Effect of Janus Kinase Inhibitors and Methotrexate Combination on Malignancy in Patients with Rheumatoid Arthritis: a Systematic Review and Meta-analysis of Randomized Controlled Trials

Overview

Journal Auto Immun Highlights

Publisher Biomed Central

Date 2021 Apr 29

PMID 33910632

Citations 9

Authors

Vinod Solipuram

Akhila Mohan

Roshniben Patel

Ruoning Ni

Affiliations

Soon will be listed here.

Abstract

Background: Rheumatoid arthritis (RA) is a systemic autoimmune disease. The combination therapy of methotrexate (MTX) and Janus kinase inhibitor (JAKi) is commonly used. Patients with RA are at increased risk of malignancy, however, it remains unclear whether the combination therapy is associated with a higher risk.

Objective: To assess the malignancy risk among patients with RA receiving combination therapy of JAKi and MTX compared to MTX alone.

Methods: PubMed, Cochrane and Embase were thoroughly searched for randomized controlled trials (RCTs) in patients with RA receiving JAKi and MTX, from inception to July 2020. Primary endpoints were malignancy events, Non melanomatous skin cancer (NMSC) and malignancy excluding NMSC and secondary endpoints were serious adverse events (SAE), deaths. Risk ratio (RR) and 95% CI were calculated using the Mantel-Haenszel random-effect method.

Results: 659 publications were screened and 13 RCTs with a total of 6911 patients were included in the analysis. There was no statistically significant difference in malignancy [RR = 1.42; 95% CI (0.59, 3.41)], neither NMSC [RR = 1.44 (0.36, 5.76)] nor malignancies excluding NMSC [RR = 1.12 (0.40, 3.13)]. No statistically significant difference between the two groups for SAE [RR = 1.15 (0.90, 1.47)] and deaths [RR = 1.99 (0.75, 5.27)] was found.

Conclusion: The adjunction of JAKi to MTX is not associated with an increased risk of malignancy when compared to MTX alone. There is no increased risk of SAE and deaths when compared to MTX alone in patients with RA.

Citing Articles

Key Determinants of Cardiovascular Outcomes in Multi-Ethnic Patients With Rheumatic Disease Using JAK Inhibitors.

Sunmboye K, Memon A, Durrani M Musculoskeletal Care. 2025; 23(1):e70066.

PMID: 39953988 PMC: 11829614. DOI: 10.1002/msc.70066.

Evaluation of Real-World Evidence to Assess Effectiveness Outcomes of Janus Kinase Inhibitors for Rheumatoid Arthritis: A Systematic Review of US Studies.

Gandy C, Bazzazzadehgan S, Bruera S, Huang Y Drug Healthc Patient Saf. 2025; 17():25-49.

PMID: 39802749 PMC: 11724667. DOI: 10.2147/DHPS.S492887.

Utilizing Clinical and Non-clinical Patient Factors in Predicting Cardiovascular Events in Patients on JAK Inhibitor Therapy: A Retrospective Cohort Study.

Sunmboye K, Petrie T, Bui B, Salim H, Khan M Cureus. 2023; 15(11):e48595.

PMID: 38084174 PMC: 10710663. DOI: 10.7759/cureus.48595.

Risk of cancer, cardiovascular disease, thromboembolism, and mortality in patients with rheumatoid arthritis receiving Janus kinase inhibitors: a real-world retrospective observational study using Korean health insurance data.

Min H, Kim H, Jeong H, Kim S, Kim H, Lee S Epidemiol Health. 2023; 45:e2023045.

PMID: 37080728 PMC: 10396807. DOI: 10.4178/epih.e2023045.

Upadacitinib for Patients with Rheumatoid Arthritis: A Comprehensive Review.

Sanmarti R, Corominas H J Clin Med. 2023; 12(5).

PMID: 36902522 PMC: 10002765. DOI: 10.3390/jcm12051734.

References

Ekstrom K, Hjalgrim H, Brandt L, Baecklund E, Klareskog L, Ekbom A . Risk of malignant lymphomas in patients with rheumatoid arthritis and in their first-degree relatives. Arthritis Rheum. 2003; 48(4):963-70. DOI: 10.1002/art.10939. View

Shamseer L, Moher D, Clarke M, Ghersi D, Liberati A, Petticrew M . Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015: elaboration and explanation. BMJ. 2015; 350:g7647. DOI: 10.1136/bmj.g7647. View

Karin M, Greten F . NF-kappaB: linking inflammation and immunity to cancer development and progression. Nat Rev Immunol. 2005; 5(10):749-59. DOI: 10.1038/nri1703. View

Chen Y, Chang Y, Wang C, Wu C . The risk of cancer in patients with rheumatoid arthritis: a nationwide cohort study in Taiwan. Arthritis Rheum. 2011; 63(2):352-8. DOI: 10.1002/art.30134. View

Fleischmann R, Pangan A, Song I, Mysler E, Bessette L, Peterfy C . Upadacitinib Versus Placebo or Adalimumab in Patients With Rheumatoid Arthritis and an Inadequate Response to Methotrexate: Results of a Phase III, Double-Blind, Randomized Controlled Trial. Arthritis Rheumatol. 2019; 71(11):1788-1800. DOI: 10.1002/art.41032. View

