Site-level cutaneous phenotyping framework for anti-MDA5-positive dermatomyositis: exploratory associations with systemic immune reference markers.

Abstract

Objectives: To propose and evaluate a CDASI-informed, medical-record-based site-by-lesion cutaneous phenotyping framework for anti-MDA5-positive dermatomyositis, using established systemic and immunological markers as reference anchors to examine whether this framework provides additional phenotypic resolution beyond conventional binary skin assessment.

Methods: This single-centre retrospective cross-sectional study enrolled 339 anti-MDA5-positive DM patients. Cutaneous involvement was coded as binary ulceration, itch, and scale features across seven prespecified anatomical regions. The framework was CDASI-informed but did not use formal CDASI activity or damage scores. FLATCAN components, PAH, IgG, and IgM were used as systemic and immunological reference markers. Analyses included FDR-corrected univariate screening, hypothesis-driven multivariable association models, restricted cubic spline analysis, exploratory internal model-performance summaries, cross-correlation SVD (CC-SVD), and exploratory clustering.

Results: The framework revealed complementary skin-systemic association patterns. First, the spatial extent of ulceration refined a conventional binary ulcer signal: any cutaneous ulceration was associated with CD8 + T-cell depletion (OR = 3.35, P < 0.001; FDR q = 0.026), and ulcer site count remained independently associated with CD8 + depletion (OR = 1.43 per site, P = 0.008). Second, anatomical location contributed distinct information: facial ulceration was associated with PAH (OR = 2.28, P = 0.003) more strongly than overall ulcer site count. Third, lesion-feature type separated different immunological patterns, with ulceration preferentially associated with CD8+/IgG-related signals and itch with IgM-related signals. CC-SVD organised these observations into exploratory dimensions, including a bootstrap-stable facial involvement-PAH/infection dimension and a statistically less stable acral ulcer-CD8+/IgG dimension.

Conclusion: Site-by-lesion cutaneous phenotyping may provide a useful framework for studying phenotypic heterogeneity in anti-MDA5-positive dermatomyositis. The observed associations are exploratory and require prospective validation using standardised skin assessment and clinical outcome follow-up.