Discussion
multiple sclerosis prognosis
DISEASE, PML, ADVERSE EFFECTS, MULTIPLE SCLEROSIS, EVENTS
This study was based on a natural experiment with patients assigned to each treatment group, depending on the JCV status. As JCV status has not been related to multiple sclerosis prognosis (excluding the occurrence of PML), it works as a natural randomization factor. This pseudo-randomization is not controlled by any investigator and is not affected by the patient’s characteristics, depending only on a natural phenomenon, thus allowing the comparison of groups with low selection bias. To our knowledge, this is the first time that JCV would be used as a random natural randomization factor, though other natural experiments have previously been used in health research, such as in mendelian randomization [No significant differences in the time to first relapse were observed between NTZ continuation and OCR treatment in our cohort. Although not statistically significant, earlier relapses in the JCV + OCR group are visible in Fig. Nonetheless, on comparing both groups since OCR real initiation (and not since the STRm when positive JCV was detected), no statistical differences were detected in first-year relapse activity (Fig. When comparing treatments since OCR initiation, no differences in disease activity were observed between NTZ and OCR, as previously suggested by other authors [A relatively high proportion of relapses was observed for both treatment arms (32.5% for JCV-NTZ and 37.0% for JCV + OCR), though this includes the totality of the follow-up, with a median time of almost 3 years for the JCV-NTZ arm and 2.5 years for the JCV + OCR arm, therefore it is reduced when analyzing the ARR only in the first year (0.18 ± 0.45 vs 0.33 ± 0.55, respectively). Furthermore, no change in EDSS or MRI was required for the definition of relapse, potentially allowing a broader inclusion of relapses that should not differ between groups.It must be considered that the time on NTZ pre-STRm was higher for the JCV + OCR group, although this is not surprising, as a longer exposure to NTZ would have implied a major number of JCV testing and so a higher cumulative probability of JCV positivity [Although our model is free of selection bias, some limitations of the present study must be considered. First, our sample had a limited number of patients and a low incidence of events during follow-up. This glaring lack of sample size may have led to the non-significant differences in the results, which probably does not reflect what is clinically significant, as for instance, time to first relapse was twice as long for the JCV-NTZ arm (1.53 years) compared to the JCV + OCR arm (0.75 years). Second, though data were collected in a prospective manner, the analysis and study design were retrospective, leading to possible information biases or confounding factors.In this study, we investigated a cohort of patients who were switched to OCR. However, it is important to note that other treatment alternatives can be considered when JCV turns positive after two years of NTZ. Fingolimod offers a viable alternative, with the comfort of oral administration; however, its adverse effects are quite common (including the risk of PML and rebound effect) [In multiple sclerosis, the comparison of highly effective disease-modifying treatments is an unsolved challenge. Randomized, double-blind clinical trials for treatment comparison are missing, probably due to ethical and economic reasons, but also due to the low incidence of events in these treated patients, which would require the design of trials with very long follow-ups. Therefore, conclusions from treatment comparisons must be based on real-world evidence from observational studies. In this context, designing studies based on natural experiments provides an opportunity for pseudo-randomization, minimizing the selection biases that are inherent to observational designs.