Idiopathic inflammatory myopathies and the anti-synthetase syndrome: a comprehensive review

Abstract

Autoantibodies are a hallmark in the diagnosis of many systemic autoimmune rheumatic diseases (SARD) including idiopathic inflammatory myopathies (IIM). Based on their specificity, autoantibodies in IIM are grouped into myositis specific (MSA) and myositis associated autoantibodies (MAA). Among the MSA, autoantibodies against aminoacyl-tRNA synthetases (ARS) represent the most common antibodies and can be detected in 25-35% of patients. The presence of ARS and other autoantibodies has become a key feature for classification and diagnosis of IIM and is increasingly used to define clinically distinguishable IIM subsets. For example, anti-ARS autoantibodies are the key features of what has become known as anti-synthetase syndrome (aSS), characterized by multiple organ involvement, primarily interstitial lung disease, often accompanied by myositis, non-erosive arthritis, Raynaud's phenomenon, fever, and "mechanic's hands". Autoantibodies directed to eight different ARS have been described: Jo-1 (histidyl), PL-7 (threonyl), PL-12 (alanyl), OJ (isoleucyl), EJ (glycyl), KS (asparaginyl), Zo (phenylalanyl) and Ha (tyrosyl). Each anti-ARS antibody seems to define a distinctive clinical phenotype. Although several research methods and commercial tests are available, routine testing for anti-ARS autoantibodies (other than anti-Jo-1/histidyl-tRNA synthetase) is not widely available, sometimes leading to delays in diagnosis and poor disease outcomes.

Keywords: Autoantibodies; Immunoassay; Jo-1; Myositis; Synthetase.

Figure 1

Detection of anti-ARS autoantibodies. A.) The classical indirect immunofluorescence (IIF) pattern of an anti-Jo-1 autoantibody positive sample is characterized by diffuse cytoplasmic staining on HEp-2 cells. Autoantibodies to other synthetases can show similar staining patterns. To differentiate the pattern from other cytoplasmic patterns (i.e. anti-ribososmal P autoantibodies), the absence of nucleolar staining is an important discriminator. It should be noted that less than half of the sera that have identifiable anti-Jo-1 will demonstrate this typical IIF pattern. The specific proteins identifying each autoantibody are marked with triangles. B.) Characterization of various anti-ARS autoantibodies (anti-Jo-1, PL-7, PL-12, OJ, EJ) by protein immunoprecipitation using ³⁵S-methionine-labeled K562 cell lysates, SDS-PAGE and autoradiography is shown (courtesy of Dr. Minoru Satoh). C.) Immunoprecipitation profile of cytoplasmic RNAs using phenol/chloroform extraction and urea-PAGE followed by silver staining demonstrating the typical tRNAs associated with each of the anti-ARS autoantibodies (courtesy of Dr. Minoru Satoh).