Long-Term DMT Exposure Prevents Disability in Multiple Sclerosis

Tomas Kalincik, MD, PhD

Study findings from an analysis of data from more than 14,000 patients with multiple sclerosis (MS) included in the MSBase registry offer class IV evidence that long-term exposure to immunotherapy prevents the development of neurological disability.

Ultimately, the data showed that continued treatment with immunotherapy reduced disability accrual by a range of 19% to 44% (95% CI, 1–62) and the risk of the need for walking aid by 67% (95% CI, 41–81). Additionally, those treated with immunotherapy experienced a reduction in the frequency of relapses ranging from 40% to 41% (95% CI, 18–57) over a 15-year period.

The authors, including Tomas Kalincik, MD, PhD, head, Clinical Outcomes Research (CORe) Unit, University of Melbourne, and head, Multiple Sclerosis and Neuroimmunology Service, Royal Melbourne Hospital, published their findings in the journal Neurology. They noted that despite the need for evidence of immunomodulation’s impact on MS-related disability, “conclusive evidence is still lacking, and it is unlikely that it will arise from randomized trials.” These data, they wrote, offer proof that disease-modifying therapies (DMTs) are effective in improving these outcomes in relapsing MS.

The data analyzed included disability outcomes for 14,717 individuals from MSBase who had follow-up for ≥1 year, with ≥3 visits, ≥1 visit per year, and exposed to MS therapy, as well as a subset of patients with ≥15-year follow-up (n = 1085). Kalincik and colleagues compared patients to untreated pseudo-cohorts. “Naturally, it is not possible to directly observe the outcomes of two mutually exclusive treatment decisions in a single cohort; therefore, we have utilized a counterfactual framework which uses a well-defined statistical methodology,” they wrote.

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The most represented therapies were interferon beta and glatiramer acetate (59% of follow-up time), followed by natalizumab (Tysabri, Biogen; 5%) and fingolimod (Gilenya, Novartis; 4%). Those with ≥15 years of follow-up were exposed to immunotherapies for 63% of the time (median follow-up, 17 years). “The time on higher-efficacy therapies was relatively less represented in this cohort compared to the full cohort, as natalizumab and fingolimod have only become available in 2006 and 2011, respectively,” Kalincik et al noted.

Among 1085 patients with ≥15-year follow-up, the treated patients were less likely to experience relapses (hazard ratio [HR], 0.59; 95% CI, 0.50–0.70; P = 10-9) and worsening of disability (HR, 0.81; 95% CI, 0.67–0.99; P = .043). The probability of disability improvement did not differ between the treated and the untreated pseudo-cohorts (HR, 0.91; 95% CI, 0.69–1.2, P = .54).

Overall, treated patients were less likely to experience relapses (HR, 0.60; 95% CI, 0.43–0.82; P = .0016), worsening of disability (HR, 0.56; 95% CI, 0.38–0.82; P = .0026) and progress to Expanded Disability Status Scale (EDSS) step 6 (HR, 0.33; 95% CI, 0.19–0.59; P = .00019).

“The results of our study are supported by a study of 5610 patients enrolled in the UK Risk Sharing Scheme, which showed, using Markov and multilevel continuous models, that treatment with interferon β or glatiramer acetate was associated with a 24% decrease in disability accrual over up to 6 years,” Kalincik and colleagues wrote, noting that another MSBase study of 2466 patients with MS also suggested that continuous exposure to interferon β or glatiramer acetate over 10 years was linked with slowed disability accrual.

This current work also explored the likelihood of relapse when the time variable in the full study cohort was defined as the time from the first symptom, finding that the treated cohort had a lower annualized relapse rate (ARR) than the untreated pseudo-cohort (0.32 vs. 0.47, respectively; HR, 0.54; 95% CI, 0.45–0.65; P = 10-10) and less likelihood of disability accumulation events (HR, 0.69; 95% CI, 0.55–0.85; P = .0007). There was no difference between the pseudo-cohorts in disability improvement (HR, 1.20; 95% CI, 0.96–1.50; P = .1).

Similarly, when assessed by patient age, the treated cohort experienced a lower ARR (0.32 vs. 0.46; HR, 0.53; 95% CI, 0.43–0.65; P = 10-9) and disability accumulation events (HR, 0.68; 95% CI, 0.55–0.85; P = .0006). The probability of disability improvement did not differ between the compared pseudo-cohorts (HR, 1.20; 95% CI, 0.95–1.50; P = .13).

“In early MS, accelerated recovery from previously accrued disability can be observed early after commencing immunotherapy,” Kalincik and colleagues wrote. “Therefore, sustained, long-term immunotherapy from [the] early stages of MS is advisable as a strategy to preserve patients’ neurological capacity over the long-term.”

REFERENCE
Kalincik T, Diouf I, Sharmin S, et al. Effect of disease-modifying therapy on disability in relapsing-remitting multiple sclerosis over 15 years. Neurology. First published December 28, 2020. doi: 10.1212/WNL.0000000000011242