Clonal hematopoiesis (CH) becomes more prevalent with age and may impact the pathophysiology of inflammatory diseases by altering immune cell function. While clonal hematopoiesis of indeterminate potential (CHIP) can promote inflammation in non-malignant conditions, the relationship with rheumatoid arthritis (RA) has not been systematically investigated. We tested whether CHIP mutations are more common in RA using two population-level cohorts and newly diagnosed RA patients. CHIP was associated with prevalent RA in the FINRISK study of 10 089 participants with whole exome sequencing (odds ratio (OR)=2.06, 95% CI=1.08-3.94, P=0.029) and in the FinnGen cohort (N=520 210, OR=1.42, 95% CI=1.09-1.84, P=0.009) using single nucleotide polymorphism (SNP) array-based CHIP annotation. In the FinnGen cohort, DNMT3A mutations were associated with seropositive RA (OR=1.73, 95% CI=1.16-2.58, P=0.007), whereas CHIP overall was more common in participants with history of seronegative RA (OR=2.16, 95% CI=1.24-3.76, P=0.006). Furthermore, CHIP was associated with inferior overall survival among FinnGen participants with prevalent RA (P=0.010). In newly diagnosed RA (N=632), seropositive, but not seronegative, patients with DNMT3A mutations had higher erythrocyte sedimentation rate (P=0.014) and disease-activity scores (P=0.030). In contrast, TET2 mutations were significantly more common in patients with seronegative RA both in univariable (P=0.009) and multivariable models (OR=0.42; 95% CI=0.20-0.89, P=0.024). In conclusion, CHIP is associated with RA and distinct RA subtypes. Although the causality and underlying mechanisms of these observations remain unknown, our findings provide further evidence for the association between CHIP and inflammation in distinct disease contexts that may have therapeutic implications in the future.

M.M. has received honoraria from Celgene and Sanofi and research support from Gilead Sciences unrelated to this study. S.M. has received honoraria and research funding from BMS and Novartis, research funding from Pfizer, and honoraria from Dren-Bio (none related to this project).

This work was supported by the Sigrid Juselius Foundation (S.M, M.M), the Research Council of Finland (S.M, M.M), the Finnish Medical Foundation (M.M.), the European Research Council (Project: M-IMM 647355), Academy of Finland Heal-Art consortium (314442), Signe and Ane Gyllenberg Foundation (S.M), Helsinki Institute for Life Science Fellow Funding (S.M).

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

Ethics committee of Helsinki University Hospital (HUS) gave ethical approval for this work

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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).

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

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Access to FinnGen and FINRISK data can be requested by contacting the FinnGen consortium and the Finnish Institute for Health and Welfare (THL) Biobank, respectively. The data for RA patient cohorts can be requested from the respective biobanks. According to constraints in the ethical permit, sequencing data of patients is only available from the corresponding author upon reasonable request.