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- PATIENTS AND METHODS
Idiopathic inflammatory myopathies are a group of acquired, heterogeneous, systemic diseases characterized by progressive symmetrical muscle weakness, elevated serum levels of muscle enzymes, electromyographic abnormalities, and inflammatory infiltrates on muscle biopsy (1). Characteristic histopathologic features allow the classification of idiopathic inflammatory myopathies into polymyositis (PM), dermatomyositis (DM), and inclusion body myositis (IBM) (2). These conditions are commonly regarded as autoimmune disorders, and various autoantibodies directed to defined nuclear and cytoplasmic antigens are found in up to 55% of patients with PM or DM. Some of these autoantibodies are frequently encountered in rheumatic disorders associated with myositis and are referred to as myositis-associated autoantibodies (3–5). Other autoantibodies are specific for idiopathic inflammatory myopathies and target a subset of aminoacyl–transfer RNA (aminoacyl-tRNA) synthetase (6), components of the signal recognition particle (SRP) (7), and nuclear helicase-ATPase Mi-2 (8–11). In addition to the useful clinical classification of Bohan and Peter (12, 13), there is another approach to the classification of idiopathic inflammatory myopathies based on determination of autoantibodies specific to or associated with myositis (14). The prevalence of these autoantibodies may vary between geographic regions because of differences in the genetic background and/or exposure to environmental factors among different populations (15). Although the association of these autoantibodies with some specific clinical features has been suggested by several authors (14, 16–19), there are still many unanswered questions concerning their clinical applicability. Our working hypothesis for this study was that determination of these autoantibodies would be useful for clinical purposes in our population of patients with myositis. The goal of the present study was to determine the prevalence of myositis-specific autoantibodies (MSAs) and myositis-associated autoantibodies (MAAs) in a series of 88 adult patients with idiopathic inflammatory myopathies and to establish clinical, serologic, and genetic correlations in this Mediterranean population from a single hospital in Barcelona, Spain.
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- PATIENTS AND METHODS
This report describes the serologic findings and their clinical associations in a large series of patients from the Mediterranean basin diagnosed with idiopathic inflammatory myopathies in a single hospital in Barcelona, Spain. Groups of patients with myositis can be defined serologically by the presence of diagnostic autoantibodies, known as myositis-specific autoantibodies, which are directed against conserved conformational epitopes on cytoplasmic and nuclear components (4). MSAs include autoantibodies that bind to and inhibit the function of aminoacyl-tRNA synthetases (antisynthetases), those directed against proteins of the SRP (anti-SRP), and those that react with a 240-kd SNF2 superfamily helicase associated with the nucleosome remodeling and deacetylase complex, known as anti–Mi-2 autoantibodies (4–11). In contrast, MAAs have an association with myositis, but also occur in other related conditions and include anti–PM-Scl antibodies directed against the exosome (24–29); antibodies to small nuclear RNPs (snRNPs) (30–32); and other cytoplasmic antibodies such as anti-Ro, anti-La, and anti-Ku (33). The prevalence of MSAs and MAAs found in this study corresponded well with findings reported for patients from other countries in general trends (14, 16, 18, 19). There were, however, some differences. More patients were positive for PM-Scl antibodies in our study (11%) than in a European study (6%) (18), a North American study (2%) (14), or a Japanese study (0%) (34), although this factor probably depends on the percentage of overlap myositis syndromes in each series. Hausmanowa-Petrusewicz et al (16) also found a higher number of patients with myositis with anti–PM-Scl antibodies, most of them with scleromyositis.
Photosensitive rashes characterize DM and distinguish it from PM. In our study, anti–Mi-2 antibodies were found only in patients with DM (10%) and not in the other groups, supporting the idea that this autoantibody is characteristic of patients with DM. This finding is in conflict with some studies, mainly with the large European study (18) including 417 patients. Nevertheless, in the European study, anti–Mi-2 antibodies were determined by an ELISA test, which may have been responsible for the high detection of these antibodies in the sera of patients with PM. Results for the incidence and clinical characteristics associated with anti–Mi-2 antibodies in other published series are consistent with our findings (8, 14, 16). A recent study by Okada et al (15) has shed light on this issue and has found that ultraviolet radiation exposure may modulate the clinical and immunologic expression of inflammatory myopathies around the world. In that investigation, anti–Mi-2 autoantibodies were strongly related with the intensity of ultraviolet radiation and with the presence of DM, contributing to the idea that anti–Mi-2 autoantibodies are specific to DM, as we also found.
