IMPORTANCE Small studies have implicated the association of specific autoantibodies with morphea subtype or severity, but no large-scale studies have been conducted. This prospective case-control study confirmed the presence of antinuclear antibodies (ANAs) and other autoantibodies in morphea but found they are of limited significance. OBJECTIVE To determine the prevalence of ANAs, extractable nuclear antigens such as antihistone antibodies (AHAs), and anti–single-stranded DNA antibodies (ssDNA abs) in patients with morphea vs a healthy control population and their association with clinical measures of morphea severity. DESIGN, SETTING, AND PARTICIPANTS Nested case-control study, conducted at the University of Texas Southwestern Medical Center, Dallas, and University of Texas Health Science Center, Houston. Study participants included individuals enrolled in the Morphea in Adults and Children (MAC) cohort and Scleroderma Family Registry and DNA Repository. MAIN OUTCOMES AND MEASURES Prevalence of ANAs, AHAs, ssDNA abs in patients with morphea vs matched controls and association of the presence of autoantibodies with clinical indicators of morphea severity. RESULTS The prevalence of ANAs, AHAs, and ssDNA abs in patients with morphea was 34%, 12%, and 8%, respectively. Antinuclear antibodies and AHAs, but not ssDNA abs, were present more frequently in cases than in controls. There was no difference in ANA prevalence among morphea subtypes. Among patients with linear morphea, the presence of autoantibodies was associated with clinical indicators of severe morphea including functional limitation (ssDNA ab, P = .005; and AHA, P = .006), extensive body surface area involvement (ssDNA ab, P = .01; and ANA, P = .005), and higher skin scores (ANA, P = .004). The presence of autoantibodies was not associated with clinical measures of morphea activity. CONCLUSIONS AND RELEVANCE Our results demonstrate that ANAs and AHAs are more prevalent among patients with morphea but are of limited clinical utility except in linear morphea, where their presence, although infrequent, is associated with greater lesion burden and functional impairment.

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