Rheumatology Advance Access originally published online on August 27, 2006
Rheumatology 2007 46(1):1-2; doi:10.1093/rheumatology/kel303

? The Author 2006. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

EDITORIALS

Lymphoma and rheumatoid arthritis?again

D. P. M. Symmons

Professor of Rheumatology and Musculoskeletal Epidemiology, University of Manchester, Manchester M13 9PT, UK

Correspondence to: Prof. D. P. M. Symmons, ARC Epidemiology Unit, Stopford Building, University of Manchester, Oxford Road, Manchester M13 9PT, UK E-mail: deborah.symmons@manchester.ac.uk

The link between lymphoma and rheumatoid arthritis (RA) continues to intrigue. It was first noted in a record linkage study from Finland published in 1978 [1]. Since then, there have been numerous reports of an increased incidence of lymphoma?in particular, non-Hodgkin's lymphoma (NHL) and more particularly diffuse large B-cell lymphoma (DLBCL) [2]?in patients with RA from around the world [3?6]. It can now be considered beyond dispute that RA and, indeed, many other autoimmune diseases are associated with an increased risk of NHL. However, the question remains as to the relative contribution of the underlying disease and the drugs used to treat it to the aetiology of the malignancy. The advent of each new treatment for RA seems to re-open the debate.

There is now considerable evidence that rheumatoid disease itself plays an important role in the aetiology of the NHL. The increased risk is manifested fairly early in the disease course. In a study from the Norfolk Arthritis Register (NOAR), the increased risk was apparent within the first 5 yrs [7]. At a median follow-up of 8.4 yrs, the standardized incidence ratio (SIR) of lymphoma compared with the general population was 2.4 (95% CI 1.2, 4.2). The risk was highest amongst those who were rheumatoid factor (RF) positive [SIR = 3.6 (95% CI 1.3, 7.8)]. Other studies have suggested that the risk of NHL is related to disease duration. However, this may simply be a function of allowing cumulative disease activity to accrue. A recent meticulous study from Sweden identified 378 patients with RA and lymphoma by linking the in-patient registry and the cancer registry [8]. The lymphomas were diagnosed between 1964 and 1995. Three control RA patients matched for gender, year of birth, year of first discharge with RA and county of residence were selected for each case. Information on disease activity was extracted for every visit for each case and each control. A relationship was found both with the average disease activity [highest vs lowest quartile unadjusted odds ratio (OR) 71.3, 95% CI 24.1, 211.4] and cumulative disease activity (10th decile vs 1st decile OR 61.6, 95% CI 21.0, 181.0).

Baecklund et al. [2] found that 22 of the 35 NHL (67%) that they were able to characterize were DLBCL. A similar proportion was found in the Norfolk study [7]. This compares with 30?40% of sporadic NHL in the general population. Immunodeficiency, in particular, impaired T-cell function such as has been reported in RA, is the main risk factor for NHL [9]. Such T-cell impairment may permit the proliferation of the oncogenic herpes virus Epstein?Barr virus (EBV). Up to 90% of post-transplant NHLs are EBV positive [9]. In the 30 NHL tested by Baecklund et al. [2], 5 (17%) were EBV+ including 4 out of 22 (18%) of the DLBCL. This compares with <5% EBV positivity in sporadic DLBCL [10].

Azathioprine was the first drug to be investigated with regards to enhancing lymphoma risk in RA. An association between azathioprine therapy and NHL had first been noted in transplant patients [11]. In 1988, Silman et al. [12] reported an excess of NHL in RA patients treated with high dose azathioprine compared with non-azathioprine treated RA controls. The Canadian registry of azathioprine use reported an 8-fold increased risk of lymphoproliferative disorders based on four cases in 530 patients [13]. The European League against Rheumatism (EULAR) Immunosuppressive Registry found an adjusted incidence rate ratio of 2.9 (95% CI 0.7, 12.7) of developing NHL in patients with rheumatic diseases who had been treated with azathioprine for ≥6 yrs compared with those treated for <1 yr [14]. In the recent Swedish case control study, azathioprine was the only disease-modifying anti-rheumatic drug (DMARD) associated with an increased risk of NHL (adjusted OR for ever vs never azathioprine 4.3; 95% CI 1.6, 12.0). The risk appeared to rise with increasing length of exposure to azathioprine [8].

