Muscle pathology of antisynthetase syndrome according to antibody subtypes

Identification of antisynthetase syndrome (ASS) could be challenging due to inaccessibility and technical difficulty of the serology test for the less common non-Jo-1 antibodies. This study aimed to describe ASS antibody-specific myopathology and evaluate the diagnostic utility of myofiber HLA-DR expression. We reviewed 212 ASS muscle biopsies and compared myopathologic features among subtypes. Additionally, we compared their HLA-DR staining pattern with 602 non-ASS myositis and 140 genetically confirmed myopathies known to have an inflammatory component. We used t-test and Fisher's exact for comparisons and used sensitivity, specificity, positive and negative predictive values to assess the utility of HLA-DR expression for ASS diagnosis. RNAseq performed from a subset of myositis cases and histologically normal muscle biopsies was used to evaluate interferon (IFN)-signaling pathway-related genes. Anti-OJ ASS showed prominent myopathology with higher scores in muscle fiber (4.6 ± 2.0 vs. 2.8 ± 1.8, p = 0.001) and inflammatory domains (6.8 ± 3.2 vs. 4.5 ± 2.9, p  = 0.006) than non-OJ ASS. HLA-DR expression and IFN-γ-related genes upregulation were prominent in ASS and inclusion body myositis (IBM). When dermatomyositis and IBM were excluded, HLA-DR expression was 95.4% specific and 61.2% sensitive for ASS with a positive predictive value of 85.9% and a negative predictive value of 84.2%; perifascicular HLA-DR pattern is common in anti-Jo-1 ASS than non-Jo-1 ASS (63.1% vs. 5.1%, p < 0.0001). In the appropriate clinicopathological context, myofiber HLA-DR expression help support ASS diagnosis. The presence of HLA-DR expression suggests involvement of IFN-γ in the pathogenesis of ASS, though the detailed mechanisms have yet to be elucidated.