A narrative review of the comparative safety of disease-modifying anti-rheumatic drugs used for the treatment of rheumatoid arthritis

ABSTRACT

Introduction

Disease-modifying anti-rheumatic drugs (DMARDs) have improved the outcomes of patients with rheumatoid arthritis (RA). DMARDs are classified into three categories: conventional synthetic DMARDs, biological DMARDs (including biosimilars), and targeted synthetic DMARDs. DMARDs, by way of their effect on the immune system, are associated with increased risk of adverse events, including infections, malignancies, cardiovascular disease, gastrointestinal perforations, and other less common events.

Areas covered

In this narrative literature review performed with searches of the PubMed database from 1 January 2010 through 1 January 2023, we compare the risk of safety events between DMARDs using data from both randomized clinical trials and observational studies.

Expert opinion

DMARD use in RA is associated with higher rates of serious infections, tuberculosis reactivation, opportunistic infections, and possibly malignancies. Specific biologic DMARDs and higher doses are associated with elevated risks of various adverse events (gastrointestinal perforations, thromboembolism, serious infection). Shared decision-making is paramount when choosing a treatment regimen for patients based on their own comorbidities. JAKi are the newest class of medications used for RA with robust safety data provided in clinical trials. However, more real-world evidence and phase-IV pharmacovigilance data are needed to better understand comparative safety profile of DMARDs in RA.

KEYWORDS:

• Biological DMARDs
• cardiovascular disease
• conventional synthetic DMARDs
• targeted synthetic DMARDs
• gastrointestinal perforations
• infections
• malignancies
• thromboembolism

Article highlights

• Compared with the general population and RA patients using csDMARDs, most bDMARDs have a higher risk of serious infection that is most pronounced in the first 1-2 years of therapy initiation.

• RA patients taking bDMARDs have higher risk of lymphoma and non-melanoma skin cancers compared with the general population; those on tsDMARDs have higher overall risk of all malignancies compared with the general population. Real-world evidence from observational studies does not show that tsDMARDs have elevated risk of cancer compared to TNFi; this contrasts with findings from a recent, important phase-IV pharmacovigilance RCT comparing tofacitinib to TNFi. In the RCT, patients were older (all patients over 50 years old) and had at least one cardiovascular risk factor (patients with previous malignancies were excluded from the study).

• RA patients with history of prior malignancy who are being treated with bDMARD do not have increased risk of future incident cancer. Patients with prior history of cancer treated with TNFi have lower risk of developing new cancer compared with patients on csDMARDs.

• In real world population getting routine care, the risk of MACE was similar between tofacitinib and bDMARDs, specifically TNFi and IL6i; however, tofacitinib was associated with an increased risk of cardiovascular outcomes in patients with RA and cardiovascular risk factors, similar to the higher risk of MACE with tofacitinib vs. TNFi in RA patients in the ORAL-Surveillance study, a randomized non-inferiority trial.

Declaration of interest

JAS has received consultant fees from ROMTech, Atheneum, Clearview healthcare partners, American College of Rheumatology, Yale, Hulio, Horizon Pharmaceuticals/DINORA, Frictionless Solutions, Schipher, Crealta/Horizon, Medisys, Fidia, PK Med, Two labs Inc., Adept Field Solutions, Clinical Care options, Putnam associates, Focus forward, Navigant consulting, Spherix, MedIQ, Jupiter Life Science, UBM LLC, Trio Health, Medscape, WebMD, and Practice Point communications; and the National Institutes of Health. JAS has received institutional research support from Zimmer Biomet Holdings. JAS received food and beverage payments from Intuitive Surgical Inc./Philips Electronics North America. JAS owns stock options in Atai life sciences, Kintara therapeutics, Intelligent Biosolutions, Acumen pharmaceutical, TPT Global Tech, Vaxart pharmaceuticals, Atyu biopharma, Adaptimmune Therapeutics, GeoVax Labs, Pieris Pharmaceuticals, Enzolytics Inc., Seres Therapeutics, Tonix Pharmaceuticals Holding Corp., Aebona Pharmaceuticals, and Charlotte’s Web Holdings, Inc. JAS previously owned stock options in Amarin, Viking and Moderna pharmaceuticals. J A Singh is on the speaker’s bureau of Simply Speaking. J A Singh was a member of the executive of Outcomes Measures in Rheumatology (OMERACT), an organization that develops outcome measures in rheumatology and receives arms-length funding from 8 companies. J A Singh serves on the FDA Arthritis Advisory Committee. J A Singh is the co-chair of the Veterans Affairs Rheumatology Field Advisory Board (FAB). J A Singh is the editor and the Director of the University of Alabama at Birmingham (UAB) Cochrane Musculoskeletal Group Satellite Center on Network Meta-analysis. J A Singh previously served as a member of the following committees: member, the American College of Rheumatology’s (ACR) Annual Meeting Planning Committee (AMPC) and Quality of Care Committees, the Chair of the ACR Meet-the-Professor, Workshop and Study Group Subcommittee and the co-chair of the ACR Criteria and Response Criteria subcommittee.The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Author contributions

(a) substantial contributions to the conception and design (all authors)

(b) the drafting of the article or critical revision for important intellectual content (all authors),

(c) final approval of the version to be published (all authors),

(d) agreement to be accountable for all aspects of the work (all authors)

Reviewer disclosures

A reviewer on this manuscript has disclosed that they have received research grant, consulting and speaker fees from several of the drug companies that market the DMARDs discussed in the manuscript. Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/14740338.2024.2348575.

Additional information

Funding

J A Singh is supported by research grants from the National Institutes of Arthritis, Musculoskeletal and Skin Diseases [NIAMS; P50 AR060772], Department of Veterans Affairs [1 I01 RX002745; I01 BX005996-01A2], and the Patient Centered Outcomes Research Institute [PCORI; SDM-2017C2-8224; CER-2020C1-19193]. J A Singh is also supported by the resources and the use of facilities at the VA Medical Center at Birmingham, Alabama, USA.