BACKGROUND: Lymphomas comprise a heterogeneous group of malignant diseases with highly variable prognosis. Rheumatoid arthritis (RA) is associated with a twofold increased risk of both Hodgkin's lymphoma (HL) and non-Hodgkin's lymphoma (NHL). It is unknown whether treatment with biologic disease-modifying antirheumatic drugs (bDMARDs) affect the risk of specific lymphoma subtypes. METHODS: Patients never exposed to (bionaïve) or ever treated with bDMARDs from 12 European biologic registers were followed prospectively for the occurrence of first ever histologically confirmed lymphoma. Patients were considered exposed to a bDMARD after having received the first dose. Lymphomas were attributed to the most recently received bDMARD. RESULTS: Among 124 997 patients (mean age 59 years; 73.7% female), 533 lymphomas were reported. Of these, 9.5% were HL, 83.8% B-cell NHL and 6.8% T-cell NHL. No cases of hepatosplenic T-cell lymphoma were observed. Diffuse large B-cell lymphoma (DLBCL) was the most frequent B-cell NHL subtype (55.8% of all B-cell NHLs). The subtype distributions were similar between bionaïve patients and those treated with tumour necrosis factor inhibitors (TNFi). For other bDMARDs, the numbers of cases were too small to draw any conclusions. Patients with RA developed more DLBCLs and less chronic lymphocytic leukaemia compared with the general population. CONCLUSION: This large collaborative analysis of European registries has successfully collated subtype information on 533 lymphomas. While the subtype distribution differs between RA and the general population, there was no evidence of any modification of the distribution of lymphoma subtypes in patients with RA treated with TNFi compared with bionaïve patients.

Arthritis Research UK Centre for Epidemiology University of Manchester Manchester UK

Center for Rheumatology and Spine Diseases Gentofte University Hospital Rigshospitalet Hellerup Denmark

CharitéUniversitätsmedizin Berlin Berlin Germany

Clinical Epidemiology Unit Karolinska Institutet Stockholm Sweden

DANBIO Copenhagen Center for Arthritis Research Centre of Head and Orthopaedics Rigshospitalet Copenhagen Denmark

Département of BIOSPIM Département BIOSPIM Hôpital Pitié Salpétrière AP HP Sorbonne Universités Université Pierre et Marie Curie Paris France

Department of Clinical Medicine Faculty of Health and Medical Sciences University of Copenhagen Copenhagen Denmark

Department of Medical Sciences Uppsala University Uppsala Sweden

Department of Rheumatology CHU Strasbourg Strasbourg France

Department of Rheumatology Hospital Clinic of Barcelona Barcelona Spain

Department of Rheumatology Université Paris Sud Hôpitaux Universitaires Paris Sud Le Kremlin Bicêtre Paris France

Department of Rheumatology University of Montpellier and Teaching Hospital Lapeyronie Montpellier France

Epidemiology Unit German Rheumatism Research Centre Berlin Germany

EpiDoC Unit Universidade Nova de Lisboa CEDOC NOVA Medical School and National School of Public Health Lisbon Portugal

Institute of Rheumatology 1st Faculty of Medicine Charles University Prague Czech Republic

Musculoskeletal Biomedical Research Unit National Institute of Health Research Manchester Central Manchester NHS Foundation Trust Manchester Academic Health Science Manchester UK

Rheumatology Unit University of Bari Bari Italy

The Parker Institute Frederiksberg Denmark

Nat Rev Rheumatol. 2017 Nov 21;13(12):697-698. doi: 10.1038/nrrheum.2017.186. PubMed

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Smith A, Crouch S, Lax S, et al. . Lymphoma incidence, survival and prevalence 2004-2014: sub-type analyses from the UK’s Haematological Malignancy Research Network. Br J Cancer 2015;112:1575–84. 10.1038/bjc.2015.94 PubMed DOI PMC

Sant M, Allemani C, Tereanu C, et al. . Incidence of hematologic malignancies in Europe by morphologic subtype: results of the HAEMACARE project. Blood 2010;116:3724–34. 10.1182/blood-2010-05-282632 PubMed DOI

