Updated observational data analyzed from a nationwide prospective registry in the UK including over 120 000 patient years (PYs) of tumor necrosis factor inhibitor (TNFi) or conventional synthetic disease-modifying antirheumatic drug (csDMARD) exposure did not find an increased risk of lymphoma through 8 years after TNFi initiation.These results, derived from ongoing data collection from the British Society for Rheumatology Rheumatoid Arthritis Register (BSRBR-RA), were recently reported in the Annals of the Rheumatic Diseases. 

Multiple registers have been created to study the longitudinal safety of TNFi use, with the identification of a possible increased risk of lymphoma in patients secondary to immunnosuppression noted in biologic DMARD (bDMARD)-naive patients receiving nonbiologic conventional synthetic DMARDS (csDMARDs) in comparison to the general population.2  Currently, the US Food and Drug Administration requires TNFis to be labelled with a warning regarding the possibility of this increased risk.  This recently published study further provides updated incidence rates of lymphoma development in the first 8 years after initiating TNFi treatment. 


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High Yield Data Summary

  • Further analysis of ongoing data collected by the BSRBR-RA registry representing 120 000 patient years of TNFi or csDMARD exposure did not detect changes in lymphoma risk between the 2 treatment groups 8 years after TNFi treatment initiation for RA

Briefly, the BSRBR-RA is a UK-based observational cohort study tasked with surveying the long-term safety of biologic therapy for the treatment of active RA. The BSRBR-RA collects baseline patient data from healthcare provider-completed questionnaires including demographic data, RA disease duration, pharmacotherapy,  28-joint Disease Activity Score (DAS28), and the adapted Health Assessment Questionnaire (HAQ).   

Patients enrolled in the registry were prospectively followed regardless of treatment modality until either electing to stop study participation or death.

The first clinically-verified lymphoma occurrence in each participant was selected as the primary outcome. To obtain lymphoma incidence rates, the National Health Service Information Centre or the Northern Ireland Cancer Registry retrospectively and prospectively identified malignancies and reported them to the BSRBR-RA.

An “ever-exposed” analysis with any dose of TNFi considered as a qualifying exposure was chosen by researchers, creating the csDMARD cohort and the TNFi cohort. Patients in the TNFi cohort had not received any prior bDMARDs for RA prior to receiving first TNFi dose.  The risk of developing first lymphoma with each individual TNFi agent was then compared to the risk present in the csDMARD cohort.

A total of 11 931 patients in the TNFi ever-exposed cohort (35% ever-exposed to etanercept, 29% to infliximab, 36% to adalimumab) were subsequently compared with 3367 bDMARD-naive/csDMARD patients with RA.  In the TNFi cohort, 84 cases of verified lymphoma were identified corresponding to a rate of 88 per 100 000 PYs (95% confidence interval [CI] 70 to 109) as compared to the 30 cases of lymphoma documented in the bDMARD-naive group (154 [95% CI 104 to 220]).  

Deciles of propensity scores were used to adjust data after which no significant differences in risk of developing first lymphoma was found in patients receiving TNFis compared with those receiving csDMARDs (HR 1.00 [95% CI 0.56 to 1.80]). Specific individual TNFi use was also not shown to influence the risk of lymphoma development. 

Summary and Clinical Applicability

“The question of whether or not anti-TNF influences the risk of lymphoma is of particular concern to rheumatologists due to the known association between severity of RA and lymphoma…  A clinically meaningful increased risk of lymphoma associated with TNFi was excluded from this analysis: the analysis had 98% power to detect a twofold relative increased risk for TNFi compared with the rate in the csDMARD cohort,” the authors stated.

Limitations and Disclosures 

  • Inability to make adjustments for cumulative RA disease effects and damage 
  • Conclusions regarding lymphoma risk over the longer-term (>8 years) have yet to be determined

The BSR receives restricted income from UK pharmaceutical companies, presently AbbVie, Merck, Pfizer, Roche, Union Chimique Belge Pharma Ltd (UCB) and Swedish Orphan Biovitrum AB (SOBI). Dr Hyrich reports receiving honoraria from AbbVie and Pfizer. 

Reference

  1. Mercer LK, Galloway JB, Lunt M, et al. Risk of lymphoma in patients exposed to antitumour necrosis factor therapy: results from the British Society for Rheumatology Biologics Register for Rheumatoid Arthritis. Annals of the Rheumatic Diseases doi:10.1136/annrheumdis-2016-209389
  2. Mercer LK, Davies R, Galloway JB, et al. Risk of cancer in patients receiving non-biologic disease-modifying therapy for rheumatoid arthritis compared with the UK general population. Rheumatology 2013;52:91–8. doi:10.1093/rheumatology/kes350

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