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The IIM are a heterogeneous group of systemic rheumatic diseases which share the common features of chronic muscle weakness and mononuclear cell infiltrates in muscle. A number of classification schemes have been proposed for them, but none takes into consideration the marked immunologic, clinical, and genetic heterogeneity of the various clinical groups. We compared the usefulness of myositis-specific autoantibodies (anti-aminoacyl-tRNA synthetases, anti-SRP, anti-Mi-2 and anti-MAS) to the standard clinical categories (polymyositis, dermatomyositis, overlap myositis, cancer-associated myositis, and inclusion body myositis) in predicting clinical signs and symptoms, HLA types, and prognosis in 212 adult IIM patients. Although patients with inclusion body myositis (n = 26) differed in having significantly more asymmetric and distal weakness, falling, and atrophy than other patients, there were few other significant differences among the other clinical groups. In contrast, autoantibody status defined distinct sets of patients and each patient had only 1 myositis-specific autoantibody. Patients with anti-amino-acyl-tRNA synthetase autoantibodies (n = 47), compared to those without these antibodies, had significantly more frequent arthritis, fever, interstitial lung disease, and "mechanic's hands"; HLA-DRw52; higher mean prednisone dose at survey, higher proportion of patients receiving cytotoxic drugs, and higher death rates. Those with anti-signal recognition particle antibodies (n = 7) had increased palpitations; myalgias; DR5, DRw52; severe, refractory disease; and higher death rates. Patients with anti-Mi-2 antibodies (n = 10) had increased "V-sign" and "shawl-sign" rashes, and cuticular overgrowth; DR7 and DRw53; and a good response to therapy. The 2 patients with anti-MAS antibodies were the only ones with alcoholic rhabdomyolysis preceding myositis; both had insulin-dependent diabetes mellitus, and both had HLA-B60, -C3, -DR4, and -DRw53. These findings suggest that myositis-specific autoantibody status is a more useful guide than clinical group in assessing patients with myositis, and that specific associations of immunogenetics, immune responses, and clinical manifestations occur in IIM. Thus the myositis-specific autoantibodies aid in interpreting the diverse symptoms and signs of myositis patients and in predicting their clinical course and prognosis. We propose, therefore, that an adjunct classification of the IIM, based on the myositis-specific autoantibody status, be incorporated into future studies of their epidemiology, etiology, and therapy.
Inclusion body myositis, polymyositis, and dermatomyositis are three distinct categories of inflammatory myopathy. Some authorities commented on the selective early weakness of the volar forearm muscles, quadriceps, and ankle dorsiflexors in inclusion body myositis. The most important feature distinguishing inclusion body myositis from the other two inflammatory myopathies is the lack of responsiveness to immunosuppressive treatment. Although most patients with inclusion body myositis have characteristic muscle biopsy findings, some cannot be distinguished histologically early from polymyositis. Predicting responsiveness to immunosuppressive medications, independent of muscle histology, would be valuable to clinicians. We retrospectively reviewed the pattern of weakness and other clinical features of 46 patients newly diagnosed with either inclusion body myositis, polymyositis, or dermatomyositis. Asymmetrical muscle weakness with prominent wrist flexor, finger flexor, and knee extensor involvement was specific for inclusion body myositis and unresponsive polymyositis. Male sex, lower creatine kinase levels, slower rate of progression, and peripheral neuropathy were also more common in inclusion body myositis and unresponsive polymyositis than in responsive polymyositis and dermatomyositis patients. Repeat muscle biopsy in 2 patients in the unresponsive polymyositis group demonstrated histological features of inclusion body myositis. We suspect that patients with clinical features of inclusion body myositis but lacking histological confirmation may nonetheless have inclusion body myositis. Our study supports the recently proposed criteria for definite and possible inclusion body myositis.
