Disease activity and risk of lymphoma in patients with rheumatoid arthritis: nested case-control study

BMJ 1998;317:180-181 ( 18 July )

Papers

Disease activity and risk of lymphoma in patients with rheumatoid arthritis: nested case-control study

Eva Baecklund, rheumatologist, ^a Anders Ekbom, associate professor, ^b Pär Sparén, statistician, ^b Nils Feltelius, associate professor, ^a Lars Klareskog, professor. ^c

^a Department of Medicine, University Hospital, S-751 85 Uppsala, Sweden, ^b Department of Medical Epidemiology, Karolinska Institute, Box 281, S-171 11 Stockholm, Sweden, ^c Department of Medicine, Karolinska Hospital, S-171 76 Stockholm, Sweden

Correspondence to: Dr Baecklund Eva.Baecklund{at}swipnet.se

Inflammatory diseases such as rheumatoid arthritis and their treatment may have a pathogenic relation with cancer. The possiblerelation also has practical implications for the care and controlof rheumatic patients.

Patients with rheumatoid arthritis have been shown to have an increased risk of developing lymphomas. ¹ ² The underlying mechanisms for this association are unclear. We performed a studyto assess to what extent disease activity, various secondary manifestationsof rheumatic disease, and drug treatment were independent riskfactors for the development of lymphoma in patients with rheumatoidarthritis.

	Subjects, methods, and results

Top Subjects, methods, and results Comment References

We performed a nested case-control study using a previously described population based cohort of all patients admitted to hospital with rheumatoid arthritis during 1965-83 in Uppsala health care region, Sweden.³ We identified 42 cases of lymphoma inthe 11 683 patients with rheumatoid arthritis through record linkageswith the Swedish cancer registry. Cases were individually matchedto three controls from the same rheumatoid arthritis cohort. Allmedical records were reviewed and data, including disease manifestationsand treatment from the first symptoms compatible with rheumatoidarthritis until the date of the diagnosis of the lymphoma in thecase, were abstracted for cases and controls. All cases and controlswere evaluated to assess if the 1987 American College of Rheumatologycriteria for rheumatoid arthritis were met, and patients not havingrheumatoid arthritis were excluded. The risk of lymphoma was measuredas unadjusted and adjusted odds ratios. The study finally consistedof 41 cases and 113 controls.

The table gives exposures linked to an increased risk of lymphoma together with the unadjusted odds ratios. High inflammatoryactivity was the most prominent risk factor for development oflymphoma, with an odds ratio of 25.8 compared with low inflammatoryactivity. Inflammatory activity was estimated by a score comprisingthe whole period of rheumatoid arthritis disease and was basedon available data on erythrocyte sedimentation rates, number ofswollen and tender joints, and the treating physician's globalassessment of disease activity. Other exposures associated withdisease severity also entailed an increased odds ratio for lymphoma,such as functional class IV of Steinbrocker (odds ratio 12.9),widespread joint involvement (odds ratio 9.3), and certain extra-articular symptoms.

View this table:
[in this window]
[in a new window]

Disease characteristics associated with increased unadjusted odds ratio for lymphoma

Few patients were treated with immunosuppressive drugs, reflecting the standard treatment during the study period. Non-steroidal anti-inflammatory drugs, aspirin, and corticosteroids were incommon use, but only a few patients were treated with antimalarials, parenteral gold, D-penicillamine, podophyllotoxin, or sulphasalazine.

We found no association between any specific drug and increased risk of lymphoma. Once drug treatment was adjusted for therewas a strong independent association between inflammatory activityand lymphoma.

	Comment

Top Subjects, methods, and results Comment References

This study shows a strong association between disease activity in patients with rheumatoid arthritis and risk of developing lymphoma. It strengthens the concept that disease related immune alterations in rheumatoid arthritis also increase the risk oflymphoma, regardless of drug treatment.⁴ The risk linked tothe disease seems larger than risks linked to immunosuppressivetreatment seen in other studies.⁵ Thus our findings provide additional arguments for use of potent immunosuppressive treatmentto reduce disease activity, not only to prevent joint damage butpossibly also to protect against lymphoma.

