Immunosuppressive therapy for multiple sclerosis
Based on the review of the literature and the authors' experience, immunosuppressive therapy plays an important role in the treatment of MS. Furthermore, given the understanding of the pathologic processes involved, the beneficial effect of immunosuppressive therapy is assumed to be greater in the earlier stages of the illness and relatively ineffective in the later stages, or in patients who have primary progressive disease. This concept is exemplified by the factors predictive of a response to cyclophosphamide, which correlate more with the inflammatory components of the disease and less with the degenerative processes (Box 3). Presumably, these factors can be applied to all immunosuppressive agents used to treat patients who are not responding to standard immunomodulatory therapy. Characteristics of patients who have active MS and are not responding to standard immunomodulatory therapy with IFN-β or GA have yet to be clearly established; however, there are typical characteristics used to define treatment failures in clinical trials (Box 4). The authors use these definitions as a guide for selecting patients for immunosuppressive therapy; however, clinical judgment based on the individual clinical situation prevails. Certainly, the severity of clinical progression, and MRI activity, as well as the severity and frequency of relapses will influence the decision to change therapy. Nevertheless, the definitions of a nonresponder from clinical trials resemble the predictive factors for a response to immunosuppressive therapy. Therefore, nonresponders potentially represent ideal candidates for this type of therapy. The authors have created an algorithm as a general guide for selecting appropriate patients and the manner in which to use each type of immunosuppressive therapy (Fig. 1). Although oral immunosuppressants and pulse MP lack the profound immunosuppressive and anti-inflammatory activity demonstrated by cyclophosphamide and mitoxantrone, studies show a beneficial effect of both and the authors believe they are used best in combination with IFN-β or GA in patients who have less severe disease activity. Based on the published literature, patients who are failing standard therapy and patients who have very active relapsing-remitting or early progressive MS, as represented by multiple characteristics of continued disease activity, should be considered candidates for either cyclophosphamide or mitoxantrone treatment. The treatment regimens and proper safety monitoring for all the immunosuppressants reviewed are outlined in Table 2. As discussed previously, induction therapy with cyclophosphamide is limited to selected cases of fulminant MS and must be used judiciously with special regard to monitoring for toxicity. Given that early inflammatory events seem to correlate with later disability, a major question is whether or not strong anti-inflammatory drugs, such as cyclophosphamide or mitoxantrone, will have an impact on later degenerative changes if given early in the disease to halt inflammation. Because standard immunomodulatory therapy is known to be only partially effective, immunosuppressive therapy plays an important role in early treatment of the inflammatory stage of the disease. The time of intervention and duration of treatment requires further study and the degree to which these agents are synergistic with IFN-β or GA is unknown. Nonetheless, cyclophosphamide and mitoxantrone are limited by their toxicity for widespread use in the early stages of MS, and testing the hypothesis that a strong anti-inflammatory or immunomodulatory regimen has a greater impact if given earlier in the disease requires less toxic immune specific agents. Additionally, because of the risk of long-term toxic effects of cyclophosphamide and mitoxantrone, there is a limited duration for their use and patients eventually need an alternative therapy. Currently, the authors reinstitute treatment with IFN-β or GA after completion of treatment with either cyclophosphamide or mitoxantrone. The role of immunosuppressive therapy is expected to change with the potential approval of natalizumab (Antegren), which may occur in 2005. Because of the safety profile and the effect on inflammatory MRI lesions demonstrated in the phase II trial of natalizumab, it might be considered first-line therapy for patients who are failing IFN-β and GA . Immunosuppressive therapy then would be considered in patients who are not responding to natalizumab.