Background/Purpose: Dermatomyositis (DM) is a heterogeneous multisystem autoimmune disease characterized by inflammation of the skin, muscle, and lung. Identifying the immune cells that drive disease activity is critical for advancing targeted therapies and improving clinical outcomes. Accordingly, we aimed to define immune cell populations associated with disease activity in DM across autoantibody-defined DM subtypes.

Methods: Bulk RNA sequencing analysis was performed on peripheral blood from 350 comprehensively phenotyped adult DM patients and 92 active DM skin biopsies. Type I (IFN-1) and type II (IFN-2) interferon scores were calculated as previously described. Immune cell proportions were estimated using CIBERSORT deconvolution, and associations with autoantibody subtypes, Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI) scores, Manual Muscle Testing (MMT) scores, and IFN scores were evaluated.

Results: Circulating pro-inflammatory M1 macrophage scores were significantly associated with cutaneous disease activity (CDASI; r=0.30, p< 0.001, Spearman's rank correlation coefficient). Concordantly, the M1 macrophage signature was markedly elevated in DM skin compared to healthy controls (18.2 fold increase, p=0.0097, Wilcoxon signed-rank test) and positively correlated with both IFN-1 (r=0.58, p< 0.001, Spearman) and IFN-2 (r=0.69, p< 0.001, Spearman) scores, suggesting a direct role for M1 macrophages in skin inflammation. Notably, the correlation between circulating M1 macrophages and CDASI scores was evident across several autoantibody groups, including anti-TIF1γ (n=105, r=0.41, p< 0.001, Spearman), anti-Mi2 (n=30, r=0.40 p< 0.03, Spearman), and anti-NXP2 (n=20, r=0.48, p< 0.03, Spearman), but was absent in anti-PM/Scl+ or anti-synthetase+ (anti-Jo1, anti-PL7, anti-PL12) DM patients, indicating that distinct immune drivers may underlie disease activity across DM subtypes. In contrast to skin, M1 macrophages were not associated with muscle disease activity in any DM subtype. Instead, increased memory B cell and plasma cell scores were most strongly associated with reduced muscle strength (MMT; memory B cells: r=-0.25, p< 0.01; plasma cells: r=-0.20, p< 0.05; Spearman). Additional immune cell associations were identified with other pathologies.

Conclusion: Our findings implicate circulating M1 macrophages as potentially key contributors to cutaneous disease activity in DM and highlight subtype-specific differences in immune pathogenesis. These results provide new insights into potential cellular therapeutic targets and raise the question of whether organ and autoantibody-specific therapeutic strategies are necessary to effectively manage the heterogeneous clinical presentations of DM.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/immune-cell-signatures-associated-with-disease-activity-in-dermatomyositis-across-autoantibody-subtypes/