Background/Purpose: Juvenile localized scleroderma (JLS) is a systemic inflammatory disease that primarily causes fibrosis of skin/subcutis resulting in pain, growth and joint restriction, and deformation. CNS inflammation can be seen in the craniofacial subtype. There are limited methods to monitor disease activity beyond clinical evaluation. S100A8/A9 (calprotectin) and S100A12 (EN-RAGE) proteins are emerging serum biomarkers in various skin and inflammatory diseases that are available for clinical use.

Methods: We measured serum concentrations of these proteins (hereon referred to collectively as S100 proteins) in a cohort of patients with JLS using a CLIA-certified immunodiagnostics lab (ELISA assay). We compared these results with cross-sectional clinical data to evaluate their potential use in JLS.

Results: Thirty nine patients were tested, mean age was 15 years (range 4-25). Most patients had a linear subtype (74%), were inactive (82%), and on treatment (60%). S100A8/A9 and S100A12 concentrations were closely correlated (R2 0.95, p< 0.001). Patients with active disease had a significantly higher concentration of S100 proteins. S100A8/A9 but not S100A12 was significantly higher in generalized and linear subtypes than plaque/circumscribed subtypes. Presence of another systemic autoimmune disease associated with elevated S100 protein levels; presence of other skin disease did not. There was signal in patients with anti-histone antibodies having lower levels of S100 proteins. S100 proteins showed significant linear correlation with CRP (R2 0.2, p< 0.01) and Physician Global Assessment of Activity (PGA-A) of R2 0.15 (p=0.02). The intrinsic cutoffs for each protein resulted in a 100% sensitivity and 66-69% specificity for active disease (LR 2.9-3.2). Use of a higher cutoff of 2x upper limit normal (ULN) resulted in a sensitivity of 29-43% and a specificity of 97% for both tests (LR 9.1-13.7). Having an S100 protein level greater than 2x ULN was associated with active disease, being on treatment but not dual therapy or a biologic, having another systemic autoimmune disease, not having another skin disease, having a negative anti-histone antibody, having a positive CRP, and having a higher PGA-A and mLoSSI. There was no association between sex, age, presence of CNS disease, arthralgia, myalgia, contracture, being on treatment, having other skin disease, being ANA positive, ESR, LoSCAT, LosDI, PGA of damage, or PGA of severity.

Conclusion: S100 proteins are potential serum biomarkers of activity but not damage in juvenile localized scleroderma that can discriminate between active and inactive disease. Further investigation is needed to determine utility in monitoring disease activity longitudinally, tapering/escalating therapy, prognosticating treatment response, determining flare risk and treatment resistance, and long term outcomes.

Association between S100 Proteins and Clinical Parameters

Comparison of S100 Concentrations between Active/Inactive Disease Status and between DIsease Subtypes

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/investigating-s100-proteins-as-biomarkers-for-pediatric-localized-scleroderma/