Background/Purpose: The microbiome and specific bacterial triggers have been hypothesised to be involved in the pathogenesis of Rheumatoid Arthritis (RA) and RA flares. Antibiotic usage can mediate changes in the microbiome, and act as a surrogate for infection with potentially pathogenic bacteria. We aimed to determine the association of antibiotic usage and RA/RA flare diagnosis.

Methods: Analyses were performed using the Catalan SIDIAP, and UK CPRD, national electronic primary care databases. Within SIDIAP, patients with an initial diagnosis of RA and 5 age, gender and practice matched patients were selected. Missing data (present for BMI, smoking and alcohol drinking) was imputed using multiple imputation with chained equations. Within CPRD, RA diagnosed patients with ≥1 RA flare recorded were included.

We performed a case-control study using SIDIAP and a self-controlled case series (SCCS) study using the UK CPRD. 

Antibiotics grouped by the WHO ATC classification were the study exposures. Outcomes of interest were initial RA diagnosis in SIDIAP and RA flare in CPRD. 

Multivariate conditional logistic regression was performed using SIDIAP data to determine associations with specific antibiotic group use, controlling for age, BMI, gender, smoking status, alcohol consumption socioeconomic status, medical co-morbidities, primary care attendance and other antibiotic group use. Conditional fixed-effects Poisson regression models were used to determine incidence rate ratios of RA flares in relation to antibiotic usage within CPRD.

Results: 13,920 RA patients and 69,535 controls from the SIDIAP database were identified. Use of beta-lactams or quinolones in the 2 years prior to diagnosis were associated with RA (OR 1.23, 1.16-1.29; OR 1.32, 1.26-1.38 respectively; p< 0.0001). Only beta-lactams showed a consistent dose-response gradient (Q1 OR 1.19, 1.10-1.29; Q2 OR 1.22, 1.12-1.34; Q3 OR 1.31, 1.20-1.42; Q4 OR 1.42, 1.31-1.54; p< 0.0001) and association with recency of use (current: OR 1.82, 1.61-2.06; recent: OR 1.54, 1.36-1.74; and previous use: OR 1.20, 1.14-1.26, p< 0.0001). In parallel, 1,192 RA patients were identified from the CPRD (from 31,992 patients), with ≥1 flare/s recorded. Sulphonamide and trimethoprim use was associated with an increased risk of RA flare at 29-90 days (IRR 1.71, CI 1.12–2.59, p=0.012); 91-183 days (IRR 1.57, CI 1.06–2.33, p=0.025); and 184-365 days (IRR 1.44, CI 1.03–2.02, p=0.033) after antibiotic treatment commencement. No other antibiotic groups were associated with RA or RA flare risk.

Conclusion: Usage of broad-spectrum beta-lactam antibiotics was associated with index RA diagnosis in the Catalan population in a dose and time-dependent manner. Usage of sulphonamide and trimethoprim antibiotics appeared associated with a 70% increased risk of RA flare at 1-3 months, which remained significant up to 12 months after treatment. We hypothesise that antibiotic use is a surrogate of a pathogenic bacterial infection in index RA and that the delayed onset of RA flares after specific antibiotics is mediated through the gut or urinary microbiomes. Further epidemiological and mechanistic research is also needed to determine whether acute infections are associated with RA.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/antibiotic-use-and-the-development-of-rheumatoid-arthritis-ra-and-risk-of-ra-flares-case-control-and-self-controlled-case-series-studies-in-two-national-electronic-patient-databases-sidiap-and-cpr/