ATLANTA — Compared with patients who received conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), those who received biologic DMARDs (bDMARDs) may be at increased risk for serious infection in rheumatoid arthritis (RA), according to study data presented at the 2019 American College of Rheumatology/Association of Rheumatology Professionals (ACR/ARP) Annual Meeting, held November 8 to 13, 2019, in Atlanta, Georgia.
These data were aligned with previous evidence and the analysis on safety signals will inform the 2019 update of the European League Against Rheumatism (EULAR) recommendations.
Investigators conducted a systematic review of MEDLINE, Embase, and Cochrane databases from 2016 to 2019 for observational studies comparing the safety of any DMARD with that of another intervention in the management of RA. Eligible interventions included any bDMARD, csDMARD, targeted sDMARD (tsDMARD), or glucocorticoid. Studies without a comparator group were excluded. For treatment modalities without registry data, safety data were instead abstracted from randomized controlled trials and long-term extension studies. Risk for bias was assessed using Hayden’s tool for observational studies and Cochrane Collaboration’s tool for randomized controlled trials.
Among 3886 screened articles, 42 observational studies were included in the analyses. Selected studies assessed the risk for infections (n=16), cancer (n=8), major adverse cardiovascular events (MACE; n=10), lower intestinal perforations (n=3), withdrawals resulting from adverse events (n=5), and immunologic reactions (n=2).
High between-study heterogeneity was observed. Two studies showed an increased risk for serious infections among patients treated with bDMARDs vs csDMARDs (adjusted incidence rate ratio, 3.1-3.9). In 9 studies (4 at low risk for bias), the risk for serious infection did not differ between bDMARDs. One of the 9 studies also suggested no difference in safety events between tofacitinib and tumor necrosis factor inhibitor biologics. Conflicting evidence was available for the relationship between bDMARDs and risk for herpes zoster infection. Risk for cancer and MACE were not elevated in bDMARDs compared with csDMARDs, nor among specific bDMARDs compared with other bDMARDs. Increased risk for lower intestinal perforations was observed for tocilizumab compared with csDMARDs and TNFis.
Additional safety data for bDMARDs and tsDMARDs were extracted from 57 manuscripts describing randomized controlled trials or long-term extension studies. In these manuscripts, no unexpected safety signals were identified, although possible increased risk for venous thromboembolism was observed for tsDMARDs. In response, the United States Food and Drug Administration/European Medicines Agency issued advisories against the use of baricitinib 4 mg or tofacitinib 10 mg twice daily in patients at high risk for venous thromboembolism. The same warning was not issued for baricitinib 2 mg or tofacitinib 5 mg twice daily.
Overall, these data were found to be consistent with prior literature. Compared with csDMARDs, bDMARDs were associated with slightly increased risk for serious infection. No differences in safety events were observed between specific bDMARDs; however, “the risk of [lower intestinal perforations] with tocilizumab and [venous thromboembolism] with tsDMARDs needs further evaluation,” the researchers concluded.
Disclosure: Several study authors declared affiliations with the pharmaceutical industry. Please see the original reference for a full list of authors’ disclosures.
Sepriano A, Kerschbaumer A, Smolen J. Safety of synthetic and biological DMARDs: a systematic literature review informing the 2019 update of the EULAR recommendations for management of rheumatoid arthritis. Presented at: 2019 ACR/ARP Annual Meeting; November 8-13, 2019; Atlanta, GA. Abstract 850.