Objective Recent studies have uncovered diverse cell types/states in the RA synovium; however limited data exist correlating these findings with patient-level clinical information. Using the largest cohort to date with clinical and multi-cell data, we determined associations between RA clinical factors with cell types/states in the RA synovium.

Methods The Accelerated Medicines Partnership Rheumatoid Arthritis study recruited subjects with active RA on no DMARDs or inadequate response to methotrexate (MTX) or tumor necrosis factor inhibitors. RA clinical factors were systematically collected. Biopsies were performed on an inflamed joint and tissue disaggregated and processed with a CITE-seq pipeline from which cell type percentages and cell type abundance phenotypes (CTAP) were derived: endothelial/fibroblast/myeloid (EFM), fibroblasts (F), myeloid (M), T/B cells (TB), T cells/fibroblasts (TF), T/myeloid cells (TM). Correlations were measured between RA clinical factors, % cell type, and CTAPs.

Results We studied 72 subjects, mean age 57 years, 75% female, 83% seropositive, mean RA duration 6.6 years, mean DAS28-CRP3 4.8. Higher DAS28-CRP3 correlated with higher % T cells (p<0.01). Subjects on MTX not on bDMARD had higher %B cells vs no DMARDs (p<0.01). The majority of subjects on bDMARDs were categorized as EFM (57%), while none were TF. No significant difference was observed across CTAPs for age, sex, RA disease duration, DAS28-CRP3.

Conclusion In this comprehensive screen of clinical factors, we observed differential associations between DMARDs and cell phenotypes, suggesting that RA therapies, more than other clinical factors may impact cell type/state in the synovium and ultimately response to subsequent therapies.

A.H.J. reports research support from Amgen, outside the submitted work. V.M.H. is a co-founder of Q32 Bio and has previously received sponsored research from Janssen and been a consultant for Celgene and BMS, outside the submitted work. A.F. reports personal fees from Abbvie, Roche, and Janssen and grant support from Roche, UCB, Nascient, Mestag, GlaxoSmithKline, and Janssen, outside the submitted work. S.R. is a founder for Mestag Therapeutics, a scientific advisor for Janssen and Pfizer, and a consultant for Gilead and Rheos Medicines.

This work was supported by the Accelerating Medicines Partnership (AMP) in Rheumatoid Arthritis and Lupus Network. AMP is a public-private partnership (AbbVie Inc., Arthritis Foundation, Bristol-Myers Squibb Company, Lupus Foundation of America, Lupus Research Alliance, Merck Sharp & Dohme Corp., National Institute of Allergy and Infectious Diseases, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Pfizer Inc., Rheumatology Research Foundation, Sanofi and Takeda Pharmaceuticals International, Inc.) created to develop new ways of identifying and validating promising biological targets for diagnostics and drug development. Funding was provided through grants from the National Institutes of Health (UH2-AR067676, UH2-AR067677, UH2-AR067679, UH2-AR067681, UH2-AR067685, UH2-AR067688, UH2-AR067689, UH2-AR067690, UH2-AR067691, UH2-AR067694, and UM2-AR067678). This work was also supported by NIH P30 AR072577 (KPL, DW).

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The Stanford IRB reviewed and approved this study.

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

This work was supported by the Accelerating Medicines Partnership (AMP) in Rheumatoid Arthritis and Lupus Network. AMP is a public-private partnership (AbbVie Inc., Arthritis Foundation, Bristol-Myers Squibb Company, Lupus Foundation of America, Lupus Research Alliance, Merck Sharp & Dohme Corp., National Institute of Allergy and Infectious Diseases, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Pfizer Inc., Rheumatology Research Foundation, Sanofi and Takeda Pharmaceuticals International, Inc.) created to develop new ways of identifying and validating promising biological targets for diagnostics and drug development. Funding was provided through grants from the National Institutes of Health (UH2-AR067676, UH2-AR067677, UH2-AR067679, UH2-AR067681, UH2-AR067685, UH2-AR067688, UH2-AR067689, UH2-AR067690, UH2-AR067691, UH2-AR067694, and UM2-AR067678). This work was also supported by NIH P30 AR072577 (KPL, DW).

All raw and processed data will be available upon publication of the primary methodology paper for the study, https://doi.org/10.1101/2022.02.25.481990.