Clonal hematopoiesis is associated with distinct rheumatoid arthritis phenotypes

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.