Jonathan Kay, MD


July 27, 2012

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Hello. I'm Jonathan Kay, Professor of Medicine at the University of Massachusetts Medical School and Director of Clinical Research in the Division of Rheumatology at UMass Memorial Medical Center. Welcome to my Medscape blog.

Today I'd like to talk about cancer in rheumatoid arthritis. It is well known that patients with rheumatoid arthritis are at increased risk of developing lymphoma. Patients with rheumatoid arthritis are also at increased risk of developing lung cancer, perhaps because cigarette smoking is a shared risk factor for both rheumatoid arthritis and the development of lung cancer. However, patients with rheumatoid arthritis probably have a lower risk of developing colorectal cancer or breast cancer. Why might this be?

Both colorectal cancer and breast cancer are potentially preventable cancers with regular screening, and patients with rheumatoid arthritis see their rheumatologist on a very regular basis, more commonly than patients who are otherwise healthy see their internist. Thus, with appropriate attention paid to routine screening, patients with rheumatoid arthritis may have better preventive care and therefore be less likely to develop a colorectal malignancy that is at a stage in which it is not resectable. Breast cancer may be recognized at a very early stage in which it is amenable to lumpectomy.

According to a meta-analysis by Bongartz and colleagues[1] that was published in 2006 in JAMA, patients are at about a 4-fold increased risk of developing cancers when treated with high-dose anti-TNF antibody therapy compared with placebo. However, most of these malignancies are nonmelanoma skin cancers. The same group from the Mayo Clinic published a subsequent study looking at etanercept in randomized controlled clinical trials.[2] In that meta-analysis, they found a trend toward increased malignancy, but not one with statistical significance among patients treated with etanercept.

The best way to look at the relative risk of developing malignancy in rheumatoid arthritis is to look at large registries. The Swedish ARTIS registry is a large registry of nearly 68,000 patients with rheumatoid arthritis from 3 overlapping national registries in Sweden. Johan Askling and colleagues[3] looked at this registry and found that there was an absolutely equivalent rate for developing cancer among patients treated with TNF inhibitors compared with biologics-naive individuals. There was no statistically significant difference between the 2 groups. Over time, there was no increase in the risk of developing cancer after initiation of a TNF inhibitor or with increased-dose TNF-inhibitor therapy.

The German RABBIT registry also found no increased risk of developing cancer among patients with rheumatoid arthritis.[4] In a meta-analysis of large, prospective, observational registry studies that was published in the Annals of Rheumatic Diseases, Xavier Mariette and colleagues[5] found no increased risk of developing lymphoma or all-site malignancies with TNF-inhibitor therapy compared with biologics-naive individuals. However, they did find an increased risk of developing nonmelanoma skin cancers.

What about melanoma? Simard and colleagues[6] looked at the Swedish ARTIS registry and found a 1.8 relative risk for developing melanoma with 95% confidence intervals not crossing unity, indicating statistical significance among individuals who were treated for 1-2 years with a TNF inhibitor. However, this relative risk was not significantly increased in individuals who were treated for less than 1 year or for longer than 2 years with a TNF inhibitor. In the same cohort, all-site malignancies were not increased.

What about patients with prior malignancy? That is a difficult topic to address because patients with prior malignancy are not likely to be prescribed a TNF inhibitor by physicians who are aware of non-evidence-based data. Thus, it's going to be difficult to generate evidence-based data to support or contradict this assumption. There is channeling bias in registry studies. However, a study that looked at the British Society for Rheumatology Biologics Register found that several patients with prior melanoma had recurrent melanoma, whereas individuals with other forms of cancer did not develop recurrent malignancy when treated with TNF inhibitors.[7] Thus, it seems that this immunologically mediated cancer, melanoma, is probably the most important cancer for which we should not prescribe a TNF inhibitor. Individuals with other forms of cancer are not likely to develop recurrent malignancy if treated with a TNF inhibitor. In fact, for lymphoma, lowering disease activity may actually reduce the likelihood of developing lymphoma.

How does one address the clinical conundrum of treating a patient with active rheumatoid arthritis but with a prior malignancy? The 2012 update of the 2008 American College of Rheumatology recommendations for the use of biologic agents in the treatment of rheumatoid arthritis suggests that for individuals with solid malignancy that was treated more than 5 years ago or nonmelanoma skin cancer that was treated more than 5 years ago, any biologic agent can be used.[8] However, for those with a solid malignancy that was treated within the last 5 years or a nonmelanoma skin cancer that was treated within the last 5 years, these guidelines recommend rituximab therapy, with level C evidence to support the recommendation. Similarly, individuals with treated skin melanoma or treated lymphoproliferative malignancy should also be treated with rituximab rather than TNF inhibitors. There is no evidence to support the safety of using tocilizumab, but because tocilizumab is used to treat Castleman disease, which is a lymphoproliferative disease, perhaps an individual with a treated lymphoproliferative malignancy might be safely treated with tocilizumab if rituximab cannot be used for any reason.

To summarize, patients with rheumatoid arthritis appear to be at higher risk of developing lymphoma -- both Hodgkin and non-Hodgkin lymphoma -- and lung cancer, and at a potentially decreased risk of developing colorectal and breast cancer compared with the general population. The risk of developing lymphoma is associated with disease activity and functional class. Patients treated with TNF inhibitors do not have a significantly higher risk of developing malignancy than patients treated with traditional disease-modifying antirheumatic drugs. Treatment of patients who had prior melanoma with TNF inhibitors has been found in the British Society for Rheumatology Biologics Register to have been associated with more incident malignancy and recurrent metastases. The risks associated with biologic agents should be weighed against their potential benefits in patients with previous malignancy as they should be done in any patient with rheumatoid arthritis.

Thank you for your attention. I welcome your questions and comments and look forward to seeing you again on Medscape.


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