Smedby KE, Hjalgrim H, Askling J, et al. . Autoimmune and chronic inflammatory disorders and risk of non-Hodgkin lymphoma by subtype. J Natl Cancer Inst 2006;98:51–60. 10.1093/jnci/djj004 PubMed DOI

Ekström K, Hjalgrim H, Brandt L, et al. . Risk of malignant lymphomas in patients with rheumatoid arthritis and in their first-degree relatives. Arthritis Rheum 2003;48:963–70. 10.1002/art.10939 PubMed DOI

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. Ann Rheum Dis 2017;76:497–503. 10.1136/annrheumdis-2016-209389 PubMed DOI PMC

Hellgren K, Baecklund E, Backlin C, et al. . Rheumatoid Arthritis and Risk of Malignant Lymphoma: Is the Risk Still Increased? Arthritis Rheumatol 2017;69:700–8. 10.1002/art.40017 PubMed DOI

Dreyer L, Mellemkjær L, Andersen AR, et al. . Incidences of overall and site specific cancers in TNFα inhibitor treated patients with rheumatoid arthritis and other arthritides - a follow-up study from the DANBIO Registry. Ann Rheum Dis 2013;72:79–82. 10.1136/annrheumdis-2012-201969 PubMed DOI

Smitten AL, Simon TA, Hochberg MC, et al. . A meta-analysis of the incidence of malignancy in adult patients with rheumatoid arthritis. Arthritis Res Ther 2008;10:R45 10.1186/ar2404 PubMed DOI PMC

Thomas E, Brewster DH, Black RJ, et al. . Risk of malignancy among patients with rheumatic conditions. Int J Cancer 2000;88:497–502. 10.1002/1097-0215(20001101)88:3<497::AID-IJC27>3.0.CO;2-J PubMed DOI

Baecklund E, Iliadou A, Askling J, et al. . Association of chronic inflammation, not its treatment, with increased lymphoma risk in rheumatoid arthritis. Arthritis Rheum 2006;54:692–701. 10.1002/art.21675 PubMed DOI

Salloum E, Cooper DL, Howe G, et al. . Spontaneous regression of lymphoproliferative disorders in patients treated with methotrexate for rheumatoid arthritis and other rheumatic diseases. J Clin Oncol 1996;14:1943–9. 10.1200/JCO.1996.14.6.1943 PubMed DOI

Parakkal D, Sifuentes H, Semer R, et al. . Hepatosplenic T-cell lymphoma in patients receiving TNF-α inhibitor therapy: expanding the groups at risk. Eur J Gastroenterol Hepatol 2011;23:1150–6. 10.1097/MEG.0b013e32834bb90a PubMed DOI

Askling J, Baecklund E, Granath F, et al. . Anti-tumour necrosis factor therapy in rheumatoid arthritis and risk of malignant lymphomas: relative risks and time trends in the Swedish Biologics Register. Ann Rheum Dis 2009;68:648–53. 10.1136/ard.2007.085852 PubMed DOI

Wolfe F, Michaud K. The effect of methotrexate and anti-tumor necrosis factor therapy on the risk of lymphoma in rheumatoid arthritis in 19,562 patients during 89,710 person-years of observation. Arthritis Rheum 2007;56:1433–9. 10.1002/art.22579 PubMed DOI

Chiu YM, Lang HC, Lin HY, et al. . Risk of tuberculosis, serious infection and lymphoma with disease-modifying biologic drugs in rheumatoid arthritis patients in Taiwan. Int J Rheum Dis 2014;17(Suppl 3):9–19. 10.1111/1756-185X.12539 PubMed DOI

Harigai M, Nanki T, Koike R, et al. . Risk for malignancy in rheumatoid arthritis patients treated with biological disease-modifying antirheumatic drugs compared to the general population: A nationwide cohort study in Japan. Mod Rheumatol 2016;26:642–50. 10.3109/14397595.2016.1141740 PubMed DOI

Lemaitre M JK. A R. Lymphoma in patients with Inflammatory Bowel Disease; a French nationwide observational cohort study UEGW, 2016:2016.

