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Myositis-specific or myositis-associated antibodies are detected in approximately 50% of patients with idiopathic inflammatory myopathies (IIMs) and help to define subgroups of patients with certain distinguishing clinical features (1, 2). Anti–signal recognition particle (anti-SRP) autoantibodies are myositis-specific antibodies found in 4–6% of patients with IIMs (2, 3). These antibodies are directed against SRP, a ribonuclear protein particle that regulates protein translocation across the endoplasmic reticulum membrane during protein synthesis. Studies have demonstrated that anti-SRP myopathy appears distinct from polymyositis (PM) and other IIMs by its clinical features and histopathology (3–6). Patients with anti-SRP antibodies often present clinically with a severe myopathy characterized by markedly elevated serum creatine kinase (CK) levels and rapidly progressive proximal muscle weakness leading to significant disability. On histopathology, anti-SRP patients demonstrate a necrotizing myopathy without primary inflammation; however, several studies have demonstrated class I major histocompatibility complex immunostaining and most histopathologic studies have found capillary pathology with deposition of the terminal components of complement C5b–9, or the membrane attack complex (4–6).
Anti-SRP myopathy also differs from other immune-mediated myopathies by its characteristically poor responsiveness to steroid monotherapy and conventional immunosuppressive therapies. Although the pathophysiologic role of B cells as causative agents in several autoimmune diseases is not entirely understood, several off-label studies have shown efficacy of the B cell depleting therapy rituximab, an anti-CD20 monoclonal antibody, in diseases that can be treatment refractory such as systemic lupus erythematosus (SLE) (7), rheumatoid arthritis (RA) (8), and systemic vasculitides (9). B cell depletion therapy has also been an encouraging option for patients with PM, dermatomyositis (DM), and juvenile DM in several case series (10–12). Thus far, reports of the efficacy of rituximab in the treatment of anti-SRP myopathy have been mixed. A recent case report described poor clinical response to rituximab in 2 anti-SRP patients (13). However, an earlier investigation by Arlet et al of 2 patients with refractory anti-SRP myopathy demonstrated marked and sustained clinical response to the combination of prednisone, plasma exchange, and repeated courses of rituximab (14).
In this case series, we report the characteristics of 8 patients with anti-SRP myopathy and their dramatic response to B cell depletion therapy when their disease was refractory to traditional therapeutic agents.
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To our knowledge, the present study is the largest case series to date of patients treated for anti-SRP–associated myopathy with B cell depletion therapy. We have identified 8 patients with anti-SRP antibodies who developed severe myopathies unresponsive to other agents, and the majority showed a robust clinical response to rituximab treatment. This series suggests that B cell depletion therapy may be effective in patients with anti-SRP–associated myopathy and especially in those with refractory disease.
The 8 patients represented in this case series demonstrated similar clinical characteristics to anti-SRP patients described by others (3, 4, 6) (Table 1). The mean age of this cohort was younger at 37 years, and was comprised of a larger proportion of African Americans (50%) than has been reported in prior studies. The higher percentage of African American subjects in our cohort could be due to our particular geographic area and referral base. Alternatively, our findings could suggest that African Americans manifest a particularly severe myopathy and may be more responsive to rituximab treatment when compared with whites, but further prospective studies are needed to support this. Clinically, all of the patients in our study presented similarly with rapidly progressive and severe proximal muscle weakness accompanied with myalgias and dysphagia. Several also had signs of distal or asymmetric weakness that is atypical of PM or DM. Generally, patients also had extremely high CK levels at presentation (mean maximum CK level 18,987 IU/liter) with either mild or no elevation in inflammatory markers (Table 2). Only 2 patients demonstrated autoantibodies other than anti-SRP, but none manifested symptoms of overlapping autoimmune disease. All of the patients demonstrated an intense and widespread increase in STIR signal on muscle MRI reported as diffuse muscle or fascial edema, a finding that we have observed in patients with anti-SRP myopathy. Despite the MRI findings of a highly inflammatory process, the histologic appearance of their muscle biopsy samples consistently demonstrated significant muscle necrosis with complete absence of primary inflammation. Consequently, the diagnosis of anti-SRP myopathy was often delayed in many patients due to the absence of inflammation on muscle biopsy sample.
Table 1. Patient demographics and presenting characteristics*
|Patient||Age at onset, years||Sex||Race||ILD||Raynaud's phenomenon||Rash||Myalgia||Arthritis||Dysphagia||Weakness on examination|
Table 2. Laboratory, EMG, and histologic features of anti-SRP myopathy*
|Patient||Max CK level, IU/liter||Max aldolase level, IU/liter||Elevated ESR/CRP level||ANA titer||SRP+ (bands)||Positive autoantibodies||EMG irritable||Muscle biopsy features|
|1||56,000||8.8||+/−||−||+ (72, 54, 19)||+Ro||+||−||−||+||−||−|
|2||21,333||55.6||−/−||−||+ (72, 19)||−||+||−||−||−||+||+|
|3||3,148||14.6||−/+||−||+ (72, 54, 19)||−||N/A||−||+||−||+||+|
|4||6,885||62||−/+||−||+ (72, 19)||−||+||−||−||−||+||+|
|5||28,000||30||+/−||−||+ (72, 54, 19)||−||+||−||+||−||+||+|
|7||7,855||N/A||+/−||N/A||+ (72, 54)||−||−||N/A||N/A||N/A||N/A||N/A|
There has been substantial interest in the role of B cells in autoimmune disease, given the success of the monoclonal anti-CD20 antibody rituximab in the treatment of SLE, RA, and other processes that can be treatment refractory. Recently, B cell depletion therapy has also been effective in diseases with myositis-specific antibodies such as Jo-1–positive myopathy (11). Several studies have demonstrated that the levels of Jo-1 autoantibodies correlate with disease activity and may moderately decrease or disappear with successful therapy (4, 11). Similarly, in our case series, we demonstrate that the levels of anti-SRP antibodies can be reduced substantially with rituximab therapy (Table 3). This suggests that B cells and anti-SRP antibodies may have a pathogenic role in the inflammatory process of these particular myopathies, and rituximab as B cell depletion therapy may serve to directly target this immune response.
