With the increasing number of DMTs developed in these last 10 years, and the lack of head-to-head randomized controlled trials to assess their comparative efficacy, data of robust observational studies are needed to support decision making by stakeholders and to assist clinicians in choosing the most favorable treatment option for their patients. This nationwide population-based observational study conducted to assess the DMTs effectiveness in a population of DMTs initiators on MS activity using robust hdPS-based methods found that the DMF treatment proved to be associated with better results than TERI and IMM regarding relapse activity, without significant difference on disability progression.
At treatment initiation, DMF patients’ characteristics were very similar to those of TERI and IMM patients: their age was 40 years on average, they were mostly female and had an annual rate of relapses of 0.13 during the pre-index period. These findings are consistent with those of other studies 4,6–8,22,23. Conversely, some baseline characteristics differed between DMF and FTY patients, although their age at treatment initiation was very similar. This suggests that FTY patients had a specific distinct profile at treatment initiation; fewer FTY patients had a complete medical monitoring before treatment initiation (i.e. medical visits to general practitioner or neurologist, lab tests related to MS or encephalic or spinal cord MRI), their pre-index ARR was slightly higher (0.17), and more patients already had a MS-related disability. These results are expected considering FTY specific indications of rapidly evolving severe RRMS 24.
In this study, DMF showed a higher clinical effectiveness than TERI or IMM with lower relapses rates. Results are consistently significant using various robust statistical methods, whether using hdPS matching which focused on patients with very similar clinical profiles or hdPS adjustment and IPTW, which considers the overall patients with more heterogeneous profiles. These consistent results through multiple methods and overlapping of hdPS between groups are suggestive of balanced groups. In addition, these results obtained in a large population during a long period of follow-up, confirm trends of most of previous real-world observational studies conducted on shorter time periods 4,6–8,22,23. Compared to FTY, DMF displayed a slightly higher rate of relapses, though the RR did not differ significantly. The partial overlap of the hdPS distribution between both groups confirms that FTY and DMF patients have a very distinct profile and are therefore difficult to compare. Indeed, only about one-fourth of DMF patients remained after matching. These patients shared the same characteristics to FTY patients and referred certainly to patients with high disease activity since FTY is the only DMT labelled specifically for the treatment of such patients. In this specific situation, the effectiveness remained similar between both groups.
In this study, the MS disability progression was found to be similar between DMF and TERI, IMM or FTY. These findings are difficult to compare to the literature, since the most popular and widely used instrument to assess disease progression is the Expanded Disability Status Scale (EDSS) score 25, which includes clinical information not available in the SNDS. Nevertheless, reimbursements for motor or sphincter medical devices or for neuromodulation device are a reliable indicator to estimate MS disability progression, although, in contrast with the EDSS, it does not include mild disabilities without medical device and visual or cognitive impairments. Globally, disability was probably underestimated, but all severe cases requiring medical devices have been identified with accuracy.
One of the main limitations of this study is that the SNDS is a database built for administrative and reimbursement purposes, not for research purposes and important data are lacking: clinical information, severity or stage of the disease, biological results and imaging results which enables to assess treatment effect on the appearance of demyelinating inflammatory lesions and on the development of cerebral atrophy. We thus had to develop an algorithm to identify relapse occurrence based on the specific therapeutic management of MS patients. This complex algorithm, refined by experts of the field, showed good diagnosis performance in a previous validation study ( PPV: 95% and NPV 96%), and has allowed to strongly mitigate any potential misclassification bias. To strengthen the validity of this algorithm, we also conducted an additional analysis by extending the period between 2 occurrences of relapses from 31 to 60 days, which did not affect fundamentally the algorithm performance. Some relapses may nevertheless not have been captured, and frequency of relapses could be underestimated but this should similarly affect all treatment groups and thus not bias the results.
As for any claims based real-world studies, this study presents an inherent risk of unmeasured confounding. To address this limit, we applied hdPS-based methods in the analysis of the outcome. The hdPS is a well-known statistical technique that attempts to estimate the effect of a treatment, policy, or other intervention by accounting for the measured and unmeasured covariates that predict receiving the treatment. It summarizes a large set of variables that characterize each subject for status and unmeasured confounders not recorded in a database (i.e. drugs, medical status, hospitalization, other co-morbidities directly, or indirectly linked with unmeasured confounders) 16,17. Matching, adjusting or weighting on large numbers of covariates ascertained from subject healthcare claims data may improve control of confounding, as these variables may collectively be proxies for unobserved factors. Furthermore, using hdPS adjusting or weighting methods in addition to matching, allowed to include all patients meeting the eligibility criteria of the study, whereas matching method excludes patients not finding a match. Using hdPS weighting or adjustment ensures transparency of included patients and validity of results in the predefined study population.
In conclusion, this study provides further insight into the therapeutic benefit of DMF in real life setting compared to other commonly used agents for RRMS including IMM and another oral drug, TERI. The ARR was significantly lower in patients treated with DMF vs IMM and TERI using robust hdPS based methods. These data will be useful to feed into physician choices of patient’s treatment.