Mariette X, Gottenberg JE, Ravaud P, et al. . Registries in rheumatoid arthritis and autoimmune diseases: data from the French registries. Rheumatology 2011;50:222–9. 10.1093/rheumatology/keq368 PubMed DOI

Horák P, Skácelová M, Hejduk K, et al. . Abatacept and its use in the treatment of rheumatoid arthritis (RA) in the Czech Republic-data from the ATTRA registry. Clin Rheumatol 2013;32:1451–8. 10.1007/s10067-013-2303-6 PubMed DOI

Carmona L, Descalzo MA, Ruiz-Montesinos D, et al. . Safety and retention rate of off-label uses of TNF antagonists in rheumatic conditions: data from the Spanish registry BIOBADASER 2.0. Rheumatology 2011;50:85–92. 10.1093/rheumatology/keq207 PubMed DOI

Ibfelt EH, Jensen DV, Hetland ML. The Danish nationwide clinical register for patients with rheumatoid arthritis: DANBIO. Clin Epidemiol 2016;8:737–42. 10.2147/CLEP.S99490 PubMed DOI PMC

Sebastiani M, Anelli MG, Atzeni F, et al. . Efficacy and safety of rituximab with and without methotrexate in the treatment of rheumatoid arthritis patients: results from the GISEA register. Joint Bone Spine 2014;81:508–12. 10.1016/j.jbspin.2014.06.011 PubMed DOI

Strangfeld A, Eveslage M, Schneider M, et al. . Treatment benefit or survival of the fittest: what drives the time-dependent decrease in serious infection rates under TNF inhibition and what does this imply for the individual patient? Ann Rheum Dis 2011;70:1914–20. 10.1136/ard.2011.151043 PubMed DOI PMC

Mariette X, Tubach F, Bagheri H, et al. . Lymphoma in patients treated with anti-TNF: results of the 3-year prospective French RATIO registry. Ann Rheum Dis 2010;69:400–8. 10.1136/ard.2009.117762 PubMed DOI PMC

Romão VC, Santos MJ, Polido-Pereira J, et al. . Comparative Effectiveness of Tocilizumab and TNF Inhibitors in Rheumatoid Arthritis Patients: Data from the Rheumatic Diseases Portuguese Register, Reuma.pt. Biomed Res Int 2015;2015:1–13. 10.1155/2015/279890 PubMed DOI PMC

Swerdlow SH, Campo E, Harris NL, et al. . WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th edn, 2008.

Baecklund E, Sundström C, Ekbom A, et al. . Lymphoma subtypes in patients with rheumatoid arthritis: increased proportion of diffuse large B cell lymphoma. Arthritis Rheum 2003;48:1543–50. 10.1002/art.11144 PubMed DOI

Deepak P, Sifuentes H, Sherid M, et al. . T-cell non-Hodgkin’s lymphomas reported to the FDA AERS with tumor necrosis factor-alpha (TNF-α) inhibitors: results of the REFURBISH study. Am J Gastroenterol 2013;108:99–105. 10.1038/ajg.2012.334 PubMed DOI

Hollander P, Rostgaard K, Smedby KE, et al. . Autoimmune and Atopic Disorders and Risk of Classical Hodgkin Lymphoma. Am J Epidemiol 2015;182:624–32. 10.1093/aje/kwv081 PubMed DOI PMC

Jaffe ES. The 2008 WHO classification of lymphomas: implications for clinical practice and translational research. Hematology Am Soc Hematol Educ Program 2009:523–31. 10.1182/asheducation-2009.1.523 PubMed DOI PMC

Hellgren K, Smedby KE, Feltelius N, et al. . Do rheumatoid arthritis and lymphoma share risk factors?: a comparison of lymphoma and cancer risks before and after diagnosis of rheumatoid arthritis. Arthritis Rheum 2010;62:1252–8. 10.1002/art.27402 PubMed DOI