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Haematopoietic malignancies in rheumatoid arthritis: lymphoma risk and characteristics after exposure to tumour necrosis factor antagonists

J Askling^1,2, C M Fored¹, E Baecklund³, L Brandt¹, C Backlin⁴, A Ekbom¹, C Sundström⁴, L Bertilsson⁵, L Cöster⁶, P Geborek⁷, L T Jacobsson⁸, S Lindblad², J Lysholm⁹, S Rantapää-Dahlqvist¹⁰, T Saxne⁷, L Klareskog², N Feltelius^2,11

¹ Clinical Epidemiology Unit, Department of Medicine, Karolinska University Hospital, Stockholm, Sweden
² Rheumatology Unit, Department of Medicine, Karolinska University Hospital, Stockholm, Sweden
³ Department of Rheumatology, Uppsala University Hospital, Uppsala, Sweden
⁴ Department of Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden
⁵ Department of Rheumatology, Sahlgrenska University Hospital, Gothenburg, Sweden
⁶ Department of Rheumatology, Linköping University Hospital, Sweden
⁷ Department of Rheumatology, Lund University Hospital, Lund, Sweden
⁸ Department of Rheumatology, Malmö University Hospital, Malmö, Sweden
⁹ Department of Rheumatology, Falu County Hospital, Falun, Sweden
¹⁰ Department of Rheumatology, University Hospital, Umeå, Sweden
¹¹ Medical Products Agency, Uppsala, Sweden

Correspondence to:
Dr J Askling
Clinical Epidemiology Unit M9:01, Karolinska University Hospital Solna, SE-171 76 Stockholm, Sweden; johan.askling{at}medks.ki.se

Background: Patients with rheumatoid arthritis (RA) are at increased risk of malignant lymphomas, and maybe also of leukaemia and multiple myeloma. The effect of tumour necrosis factor (TNF) antagonists on lymphoma risk and characteristics is unclear.

Objective: To assess expected rates and relative risks of haematopoietic malignancies, especially those associated with TNF antagonists, in large population based cohorts of patients with RA.

Methods: A population based cohort study was performed of patients with RA (one prevalent cohort (n = 53 067), one incident cohort (n = 3703), and one TNF antagonist treated cohort 1999 through 2003 (n = 4160)), who were linked with the Swedish Cancer Register. Additionally, the lymphoma specimens for the 12 lymphomas occurring in patients with RA exposed to TNF antagonists in Sweden 1999 through 2004 were reviewed.

Results: Study of almost 500 observed haematopoietic malignancies showed that prevalent and incident patients with RA were at increased risk of lymphoma (SIR = 1.9 and 2.0, respectively) and leukaemia (SIR = 2.1 and 2.2, respectively) but not of myeloma. Patients with RA treated with TNF antagonists had a tripled lymphoma risk (SIR = 2.9) compared with the general population. After adjustment for sex, age, and disease duration, the lymphoma risk after exposure to TNF antagonists was no higher than in the other RA cohorts. Lymphomas associated with TNF antagonists had characteristics similar to those of other RA lymphomas.

Conclusion: Overall, patients with RA are at equally increased risks for lymphomas and leukaemias. Patients with RA treated with TNF antagonists did not have higher lymphoma risks than other patients with RA. Prolonged observation is needed to determine the long term effects of TNF antagonists on lymphoma risk.

Abbreviations: EBV, Epstein-Barr virus; DAS, Disease Activity Score; ICD, International Classification of Diseases; NRN, national registration number; RA, rheumatoid arthritis; SIR, standardised incidence ratio; TNF, tumour necrosis factor

Keywords: lymphomas; rheumatoid arthritis; epidemiology; Sweden; tumour necrosis factor

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