Key Points

Introduction

The management of rheumatoid arthritis (RA) dramatically changed in 1998 with the introduction of etanercept and infliximab, biospecific inhibitors of tumor necrosis factor (TNF) α, for the treatment of RA and Crohn colitis. Since then, 9 biologic agents have met regulatory approval for use in RA. As these agents aim to specifically mitigate the excessive cytokine or cellular activity seen in RA, speculation has grown that the long-term use of these biopharmaceuticals may alter normal immunosurveillance, thereby contributing to an individual’s cancer risk. Many studies and reports have speculated on the associations between cancer, RA, and biologic therapy. Whether malignancy is a consequence of rheumatoid inflammation or the therapies used to treat RA has been unclear until recently. This article addresses the growing data on the short- and long-term cancer risks associated with biologic use in RA.

Introduction

The management of rheumatoid arthritis (RA) dramatically changed in 1998 with the introduction of etanercept and infliximab, biospecific inhibitors of tumor necrosis factor (TNF) α, for the treatment of RA and Crohn colitis. Since then, 9 biologic agents have met regulatory approval for use in RA. As these agents aim to specifically mitigate the excessive cytokine or cellular activity seen in RA, speculation has grown that the long-term use of these biopharmaceuticals may alter normal immunosurveillance, thereby contributing to an individual’s cancer risk. Many studies and reports have speculated on the associations between cancer, RA, and biologic therapy. Whether malignancy is a consequence of rheumatoid inflammation or the therapies used to treat RA has been unclear until recently. This article addresses the growing data on the short- and long-term cancer risks associated with biologic use in RA.

Population cancer risk

According to a 2009 cancer statistics review performed by the Surveillance, Epidemiology and End Results (SEER) registry, the U.S. population risk of developing cancer is 41%, with a 21% chance of dying from cancer. The SEER database collects data on cancer events from 17 regional population registries in the United States and represents 28% of the population. The most common cancers involve the skin (affecting 20% of the population), prostate (15% of men), breast (11% of women), lung (6%), and colon (5.3%). Risk factors underlying neoplasia may be constitutive, genetically determined, or enhanced by exogenous factors known to augment risks, such as age, carcinogens, radiation, infection, immunosuppression, or inflammation.

Cancer risk in RA

In the prebiologic era, numerous studies showed the overall cancer risk to be the same in RA as in the general population (hence the standardized incidence ratio [SIR] is roughly 1.0). The SIR is calculated by comparing observed with expected cancer rates (usually derived from age- and era-matched populations drawn from the SEER database). Hence, numerous analyses have concluded that there is no overall increase in malignancy in RA. However, this summary belies the fact that there is a decreased risk of several malignancies in RA, notably adenocarcinoma of colon and breast cancer (owing to chronic nonsteroidal anti-inflammatory drug use and cyclooxygenase-2 inhibition) ( Table 1 ). At the same time, there is a higher risk of certain cancers, including lymphoma, lung cancer (SIR, 1.2–4.0), nonmelanomatous skin cancers (NMSC) (SIR, 1–3), and possibly melanoma and leukemia. Current evidence suggests these are augmented by chronic uncontrolled inflammation and possibly tobacco use.

Lymphoma risk with RA and biologic therapy

Lymphoma With Biologic Therapy

The issue of lymphoma risk with TNF inhibitors arose in 2003 when an analysis by the U.S. Food and Drug Administration (FDA) of the first 6303 patients with RA treated with etanercept, infliximab, and adalimumab found 6 lymphomas in those on TNF inhibitors but none in the placebo-treated controls in the first 6 months of exposure. When patients on placebo went on to receive the TNF inhibitor, 23 total lymphomas were found. Hence, the lymphoma risk was increased for etanercept (SIR, 3.47), infliximab (SIR, 6.4), and adalimumab (SIR, 4.35) ( Table 2 ). These elevated SIR values and wide CIs clearly overlap the elevated lymphoma SIR observed in patients with RA from the prebiologic era ( Fig. 1 ). These data suggested that patients with RA that was active and severe enough to receive biologic agent assumed an inflammation-dependant risk that was not substantially augmented by use of a TNF inhibitor. Numerous observational studies and metanalyses have shown that lymphoma rates in patients with RA are higher than in the general population, and those on biologic agents have the same risk as that seen in patients receiving methotrexate or disease-modifying antirheumatic drugs (DMARDs). A Cochrane meta-analysis examined lymphoma risk in 57 randomized clinical trials involving 22,657 patients treated for a total of 526.3 months with biologics (etanercept, adalimumab, infliximab, golimumab, certolizumab, anakinra, tocilizumab, abatacept, rituximab) and found that patients treated with biologics (0.093%) and controls or those treated with DMARDs (0.091%) had similar lymphoma rates. Their effect estimate for lymphoma was 0.53 (95% CI, 0.17, 1.66) suggesting a risk that was not higher than that seen among patients with RA receiving DMARD therapy alone. The SIR rates from randomized controlled trials of other new biologics have followed those seen with the TNF inhibitors (see Table 2 ). The package inserts for many of these biologics note that more malignancies (especially lymphomas) are noted in patients treated with TNF blockers that in those treated with placebo. The same product labeling estimates the SIR to be between 2 and 6 and that patients with chronic inflammatory disorders such as RA may be at higher risk for lymphoma (and leukemia) compared with the general population, even in the absence of a biologic. The package inserts state, “the potential role of TNF blocker therapy in the development of malignancies is not known.” Many of the RA registries listed in Fig. 2 have also shown lymphoma rates similar to those reported on the product label. Lastly, no evidence has been seen of increasing risk of cancer or lymphoma over time while on a TNF inhibitor.

Table 2

SIRs for lymphoma and malignancies in RA on biologics versus the population rate

Biologic	Registration Randomized Controlled Trials or Package Insert a
	Lymphoma SIR (95% CI)	Malignancy SIR (95% CI)	Malignancy Rate Biologic vs Placebo
Abatacept	3.5	0.9 (0.6–1.3)	1.3% vs 1.1%
Adalimumab	4.35 (2.6–10)	1.0 (0.7–1.3)	0.6 vs 0.5 per 100 PY
Anakinra	ND	ND	0.83
Certolizumab	2.06 (0.42–6.02)	0.86 (0.59–1.22)	0.5 vs 0.6 per 100 PY
Etanercept	3.47 (1.6–6.59)	0.98	ND
Golimumab	3.8	Equal to placebo
Infliximab	6.4 (1.7–16.3)	0.91 (0.53–1.46)	1.31 vs 0.46 per 100 PY
Rituximab	ND	ND	Not increased
Tocilizumab	ND	0.80 (0.77–0.83)	1.32 vs 1.37 per 100 PY

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