Table 3. Percent decrease in SRP autoantibody levels after rituximab treatment*
|Patient||Anti-SRP 54||Anti-SRP 19||Anti-SRP 72||Anti–Jo-1||Time from last rituximab treatment to autoantibody analysis, months|
In this study, treatment with rituximab resulted in a dramatic and sustained clinical improvement in the majority of patients with anti-SRP myopathy (Table 4). Prior to rituximab therapy, many of these patients had continued to clinically deteriorate with marked weakness and severe disability. Several required the use of a wheelchair or could not get out of bed without assistance, and one had entered hospice despite maximal immunosuppression with multiple agents. One patient in particular (patient 2) had developed severe respiratory muscle weakness requiring prolonged intubation even after treatment with high-dose corticosteroids, methotrexate, azathioprine, cyclophosphamide, and plasma exchange. Now, 18 months after receiving 4 total doses of rituximab with adjunct corticosteroid therapy, this patient is able to walk, independently perform all of her activities of daily living, and has returned to work. Her response is similar to the other patients we have reported, as 6 of 8 patients showed a marked improvement in strength and/or decline in CK levels as early as 2 months after receiving 2 doses of rituximab. Three patients were readministered rituximab 6–8 months after initial dosing primarily to sustain the benefits achieved with the initial doses. Three patients have maintained this clinical improvement for as long as 12–18 months since the initial dose. Manual muscle strength data were incomplete for 2 patients who were either lost to followup (patient 7) or died (patient 4); in these patients, clinical response to rituximab was demonstrated by a decline in CK levels. Despite a lack of inflammation on histology, all of the patients were continued on adjunctive corticosteroid treatment after rituximab dosing since the anti-SRP myopathy can be responsive to steroids. However, in all 8 patients, the doses of corticosteroids were able to be substantially reduced after treatment with rituximab (Table 4).
Table 4. Summary of response to B cell depletion therapy and outcome*
|Patient||CK level prior to therapy, IU/liter||Highest prednisone dosage, mg/day||Previous treatments||Doses of B cell depletion therapy||Lowest prednisone dosage posttherapy, mg/day||Lowest CK level posttherapy, IU/liter||Outcome post–B cell depletion and duration of remission|
|1||2,710||60||AZA, MTX||1,000 mg IV × 2 doses||20||622||Decline in CK and improvement in strength for 10 months|
|2||1,000||160||MTX, AZA, IVIG, plasma exchange||1,000 mg IV × 4 doses||5||163||Normalization of CK and improvement in strength for 18 months|
|3||550||40||MTX, AZA, IVIG, MMF||1,000 mg IV × 5 doses||15||126||Normalization of CK and improvement in strength for 19 months|
|4||1,063||80||IVIG, plasma exchange||1,000 mg IV × 1 dose||50||22||No outcome data; died 1 month later from pneumonia and CHF|
|5||2,900||80||MTX, IVIG||1,000 mg IV × 4 doses||10||963||Decline in CK for 12 months, re-dosed for increased CK|
|6||2,100||60||MTX, MMF, IVIG||1,000 mg IV × 2 doses||30||1,144||Improvement in strength and decline in CK for 9 months|
|7||1,250||60||MTX, MMF||1,000 mg IV × 2 doses||N/A||1,080||Decline in CK for 5 months|
|8||3,110||60||AZA, MTX, IVIG, plasma exchange||1,000 mg IV × 2 doses||15||2,100||Modest decline in CK after 6 months with persistent proximal lower extremity weakness|
Anti-SRP antibody levels were quantitated pre– and post–rituximab treatment in 5 patients (Table 3). Similar initial levels of anti-SRP autoantibodies were detected in all 5 patients prior to rituximab treatment. In 4 of the 5 patients, anti-SRP antibody levels decreased significantly after rituximab therapy. In those patients, the time between treatment and autoantibody analysis ranged from 1–4 months. Clinical treatment response in terms of manual muscle strength testing and/or decline in CK level was robust and sustained in those 4 patients. Rituximab had no effect on anti-SRP antibody levels in 1 of the 5 patients (patient 5); however, this patient also had the longest time period between autoantibody analysis and rituximab treatment (9 months). Although patient 5 demonstrated an initial clinical response to rituximab, she began to manifest increased CK levels 2 months after autoantibody analysis, which prompted retreatment with rituximab 12 months after the initial dose. This suggests that the effect of rituximab may wane over time, and decreases in SRP autoantibody levels may be the most accurately quantified when performed soon after rituximab administration.
We conclude that B cell depletion with rituximab may be an effective and often life-saving therapy for patients with anti-SRP myopathy. Given that the manifestations of this myopathy can be quite severe and refractory to standard medications, prompt recognition of the disease and aggressive treatment has become increasingly important to prevent irreversible muscle damage and atrophy. Further studies are needed to elucidate the underlying disease pathogenesis and the precise role of anti-SRP antibodies in this unique subset of myopathies.
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- PATIENTS AND METHODS
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All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be submitted for publication. Dr. Christopher-Stine had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study conception and design. Valiyil, Casciola-Rosen, Christopher-Stine.
Acquisition of data. Valiyil, Casciola-Rosen, Hong, Mammen, Christopher-Stine.
Analysis and interpretation of data. Valiyil, Casciola-Rosen, Mammen, Christopher-Stine.