Doctors need to be aware of the risk of lymphoma in certain groups of patients with rheumatoid arthritis. In addition, clinicalinvestigators into new drugs for rheumatoid arthritis should takeinto account the "background" risk of lymphoma in patients withhighly active rheumatoid arthritis, who are usually preferredin these trials.

	Acknowledgments

Contributors: EB collected and analysed data, participated in interpreting the data, and wrote the paper. AE initiated and designed the study, supervised data collection, contributed to interpreting the data and writing the paper, and is the study guarantor. PS was responsible for the statistical parts of the study, and helped with analysis, data interpretation, and writing the paper. NF helped with the study design, data interpretation, and writing the paper. LK discussed core ideas and helped in interpreting the data and writing the paper.

Funding: None

Conflict of interest: None.

References

Top
Subjects, methods, and results
Comment
References

Prior P, Symmons DPM, Hawkins CF, Scott DL, Brown R. Cancer morbidity in rheumatoid arthritis. Ann Rheum Dis 1984; 43: 128-131 [Abstract/Free Full Text].
Myllykangas-Luosujärvi R, Aho K, Isomäki H. Mortality from cancer in patients with rheumatoid arthritis. Scand J Rheumatol 1995; 24: 76-78 [Medline].
Gridley G, McLaughlin JK, Ekbom A, Klareskog L, Adami HO, Hacker DG, et al. Incidence of cancer among patients with rheumatoid arthritis. J Natl Cancer Inst 1993; 85: 307-311 [Abstract/Free Full Text].
Symmons DPM. Neoplasms of the immune system in rheumatoid arthritis. Am J Med 1985; 78: 22-28 [Medline].
Silman AJ, Petrie J, Hazleman B, Evans SJW. Lymphoproliferative cancer and other malignancy in patients with rheumatoid arthritis treated with azathioprine: a 20 year follow up study. Ann Rheum Dis 1988; 47: 988-992 [Abstract/Free Full Text].

(Accepted 27 January 1998)

© BMJ 1998

CiteULike

Complore

Connotea

Del.icio.us Add to Digg

Digg

StumbleUpon Add to Technorati

Technorati What's this?

This article has been cited by other articles:

Salliot, C, van der Heijde, D (2009). Long-term safety of methotrexate monotherapy in patients with rheumatoid arthritis: a systematic literature research. Ann Rheum Dis 68: 1100-1104 [Abstract] [Full text]
KHRAISHI, M. (2009). Comparative Overview of Safety of the Biologics in Rheumatoid Arthritis. The Journal of Rheumatology Supplement 82: 25-32 [Abstract] [Full text]
Furst, D E, Keystone, E C, Kirkham, B, Fleischmann, R, Mease, P, Breedveld, F C, Smolen, J S, Kalden, J R, Burmester, G R, Braun, J, Emery, P, Winthrop, K, Bresnihan, B, De Benedetti, F, Dorner, T, Gibofsky, A, Schiff, M H, Sieper, J, Singer, N, Van Riel, P L C M, Weinblatt, M E, Weisman, M H (2008). Updated consensus statement on biological agents for the treatment of rheumatic diseases, 2008. Ann Rheum Dis 67: iii2-iii25 [Full text]
Lofstrom, B, Backlin, C, Sundstrom, C, Ekbom, A, Lundberg, I E (2007). A closer look at non-Hodgkin's lymphoma cases in a national Swedish systemic lupus erythematosus cohort: a nested case-control study. Ann Rheum Dis 66: 1627-1632 [Abstract] [Full text]
Furst, D E, Breedveld, F C, Kalden, J R, Smolen, J S, Burmester, G R, Sieper, J, Emery, P, Keystone, E C, Schiff, M H, Mease, P, van Riel, P L C M, Fleischmann, R, Weisman, M H, Weinblatt, M E (2007). Updated consensus statement on biological agents for the treatment of rheumatic diseases, 2007. Ann Rheum Dis 66: iii2-iii22 [Full text]
Mikuls, T. (2007). The treatment of lymphoma complicating autoimmune disease: two birds with one stone?. Ann Oncol 18: 615-618 [Full text]
Chang, E. T., Balter, K. M., Torrang, A., Smedby, K. E., Melbye, M., Sundstrom, C., Glimelius, B., Adami, H.-O. (2006). Nutrient Intake and Risk of Non-Hodgkin's Lymphoma. Am J Epidemiol 164: 1222-1232 [Abstract] [Full text]
Smedby, K. E., Baecklund, E., Askling, J. (2006). Malignant Lymphomas in Autoimmunity and Inflammation: A Review of Risks, Risk Factors, and Lymphoma Characteristics.. Cancer Epidemiol. Biomarkers Prev. 15: 2069-2077 [Abstract] [Full text]
Furst, D E, Breedveld, F C, Kalden, J R, Smolen, J S, Burmester, G R, Emery, P, Keystone, E C, Schiff, M H, van Riel, P L C M, Weinblatt, M E, Weisman, M H (2006). Updated consensus statement on biological agents for the treatment of rheumatic diseases, 2006. Ann Rheum Dis 65: iii2-iii15 [Full text]
Moul, D. K., Korman, N. J. (2006). Severe hidradenitis suppurativa treated with adalimumab.. Arch Dermatol 142: 1110-1112 [Full text]
Fleischmann, R M, Tesser, J, Schiff, M H, Schechtman, J, Burmester, G-R, Bennett, R, Modafferi, D, Zhou, L, Bell, D, Appleton, B (2006). Safety of extended treatment with anakinra in patients with rheumatoid arthritis. Ann Rheum Dis 65: 1006-1012 [Abstract] [Full text]
Schiff, M H, Burmester, G R, Kent, J D, Pangan, A L, Kupper, H, Fitzpatrick, S B, Donovan, C (2006). Safety analyses of adalimumab (HUMIRA) in global clinical trials and US postmarketing surveillance of patients with rheumatoid arthritis. Ann Rheum Dis 65: 889-894 [Abstract] [Full text]
Sagaert, X., de Paepe, P., Libbrecht, L., Vanhentenrijk, V., Verhoef, G., Thomas, J., Wlodarska, I., De Wolf-Peeters, C. (2006). Forkhead Box Protein P1 Expression in Mucosa-Associated Lymphoid Tissue Lymphomas Predicts Poor Prognosis and Transformation to Diffuse Large B-Cell Lymphoma. JCO 24: 2490-2497 [Abstract] [Full text]
Kling, A, Rantapaa-Dahlqvist, S, Stenlund, H, Mjorndal, T (2006). Decreased density of serotonin 5-HT2A receptors in rheumatoid arthritis.. Ann Rheum Dis 65: 816-819 [Abstract] [Full text]