Idiopathic inflammatory myositis is characterized by progressive weakness of the proximal muscles. There is a higher risk of malignancy than in the normal population. The aim of this study was to evaluate the frequency of malignancy among 251 myositis patients. We also compared clinical and immunological characteristics of cancer-associated myositis with primary myositis. There were no malignancies among polymyositis, overlap, or juvenile myositis patients. Twenty-two of ninety dermatomyositis patients also had a malignant disease. Patients with cancer-associated dermatomyositis were significantly older than primary myositis patients and had more severe cutaneous and muscle symptoms. Dysphagia and diaphragmatic involvement were more frequent among cancer-associated patients, while extramuscular features were less frequent. After successful treatment of the malignancy, we were able to manage myositis symptoms. One-year survival rate was significantly better in primary dermatomyositis patients. The subset of cancer-associated myositis differs from primary myositis in many aspects of its clinical and immunological features. Prognosis and life expectancy in cancer-associated myositis patients is determined by the underlying malignant disease. Therefore, age- and sex-specific examinations for detection of an underlying malignancy are important in the management of patients with dermatomyositis.
OBJECTIVE: To examine interrelationships among myositis subsets, autoantibodies, and major histocompatibility complex (MHC) class II alleles across ethnic lines, and to localize genetic susceptibility (presence of HLA-DR versus DQ) to myositis within the MHC class II region. METHODS: MHC class II alleles (HLA-DRB1, DQA1, and DQB1, detected by DNA oligotyping) and myositis-specific autoantibodies (MSA) were determined in 224 patients with various myositis syndromes, including 89 whites, 89 African-Americans, 25 Mexican-Americans, and 21 Japanese. RESULTS: Anti-Jo-1 (histidyl-transfer RNA [tRNA] synthetase) and other MSAs (anti-PL-12, anti-PL-7, anti-OJ, anti-EJ, anti-KJ, anti-tRNA, and anti-signal recognition particle) were equally distributed among the races, but occurred more often in patients with polymyositis (PM) than in those with dermatomyositis (DM) or other myositis syndromes. MSA frequencies were significantly positively associated with anti-Ro (SS-A) (P = 0.002), and significantly negatively associated with anti-U1 RNP (P = 0.003). Frequencies of the HLA-DRB1*0301 (DR3), DQA1*0501, and DQB1*0201 (DQ2) alleles (and haplotype) were each increased in white patients with myositis, especially those with PM, but most strikingly in those with MSAs. However, in the other ethnic groups, except the Japanese group, only frequencies of HLA-DQA1*0501 and the structurally similar DQA1*0401 alleles were significantly increased. The presence of HLA-DQA1*0501 or *0401 was most significantly associated with anti-Jo-1, anti-PL-12, and other MSAs, compared with myositis patients without MSAs (P = 0.0008, Pcorr = 0.01, odds ratio [OR] = 3.7), and with normal, ethnically matched controls (P = 3 x 10(-7), Pcorr = 1 x 10(-6), OR = 6.5). Among MSA-positive patients who were negative for HLA-DQA1*0501 and *0401, including Japanese patients, the HLA-DQA1*0102 and *0103 alleles predominated. In addition, there appeared to be a negative association of the HLA-DR2 alleles (DRB1*1501 and *1503) with PM (P = 0.007, Pcorr not significant, OR = 0.39), but not with DM or myositis overall. CONCLUSION: By transracial gene mapping, genetic susceptibility to anti-Jo-1 and other MSAs in patients with myositis can be localized within the MHC region to the HLA-DQA1 locus.
PURPOSE OF REVIEW: Sporadic inclusion-body myositis, the most common muscle disease of older persons, is of unknown cause, and there is no successful treatment. Interest in sporadic inclusion-body myositis has been enhanced by the recent identification within the sporadic inclusion-body myositis muscle fibers of several abnormally accumulated proteins, which provides novel and important clues to the pathogenesis of sporadic inclusion-body myositis. RECENT FINDINGS: This article summarizes the most recent findings leading to better understanding of the players in the pathogenetic cascade. It is suggested that lymphocytic inflammatory component is probably secondary, and it may contribute only slightly to muscle fiber damage in sporadic inclusion-body myositis. However, it is proposed that the identified abnormal accumulation, aggregation, and misfolding of proteins, combined with and perhaps provoked by an aging intracellular milieu, more essentially lead to the vacuolar degeneration and atrophy of the muscle fibers that are specific to sporadic inclusion-body myositis. Abnormal accumulations of the amyloid-beta precursor protein and of its proteolytic fragment, amyloid-beta, associated with the aging cellular muscle fiber environment, appear to be key pathogenic events. SUMMARY: In conceptualizing a treatment for sporadic inclusion-body myositis, the accumulations of amyloid-beta42 and other unfolded proteins are now phenomena to be reckoned with. One would like to stop intracellular increase of the unfolded/misfolded proteins by reducing their formation and/or increasing their disposal. In addition, the identification of factors that would decrease intra-muscle fiber expressions of beta- and gamma-secretases might lead to decreased production of putatively myotoxic oligomeric amyloid-beta42. Better understanding of the mechanisms and consequences of genes that predispose to sporadic inclusion-body myositis, and of human muscle fiber aging, could also provide new avenues toward the therapy of sporadic inclusion-body myositis. How to therapeutically capitalize on the new findings is now the challenge.
