Clinical features and prognostic analysis of anti-MDA5 and anti-aminoacyl-tRNA synthetase antibodies double-positive idiopathic inflammatory myopathy patients: A retrospective multicenter study

Abstract Background Idiopathic inflammatory myopathies (IIMs) encompass heterogeneous autoimmune muscle disorders. Among them, the coexistence of anti-melanomadifferentiation-associated protein 5 (anti-MDA5) and anti-aminoacyl-tRNA synthetase (anti-ARS) antibodies has rarely been reported, and their clinical significance remains unclear. This study aimed to delineate the clinical spectrum and outcomes of such patients. Methods We retrospectively reviewed 528 IIM patients from three tertiary medical centers and conducted a systematic literature search across PubMed, EMBASE, and Web of Science up to March 2025. In total, 37 double-positive cases (26 reported previously and 11 from the present study) were included. Clinical features, laboratory findings, treatment, and survival data were analyzed. Cox regression was applied to identify prognostic factors, and Kaplan–Meier analysis was used for survival comparison. Results Among the 11 patients from our cohort, pulmonary involvement was universal, and 72.7% developed rapidly progressive interstitial lung disease (RP-ILD). Elevated liver enzymes with AST predominance, lymphopenia, and high neutrophil-to-lymphocyte ratio were common. Kaplan–Meier curves suggested a worse outcome in anti-Ro52-positive and RP-ILD subgroups, though statistical significance was not reached. In pooled analysis, higher lactate dehydrogenase (LDH) and ferritin (FER) levels were independently associated with poor prognosis. Conclusion Patients double-positive for anti-MDA5 and anti-ARS antibodies present with frequent ILD, particularly RP-ILD, and display combined clinical features of both antibody subsets. Laboratory markers such as LDH and FER may serve as predictors of unfavorable prognosis. These findings enhance the understanding of this rare phenotype and may help optimize clinical management strategies. Trial registration Clinical trial number: not applicable.