Worsening of disability caused by relapses in multiple sclerosis: A different approach

Background: In multiple sclerosis (MS) the quantitative role of relapses in Expanded Disability Status Scale (EDSS) worsening beyond the recovery phase is not well known. Most studies have examined the predictive role of early relapses in more distant endpoints. Relapses and worsening may be associated because they could be independent effects of the same underlying disease characteristics without causal relationship. With the design of the present study we aim to estimate the direct effect on disability of relapses. Methods: We used data from the obligatory bi-annually registration in the Danish Multiple Sclerosis Registry of relapses and EDSS for all patients treated with disease modifying drugs for relapsing/remitting MS from 1996 to 2015 with exclusion of patients in whom no relapses had ever been recorded during treatment. We paired two consecutive control periods into study intervals which were the actual study units. Study intervals were qualified and included if they were at length 12-24 months, with EDSS <= 5.5 at start, and if a preceding relapse had been no closer than nine months to the EDSS assessment at the start or end of the study interval to eliminate relapse-related temporary EDSS worsening. We compared EDSS worsening in study intervals with and without relapses. The same patients could contribute with study intervals with and without relapses. For statistical analyses we used Generalized Estimating Equations to account for intra-patient correlations. Results: We analysed 5187 study intervals from 2015 MS patients. The mean of EDSS increase was 0.205 units in qualifying study intervals with relapses and 0.065 without relapses when adjusted for length of study interval, sex, and EDSS at start of interval; p < 0.0001. However, the effect of relapses on EDSS was absent in male patients (p = 0.521), and when EDSS was >= 4.0 at start of the study interval (p = 0.726). Conclusion: Relapses play an independent and significant role for worsening of MS in patients under disease-modifying therapy (DMT) and eliminating relapses would not only free the patients from the temporary perils of relapses but would also reduce the worsening of the disease.