In this study of 95 patients with breakthrough relapsing MS on first-line DMTs, we found that switching to either natalizumab or immunosuppressant achieved large net reductions in the relapse rate. The reduction in the relapse rate among the natalizumab switchers was similar in magnitude to the effect size reported in the pivotal trial of natalizumab monotherapy, in which the annualized relapse rate was reduced by 68% compared to placebo 
. Reported rates of relapse reduction in both the mitoxantrone and cyclophosphamide trials were 63% compared to the control groups in the first year 
. However, these studies included greater proportion patients with SPMS or who received combination therapy.
Although immunosuppressants and natalizumab had a similar impact on reducing the relapse rate in our study, the exposure to strong immunosuppressants may be associated with an increased risk of serious infection or secondary neoplasm 
or, in the case of mitoxantrone, with cardiotoxicity 
. While there are risks associated with natalizumab, particularly that of progressive multifocal leukoencephalopathy, such adverse events appear to be fairly infrequent 
. Some clinicians have considered the use of drug holidays to reduce the risk of developing PML. However this interruption might lead to a return of clinical flares and radiologic activity 
or at least to the pre-treatment level of disease activity 
. Active monitoring of patients receiving natalizumab by regular MRI scanning, careful assessment of new MRI lesions or symptoms and, when necessary, CSF analysis is crucial for detecting JC virus infection. Treatment with plasma exchange (PLEX) followed by steroids when there is neurologic progression due to an immune reconstitution inflammatory syndrome (IRIS) is considered the treatment of choice after the diagnosis of PML, although there are no clinical trials 
Another question that remains unclear is whether combination therapy is helpful and safe for patients with breakthrough disease on the first-line DMT. Some studies have shown that the combination of first-line and second-line therapies is effective in reducing disease activity 
. Although using multiple therapies with different mechanisms of action in other diseases supports a similar approach in MS, the evidence for doing so is limited 
. More studies are needed to clarify the usefulness and safety of combination therapy.
The balance in the risk/benefit ratio of natalizumab versus immunosuppression as second-line therapy is unknown and may be influenced not only by potential adverse effects but also by factors such as drug- and infusion-related costs and ease of access.
While our study addresses an important clinical question, it has some limitations. Since the treatment assignment was not randomized, there might be differences in the groups that led to a different response to second-line therapies. Although the model was adjusted for all known potential confounders, there may be important covariates for which we did not account. In addition, since patients had breakthrough disease before the switch, it is important to consider the possible effect of regression to the mean, which may lead to a falsely high reduction in the relapse rate within groups. However, the three groups had similar relapse rates before switching both overall and in the last year on first-line DMT, such that if disease activity was unusually high in the pre-switch period, one would expect regression to the mean to occur in a non-differential manner during the follow-up period. As such, any difference between groups is likely a true effect rather than a result of regression to the mean, which could only explain differences within groups. Information on progression of disability as documented by EDSS after the switch to second-line DMT was not available for all patients.
Immunosuppressants were available before natalizumab and the factors influencing a decision to switch may have changed over time, leading to differences between the immunosuppressant and natalizumab groups for which we cannot account. A further potential problem is that the threshold for recommending a switch may differ among our center's neurologists, in part due to the lack of definition of breakthrough disease. A standard definition of breakthrough disease should be established in order to promptly identify sub-optimal responders to first-line therapies who may benefit from switching to second-line therapies. In our study, breakthrough was defined clinically and/or radiologically by the patient's MS specialist. As recommended in the literature 
, the monitoring strategies to evaluate DMT effectiveness at our center included regular follow-up visits by the same neurologist, and monitoring of relapses, disease progression by EDSS, and new T2-bright and gadolinium-enhancing lesions on brain MRI scans. We also excluded reasons other than breakthrough disease for stopping first-line DMT such as poor compliance or side effects. Besides this, patients treated with IFNB are tested for neutralizing antibodies to IFNB when suspecting breakthrough disease and considering a switch to another therapy 
While second-line therapies are more likely to be associated with rare but serious adverse effects, our data provide strong evidence for switching to such treatments when patients experience breakthrough disease on first-line agents. These results do not negate previous observations that patients may benefit from switching from one to another first-line therapy 
. Defining an algorithm for the timing and indications for treatment switch would be of great clinical utility but requires a consensus definition of breakthrough disease.