Then the spotlight fell on methotrexate (MTX). The first report of a lymphoma developing in a rheumatoid patient treated with MTX appeared in 1991 [15]. However, three large epidemiological studies have failed to find an association between MTX exposure and the development of NHL in RA patients [16?18]. In the most recent study, Wolfe and Michaud [18] reported an SIR of 1.5 (95% CI 0.8, 2.7) based on 10 cases of lymphoma occurring in 6396 RA patients exposed to MTX. The exception is the Norfolk study that found a SIR of 4.9 (95% CI 1.88, 10.6) in MTX-exposed patients with inflammatory polyarthritis but, as the authors acknowledge, this is an unadjusted figure and may be due to confounding by indication [7]. There are around 50 cases in the literature of regression of NHL following withdrawal of MTX in RA patients [19]. This is a phenomenon also seen in post-transplant patients associated with EBV positivity. Around 16?44% of NHL associated with MTX are EBV + [17, 20, 21]. It has been shown that MTX can re-activate latent EBV and this may contribute to the development of NHL in some cases [22].

Now the introduction of the anti-TNF{alpha} agents once again brings attention to the link between lymphoma and RA. TNF{alpha} promotes a T-cell cytotoxic response against B-cell malignancies, and so right from the beginning there has been anxiety that anti-TNF{alpha} therapy might be associated with an increased risk of NHL. In 2002, Brown et al. [23] published details of 26 cases of lymphoma that had been spontaneously reported to the US Food and Drug Administration up to December 2000. There were no denominator data so it was impossible to be sure whether this was more or less than would be expected. Wolfe and Michaud [18] reported a SIR of 2.9 (95% CI 1.7, 4.9) of NHL developing in 8614 RA patients exposed to either infliximab or etanercept [18]. Based on five cases occurring in 757 patients from southern Sweden exposed to either infliximab or etanercept, Geborek et al. [24] reported a SIR of 11.5 (95% CI 3.5, 26.9). The SIR in their comparison group of non-biologically exposed RA patients (based on two cases) was 1.4 (95% CI 1.1, 1.8). Thus, the rate in the biologically treated group was increased 5-fold compared with the comparison cohort [24]. By comparison Askling et al. [25] investigated the incidence of lymphoma in the whole Swedish Biologics Register (n = 4160) exposed to etanercept, infliximab or adalimumab. Based on nine cases, they estimated a SIR of 2.9 (95% CI 1.3, 5.5). However, the risk was not increased compared with that in a prevalent cohort of RA in-patients: risk ratio (RR) 1.1 (95% CI 0.6, 2.1). Clearly, these reports are all based on small numbers of cases and so are somewhat unstable. They also represent experience in the early months of treatment with anti-TNF{alpha} therapy. It remains to be seen whether long-term anti-TNF{alpha} therapy will increase or decrease the risk of NHL in RA.

A recently published meta-analysis examined the malignancy risk in nine published randomized controlled trials (RCTs) of infliximab and adalimumab [26]. They identified four lymphomas which occurred during the trials and an additional six, which occurred after the trials were over. All were in the biologically treated arm of the trial. The authors did not present an odds ratio based on these data-focusing, instead on the overall risk of malignancy. While observations of increased risk coming from the Biologics Registers may be criticized for confounding by indication (control group not adequately matched for disease severity) or protopathic bias (patients with latent NHL having increased joint symptoms so likely to have their treatment changed), this does not apply to RCTs. It is possible, however, that the biologically treated patients may have been subjected to greater surveillance than the placebo arm in the unblinded follow-up phase of the RCT and also that the drop-out rate may have been higher in the placebo arm leading to less person-time of observation.

It seems likely that there is the potential for RA treatment both to increase and to reduce lymphoma risk in RA. Lymphoma risk is greatest in RA patients with the highest cumulative disease activity [8]. Yet of the 35 RA patients with NHL in Baecklund's study, 17 had never received any DMARD treatment and a further 10 had received it for <1 yr [2]. Despite the impressive efficacy of the anti-TNF{alpha} agents, most patients enrolled in the RCTs still satisfied the entry criteria for the trial at the end of the study (i.e. they still had significant disease activity). Perhaps the way to abolish the excess risk of NHL in patients with RA is to treat the disease adequately but not to overtreat.

The author has declared no conflict of interest.

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Accepted 18 July 2006