RA lymphoma risk tied to inflammation, not DMARD treatment

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RA lymphoma risk tied to inflammation, not DMARD treatment



Mar 21, 2006



Janis

Uppsala, Sweden - The elevated lymphoma rates associated with TNF-

inhibitor treatment in some rheumatoid-arthritis (RA) patients raised

questions about the relationship between lymphoma, underlying RA

disease processes, and the possibly cancer-promoting effects of

immunosuppressive therapy. Dr Eva Baecklund (Akademiska Hospital,

Uppsala, Sweden) and colleagues answer many of those questions in a

large case-control study of Swedish RA patients with and without

lymphoma [1]. The study is published in the March 2006 issue of

Arthritis & Rheumatism.

" Our most important findings were that lymphoma risk is significantly

increased only in the subset of RA patients with very severe disease

activity and that common [disease-modifying antirheumatic drug] DMARD

therapy (antimalarials, auranofin, cyclosporine, D-penicillamine,

intramuscular gold, methotrexate, or sulfasalazine) is not associated

with increased lymphoma risk in RA patients, " Baecklund told rheumawire.

Lymphoma risk skyrockets in patients at the 3 highest levels of

disease activity





Lymphoma risk is significantly increased only in the subset of RA

patients with very severe disease activity, and common DMARD therapy

is not associated with increased risk.





The researchers used data from a population-based cohort of 74 651 RA

patients to identify 378 consecutive Swedish RA patients who

developed malignant lymphoma between 1964 and 1995 (before the

introduction of TNF inhibitors). They matched patients with 378 RA

patients who were free from any registered cancer at the time their

matched case patients were diagnosed with lymphoma. Cases and

controls were matched by sex, year of birth, year of first RA

discharge, and county of residence.

Information on disease characteristics and treatments from RA onset

until lymphoma diagnosis was abstracted from medical records. Tissue

blocks were reexamined to confirm the lymphoma diagnosis and to test

for Epstein-Barr virus (EBV).

RA disease activity was assessed both as overall disease activity for

the whole RA disease period and as cumulative disease activity from

the onset of RA, both based on swollen and tender joint counts,

erythrocyte sedimentation rate, and physician's global assessments.

This revealed that lymphoma risks were only slightly elevated for

most patients but spiked sharply upward beginning at the seventh

decile of cumulative disease activity. The odds ratio (OR) for

lymphoma was 9.4 for patients in the ninth decile of cumulative RA

disease activity and 61.6 for those in the highest decile of disease

activity



Baecklund said that this might be because in RA patients with severe

disease and long-standing immune activation, the persistent

proliferative drive increases the probability for genetic aberrations

in immune cells and a subsequent malignant transformation. " This

appears to happen preferentially in B cells and may be followed by

the expansion of an uncontrolled B-cell clone and eventually the

development of a diffuse large B-cell lymphoma, " she said.

Other factors might include the accelerated aging of the immune

system associated with severe RA, which results in diminished

immunosurveillance and an impaired ability to eliminate emerging

premalignant and malignant cell clones. " Patients with less severe RA

could have either fewer premalignant/malignant cells to cope with or

a better immunocompetence to handle these cells, " Baecklund suggested.



We should not be afraid of but encourage use of DMARDs to reduce

inflammation.



Coauthor Dr Lars Klareskog (Karolinska University Hospital,

Stockholm, Sweden) summarized the clinical implications for

rheumawire, " Disease activity rather than treatment with DMARDs is

the major determinant for lymphoma development in RA. This means that

rheumatologists should be very aware of the lymphoma risk in patients

with long-standing high disease activity and that we should not be

afraid of but instead encourage use of DMARDs to reduce inflammation

in these cases. "

Baecklund added that these findings reinforce current approaches to

RA treatment, including early arthritis clinics, early introduction

of aggressive antirheumatic treatment with disease-modifying drugs

and corticosteroids, and efforts to achieve remission of RA.

The study also provides important data on the " background " risk of

lymphoma in RA patients for use in clinical trials of new RA drugs.

In an accompanying editorial, Drs Cornelia M Weyand, Jorg J Goronzy,

and J Kurtin highlight the study finding that oral steroids

reduced the risk of lymphoma (OR 0.6) and that intra-articular

steroids reduced the risk by about two thirds [2]. They argue for

greater efforts to suppress inflammation in RA, writing, " We can

simultaneously suppress rheumatoid inflammation and reduce the risk

for lymphoma development. "



Sources



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. 

Weyand CM, Goronzy JJ, Kurtin PJ, et al. Lymphoma in rheumatoid

arthritis: An immune system set up for failure. Arthritis Rheum 2006;

54:685-689. 

http://www.jointandbone.org/viewArticle.do?primaryKey=673505