TNF inhibitors, MTX, RA, and lymphoma

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Abstract 543

Lymphoma in Rheumatoid Arthritis: the Effect of

Methotrexate and Anti-TNF Therapy in 18,572 Patients.

Wolfe and Michaud

Background: The risk of lymphoma is increased in patients with

rheumatoid arthritis (RA). It remains unclear whether treatment with

methotrexate or TNF inhibitors is associated with an increased risk for

developing lymphoma in RA patients. Previous studies (prior to the

anti-TNF era) have shown strong correlations between disease activity

and lymphoma development. This study was undertaken to determine the

rate and standardized incidence ratio (SIR) for lymphoma in RA patients,

and in subsets of patients by treatment group. In addition, the

investigators sought to determine predictors of lymphoma in RA.

Methods: A prospective study of 18,572 RA patients who were surveyed

biannually in a long-term outcome study (1998-2002). Potential lymphoma

cases received detailed follow-up. The SIR was calculated with data from

the SEER cancer data resource.

Results: Twenty-nine (29) cases of lymphoma were identified, yielding a

rate of 98.9 per 100,000 patient years of observation. The following SIR

rates were observed/calculated:

1.9 (95% C.I. 1.3, 2.7), overall

2.9 (1.7, 4.9), for biologic use

2.6 (1.4. 4.5), for infliximab, with or without etanercept

3.8 (1.9, 7.5), for etanercept, with or without infliximab

1.7 (0.9, 3.2), for MTX

1.0 (0.4, 2.5), for those not using MTX or biologics

Lymphoma was associated with increasing age (hazard ratio 1.58 per 10

year increase (95% C.I. 1.16, 2.18), male sex (HR 3.70 (1.79, 7.68)) and

education (1.16 (0.99, 1.37)), but not with current or previous therapy.

There was no temporal pattern for the development of lymphoma after the

start of anti-TNF therapy. A wide variety of lymphoma cell types were

identified. Patients receiving anti-TNF therapy had more severe RA at

enrollment than did non anti-TNF patients.

Conclusion: The incidence of lymphomas is increased in RA, but

confidence intervals overlap among all treatment groups. The apparent

increase in lymphomas in patients treated with TNF inhibitors may be due

to confounding by indication - that is, that patients with severe

disease who are (historically) most likely to develop lymphomas are also

the ones most likely to receive TNF inhibitors.

Editorial Comment: There has been significant concern as to whether TNF

inhibitors increase an RA patient's risk for developing lymphoma.

Defining this risk accurately has been difficult. To date, incidence

rates for lymphomas in TNF antagonist-treated patients have been

compared to contemporaneous non-RA controls, or to historical RA

controls, due to lack of data in contemporaneous RA controls not

receiving TNF antagonists. The validity of these comparisons is

questionable. Dr. Wolfe herein provides the first estimates of lymphoma

rates in a prospective cohort of RA patients, some of whom received TNF

antagonists and some who did not. Interestingly, the patients who were

not receiving MTX or TNF antagonists did not exhibit a higher incidence

of lymphomas compared to the SEER data base controls, perhaps reflecting

milder disease. Likewise, the mild increase in lymphoma incidence in the

TNF antagonist treated patients could be explained by more severe

disease which is a known risk factor for lymphoma in RA.

http://www.hopkins-arthritis.som.jhmi.edu/edu/acr2003/ra-treatments.html#543

Abstract 543

ACR 2003 National Scientific Meetings

" Lymphoma in Rheumatoid Arthritis: the Effect of Methotrexate and

Anti-TNF Therapy in 18, 572 Patients "

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Mayo Clinic in Rochester

http://www.mayoclinic.org/rochester

s Hopkins Medicine

http://www.hopkinsmedicine.org