Extended Data Fig. 4: RA fibrogenic fibroblast subtyping and quantification.

a, UMAP projection of synovial fibroblasts with cluster annotations (top, ref.¹⁵) and projection of the fibrogenic score onto the UMAP as calculated by UCell (below). b, UMAP projection (top) of subsetted and re-clustered fibroblasts that had fibrogenic signature scores in the top decile. Dotplot of selected genes differentially expressed across clusters with the color representing scaled expression and size of the dot representing percent of cells expressing the gene. c, Violin plot of select genes differentially enriched in the POSTNhi versus COMPhi clusters with the bar representing median expression and p-values calculated using a two-sided Wilcoxon test. (Top) p < 2.2e-16 between POSTNhi cluster and other clusters, (Bottom) p < 2.2e-16 between COMPhi cluster and other clusters for indicated genes. d, Volcano plot representing differentially expressed genes in non-responders versus responders from bulk RNA-sequencing analysis of synovial tissue derived from treatment naïve patients. Genes in the upper right quadrant are log2 fold change > 1, padj < 0.05 between non-responders and responders. Differential expression was tested with DESeq2 (negative-binomial GLM; Wald test); p-values are FDR-corrected. Genes part of the fibrogenic signature are highlighted. e, Jitter plot representing normalized transcript detection of DKK3, FMOD, and POSTN from pre-treatment spatial transcriptomics data by response status. Statistics by two-sided Wilcoxon test. f, UMAP projection of COMP expression separated by remission status. g, plots showing correlation between baseline COMP+ cell abundance and indicated DAS28-ESR timepoint or changes in DAS28-ESR components. Statistical evaluation by two-sided Pearson correlation test. h, Stacked barplot representing the cell type composition of niche tiles that were classified as low (“lo”), medium (“mid”) or high (“hi”) for fibrogenic scores. i, violin plots representing the distribution of tile-level fibrogenic scores per indicated niche by remission status. The dots represent the median fibrogenic score per patient. Statistical comparison by GLM with dataset (biopsy) as a cofactor, FDR-corrected.