Association Between Methotrexate Use and Lymphoma in Rheumatoid Arthritis: A Systematic Literature Review

Background Rheumatoid Arthritis (RA) is associated with an increased risk of lymphoma compared to the general population, which has been attributed to increased disease activity (1, 2). By decreasing RA disease activity, methotrexate could potentially help to reduce the risk of lymphoma development; however, there are conflicting data in the literature. Objectives To perform systematic literature review to evaluate the association between use of methotrexate in RA and the risk of developing lymphoma. Methods A systematic literature search was performed using the PubMed, Embase, and Cochrane Central Register of Controlled Trials from inception through December 9, 2021. The search was limited to observational studies and randomized controlled trials (RCT) published in English that evaluated the association between use of MTX in RA and the development of lymphoma. Case series and reports were excluded. Two authors independently extracted data from final articles using a predefined data abstraction form and conflicts were resolved by a third reviewer. Quality assessments were performed. Results The study identification and selection process are summarized in Figure 1. Of the initial 839 articles identified, only eight articles met the eligibility criteria. The characteristics of these studies are depicted in Table 1 . These were mostly observational studies except one RCT. Study sample sizes varied from 160 to 20,000 patients with RA. Five studies reported the odds/hazards ratio of occurrence of lymphoma in patients exposed to methotrexate versus not exposed to methotrexate. Three studies compared risk of lymphoma development in RA patients treated with methotrexate versus other biological DMARD of which one was an RCT. Most of the studies adjusted for variables such as age, sex, RA disease activity measures and inflammatory markers, concomitant RA medications and risk factors for cancer and RA. Of the eight studies, six did not find a significant association between MTX use and lymphoma, while two studies, conducted in Japan, reported a significant association. Included studies were of moderate to high quality. The heterogeneity of the included studies precluded conducting a meta-analysis. Conclusion While there are conflicting data regarding the role of MTX in lymphomagenesis in RA, we observed that a majority of high-quality epidemiologic studies did not support an association between MTX use and development of lymphoma. Only two studies from Japan reported an association between MTX use and development of lymphoma. References [1]Baecklund E, et al. Lymphoma development…the driving forces? Seminars in cancer biology; 2014: Elsevier. p. 61-70. [2]Smitten AL, et al. A meta-analysis of the…rheumatoid arthritis. Arthritis research & therapy. 2008;10(2):1-8. Table 1. Characteristics of the included studies Author, year Study location; period Number of patients with RA Number of patients with lymphoma Effect estimates of the association (95% CI) Bernatsky, 2008 Canada; 1980-2003 23 733 346 OR 1.23 (0.97-1.57) Hashimoto, 2015 Japan; 2002 - 2012 66,953 patient - years 63 OR 3.5 (2.0–6.3 ) Hellgren, 2017 Sweden; 1997-2012 12,656 62 RR =0.9 (0.8–1.0) Kedra, 2021 France; 1971–2016 162 54 -Univariate analysis: OR - 1.0 (0.3 to 3.4); p value 0.97 -Sensitivity analysis: OR - 0.78 (0.10-5.93); p value 1.00 Honda, 2022 Japan; 2011 9815 68 MTX use versus no MTX use based on MTX dose: 0 to 8 mg: HR: 2.35 (1.25-4.42 ); >8 mg: HR 4.39 (2.07-9.32 ) Setoguchi, 2006 US and Canada; 1994 -2004 7,830 58 bDMARD versus MTX; HR:1.11 (0.51–2.37) Lee, 2014 151 centers worldwide; 2010- 2013. 958 3 3 lymphomas in Tofacitinib group; 0 in MTX group Solomon, 2014 US; 2001 -2010 6806 2865 Person-years TNFI versus MTX; HR- 0.15 (0.01–2.19) CI- Confidence Interval; OR- Odds Ratio; RR- Relative Risk; MTX- Methotrexate; HR- Hazard Ratio; DMARD- Disease Modifying Antirheumatic Drug; TNFI- Tumor Necrosis Factor Inhibitor; RA- Rheumatoid arthritis Acknowledgements: NIL. Disclosure of Interests None Declared.