Dermatomyositis (DM) is a chronic and debilitating inflammatory disease of skin and muscle that affects people of all ages. It has an annual reported incidence of 1 per 100,000 persons and can lead to disability and death (1–5). Patients usually present with progressive muscle weakness, which is often accompanied by an erythematous rash over the extensor surfaces of the joints and across the face. Articular, cardiac, pulmonary, and gastrointestinal manifestations occur in up to half of the patients (6–8), and the illness can be associated with severe morbidity. Consistent with the pathologic skin changes associated with other autoimmune connective tissue diseases, such as systemic lupus erythematosus (SLE), there are perivascular infiltrates of inflammatory cells in the skin, with an interface dermatitis consisting of lymphocytes causing ballooning degeneration at the dermoepidermal junction (9, 10). Diagnosis is confirmed by a muscle biopsy, which shows several pathognomonic changes, including perivascular inflammatory cells, immune complex deposition in the walls of intramuscular arteries and veins, and perifascicular muscle fiber atrophy (11).
Current evidence suggests that the idiopathic inflammatory myopathies, including DM, may be humorally mediated (12) because they are often associated with a panel of myositis-specific autoantibodies (MSAs) (6). In some patients these MSAs may be helpful in defining clinically homogeneous patient subsets and may predict the presence of associated rash or interstitial lung disease. The presence of autoantibodies lends support to the humoral basis of this illness (13). In addition, immunophenotyping has revealed that B cells are the most abundant inflammatory cells at the perivascular sites (11).
The traditional treatment approach to DM is immunosuppressive therapy, usually beginning with corticosteroids. However, up to 70% of patients treated with corticosteroids show an incomplete response, including 10% who are unresponsive (14). Corticosteroid treatment is also associated with important unwanted effects, such as weight gain, glucose intolerance, cataracts, osteoporosis, steroid-induced myopathy, and growth arrest in children. In patients who have an inadequate response to, or intolerable side effects with, these treatments, alternative approaches to treatment, including the use of azathioprine (15–18), methotrexate (17–20), cyclophosphamide (21), and/or cyclosporin A (20, 22), have been investigated in small-scale clinical trials, but with limited success. Human intravenous immunoglobulin (IVIG) may provide some benefit in refractory disease (22–31), although the effect is short-lived.
Consistently effective treatment regimens for DM remain elusive, and this illness therefore continues to pose a management challenge. In the search for alternative approaches, 2 lines of reasoning have led to the hypothesis that B cell depletion may be effective in the treatment of DM. First, in humorally mediated autoimmune peripheral neuropathies, the use of the CD20+ B cell–depleting monoclonal antibody rituximab directed against the CD20 antigen resulted in the depletion of circulating B cells with an accompanying significant improvement in muscle strength and without significant side effects (32, 33). Second, anecdotal experience in the use of rituximab in 2 patients, ages 11 and 26 years with refractory DM, seemed promising (34). Prior to treatment with rituximab, neither of these patients could walk unassisted, and both had a marked rash. Within 4 weeks of treatment with rituximab, each patient noted significant improvement in the rash and muscle strength, and by 3 months, both patients were walking without assistance.
This report presents the response data for the first 7 patients recruited into an open-label pilot study of rituximab in DM patients.
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- PATIENTS AND METHODS
DM is a debilitating condition, which if untreated, is associated with serious consequences. Even with currently available treatment, such consequences are not always obviated. While corticosteroids are the most frequently used primary treatment for DM, most patients derive only limited benefit, necessitating the use of add-on treatments. However, the choice of such treatment remains essentially empirical because all are associated with some important limitations, particularly side effects. Any putative alternative treatment that is both effective and well tolerated in these patients can therefore be regarded as an advancement. The striking results of B cell depletion therapy on the symptoms of DM in this small series show promise in fulfilling these criteria, and although this is not a definitive trial, it is the first to document the potential utility of rituximab as an effective approach to the treatment of this condition.
Rituximab is a genetically engineered (chimeric murine/human) monoclonal antibody directed against the CD20 antigen. The CD20 surface antigen is widely expressed during B cell ontogeny but is not found on hemopoietic stem cells, pro–B cells, mature plasma cells, or other normal tissues (37–39). CD20 regulates early steps in activation and differentiation, and may function as a calcium ion channel (40, 41). Rituximab's property of depleting CD20+ B cell lines while sparing stem and plasma cells has been used successfully in the treatment of non-Hodgkin's lymphoma (NHL) (42) and other autoimmune disorders, such as rheumatoid arthritis (RA), SLE, and IgM-mediated neuropathies (32, 33, 43–45). In addition, the presence of myositis-specific antibodies points to B cell–mediated humoral abnormalities in DM (9–11).
This study of up to 1 year in duration has indicated that B cell depletion coincides with a decrease in the symptoms of DM, notably, improvements in muscle strength, rash, vital capacity, and enzyme markers. Furthermore, the data indicate a trend, in that 4 of the 6 patients experienced symptoms of relapse, beginning by 24–36 weeks, associated with the return of B cells. This adds support to the contention that B cells play a pivotal role in the pathophysiology of DM. In addition, the duration of B cell depletion and associated reduction in symptoms following a single course of treatment with rituximab in patients with DM is consistent with that seen in other conditions such as NHL and IgM-mediated neuropathies. It is interesting that 2 of the 6 patients in this study experienced a much more sustained response that lasted beyond the 52-week followup period, despite a documented complete return of B cells in 1 patient.
The good tolerability of rituximab in this series of patients with DM is consistent with the experience in RA and SLE (46, 47), in that there were no serious adverse events associated with its infusion. Such reactions appear to be less frequent in patients with autoimmune conditions compared with patients with NHL (45). In NHL patients, lysis of tumor burden may contribute the mostly mild-to-moderate transient infusion reactions seen in this group, the frequency of which is greater during the first infusion than in subsequent infusions (42, 48).
The results of this study, therefore, help to establish the critical role of B cells in the pathophysiology of DM and indicate that B cell depletion with rituximab appears to be effective in the treatment of this condition. These results suggest that this approach is well tolerated, convenient, safe, and without complications such as increased infection rates. However, the optimal therapeutic dose of rituximab in DM is currently unclear, and the schedule for re-treatment, based on the return of signs and symptoms of the illness, has not been evaluated in this pilot study. Therefore, further investigation to understand the processes involved and to ascertain the effect of re-treatment at relapse is warranted from larger controlled clinical trials.
In this small open-label study of patients with DM, rituximab consistently depleted B cell levels. This corresponded to an improvement in the symptoms of the illness. These results are sufficiently encouraging to prompt a more formal evaluation of the role of B cells in the pathophysiology of DM, and the value and place of rituximab in its treatment.