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Background: Epidemiologic studies suggest that disease duration and degree of inflammatory activity of rheumatoid arthritis (RA) contribute to lymphoma development (1). Whether the decrease in inflammatory burden seen with use of biologic or targeted synthetic disease modifying anti-rheumatic drugs (bDMARDs or tsDMARDs) translates into a lower risk of lymphoma in RA needs to be studied.
Objectives: The objective of our study was to examine the effect of administration of b/tsDMARDS on the incidence of lymphoma relative to conventional synthetic DMARDs (csDMARDs) in an inception cohort of Veterans with RA.
Methods: We identified patients >18 years of age diagnosed with RA in any US Veterans Affairs (VA) facility from 1/1/2002 and 12/31/2018 using the VA Corporate Data Warehouse (CDW). To be included, each patient was required to meet the following criteria: 2+ RA diagnostic codes at least 7 days apart but no more than 365 days apart; 2) a prescription for a csDMARD within 90 days of the first RA diagnosis; and 3) an inpatient or outpatient visit 30 days to 2 years preceding first RA diagnosis (indicating they are a regular user of the VA). The csDMARDs included in these analyses were: methotrexate, sulfasalazine, leflunomide, and hydroxychloroquine. The bDMARDs included were tumor necrosis factor inhibitors (TNFi) and non-TNFi biologics such as tocilizumab, rituximab, abatacept, and biosimilars; tsDMARD was tofacitinib. Patients with prevalent lymphoma were excluded. Lymphoma diagnoses were identified using International Classification of Diseases Version 9, 10 and Oncology (ICD9, ICD10, ICDO) codes.
We used marginal structural models as described by Hernan et al (2) and time-varying Cox models to control for confounding by indication while evaluating this association. We adjusted for baseline demographics (age, sex, race, ethnicity, year of cohort entry, rheumatology visits), and time-varying CRP and time-varying Rheumatoid Disease Comorbidity Index (RDCI) (3) to control for confounding.
Results: 27,421 Veterans with RA met our eligibility criteria. Most of the Veterans (56%) were in the age range 61-80 years old; 89% male, 76% White, 14% African American. 8,225 (30%) patients were treated with a b-/tsDMARD. The crude incidence rates were 1.71 (95% CI 1.5-1.94) per 1000 person-years for those only on csDMARDs and 1.78 (95% CI 1.44-2.18) for patients during or following use of a b/tsDMARDs. After adjustment with both time-fixed and time-varying covariates using marginal structural models, the incidence of lymphoma was not different between patients who did and did not use a b/tsDMARD (hazard ratio=1.06, 95% CI= 0.82-1.37) (
Estimates of Effect of bDMARD or tsDMARD use on Lymphoma relative to use of csDMARDs
| Marginal Structural Models; adjusted for: | ||
|---|---|---|
| @ Demographics | 1.04 | (0.80, 1.34) |
| # Demographics + CRP | 1.06 | (0.82, 1.37) |
* per 1000 person-years
@ Demographics = age, gender, race, ethnicity, rheumatology visits, and year of cohort entry
# Adjusts for CRP, baseline rheumatology visits (yes/no) and RDCI.
CRP = C-Reactive Protein, RDCI = Rhematic Disease Comorbidity Index, CI = Confidence Interval, b/tsDMARD = biologic or targeted synthetic DMARD, csDMARD = conventional synthetic DMARD
Conclusion: In this large study using the nationwide VA data, we did not observe an association between the use of b/ts DMARDs and an increased risk of lymphoma.
REFERENCES:
[1]Baecklund E, Iliadou A, Askling J, Ekbom A, Backlin C, Granath F, et al. Association of chronic inflammation, not its treatment, with increased lymphoma risk in rheumatoid arthritis. Arthritis Rheum. 2006;54(3):692-701.
[2]Robins JM, Hernan MA, Brumback B. Marginal structural models and causal inference in epidemiology. Epidemiology. 2000;11(5):550-60.
[3]England BR, Sayles H, Mikuls TR, Johnson DS, Michaud K. Validation of the rheumatic disease comorbidity index. Arthritis care & research. 2015;67(6):865-72.
Disclosure of Interests: None declared