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Association of chronic inflammation, not its treatment, with increased lymphoma risk in rheumatoid arthritis
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
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2006 (English)In: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 54, no 3, 692-701 p.Article in journal (Refereed) Published
Abstract [en]


Chronic inflammatory conditions such as rheumatoid arthritis (RA) have been associated with malignant lymphomas. This study was undertaken to investigate which patients are at highest risk, and whether antirheumatic treatment is hazardous or protective.


We performed a matched case-control study of 378 consecutive Swedish RA patients in whom malignant lymphoma occurred between 1964 and 1995 (from a population-based RA cohort of 74,651 RA patients), and 378 controls. Information on disease characteristics and treatment from onset of RA until lymphoma diagnosis was abstracted from medical records. Lymphoma specimens were reclassified and tested for Epstein-Barr virus (EBV). Relative risks (odds ratios [ORs]) for lymphomas (by subtype) associated with deciles of cumulative disease activity were assessed, as were ORs associated with drug treatments.


The relative risks of lymphoma were only modestly elevated up to the seventh decile of cumulative disease activity. Thereafter, the relative risk increased dramatically (OR ninth decile 9.4 [95% confidence interval 3.1-28.0], OR tenth decile 61.6 [95% confidence interval 21.0-181.0]). Most lymphomas (48%) were of the diffuse large B cell type, but other lymphoma subtypes also displayed an association with cumulative disease activity. Standard nonbiologic treatments did not increase lymphoma risk. EBV was present in 12% of lymphomas.


Risk of lymphoma is substantially increased in a subset of patients with RA, those with very severe disease. High inflammatory activity, rather than its treatment, is a major risk determinant.

Place, publisher, year, edition, pages
2006. Vol. 54, no 3, 692-701 p.
Keyword [en]
Adolescent, Adult, Aged, Aged; 80 and over, Antirheumatic Agents, Arthritis; Rheumatoid/*complications/drug therapy, Case-Control Studies, Chronic Disease, Female, Herpesvirus 4; Human/isolation & purification, Humans, Inflammation/*complications, Lymphoma/*etiology/virology, Male, Middle Aged, Research Support; Non-U.S. Gov't, Risk Factors
National Category
Medical and Health Sciences
URN: urn:nbn:se:uu:diva-102195DOI: 10.1002/art.21675PubMedID: 16508929OAI: oai:DiVA.org:uu-102195DiVA: diva2:214505
Available from: 2009-05-05 Created: 2009-05-05 Last updated: 2015-02-24
In thesis
1. Associations Between Rheumatoid Arthritis and Malignant Lymphomas
Open this publication in new window or tab >>Associations Between Rheumatoid Arthritis and Malignant Lymphomas
2005 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Patients with rheumatoid arthritis (RA) are at increased risk of developing malignant lymphoma, although details about this association remain unclear. The aims of this thesis were to investigate risk factors for lymphoma in patients with RA and to characterize these lymphomas regarding subtype, presence of Epstein-Barr virus (EBV), clinical manifestations and prognosis.

The Swedish hospital discharge register and the cancer register were used to identify RA patients with lymphoma. Two case-control studies were performed, one smaller including RA patients with lymphoma hospitalised in Uppsala health care region 1964-1983 (n=41) and one larger study of hospitalised RA patients with lymphoma in Sweden 1964-1995 (n=378). RA patients from the same cohorts, but without lymphoma, were matched as controls. Medical records for cases and controls were scrutinized for exposure information. The lymphoma tissues were reclassified according to the WHO classification, and presence of EBV was analysed by EBER in situ hybridisation.

The most important risk factor for lymphoma development was high RA disease activity. No association was determined between treatment with traditional disease modifying drugs, non-steroidal anti-inflammatory drugs, aspirin, peroral and intra-articular corticosteroids and lymphoma risk. Diffuse large B-cell lymphoma (DLBCL) was more frequent in RA patients than in lymphoma patients in the general population and displayed stronger association with RA disease activity than other lymphoma subtypes. RA patients with DLBCL had increased extranodal involvement and more advanced lymphoma stage at presentation than DLBCL patients in general, and the prognosis was poor.

A further subdivision of DLBCL into germinal centre (GC) and non-GC subtypes by the expression patterns of CD10, bcl-6 and IRF-4 showed a predominance of the non-GC subtype. This suggested peripheral activated B-cells as the cells of origin in these lymphomas.

The presence of EBV was low in lymphomas in RA patients (12%).

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2005. 75 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 68
Medicine, rheumatoid arthritis, malignant lymphoma, diffuse large B-cell lymphoma, disease activity, disease modifying anti-rheumatic drug, Epstein-Barr virus, germinal centre-like/ non-germinal centre-like subtype, Medicin
National Category
Dermatology and Venereal Diseases
urn:nbn:se:uu:diva-5928 (URN)91-554-6335-5 (ISBN)
Public defence
2005-10-07, Fåhraeussalen, Patologen, Akademiska sjukhuset, ing C5, Uppsala, 09:15
Available from: 2005-09-16 Created: 2005-09-16 Last updated: 2013-06-18Bibliographically approved

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Baecklund, EvaBacklin, CarinRosenquist, RichardSundström, Christer
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