Xie W, Huang Y, Xiao S, Sun X, Fan Y, Zhang Z . Impact of Janus kinase inhibitors on risk of cardiovascular events in patients with rheumatoid arthritis: systematic review and meta-analysis of randomised controlled trials. Ann Rheum Dis. 2019; 78(8):1048-1054. DOI: 10.1136/annrheumdis-2018-214846. View

Higgins J, Altman D, Gotzsche P, Juni P, Moher D, Oxman A . The Cochrane Collaboration's tool for assessing risk of bias in randomised trials. BMJ. 2011; 343:d5928. PMC: 3196245. DOI: 10.1136/bmj.d5928. View

Buchbinder R, Barber M, Heuzenroeder L, Wluka A, Giles G, Hall S . Incidence of melanoma and other malignancies among rheumatoid arthritis patients treated with methotrexate. Arthritis Rheum. 2008; 59(6):794-9. DOI: 10.1002/art.23716. View

Askling J, Fored C, Baecklund E, Brandt L, Backlin C, Ekbom A . Haematopoietic malignancies in rheumatoid arthritis: lymphoma risk and characteristics after exposure to tumour necrosis factor antagonists. Ann Rheum Dis. 2005; 64(10):1414-20. PMC: 1755232. DOI: 10.1136/ard.2004.033241. View

10.

Tanaka Y, Emoto K, Cai Z, Aoki T, Schlichting D, Rooney T . Efficacy and Safety of Baricitinib in Japanese Patients with Active Rheumatoid Arthritis Receiving Background Methotrexate Therapy: A 12-week, Double-blind, Randomized Placebo-controlled Study. J Rheumatol. 2016; 43(3):504-11. DOI: 10.3899/jrheum.150613. View

11.

Williams C, Bloch D, Sibley J, Haga M, Wolfe F, Raynauld J . Lymphoma and luekemia in rheumatoid arthritis: are they associated with azathioprine, cyclophosphamide, or methotrexate?. J Clin Rheumatol. 2008; 2(2):64-72. View

12.

van Vollenhoven R, Fleischmann R, Cohen S, Lee E, Garcia Meijide J, Wagner S . Tofacitinib or adalimumab versus placebo in rheumatoid arthritis. N Engl J Med. 2012; 367(6):508-19. DOI: 10.1056/NEJMoa1112072. View

13.

Owen K, Brockwell N, Parker B . JAK-STAT Signaling: A Double-Edged Sword of Immune Regulation and Cancer Progression. Cancers (Basel). 2019; 11(12). PMC: 6966445. DOI: 10.3390/cancers11122002. View

14.

Hemminki K, Li X, Sundquist K, Sundquist J . Cancer risk in hospitalized rheumatoid arthritis patients. Rheumatology (Oxford). 2008; 47(5):698-701. DOI: 10.1093/rheumatology/ken130. View

15.

Simon T, Thompson A, Gandhi K, Hochberg M, Suissa S . Incidence of malignancy in adult patients with rheumatoid arthritis: a meta-analysis. Arthritis Res Ther. 2015; 17:212. PMC: 4536786. DOI: 10.1186/s13075-015-0728-9. View

16.

Andersen C, Lindegaard H, Vestergaard H, Siersma V, Hasselbalch H, Olivarius N . Risk of lymphoma and solid cancer among patients with rheumatoid arthritis in a primary care setting. PLoS One. 2014; 9(6):e99388. PMC: 4051682. DOI: 10.1371/journal.pone.0099388. View

17.

Hosseini A, Gharibi T, Marofi F, Javadian M, Babaloo Z, Baradaran B . Janus kinase inhibitors: A therapeutic strategy for cancer and autoimmune diseases. J Cell Physiol. 2020; 235(9):5903-5924. DOI: 10.1002/jcp.29593. View

18.

Genovese M, Smolen J, Weinblatt M, Burmester G, Meerwein S, Camp H . Efficacy and Safety of ABT-494, a Selective JAK-1 Inhibitor, in a Phase IIb Study in Patients With Rheumatoid Arthritis and an Inadequate Response to Methotrexate. Arthritis Rheumatol. 2016; 68(12):2857-2866. PMC: 5132065. DOI: 10.1002/art.39808. View

19.

Kivitz A, Gutierrez-Urena S, Poiley J, Genovese M, Kristy R, Shay K . Peficitinib, a JAK Inhibitor, in the Treatment of Moderate-to-Severe Rheumatoid Arthritis in Patients With an Inadequate Response to Methotrexate. Arthritis Rheumatol. 2016; 69(4):709-719. DOI: 10.1002/art.39955. View

20.

Taylor P, Keystone E, van der Heijde D, Weinblatt M, Del Carmen Morales L, Reyes Gonzaga J . Baricitinib versus Placebo or Adalimumab in Rheumatoid Arthritis. N Engl J Med. 2017; 376(7):652-662. DOI: 10.1056/NEJMoa1608345. View