Rethinking the Role of Relapse in Multiple Sclerosis

Sunday, March 17, at the 65th American Academy of Neurology Annual Meeting, speakers at the “Criteria for Stopping and Starting Multiple Sclerosis Therapy” seminar tackled the thorny issue of when to start (and stop) disease-modifying therapy (DMT) in relapsing-remitting multiple sclerosis (RRMS). Helen Tremlett, PHD, BPharm, from the University of British Columbia Hospital MS Clinic, Vancouver, re-examined the conventional wisdom that relapses are crucial to the course of multiple sclerosis (MS) disease progression and are responsible for disability in MS. Tremlett argued that such concepts are largely based on results of short-term, controlled clinical trials, published in dated literature, on highly selected MS study subjects with no significant comorbidities. She said that data from such studies do not adequately reflect “real world” clinical practice involving long-term treatment of more diverse patients. The patient’s age at onset influences disease progression, with younger patients (<25 years) appearing to respond to treatment better than older patients (>35 years). Furthermore, Tremlett said relapse rates in untreated patients decrease over time, by an average of 17% every five years, and three quarters of untreated RRMS patients experience a five-year relapse-free period.

Tremlett and her colleagues have analyzed a large body of clinical data from the British Columbia Multiple Sclerosis database, which captures some 80% of the British Columbia MS population. The BC study compared three cohorts, each containing about 900 patients with confirmed RRMS. One cohort comprised patients treated with interferon beta, a second cohort served as an untreated contemporary control group, and the third was a historical control group of patients diagnosed with MS before the advent of interferon beta therapy and not treated subsequently with this drug. The main study outcome was the time from interferon beta eligibility (baseline) to a confirmed and sustained Expanded Disability Status Scale (EDSS) score of 6 (EDSS range 1-10; a higher score indicating higher disability). Median follow-up times were approximately five years for the interferon-treated cohort, four years for the contemporary control group, and 11 years for the historical controls.

The statistical model developed by the Vancouver-based team took into account “immortal time bias” by treating exposure as a time-dependent variable, and included adjustments for baseline covariates such as sex, age, disease duration, and EDSS score. There were no statistically significant differences for interferon beta treatment and disability progression in RRMS compared with either the contemporary or the historical control cohorts. The findings suggested that relapses are not responsible for long-term disability in all patients receiving interferon beta therapy but both age and timing of treatment initiation play a role. There may be more responsive subgroups. Tremlett said that their findings were consistent with other adequately controlled (clinical trial-related) longitudinal studies (with up to 16 years follow-up).

In response to a question from the audience about the problem of predicting the location and severity of relapses in individual patients, Tremlett indicated that the decision on when or whether to start DMT was complex and that the study she presented could not answer all the questions.