Myositis-specific autoantibodies (MSAs) include those directed against aminoacyl–transfer RNA (aminoacyl-tRNA) synthetases (antisynthetase), signal recognition particle (SRP), and the helicase enzyme (1–4). MSAs define subgroups of idiopathic inflammatory myopathy (IIM) patients with distinguishing clinical features. Anti-SRP autoantibodies are mainly associated with polymyositis (PM), persistent elevation of the creatine kinase level, and severe myositis that is often resistant to treatment with corticosteroids and other immunosuppressive agents. Unlike patients with antisynthetase syndrome, patients with anti-SRP are reported to have a low frequency of pulmonary fibrosis, arthritis, and Raynaud's phenomenon (2), and may not have inflammatory myopathy (5, 6).
SRP, one of the most abundant and best-characterized RNP particles, consists of the 7SL RNA molecule and 6 polypeptides with molecular weights of 72 kd, 68 kd, 54 kd, 19 kd, 14 kd, and 9 kd. SRP regulates the translocation of proteins across the endoplasmic reticulum membrane during protein synthesis, and autoantibodies that react with SRPs are defined by their ability to immunoprecipitate the 7SL RNA (7, 8).
We have longitudinally followed up a large cohort of IIM and connective tissue disease (CTD) patients who had serum specimens collected. The goal of the present study was to determine the clinical, serologic, and muscle pathologic features, and long-term prognosis among patients with the anti-SRP autoantibody. We compared these findings and patient survival with those in IIM patients with and IIM patients without antisynthetase autoantibodies.
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- PATIENTS AND METHODS
The prevalence of anti-SRP antibodies in our prospective IIM cohort is 6%, similar to earlier reports of 4–5% (2, 3, 6). Although the presence of 2 different MSAs in the same patient is distinctly unusual (13, 14) and SRP is predominantly specific for PM (1–3), we have identified another patient with 2 MSAs (anti-SRP and anti–PL-12). Furthermore, 3 of the 19 SRP-positive patients in our cohort (16%) have no evidence of myositis. Anti-Ro/SSA was detected in 4 (21%) of the 19 SRP-positive patients and anti-Th/To was found in 1 SRP-positive patient, who had limited SSc and did not have myositis. The latter antibody is found predominantly in patients with limited SSc and is associated with pulmonary hypertension and pulmonary fibrosis (15).
ILD was present in the 3 SRP-positive patients without myositis, but these patients had a CTD or autoantibody associated with ILD. However, 3 SRP-positive PM patients also had evidence of ILD, an unexpected finding. We did not observe overt cardiac involvement in our SRP-positive PM patients as previously reported, but this discrepancy may be due to the varying definitions of cardiac involvement in different studies as well as a lower frequency of African Americans in our cohort (2, 3). Love et al (3) noted palpitations in all 7 of their SRP-positive PM patients, but there was no further diagnostic investigation described. Targoff et al (2) reported that 4 of their 12 SRP-positive PM patients had cardiac involvement (arrhythmias in 3 and cardiomyopathy with fibrosis in 1).
Severe proximal muscle weakness and muscle atrophy were prominent findings at initial presentation in the SRP-positive PM patients compared with the SRP-negative PM control group. This could not be explained by a delay in diagnosis in the SRP-positive PM patients. Proximal esophageal dysmotility was a significant feature in SRP-positive PM patients who had swallowing studies performed, although the majority of patients did not have these diagnostic studies. Therefore, it is prudent to screen for proximal esophageal dysmotility, especially in older PM patients with severe proximal muscle weakness, who are at increased risk of aspiration-induced pneumonia and increased mortality (16). Two of the 4 deaths (both elderly patients) in the SRP-positive PM group were related to pneumonia; 1 of these patients had esophageal dysmotility with aspiration pneumonia. Although there were 2 deaths related to PM, survival in our SRP-positive PM patients was comparable with that in the cohort of 118 SRP-negative PM patients, in contrast with earlier reports (2, 3).
Although we were unable to assess treatment outcome in this retrospective study, it would appear that the SRP-positive PM patients had refractory disease since ∼50% of them underwent at least 3 drug trials. However, one-third of our SRP-positive PM patients had favorable responses to immunosuppressive therapy.
Similar to findings reported by Miller et al (17), we noted minimal endomysial inflammation in specimens from SRP-positive PM patients, and there was no significant increase in the degeneration, regeneration, myofibrillar disruption, or red/round clusters of the myofibers in our SRP-positive PM group. Interestingly, there was a paucity of hypertrophic myofibers in the SRP-positive PM patients compared with the SRP-negative PM controls, suggesting that persistent muscle weakness in these patients may be due to the lack of compensatory muscle hypertrophy. There was a potential selection bias because only the available muscle biopsy specimens were reexamined and the SRP-negative PM controls were older at symptom onset. However, disease duration at myositis diagnosis and other demographic and clinical features were comparable in the SRP-positive PM and SRP-negative PM subgroups that had muscle biopsy results reviewed.
In conclusion, anti-SRP antibodies occurred in a small group of patients with PM who had early severe proximal muscle weakness and muscle atrophy at initial presentation. Esophageal dysmotility was prominent. Despite the presumed autoimmune etiology of the myopathy associated with the anti-SRP autoantibody, endomysial inflammation is uncommon and no specific immunosuppressive regimen is currently tailored to treat the SRP-positive PM patient. However, the prognosis of SRP-positive PM is better than previously reported: one-third of our patients responded to therapy and their survival is comparable with that of the PM controls. Although anti-SRP remains an autoantibody specific for PM, it is occasionally detected in patients with other immunologic syndromes in the absence of PM (5).