Askling, J, Fored, C M, Geborek, P, Jacobsson, L T H, van Vollenhoven, R, Feltelius, N, Lindblad, S, Klareskog, L (2006). Swedish registers to examine drug safety and clinical issues in RA. Ann Rheum Dis 65: 707-712 [Abstract] [Full text]
Franklin, J, Lunt, M, Bunn, D, Symmons, D, Silman, A (2006). Incidence of lymphoma in a large primary care derived cohort of cases of inflammatory polyarthritis. Ann Rheum Dis 65: 617-622 [Abstract] [Full text]
Ang, Y S, Farrell, R J (2006). Risk of lymphoma: inflammatory bowel disease and immunomodulators.. Gut 55: 580-581 [Full text]
Mikuls, T. R., Endo, J. O., Puumala, S. E., Aoun, P. A., Black, N. A., O'Dell, J. R., Stoner, J. A., Boilesen, E. C., Bast, M. A., Bergman, D. A., Ristow, K. M., Ooi, M., Armitage, J. O., Habermann, T. M. (2006). Prospective Study of Survival Outcomes in Non-Hodgkin's Lymphoma Patients With Rheumatoid Arthritis. JCO 24: 1597-1602 [Abstract] [Full text]
Symmons, D P., Silman, A J (2006). The world of biologics. Lupus 15: 122-126 [Abstract]
Fleischmann, R, Baumgartner, S W, Weisman, M H, Liu, T, White, B, Peloso, P (2006). Long term safety of etanercept in elderly subjects with rheumatic diseases. Ann Rheum Dis 65: 379-384 [Abstract] [Full text]
Smedby, K. E., Hjalgrim, H., Askling, J., Chang, E. T., Gregersen, H., Porwit-MacDonald, A., Sundstrom, C., Akerman, M., Melbye, M., Glimelius, B., Adami, H.-O. (2006). Autoimmune and Chronic Inflammatory Disorders and Risk of Non-Hodgkin Lymphoma by Subtype. JNCI J Natl Cancer Inst 98: 51-60 [Abstract] [Full text]
Engels, E. A., Cerhan, J. R., Linet, M. S., Cozen, W., Colt, J. S., Davis, S., Gridley, G., Severson, R. K., Hartge, P. (2005). Immune-Related Conditions and Immune-Modulating Medications as Risk Factors for Non-Hodgkin's Lymphoma: A Case-Control Study. Am J Epidemiol 162: 1153-1161 [Abstract] [Full text]
Askling, J, Klareskog, L, Hjalgrim, H, Baecklund, E, Bjorkholm, M, Ekbom, A (2005). Do steroids increase lymphoma risk? A case-control study of lymphoma risk in polymyalgia rheumatica/giant cell arteritis. Ann Rheum Dis 64: 1765-1768 [Abstract] [Full text]
Furst, D E, Breedveld, F C, Kalden, J R, Smolen, J S, Burmester, G R, Bijlsma, J W J, Dougados, M, Emery, P, Keystone, E C, Klareskog, L, Mease, P J (2005). Updated consensus statement on biological agents, specifically tumour necrosis factor {alpha} (TNF{alpha}) blocking agents and interleukin-1 receptor antagonist (IL-1ra), for the treatment of rheumatic diseases, 2005. Ann Rheum Dis 64: iv2-iv14 [Full text]
Watson, K, Symmons, D, Griffiths, I, Silman, A (2005). The British Society for Rheumatology Biologics Register. Ann Rheum Dis 64: iv42-iv43 [Abstract] [Full text]
Askling, J, Fored, C M, Baecklund, E, Brandt, L, Backlin, C, Ekbom, A, Sundstrom, C, Bertilsson, L, Coster, L, Geborek, P, Jacobsson, L T, Lindblad, S, Lysholm, J, Rantapaa-Dahlqvist, S, Saxne, T, Klareskog, L, Feltelius, N (2005). Haematopoietic malignancies in rheumatoid arthritis: lymphoma risk and characteristics after exposure to tumour necrosis factor antagonists. Ann Rheum Dis 64: 1414-1420 [Abstract] [Full text]
Doan, T., Massarotti, E. (2005). Rheumatoid Arthritis: An Overview of New and Emerging Therapies. J Clin Pharmacol 45: 751-762 [Abstract] [Full text]
Askling, J, Brandt, L, Lapidus, A, Karlen, P, Bjorkholm, M, Lofberg, R, Ekbom, A (2005). Risk of haematopoietic cancer in patients with inflammatory bowel disease. Gut 54: 617-622 [Abstract] [Full text]
Franklin, J P, Symmons, D P M, Silman, A J (2005). Risk of lymphoma in patients with RA treated with anti-TNF{alpha} agents. Ann Rheum Dis 64: 657-658 [Full text]
