Lymphomas in Rheumatoid Arthritis Patients Treated with Anti-TNF Therapy: A Report from the Swedish Biologics Register (ARTIS) and the ARTIS Study Group 1998–2006
Authors: Baecklund Eva , Backlin Carin , Askling Johan , Enblad Gunilla , Sundstrom Christer , Rosenquist Richard , Feltelius Nils 
Published: October 2019

Abstract
Background Anti-tumor necrosis factor (TNF) therapy has emerged as an effective therapy in inflammatory diseases such as rheumatoid arthritis (RA). One concern is reports of lymphoma development in RA patients receiving such therapy. We performed a population-based and detailed survey of RA and lymphoma characteristics in anti-TNF-treated RA patients with lymphoma.
Methods Cross-linkage between the Swedish Biologics Register and the Swedish Cancer Register 1998 through 2006 identified 26 RA patients with lymphoma after start of anti- TNF therapy. The 26 cases correspond to a 3-fold increased risk compared to a general population comparator and a 30% non-significant increased risk compared to anti-TNF-naïve RA patients (Ref 1). The medical records were scrutinized, the lymphoma tissues reclassified, Epstein-Barr virus assessed by EBER in situ hybridization and patients followed-up for survival through March, 2008.
Results The patients had longstanding, active RA before start of anti-TNF therapy; mean RA duration 13.9 years and mean number of other disease-modifying anti-rheumatic drugs before anti-TNF therapy 4.5. Treatment response to anti-TNF therapy was poor; 23 of the patients continued to have active RA disease despite anti-TNF therapy. The mean duration of anti-TNF therapy before lymphoma was 28 months (2 weeks-72 months). Six patients had lymphoma diagnosed during the first year after anti-TNF start. Seen in retrospect, 3 of the patients had signs of the lymphoma already before treatment start. Reclassification revealed that 14 patients had aggressive lymphomas (8 diffuse large B-cell lymphoma [31%]), 8 indolent lymphomas and 4 could not be further specified (NHL unspecified). Two of 20 (10%) examined lymphomas were EBV-positive. The main initial symptom of the lymphoma was palpable mass in 8 patients, impaired general health in 3, and the remaining had all different symptoms depending on organ involvement. At diagnosis, 12 patients (46%) had wide-spread lymphoma (Ann Arbor stage IV). Of the 26 patients, 13 had died. The mean survival from diagnosis of lymphoma was 14.7 months. 8 of the patients died within 5 months from diagnosis. Most of the remaining (n=14) had active RA after lymphoma diagnosis/treatment and received specific RA therapy. Lymphoma treatment which included rituximab (n=4) was associated with good RA-response and long duration between start of lymphoma therapy and start of specific RA therapy (mean duration 19 months, min-max: 12–26). The corresponding figure for other lymphoma treatments was 5 months (min-max: 2–9).
Conclusion In routine clinical care, a majority of RA patients who developed lymphoma after start of anti-TNF therapy had active RA and poor response to anti-TNF therapy, in line with previous findings of an association between RA disease activity and lymphoma risk (Ref 2). Lymphoma characteristics did not differ from what has been reported in lymphomas in anti-TNF-naïve RA patients (Ref 2). A subgroup of patients had aggressive lymphomas with poor prognosis. Most RA-lymphoma patients surviving first lymphoma treatment experienced relapse of RA. Lymphoma treatment which included rituximab was associated with long periods of improved RA.