Looking beyond incidence in the relationship between anti-tumor necrosis factor therapy and malignancy

Abstract

Concern about the long-term safety of anti– tumor necrosis factor (anti-TNF) therapy has been present since its introduction for the management of rheumatoid arthritis (RA). Initial concern existed because of the biologic plausibility of anti-TNF therapy increasing the risk of certain adverse events, most notably, infection and malignancy. This led to the inception of several European academic-led national biologic registries specifically designed to monitor real-world safety (1). Long-term safety outcomes such as cancer cannot be addressed in clinical trials because of their short duration, making registries a vital source of safety information about these rare but important outcomes. Their success in rheumatology has led to a paradigm shift in postmarketing drug surveillance across many specialties. The possible effects of anti-TNF therapy on malignancy are difficult to predict accurately given the pleiotropic effects of TNF and the complexity of cytokine pathways and interactions. TNF has both tumorpromoting and tumor-inhibiting properties (2). TNF acts as a tumor promoter through mechanisms such as up-regulating the production of nitric oxide leading to DNA mutations, acting as an autocrine growth signal, promoting angiogenesis, increasing tumor cell invasion via induction of matrix metalloproteinases, and inducing resistance to cytotoxic drugs (2). On this premise, antiTNF therapy has been used in phase I and II trials to treat patients with solid and hematologic malignancies. Conversely, TNF also has powerful antineoplastic properties. High-dose TNF has been administered via isolated limb perfusion to treat melanoma and sarcoma (3). As our colleague Deborah Symmons says, “It isn’t called tumor necrosis factor for nothing.” It is only now, after nearly 10 years of followup, that registries are starting to be able to tackle the complex questions around the association between antiTNF therapy and malignancy. “Complex” because of the many possible (and sometimes bidirectional) effects that anti-TNF therapy might have on cancer incidence, progression, and outcome, as well as timeand dosedependent relationships that might exist. Given the underlying association between RA itself and certain specific cancers, one might anticipate a differential effect between cancer subtypes, for example, an increase in nonmelanoma skin cancer associated with immunosuppression, but a reduction in lymphoma secondary to a reduction in chronic inflammation. Most of the existing literature on the association between anti-TNF therapy and malignancy has focused on the incidence of cancer, which as been carefully reviewed elsewhere (4). In contrast, we know little about the influence of anti-TNF therapy on the progression and outcome of cancer in patients with RA or on the possible differential risk by cancer subtype. In this issue of Arthritis & Rheumatism, Raaschou and coworkers use the Swedish RA registries to investigate the influence of anti-TNF on both the stage of cancer at the time of diagnosis and survival following the diagnosis (5). This study is a very welcome addition to the existing literature, as it is a first step toward exploring these important issues. The authors investigated, in a typically thoughtful and fastidious manner, whether cancers that are diagnosed in patients exposed to anti-TNF are more aggressive than those in biologics-naive patients with RA. They found that under routine care in Sweden, the stage at presentation and survival following diagnosis did not differ between anti-TNF–exposed and biologics-naive patients with RA. The Swedish health care system and its data are the envy of many international epidemiologists. Unique patient identifiers allow electronic linkage of multiple national registries: inpatient and outpatient RA registries, the cancer registry, the prescribed drug registry, the cause of death registry, and in this instance, the Swedish Biologics Register, Anti-Rheumatic Therapy in Louise K. Mercer, MBChB, William G. Dixon, MRCP, PhD: University of Manchester, Manchester, UK. Address correspondence to William G. Dixon, MRCP, PhD, Arthritis Research UK Epidemiology Unit, Manchester Academic Health Science Centre, University of Manchester, Manchester M13 9PT, UK. E-mail: Will.dixon@manchester.ac.uk. Submitted for publication November 25, 2010; accepted in revised form January 6, 2011.