Ira N. Targoff

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.

Our objective was to improve the currently imperfect classifications of idiopathic inflammatory myopathies (IIM). In clinical practice, overlap features are common in IIM. This provided a rationale for positioning overlap clinical features at the core of a new classification system. We conducted a longitudinal study of 100 consecutive adult French Canadian patients with IIM. Clinical and laboratory data were obtained by retrospective chart review. Sera were analyzed for autoantibodies (aAbs) by protein A-assisted immunoprecipitation and double immunodiffusion. Overlap aAbs encompassed aAbs to synthetases, systemic sclerosis-associated aAbs, anti-signal recognition particle (SRP) and anti-nucleoporins. Patients were classified both at IIM diagnosis, based on data at presentation, and at the end of follow-up, based on cumulative findings. Three classifications were used: 1) the Bohan and Peter original classification, 2) a new version of that classification as modified by us, and 3) a novel clinicoserologic classification. As investigators were blinded to aAb results, the modified classification is strictly a clinical classification. Its core concept is the attribution of diagnostic significance to the presence of overlap features, that is, their presence resulted in a diagnosis of overlap myositis (OM). This approach allowed direct comparison with the original Bohan and Peter classification. By integrating aAb results to the modified classification, we also defined the clinicoserologic classification, which allowed to examine the added value of aAbs to diagnostic, therapeutic and prognostic stratification. Whereas polymyositis (PM) was the most common IIM according to the original classification, accounting for 45% of the cohort at diagnosis, its frequency fell to 14% with the modified classification. Conversely, while the frequency of myositis associated with connective tissue disease was 24% according to the original classification, the frequency of OM was 60% when using the modified classification. At last follow-up, the frequency of PM fell further to only 9%, while the frequency of OM rose to 67%. Systemic sclerosis was the most common connective tissue disease associated with IIM, accounting for 42.6% of OM patients and 29% of the cohort. The frequencies of overlap aAbs in the cohort and in OM patients were 48% and 70.5% (n =48/68), respectively. The presence of overlap aAbs at IIM diagnosis identified additional OM patients unrecognized by the modified classification. The sensitivity of the modified classification for OM at diagnosis was 87%, suggesting that clinicians may rely on the modified classification for identification of most OM patients, while awaiting results of aAb assays. The new classifications predicted the response to prednisone and IIM course. Using stringent definitions, IIM was classified as responsive or refractory after an adequate initial corticosteroid therapy, and the disease course as monophasic or chronic after a single adequate trial of prednisone. PM was always chronic and was associated with the highest rate (50%) of refractoriness to initial corticosteroid treatment. Dermatomyositis was almost always chronic (92% rate); however, its responsiveness to initial corticosteroid treatment was high (87%). OM was almost always responsive to corticosteroids (89%-100% rates). When OM patients were divided according to aAb subsets, anti-synthetase, SRP, or nucleoporin aAbs were markers for chronic myositis, whereas aAbs to U1RNP, Pm-Scl, or Ku were markers for monophasic myositis. We conclude that the original Bohan and Peter classification should be abandoned as it leads to misclassification of patients. Much of IIM is composed of OM. The proposed modified and clinicoserologic classifications have diagnostic, prognostic, and therapeutic value.

OBJECTIVE: In polymyositis and dermatomyositis (DM), identified autoantibodies occur in <50% of adult patients and in a smaller proportion of children. This study was undertaken as part of a larger effort to define novel autoantibodies that assist in the clinical evaluation of myositis. METHODS: Sera from children and adults satisfying criteria for idiopathic inflammatory myopathies and from patients with other connective tissue diseases (CTDs), patients with noninflammatory myopathies, and healthy individuals were tested for autoantibodies by immunoprecipitation (IP). A previously unrecognized autoantibody that immunoprecipitated a 155-kd protein along with a weaker 140-kd protein was seen. When the presence of this anti-p155 autoantibody in test sera was suggested based on IP results, it was confirmed by immunoblotting of immunoprecipitates. RESULTS: Sera from 51 of 244 myositis patients (21%), including 30 with juvenile DM (29%), 5 with juvenile CTD-associated myositis (33%), 8 with adult DM (21%), 6 with cancer-associated DM (75%), and 2 with adult CTD-associated myositis (15%), were found to have anti-p155 autoantibody. One of 49 patients with lupus, and none of 89 others without myositis, had anti-p155. Caucasian patients with anti-p155 had a unique HLA risk factor, DQA1*0301 (odds ratio 5.4, corrected P = 0.004). In adults with anti-p155, of several clinical features assessed only the frequency of V-sign rash was increased, but patients with this antibody were clinically distinct from those with autoantibodies to aminoacyl-transfer RNA synthetases. CONCLUSION: A newly recognized autoantibody, anti-p155, is associated with DM and cancer-associated DM, and is one of the most common autoantibodies in this condition, occurring as frequently in children as in adults. The clinical features and immunogenetics associated with anti-p155 differ from those associated with antisynthetases.

Using immunoprecipitation, we identified 13 patients with antibodies to the signal recognition particle (SRP) from a collection of sera representing 265 polymyositis/dermatomyositis (PM/DM) patients. Antibody reactivity with SRP was confirmed by enzyme-linked immunosorbent assay and immunoprecipitation with isolated dog pancreas SRP. The antibody was present in the serum of 4% of PM/DM patients, and 18% of PM/DM patients with anticytoplasmic antibodies other than anti-Jo-1, but not in patients with other conditions who had anticytoplasmic antibodies. Anti-SRP was associated with classic adult PM, and some of these cases were unusually severe and/or of rapid onset; it was not found in patients with overlap syndromes or with DM involvement. Unlike patients with antibodies to aminoacyl-transfer RNA synthetases, patients with anti-SRP had a low frequency of pulmonary fibrosis, as well as of arthritis and Raynaud's phenomenon. Anti-SRP antibodies may serve as a marker for a second, distinct subgroup of adult PM.