Myositis describes a heterogeneous group of disorders whose main pathologic feature is chronic inflammation of the affected muscles. The association of myositis with other autoimmune diseases, the response to corticosteroid and immunosuppressive therapy, the frequent occurrence of autoantibodies, and the presence of chronic inflammatory cells in the affected muscles of patients with myositis indicate that the myositis syndromes are autoimmune diseases. This review summarizes recent observations on the role of humoral and cellular mechanisms in myositis. During the past year, the most notable contributions included studies on the relationship among autoantibodies and various clinical and epidemiologic features of patients with myositis; further evidence for T-cell involvement in the pathogenesis of myositis; demonstration of amyloid proteins in muscle fibers of patients with inclusion body myositis; and a controlled trial of plasma exchange and leukapheresis in myositis.
OBJECTIVE: To devise new tools to assess activity and damage in patients with idiopathic myopathies (IIM). METHODS: An international multidisciplinary consensus effort to standardize the conduct and reporting of the myositis clinical trials has been established. Two tools, known as the myositis intention to treat index (MITAX) and the myositis disease activity assessment visual analogue scale (MYOACT), have been developed to capture activity in patients with IIM. In addition, the myositis damage index (MDI) has been devised to assess the extent and severity of damage developing in different organs and systems. These measures have been reviewed by the myositis experts participating in the International Myositis Assessment and Clinical Studies (IMACS) group and have been found to have good face validity and to be comprehensive. The instruments were assessed in two real patient exercises involving patients with adult dermatomyositis and inclusion body myositis. RESULTS: The reliability of MITAX, MYOACT and MDI, measured by the intraclass correlation coefficient among the physicians, and the inter-rater reliability, as assessed by variation in the physicians' rating of patients, was fair to good for most aspects of the tools. Reliability and inter-rater agreement improved at the second exercise after the participants had completed additional training. CONCLUSIONS: The MITAX, MYOACT and MDI tools, which are now undergoing validity testing, should enhance the consistency, comprehensiveness and reliability of disease activity and damage assessment in patients with myositis.
BACKGROUND: Chronic generalized myositis has not so far been reported as a complication of chronic active Epstein-Barr virus infection (CAEBV). We encountered three patients with chronic generalized myositis mimicking polymyositis associated with CAEBV. METHODS: To clarify the pathological character of this myositis, we investigated the distribution, clonality, and the immunophenotype of EBV-infected cells and lymphocytes infiltrating in muscles. RESULTS: Clinically, two patients showed symmetrical proximal weakness and muscle atrophy as the initial and main symptom. Although the condition resembled polymyositis, they had also lingual and/or orbital myositis. The other patient showed generalized myositis at the late phase of CAEBV. In all of them, immunotherapy was ineffective and prognosis was poor. Intramuscular infiltrating lymphocytes in our patients were mainly CD45RO+, CD3+, CD4-, CD8-, TCR betaF1-, TCR deltaTCS1-, CD56-, CD79a-, CD21-, HLA-DR+, ZEBRA -, LMP1-, and EBER+ T cells. Oligoclonal expansion of EBV-infected T cells was shown in the muscles. However, there were no malignant lymphocytes. CONCLUSIONS: This new form of myositis must be distinguished from polymyositis and the other conventional forms of myositis. Careful investigation of hidden CAEBV is recommended when patients present with steroid non-responsive chronic progressive generalized myositis, in particular, with lingual or orbital involvement.