Tumor Necrosis Factor-Alpha Inhibitor Use and Malignancy Risk: A Systematic Review and Patient Level Meta-Analysis

Abstract

Background/Objectives: Tumor necrosis factor-alpha inhibitors (TNF-I) are widely prescribed for chronic inflammatory conditions. Prior studies of TNF-I use and malignancy risk have not demonstrated consistent associations outside non-melanoma skin cancers. We performed an updated systematic review and meta-analysis of interventional and observational studies to investigate this potential relationship. Methods: We searched MEDLINE, EMBASE, CENTRAL Register, Cochrane Library, and Scopus for studies published between 1996 and 2020. Two observers independently extracted the data; differences were resolved by consensus. Candidate studies were classified as interventional or observational per study design. A random-effects meta-analysis estimated malignancy rate ratios (MRRs) for cancers in TNF-I-exposed patients. Forest plots used a standard rate scale, and funnel plots used a random-effects model to assess for publication bias. Results: 45 interventional studies contributing 22,652 patients and 10 observational studies contributing 34,866 patients met the meta-analysis inclusion criteria. The plurality of these studies focused on adalimumab for both interventional (38%) and observational (50%) studies. TNF-I exposure was not associated with overall cancer risk in interventional (RR = 1.04, 95% CI 0.71–1.51) or observational studies (RR = 1.42, 95% CI 0.72–2.79). In total, 9/45 (20%) interventional studies and 0/10 (0%) observational studies had adequate quality of adverse event reporting, and 52/55 (95%) had either industry or unknown funding sources. Conclusions: Our synthesis of published findings from interventional and observational studies had inconclusive evidence on TNF-I exposure and cancer risk. Given the small number of studies designed to investigate malignancy risk, the low number of studies with adequate adverse event reporting, and the high number of industry-funded studies, it suggests that higher quality prospective studies are warranted to investigate the risk of malignancy for patients on chronic TNF-I.