Shift in perspective: autoimmunity protecting against rheumatoid arthritis

Objective: Rheumatoid arthritis (RA) is a systemic autoimmune disease with complex pathogenesis involving the innate and adaptive immune system. Clonal hematopoiesis of indeterminate potential (CHIP) is defined by clonal proliferation of one hematopoietic stem cell and is typically asymptomatic. Both are common among older adults. CHIP is associated with multiple autoimmune diseases, but has not been thoroughly evaluated for its relationship with RA. Methods: We examined three large biobanks where CHIP status of participants has been determined from whole genome sequencing data. We ascertained cases of RA, seropositive RA (SPRA), and seronegative RA (SNRA) using established methods and used survival analysis to test whether CHIP status was predictive of incident disease. We combined the results of the three biobank studies using random effects meta-analysis. For validation, we performed deep, targeted sequencing of CHIP-causing genes in an established clinical cohort of 132 RA cases, 56 controls, and 544 external controls. We compared the rates of CHIP between cases and controls using logistic linear regression. Results: In the UKBiobank and in meta-analysis, the presence of a large CHIP clone was associated with an increased risk for SPRA (HR = 2.57 with CI [1.46, 4.52] and p = 0.001) and RA (HR = 1.43 with CI [1.16, 1.75] and p = 7 x 10-4). Medium CHIP clones were associated with smaller increases in risk for SPRA and RA, and small CHIP clones carried no increased risk of any outcome. There were no associations detected between SNRA and CHIP of any size. In the clinical RA cohort, cases were more likely to have CHIP than controls after correcting for age, age2, and sex (OR: 2.08, HR [1.09, 3.83], p = 0.02). Conclusion: In a meta-analysis combing data from three large biobanks, large CHIP clones were associated with an increased risk for incident SPRA and, to a lesser extent, increased risk for RA. Validating this biobank-based finding, in a well-phenotyped clinical cohort, cases had higher rates of CHIP than age-matched controls. The mechanism by which CHIP drives the increased risk for SPRA is not known, but if it were discovered, could inform early intervention for patients with CHIP to prevent RA or personalized therapy for patients with RA based on CHIP status.

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Rheumatoid factor or interleukin-6 receptor inhibition predicts the long-term effectiveness of certolizumab pegol in Japanese patients with rheumatoid arthritis: A two-center retrospective study

Mutoh,

Okazaki,

Shirai

et al. 2024

Preprint

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Objectives To assess long-term retention rates associated with effectiveness of certolizumab pegol (CZP) and identify determinants of its effectiveness in patients with rheumatoid arthritis (RA). Methods This retrospective observational study enrolled 107 patients with RA. Retention rates based on effectiveness were investigated using the Kaplan–Meier method. Cox regression analysis was used to identify predictors of CZP effectiveness. In subgroup analyses, patients were categorized according to history of biological/targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs) to detect the determinants of CZP effectiveness in each group. Receiver operating characteristic analysis was performed to detect the optimal cut-off point for rheumatoid factor (RF). Results During a median of 56.0 months, overall retention rates at 12, 24, 48, and 60 months were 65.0%, 55.8%, 46.4%, and 40.2%, respectively. Multivariate analysis revealed that a b/tsDMARD-naïve group exhibited lowest likelihood of non-response to CZP (hazard ratio [HR]: 0.38, 95% confidence interval [CI]: 0.19–0.73, P = 0.003). In the sub-analyses, RF titer (HR per 100 IU/mL increment: 1.25, 95% CI: 1.06–1.60, P = 0.009) and prior interleukin-6 receptor (IL-6R) blockade (HR: 2.46, 95% CI: 1.11–5.57, P = 0.027) were strong determinants for CZP ineffectiveness in the b/tsDMARD-naïve and b/tsDMARD-switched groups, respectively. Highest retention rate was observed in the b/tsDMARD-naive population with an RF of < 79.9 IU/mL. Conclusions Overall, b/tsDMRAD-naïve status was the strongest predictor of long-term CZP effectiveness. RF elevation in b/tsDMARD-naïve and preceding IL-6R inhibition in b/tsDMARD-switched populations are significantly associated with reduced therapeutic effects of CZP.

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Shift in perspective: autoimmunity protecting against rheumatoid arthritis

Cited by 4 publications

References 60 publications

Combination of inorganic nitrate and vitamin C prevents collagen-induced arthritis in rats by inhibiting pyroptosis

Combination of inorganic nitrate and vitamin C prevents collagen-induced arthritis in rats by inhibiting pyroptosis

Clonal Hematopoiesis and the Risk for Rheumatoid Arthritis

Rheumatoid factor or interleukin-6 receptor inhibition predicts the long-term effectiveness of certolizumab pegol in Japanese patients with rheumatoid arthritis: A two-center retrospective study

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