ObjectiveTo identify the characteristic pathologic features of dermatomyositis (DM) associated with anti-Mi-2 autoantibodies (anti-Mi-2 DM).MethodsWe reviewed 188 muscle biopsies from patients (1) pathologically diagnosed with DM through the sarcoplasmic expression for the myxovirus-resistant protein A and (2) serologically positive for 1 of 5 DM-specific autoantibodies (DMSAs) (anti-Mi-2, n = 30; other DMSAs, n = 152) or negative for all 5 DMSAs (n = 6). We then compared the histopathologic and immunohistochemical features of patients with anti-Mi-2 DM to those with non-Mi-2 DM and patients with anti-synthetase syndrome (ASS) (n = 212) using the t test, Fisher exact test, and a logistic regression model.ResultsPatients with anti-Mi-2 DM showed significantly higher severity scores in muscle fiber and inflammatory domains than non-Mi-2 DM patients. The presence of perifascicular necrosis, increased perimysial alkaline phosphatase activity, and sarcolemmal membrane attack complex deposition was more frequent in patients with anti-Mi-2 DM (p < 0.01). After Bonferroni correction, there were no significant differences in the percentages of the features mentioned above between the patients with anti-Mi-2 DM and those with ASS (p > 0.01).ConclusionPerifascicular necrosis and perimysial pathology, features previously reported in ASS, are common in patients with anti-Mi-2 DM. Our findings not only assist in differentiating anti-Mi-2 DM from other DM subtypes but also suggest the possibility of an overlapping mechanism between anti-Mi-2 DM and ASS.Classification of EvidenceThis study provides Class II evidence that the muscle biopsies of DM patients with anti-Mi-2 autoantibodies are more likely to demonstrate higher severity scores in muscle fiber and inflammatory domains.

IMPORTANCEReports on dermatomyositis (DM) sine dermatitis (DMSD) are scarce, and the concept of the disease has not been widely accepted.OBJECTIVE To confirm the existence of DMSD, determine its prevalence, and characterize its serologic features. DESIGN, SETTING, AND PARTICIPANTSThis is a cohort study that reviewed clinical information, laboratory data, and muscle pathology slides from January 2009 to August 2019. We further assessed the follow-up data of 14 patients with DMSD. The median (interquartile range) follow-up period was 34 (16-64) months. Muscle biopsy samples, along with clinical information and laboratory data, were sent to a referral center for muscle diseases in Japan for diagnosis. Of patients whose myopathologic diagnosis was made at the National Center of Neurology and Psychiatry between January 2009 and August 2019, 199 patients were eligible for inclusion. These patients underwent full investigation for DM-specific autoantibodies (against transcriptional intermediary factor γ, Mi-2, melanoma differentiation-associated gene 5, nuclear matrix protein 2 [NXP-2], and small ubiquitin-like modifier activating enzyme ); however, 17 patients were excluded because their muscle fibers did not express myxovirus resistance protein A, a sensitive and specific marker of DM muscle pathology. MAIN OUTCOMES AND MEASURESDiagnosis of DMSD was based on the absence of a skin rash at the time of muscle biopsy. RESULTSOf the 182 patients, 93 were women (51%) and 46 were children (25%) (<18 years). Fourteen patients (8%) had DMSD and none were clinically diagnosed with DM. Among the 14 patients with DMSD, 12 (86%) were positive for anti-NXP-2 autoantibodies, while the remaining 2 were positive for anti-transcriptional intermediary factor γ and anti-Mi-2 autoantibodies, respectively. Only 28% of patients (47 of 168) with a skin rash were positive for anti-NXP-2 autoantibodies, indicating a significant association between anti-NXP-2 autoantibodies and DMSD (86% [12 of 14] vs 28% [47 of 168]; P < .001). This association was also supported by multivariable models adjusted for disease duration (odds ratio, 126.47; 95% CI, 11.42-1400.64; P < .001).CONCLUSIONS AND RELEVANCE Dermatomyositis sine dermatitis does exist and accounts for 8% of patients with DM confirmed with muscle biopsy. Dermatomyositis sine dermatitis is significantly associated with anti-NXP-2 autoantibodies, which contrasts with anti-MDA5 DM, which is typically clinically amyopathic in presentation. It is essential to distinguish DMSD from other types of myositis because DM-specific therapies that are currently under development, including Janus kinase inhibitors, may be effective for DMSD.

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.