Background/Purpose: Juvenile idiopathic arthritis (JIA) and juvenile dermatomyositis (JDM) are among the most common forms of inflammatory autoimmune diseases in children. JDM is characterized by prominent perivascular inflammation in affected skeletal muscles; however, the mechanisms of the vessel injury remains unknown. Anti-endothelial cell antibodies (AECA) are frequently detected in inflammatory, infectious, and autoimmune diseases. We therefore used proteomic approaches to identify target autoantigens for AECA in plasma from the pediatric inflammatory autoimmune diseases.

Methods: We screened plasma from children with JDM and polyarticular JIA (pJIA) for the presence of AECA by western blotting and two-dimensional (2D) gel electrophoresis using proteins extracted from human aortic endothelial cells (HAEC). The detected proteins were identified by peptide mass finger-printing. We used ELISA assays to corroborate the mass spectrometry data, using plasma samples from 63 patients with JDM, 50 patients with pJIA and 40 sex- and age-matched healthy controls (HC). The differences of autoantibody levels and the frequency of autoantibodies between the groups were compared by Mann-Whitney U test and by chi-squared or Fisher’s exact tests, respectively.

Results: More than 600 proteins were identified as candidate targets of AECA in plasma from pediatric inflammatory autoimmune diseases. Among these autoantigens were muscle proteins, such as tropomyosin alpha-4 (TPM4). On ELISA assays, autoantibodies against TPM4 (anti-TPM4) were detected in 30% of patients with JDM, in 2% of patients with pJIA (p< 0.0001), and in 0% of HC (p< 0.0001). The median plasma levels of anti-TPM4 were higher in children with JDM than in children with pJIA (p< 0.0001), and in HC (p< 0.0001). The presence of AECA correlated with the presence of other previously described myositis-associated autoantibodies (MAAs). For example, autoantibodies against NT5C1A and Ro52 were more frequent in patients with anti-TPM4 (83%, P=0.002 and 44%, P=0.03). Interestingly, the presence of anti-TPM4 was associated with the presence of cutaneous ulcer (53%, P=0.02), mucous membrane lesions including gingival capillary changes (84%, P=0.02), and shawl sign rash (47%, P=0.03). Anti-TPM4-positive patients with JDM frequently had heliotrope rash, malar erythema, and periungual capillary dilatation. Lower median serum levels of aldolase were found in JDM children with anti-TPM4 compared to without (P=0.02). The presence of anti-TPM4 significantly correlates with use of IV pulse steroids and intravenous immunoglobulin therapy in JDM patients (both P=0.01). The total number of medications taken was significantly associated with the presence of anti-TPM4 (P=0.02). Furthermore, the presence of anti-TPM4 was associated with the presence of HLA-C*04 [18.8% vs. 4.2%, OR 0.19 (95% CI 0.05- 0.72), p=0.02].

Conclusion: Autoantibodies to TPM4 in the proteome of HAEC are present in the plasma of patients with JDM, and are novel MAAs correlating with cutaneous manifestations in JDM. Larger studies will be required to determine the clinical utility of monitoring for these autoantibodies.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/association-of-anti-tropomyosin-alpha-4-autoantibodies-with-cutaneous-manifestations-in-juvenile-dermatomyositis/