Observational studies on the risk of cancer associated with tumor necrosis factor inhibitors in rheumatoid arthritis: a review of their methodologies and results.

Inhibitors of the inflammatory cytokine tumor necrosis factor (TNF) have proven to be highly effective in the treatment of various autoimmune conditions, including rheumatoid arthritis (RA). Indeed, according to several international guidelines that were based upon abundant evidence from therapeutic trials and clinical experience, these agents have come to be considered a cornerstone of therapy for RA patients with severe or refractory disease (1, 2) However, in addition to its central role in the immune driven systemic inflammation of RA, TNF is also important to immunologic surveillance. Because of the key role that the immune system plays in host defense, there is concern that therapy with TNF inhibitors (TNFi) might predispose patients to adverse effects related to impaired immunity, including an increased incidence of infections and/or cancer. Despite many years of clinical research and more than a decade since the introduction of TNF inhibitors into the clinic, there is disagreement about the potential association between use of these agents and malignancy. From a mechanistic standpoint, it could be hypothesized that inhibition of TNF could either enhance or inhibit cancer development (3–6). On the one hand, via mechanisms such as induction of apoptosis or suppressive effects on gene expression, TNF may suppress the development of certain tumors (5). Indeed, the name ‘TNF’, which was coined well before the role of this cytokine in inflammation and in numerous autoimmune diseases was known, reflects the observed inhibitory effects of this cytokine on certain tumors. Therefore, blockade of TNF may enhance the risk of cancer. In addition, TNF serves as a key element of the inflammatory response whose inhibition may increase the risk to various infections. This could potentially place the host at greater risk of cancers driven by chronic infections, particularly viral (7). By these mechanisms, inhibiting TNF might increase the risk of cancer. On the other hand, uncontrolled inflammation itself may also potentiate cancer (3, 4). Also, among the myriad activities of TNF is its profound effect on angiogenesis, which is critical to tumor growth, survival, and metastasis (3, 4). Therefore, potent anti-inflammatory treatments, such as TNFi, could decrease the risk of cancer through suppressing inflammation and reducing angiogenesis. This concept is supported by two lines of data. First, patients with higher levels of systemic inflammation, such as those with RA, are at a greater risk for developing lymphomas (8). Second, treatment with corticosteroids, which possess diverse anti-inflammatory properties, appear to be associated with a lesser risk of lymphoma development (9). Similar to the basic science suggesting that TNFi may increase or decrease the risk of cancer, randomized controlled trials do not provide definitive evidence about this relationship. Two recent meta-analyses found no clear evidence of increased cancer risk with the use of TNFi. (10, 11). One large meta-analysis that included only the monoclonal antibodies, infliximab and adalimumab, found an increased risk of cancer (12). A meta-analysis focused on etanercept suggested a trend toward an increased risk but the confidence interval spanned one for the primary analysis and secondary analyses did not all suggest increased cancer risk (13). Furthermore, a study of patients enrolled in adalimumab trials for early RA found no significant increase in cancer risk (14). While randomized controlled trials are the gold standard for efficacy, they may not provide the best information regarding a drug’s toxicity, owing to their relatively short duration and strict inclusion criteria that may exclude important at-risk groups (15). Epidemiologic studies of patients in typical care allows for analysis of more relevant subjects with a variety of comorbid conditions using concomitant treatments. With this background, we undertook a systematic review of epidemiologic studies of the relationship between TNFi and cancer. Prior reviews have examined this risk of cancer in RA (16). Whereas, this review focuses on both the methodologic attributes of studies examining TNFi and cancer, as well as their results. We did not attempt a meta-analysis because of the obvious methodological heterogeneity and opted to present the findings as a systematic review, as suggested by the Cochrane Collaboration (17).