RA and Cancer: Can Biologics Lower Risk?

Published: Oct 3, 2014

By Nancy Walsh, Senior Staff Writer, MedPage Today

Patients with rheumatoid arthritis (RA) who were treated with tumor necrosis factor (TNF) inhibitors had lower rates of incident cancer compared with those on conventional disease-modifying anti-rheumatic drugs (DMARDs), a cohort study in Taiwan found.

The cumulative incidence of all cancers over 7 years, with adjustment for competing mortality, was 3.84% (95% CI 2.91-4.77) among patients receiving anti-TNF therapy compared with 5.22% (95% CI 4.69-5.75) for those on conventional DMARDs (P=0.005), according to Yi-Ju Chen, MD, of National Yang-Ming University in Taipei, and colleagues.

And the overall incidence rates were 5.35 (95% CI 4.23-6.46) per 1,000 patient-years for the anti-TNF group compared with 7.41 (6.75-8.07) per 1,000 in the DMARD group (P=0.0046), the researchers reported online in Arthritis Research and Therapy.

"The introduction of biologic therapies to the management of RA has raised concerns about the risk of cancer, particularly with respect to anti-TNF therapies because of the role of TNF in tumor progression and surveillance," they wrote.

The evidence for cancer promotion in patients treated with biologics has been conflicting, with earlier meta-analyses suggesting heightened short-term risks but a more recent meta-analysis that included 63 studies finding no increase.

To clarify this, Chen and colleagues analyzed data from the National Health Insurance Research Database, which includes almost all of the population of Taiwan, for the years 1997 through 2011.

In Taiwan, patients with RA become eligible for biologic treatment if they fail to respond to at least 6 months of treatment with more than two DMARDs such as methotrexate and hydroxychloroquine.

Biologics available in the national health program were the TNF inhibitors adalimumab (Humira), etanercept (Enbrel), and golimumab (Simponi), and the anti-CD20 monoclonal antibody rituximab (Rituxan).

Patients in the biologic group (n=4,426) were matched with DMARD-only patients (n=17,704) by age, sex, disease duration, and comorbidities.

Mean age was 54, and more than 85% were women. Mean disease duration was slightly more than 9 years.

A total of 73.9% received etanercept at some point, 35.6% were given adalimumab, and 13.1% were treated with rituximab; switching agents was common.

Cancer cases were included if they were diagnosed at least 6 months after the initiation of treatment, and were classified as hematologic and non-hematologic.

During the study period, 89 patients receiving biologics and 486 patients on conventional DMARDs were diagnosed with cancer.

The incidence rate for patients whose only biologic was adalimumab was 3.63 (95% CI 1.11-6.15) per 1,000 patient-years, compared with 6.85 (95% CI 5.26-8.44) per 1,000 for those whose only biologic was etanercept, which was not a significant difference. No cases of cancer were seen among patients whose only biologic was rituximab.

After adjustment for multiple potential confounders, including use of steroids, prior treatment with DMARDs, duration of disease, and comorbidities, the risk of cancer was significantly reduced in biologic users compared with DMARD-only patients (HR 0.63, 95% CI 0.49-0.80, P<0.0001), according to Chen and colleagues.

A link between malignancy and chronic inflammation, such as is seen in uncontrolled RA, is well recognized. "We assumed that patients taking biologics had more severe disease and were more likely to develop malignant disease," the authors wrote.

But the finding that those patients were less likely to be diagnosed with cancer "implies that the use of biologics attenuates the disease activity and then reduces the risk of cancer development to a level that is even lower than in subjects taking nonbiologic DMARDs," they noted.

Additional factors associated with a lower cancer risk were having ischemic heart disease, the use of certain medications such as statins and beta-blockers, and lengthy disease duration, while older age and more frequent hospitalization were associated with higher risk.

The negative association with ischemic heart disease may reflect the fact that those patients are more likely to die from cardiovascular causes before developing cancer, according to the authors.

The researchers then compared risks by cancer category and found that risks were higher among the DMARD group for both hematologic cancers (SIR 2.28, 95% CI 1.55-3.24) and non-hematologic (SIR 1.31, 95% CI 1.19-1.44) compared with the general population.

Risk of any cancer was similar for biologics compared with the general population (SIR 0.97, 95% CI 0.78-1.19)

However, the risk of hematologic cancer was significantly higher than the general population both for patients receiving biologics (SIR 4.64, 95% CI 2.65-7.53) and also among those on DMARDs (SIR 2.28, 95% CI 1.55-3.24).

"The association between lymphoma occurrence and use of biologics in RA has been of major concern," the authors noted.

That concern was borne out in this analysis, where the standardized incidence ratios for biologics and DMARDs were 6.13 (95% CI 3.26-10.49) and 2.52 (95% CI 1.56-3.85), respectively. But patients with moderate-to-severe RA are at increased risk for lymphoma regardless of treatment.

Limitations of the study included its observational design, a lack of information on various factors such as family history of cancer, disease severity, and lifestyle. In addition, only two of the five anti-TNF agents were included.

"Nonetheless, our study provides important evidence of the safety, in terms of cancer risk, of anti-TNF antagonists in RA patients," they concluded.