Machine learning integration of scleroderma histology and gene expression identifies fibroblast polarisation as a hallmark of clinical severity and improvement.

We sought to determine histologic and gene expression features of clinical improvement in early diffuse cutaneous systemic sclerosis (dcSSc; scleroderma). Fifty-eight forearm biopsies were evaluated from 26 individuals with dcSSc in two clinical trials. Histologic/immunophenotypic assessments of global severity, alpha-smooth muscle actin (aSMA), CD34, collagen, inflammatory infiltrate, follicles and thickness were compared with gene expression and clinical data. Support vector machine learning was performed using scleroderma gene expression subset (normal-like, fibroproliferative, inflammatory) as classifiers and histology scores as inputs. Comparison of w-vector mean absolute weights was used to identify histologic features most predictive of gene expression subset. We then tested for differential gene expression according to histologic severity and compared those with clinical improvement (according to the Combined Response Index in Systemic Sclerosis). aSMA was highest and CD34 lowest in samples with highest local Modified Rodnan Skin Score. CD34 and aSMA changed significantly from baseline to 52 weeks in clinical improvers. CD34 and aSMA were the strongest predictors of gene expression subset, with highest CD34 staining in the normal-like subset (p<0.001) and highest aSMA staining in the inflammatory subset (p=0.016). Analysis of gene expression according to CD34 and aSMA binarised scores identified a 47-gene fibroblast polarisation signature that decreases over time only in improvers (vs non-improvers). Pathway analysis of these genes identified gene expression signatures of inflammatory fibroblasts. CD34 and aSMA stains describe distinct fibroblast polarisation states, are associated with gene expression subsets and clinical assessments, and may be useful biomarkers of clinical severity and improvement in dcSSc.

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Competing interests: RSpiera reports receiving funds for the following activities: Research support: GlaxoSmithKline, Genentech/Roche, Novartis, Corbus Pharmaceuticals, Cytori Therapeutics, Evidera, Actelion Pharmaceuticals, ChemoCentryx, Boehringer Ingelheim Pharmaceuticals, Forbius, InfaRx, Sanofi, Kiniksa Pharmaceuticals; Consulting: GlaxoSmithKline, Janssen Pharmaceuticals, Sanofi Aventis, ChemoCentryx, Forbius, CSL Behring; MLW reports grants and personal fees from Celdara Medical, grants and personal fees from Bristol Myers Squib, personal fees from Acceleron, personal fees from Abbvie, grants and personal fees from Corbus and other fees from Boehringer Ingelheim, outside the submitted work; DEO reports receiving funds from Pfizer and personal fees from Astra Zeneca, outside the submitted work; JG reports receiving funds for the following activities: Consulting: Eicos Sciences; Research Support: Corbus Pharmaceuticals, Cumberland Pharmaceuticals and Eicos Sciences, outside the submitted work.