Safety of longterm anti-TNF use, with respect to malignancy, in a national cohort of people with rheumatoid arthritis

Cancer is more common in people who have rheumatoid arthritis (RA), a painful disease of the joints. This is especially true for skin and lung cancer and lymphoma, a cancer of the immune system. This may be due to persistent inflammation. A new drug, called anti-TNF, controls this inflammation and may therefore, reduce the risk of cancer. However, there is a risk that this drug may actually cause cancer because it blocks the action of TNF, a protein which protects the body from cancer. Therefore, many physicians and patients are nervous about prescribing this drug. Using data from people with RA who have enrolled in a long-term study of anti-TNF use, I will measure inflammation as well as the duration of treatment with anti-TNF. I will then use statistical tests to estimate whether the drug or the inflammation is responsible for causing any cancers that develop. The results will inform doctors better on the use of these drugs. Although this study is specific to cancer and arthritis, the skills acquired will be applicable to other drugs and other diseases where a drug may have dual actions in the body.

Background: Rheumatoid arthritis (RA) is associated with an increased risk of certain malignancies, including lymphoproliferative malignancies (LPM), skin and lung cancers. The increased risk of LPM may relate in part to chronic immune stimulation. Drugs which block the action of tumour necrosis factor (anti-TNF) are very effective in controlling this inflammation. However, as a cytokine of the innate immune system, TNF plays a critical role in tumour surveillance and therefore, there is a concern that blockade of this cytokine may increase further this risk of malignancy. Alternatively, patients who receive anti-TNF therapies, by way of improved disease control, may ultimately have a lower risk of malignancy.
Aim: To develop an expertise in epidemiological research methods, with a particular focus on long-term malignancy risk in RA patients treated with anti-TNF drugs.
Research Methods: The incidence of malignancy in an anti-TNF treated RA cohort will be measured, and the relative risk of malignancy compared to a non-biologic disease modifying anti-rheumatic drug (DMARD) cohort will be determined. Using both prospective data modelling as well as undertaking a smaller nested case-control study, the influence of cumulative disease activity, and in particular, disease control on the risk of LPM and other malignancies will be determined. The importance of a past diagnosis of malignancy on recurrent disease will also be addressed. Data for this project will be obtained from the large British Society for Rheumatology Biologics Register (BSRBR), a longitudinal observational study of patients receiving anti-TNF therapies for RA. To date, over 11000 anti-TNF patients have been recruited to this study and over 3100 DMARD control patients. In addition to the data held in this register, further disease and histopathology data will be obtained, either by questionnaire or where appropriate, individual case note review, in patients who develop a malignancy during the course of study to address further the association between inflammation and LPM.
Medical Opportunities: These results will inform the wider medical and patient communities on the long-term cancer risk of anti-TNF use. If the results show an increase in malignancy risk, use of these drugs may need to be limited. Alternatively, if a decrease is seen, the results may support the wider and earlier use of these drugs in RA, which currently have tight prescribing guidelines.