The risk of lymphoma among patients with rheumatoid arthritis (RA) was not increased if they were treated with tumor necrosis factor (TNF) inhibitors, analysis of data from the British biologics registry found.
Compared with RA patients treated with conventional disease-modifying anti-rheumatic drugs (DMARDs) and after propensity score adjustment, the hazard ratio for lymphoma with anti-TNF treatment was 1 (95% CI 0.56 to 1.80), according to Kimme L. Hyrich, MD, PhD, of the University of Manchester, and colleagues.
There also was no increased risk for the individual TNF inhibitors, with hazard ratios of 1 (95% CI 0.49 to 2.03) for adalimumab (Humira), 1.02 (95% CI 0.45 to 2.33) for etanercept (Enbrel), and 0.91 (95% CI 0.39 to 2.13) for infliximab (Remicade), the researchers reported online in Annals of the Rheumatic Diseases.
The risk of lymphoma is increased among patients with RA, particularly the diffuse large B-cell subtype, and concerns about a further increase with TNF inhibition have been present since these treatments were introduced. "The possible effects of TNF inhibition on lymphomagenesis are difficult to predict. TNF has pleiotropic effects in the promotion and progression of malignancy, with both tumor-promoting and tumor-inhibiting actions," they explained.
In a Swedish study from a decade ago, patients in the top decile of cumulative disease activity had a 60-fold increased risk of lymphoma compared with those with the lowest activity. In addition, an earlier study by the current researchers from the British Society for Rheumatology (BSR) registry found increased risks for both Hodgkin's lymphoma (standardized incidence ratio 12.82) and non-Hodgkin's lymphoma (SIR 3.12) among patients with RA not receiving biologics.
"Therefore, given the strong association between chronic inflammation and lymphoma development in RA, it is plausible that TNF inhibition could reduce the risk of lymphoma by reducing ongoing inflammation," Hyrich and colleagues wrote.
Yet the TNF inhibitors carry a black box warning citing risks of lymphoma.
Accordingly, to provide more comprehensive and detailed information and help clarify lymphoma risks, Hyrich and colleagues analyzed data from the BSR registry for 11,931 patients with exposure to TNF inhibitors and 3,367 with conventional DMARD treatment only.
Patients receiving TNF inhibitors were younger (56 versus 60, P<0.001), had longer disease duration (11 years versus 6 years, P<0.001), had higher Disease Activity Scores in 28 joints (6.6 versus 5.3, P<0.001), and higher mean Health Assessment Questionnaire scores (2 versus 1.5, P<0.001), indicating worse disability.
They also were more often steroid users (44% versus 23%, P<0.001) and had previous exposure to more conventional DMARDs (four versus two, P<0.001).
During a median follow-up of 6.5 years in the DMARD group and 8.6 years in the anti-TNF group, 114 lymphomas were diagnosed. Among the DMARD group, there were 30 cases in 19,473 patient-years, and in the anti-TNF group, there were 84 during 95,126 patient-years.
The unadjusted hazard ratio for lymphoma in the anti-TNF group was 0.61 (95% CI 0.40 to 0.92). The final model with the propensity score included adjustments for age and sex, as well as multiple comorbidities including hypertension, ischemic heart disease, renal and liver disease, and diabetes, and disease characteristics such as severity, duration, and previous treatments.
In the conventional DMARD group, there were five Hodgkin's and 25 non-Hodgkin's lymphomas, while in the anti-TNF group, there were 12 Hodgkin's and 72 non-Hodgkin's cases. The most common subtype was diffuse large B-cell lymphoma.
Risks of lymphoma in the specific subtypes of lymphoma were not increased with anti-TNF treatment after propensity score adjustment:
- Hodgkin's lymphoma: HR 0.54 (95% CI 0.12 to 2.50)
- Non-Hodgkin's lymphoma: HR 1.10 (95% CI 0.58 to 2.08)
- Diffuse large B-cell lymphoma: HR 1.54 (95% CI 0.60 to 3.95)
Two patients in the DMARD group and three in the anti-TNF group had T-cell lymphomas, but none were the aggressive hepatosplenic subtype.
The authors noted, however, that the study was not powered to evaluate the relative risks of the specific subtypes of lymphoma. It also was not possible to adjust for cumulative disease activity.
"In conclusion, this study has ruled out an important risk of lymphoma in patients with RA exposed to TNF inhibitors over the background risk associated with RA .... This is consistent with other published data and the biological expectation that disease activity is the primary driver for lymphoma in RA," Hyrich and colleagues stated.
They called for additional follow-up to see if risks are altered by longer term and cumulative exposure to anti-TNF treatment.
BSR receives funding from AbbVie, Merck, Pfizer, Roche, Union Chimique Belge Pharma, and Swedish Orphan Biovitrum.
Hyrich disclosed relevant relationships with AbbVie and Pfizer.
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