Skin biopsies enhance prediction of clinical trajectory in diffuse cutaneous systemic sclerosis

Abstract

Objectives: To evaluate the relationship of skin fibroblast CD34 and aSMA and immune cell infiltration with disease duration in diffuse cutaneous systemic sclerosis (dcSSc) and identify predictors of improvement.

Methods: Skin biopsies and clinical data were analyzed from dcSSc patients enrolled in Lenabasum (n=79), Belimumab (n=18), or Nilotinib (n=8) trials. CD34 and aSMA were scored semi-quantitatively. Immune cells (CD20+, CD3+, CD123+) were counted. Clinical and histological features were compared between those with early (<18 months) versus later disease (≥18 months). 52-week clinical improvement was defined as >5-point decrease in modified Rodnan skin score (mRSS). An AIC-optimal multiple logistic regression model for clinical improvement among 68 mycophenolate mofetil (MMF) users was developed. Fibroblast spatial organization was visualized using imaging mass cytometry (IMC) in a representative sample.

Results: Despite similar baseline mRSS, early disease was associated with lower CD34, higher aSMA, increased B cells, and greater mRSS improvement compared to later SSc. IMC demonstrated regions of CD34⁺ fibroblasts in superficial dermis and aSMA⁺ fibroblasts in deeper, collagen-dense regions. Among MMF users, high CD34 and aSMA predicted improvement in early SSc; however, high aSMA predicted lower odds of improvement in later SSc. The probability of improvement was lowest in early SSc with aSMA^low/CD34^low immunophenotype and later SSc with aSMA^high. In later SSc, B cells were higher in aSMA^high versus aSMA^low skin.

Conclusion: Fibroblast immunophenotype varied by baseline disease duration and improved model performance for identifying those with improvement on MMF. Skin biopsies may be useful for refining prognosis and guiding patient management decisions.