathy under therapy with DMF and also fingolimod have caused more uncertainty. Guidelines and also expert opinions suggest a need for switch of treatment including escalation to more active medications if disease activity is persistent, although criteria for non-responders have not yet been conclusively defined. In this situation, the benefit of long-term treatment with one single therapy is frequently lost and patients are passing through multiple medications often only for a short duration.
However, there are data published from extension studies with IFNβ-1b, IFNβ-1a, applied intramuscularly or subcutaneously and also for glatiramer acetate,1–3 which suggest a long-term benefit of sustained treatment.
In their JNNP paper Kappos et al,4 report results from an exploratory analysis on the long-term clinical outcome of patients from the original PRISMS (Prevention of Relapses and disability by Interferon beta-1a Subcutaneously in Multiple Sclerosis) study5 15 years after initial randomisation (PRISMS-15). In the PRISMS study, the efficacy of subcutaneous IFNβ-1a three times weekly, 22 µg or 44 µg, was tested clinically including relapse rate and MRI parameters over 2 years versus placebo. Patients were rerandomised after 2 years to active treatment and studied for a further 4 years in a blinded study. This was continued by follow-up visits for another 1–2 years. Separate results from this exploratory analysis after 7–8 years were published earlier by Uitdehaag et al.3
In this 15-year analysis, collecting 291 of the 560 originally randomised patients with PRISMS, the progression of expanded disability status scale (EDSS) during the first 24 months was a strong predictor of clinical outcome. Patients were, as in the former analysis, compared according to the minimum and maximum cumulative dose exposure (both with respect to period and frequency of dosing). This resulted in a better outcome for patients treated with higher cumulative dose exposures.
These results are in favour of adherence to a long-term treatment with DMDs including IFNβ-1a and are in line with similar post-hoc analyses from extension studies of placebo-controlled DMD studies. However, as the authors clearly state, there are cautions to be considered in the context of the study limitations. This is mainly due to the possible preselection of patients with a more severe disease course in the group with minimum cumulative dose exposure who are likely to switch to other DMDs more frequently.
In summary, however, this study adds to the results from earlier analysis of PRISMS extension studies with shorter follow-up periods and confirms similar analysis from other DMDs. It should prompt MS specialists to encourage patients to continue with IFNβ-1a (or glatiramer acetate) treatment more resolutely instead of frequently switching their therapeutic regime.
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