Xu, B-Y, Arlehag, L, Rantapaa-Dahlquist, S-B, Lefvert, A K (2005). {beta}2 Adrenoceptor gene single nucleotide polymorphisms are associated with rheumatoid arthritis in northern Sweden. Ann Rheum Dis 64: 773-776 [Abstract] [Full text]
Ledingham, J., Deighton, C., on behalf of the British Society for Rheumatology, (2005). Update on the British Society for Rheumatology guidelines for prescribing TNF{alpha} blockers in adults with rheumatoid arthritis (update of previous guidelines of April 2001). Rheumatology (Oxford) 44: 157-163 [Full text]
Feng, W.-h., Cohen, J. I., Fischer, S., Li, L., Sneller, M., Goldbach-Mansky, R., Raab-Traub, N., Delecluse, H.-J., Kenney, S. C. (2004). Reactivation of Latent Epstein-Barr Virus by Methotrexate: A Potential Contributor to Methotrexate-Associated Lymphomas. JNCI J Natl Cancer Inst 96: 1691-1702 [Abstract] [Full text]
Furst, D E, Breedveld, F C, Kalden, J R, Smolen, J S, Burmester, G R, Bijlsma, J W J, Dougados, M, Emery, P, Keystone, E C, Klareskog, L, Mease, P J (2004). Updated consensus statement on biological agents, specifically tumour necrosis factor {alpha} (TNF{alpha}) blocking agents and interleukin-1 receptor antagonist (IL-1ra), for the treatment of rheumatic diseases, 2004. Ann Rheum Dis 63: ii2-ii12 [Full text]
Olsen, N. J., Stein, C. M. (2004). New Drugs for Rheumatoid Arthritis. NEJM 350: 2167-2179 [Full text]
Feltelius, N, Ekbom, A, Blomqvist, P (2003). Cancer incidence among patients with ankylosing spondylitis in Sweden 1965-95: a population based cohort study. Ann Rheum Dis 62: 1185-1188 [Abstract] [Full text]
Furst, D E, Breedveld, F C, Kalden, J R, Smolen, J S, Burmester, G R, Dougados, M, Emery, P, Gibofsky, A, Kavenaugh, A F, Keystone, E C, Klareskog, L, Russell, A S, van de Putte, L B A, Weisman, M H (2003). Updated consensus statement on biological agents for the treatment of rheumatoid arthritis and other immune mediated inflammatory diseases (May 2003). Ann Rheum Dis 62: ii2-9 [Full text]
Keystone, E C (2003). Advances in targeted therapy: safety of biological agents. Ann Rheum Dis 62: ii34-36 [Full text]
Cvetkovic, J. T., Wallberg-Jonsson, S., Ahmed, E., Rantapaa-Dahlqvist, S., Lefvert, A. K. (2002). Increased levels of autoantibodies against copper-oxidized low density lipoprotein, malondialdehyde-modified low density lipoprotein and cardiolipin in patients with rheumatoid arthritis. Rheumatology (Oxford) 41: 988-995 [Abstract] [Full text]
Mariette, X., Cazals-Hatem, D., Warszawki, J., Liote, F., Balandraud, N., Sibilia, J. (2002). Lymphomas in rheumatoid arthritis patients treated with methotrexate: a 3-year prospective study in France. Blood 99: 3909-3915 [Abstract] [Full text]
O'Quinn, R. P., Miller, J. L. (2002). The Effectiveness of Tumor Necrosis Factor {alpha} Antibody (Infliximab) in Treating Recalcitrant Psoriasis: A Report of 2 Cases. Arch Dermatol 138: 644-648 [Abstract] [Full text]
Hjelmström, P. (2001). Lymphoid neogenesis: de novo formation of lymphoid tissue in chronic inflammation through expression of homing chemokines. J. Leukoc. Biol. 69: 331-339 [Abstract] [Full text]
Kroot, E J A, van Leeuwen, M A, van Rijswijk, M H, Prevoo, M L L, Van 't Hof, M A, van de Putte, L B A, van Riel, P L C M (2000). No increased mortality in patients with rheumatoid arthritis: up to 10 years of follow up from disease onset. Ann Rheum Dis 59: 954-958 [Abstract] [Full text]
ASKLING, J., GRUNEWALD, J., EKLUND, A., HILLERDAL, G., EKBOM, A. (1999). Increased Risk for Cancer Following Sarcoidosis. Am. J. Respir. Crit. Care Med. 160: 1668-1672 [Abstract] [Full text]