A relevant finding of our study was the lack of detection of anti-SRP antibodies. These antibodies have been classically related to a poor prognosis, with high levels of creatine kinase and cardiac involvement, mainly in black patients (7, 14, 35). It has also been found that patients with anti-SRP have a low frequency of pulmonary fibrosis, Raynaud's phenomenon, and inflammatory myopathy (18, 35). Moreover, a recent article has reported that anti-SRP autoantibodies are found in other connective tissue diseases and in white patients, and that cardiac involvement in patients with PM is less frequent and the prognosis is not as bad as has been previously reported (36). Anti-SRP autoantibodies are not common, with an incidence that ranges from 1% to 6% in different studies (14, 16, 18, 19, 24, 36), mainly in patients with PM. The absence of black patients and the higher number of DM cases in our series could explain the fact that anti-SRP autoantibodies were not found in our patients.
Among MSAs, the most prevalent are antisynthetase antibodies directed against aminoacyl-tRNA synthetase, mainly anti–Jo-1 (his-tRNA synthetase), which are usually associated with clinical manifestations such as interstitial lung disease, arthritis, fever, Raynaud's phenomenon, mechanic's hands, and other conditions (37). There are few exceptions, such as the French Canadian study, which did not find any patients with antisynthetase antibodies in a series of 30 patients with inflammatory myopathy (38). Some of the manifestations classically related to the antisynthetase syndrome are also frequently present in patients with anti–PM-Scl antibodies, raising the possibility that the immunogenetic background influences the autoantibody status of these patients. HLA–DR3 has been found in association with antisynthetase antibodies (39) and with anti–PM-Scl antibodies (28, 29). Our results agree not only with these clinical-serologic associations but also with the presence of interstitial lung disease, leading us to suggest that the constellation of signs and symptoms of the so-called antisynthetase syndrome could be more closely related with the HLA system (DR3) than with the antibodies. Recent advances in the pathogenesis of antisynthetase antibodies suggest that anti–Jo-1, an ubiquitous enzyme of cytoplasmic localization, is not only highly specific for PM/DM and not merely related to muscle inflammation, but actually acts as a chemokine with a potential role in the immune response of myositis (40–42). Patients with non–Jo-1 antisynthetase autoantibodies seem to have less muscle involvement (43), as was true in our 3 patients with interstitial lung disease and antisynthetase antibodies. In our study, antisynthetase antibodies were detected in patients with PM and in those with DM at similar rates, and were not specific for PM as other studies have suggested.
Other MAAs such as anti-Ro and anti-La autoantibodies, as well as anti-Ku and the different epitopes of anti-RNP antibodies (anti–U1 snRNPs and non–U1 snRNPs) are related with the presence of myositis. Anti–Ro 52 and anti–Ro 60 were both associated with antisynthetase antibodies, suggesting a coupled autoimmune response, as has been previously described (44, 45). The only patient with anti-Ku antibodies in our series had DM-antiphospholipid overlap syndrome and died due to breast cancer at the age of 35. Two of the 6 patients with anti–U1 snRNP antibodies included in the study were diagnosed as having gastric cancer and lung cancer, respectively, which is unusual, and the other 4 had a good clinical prognosis, as has been reported previously (31). Two patients with anti–U5 snRNP presented with scleroderma-PM overlap syndrome, which is in agreement with previous reports (32).
The results obtained in this study support the idea that different autoantibodies can help in the diagnosis of patients with inflammatory myopathies, and that different subgroups can be defined. Classic DM with characteristic skin lesions and dysphagia is associated with anti–Mi-2 antibodies, whereas nonerosive arthritis, interstitial lung disease, and mechanic's hands are associated with antisynthetase antibodies (the so-called antisynthetase syndrome). Some of these manifestations can also be found in patients with anti–PM-Scl antibodies, which are usually present in overlap syndromes of myositis and scleroderma.
Our study has certain limitations. First, we did not include patients age <18 years; therefore, the juvenile DM group was not represented in our study, because we usually only treat adults. Second, this study was retrospective in nature, but the low incidence of these rare diseases makes it very difficult to design and carry out prospective studies, even though recent efforts have been made by the International Myositis Assessment and Clinical Studies Group to improve this point. One drawback of this study was that the number of patients in some subgroups was rather small. Holm's procedure was used to correct for the effect of multiple comparisons, which may have masked some statistically significant results. In summary, our results support the idea that MSAs and MAAs are associated with different and characteristic clinical manifestations that could help in the diagnosis and management of inflammatory myopathies in our Mediterranean population.