Rheumatoid arthritis (RA) is associated with an increased occurrence of lymphomas (1–5), amounting to an average doubling of the lymphoma risk (2–5). There are, however, indications of marked variations in risk between patients (1, 6, 7). In a pilot study of 41 Swedish patients with RA-associated lymphoma occurring between 1965 and 1984, we observed an association between high disease activity and lymphoma risk (6). Findings in a recent cohort study whose subjects included 29 patients with RA-associated lymphoma (8) provide further indirect evidence of this association. While these findings suggest that inflammatory activity may be a driving force in lymphoma development, we are at present unable to determine what amount of inflammatory activity increases lymphoma risk. Likewise, there is very little information on the effect of antiinflammatory and immunosuppressive treatment on lymphoma risk in RA.
The basis for this uncertainty is that in several case series (9–12) as well as cohort studies (13–17) on patients treated with disease-modifying antirheumatic drugs (DMARDs) including methotrexate, information on lymphoma development (and elevated risk) in conjunction with RA was collected, but possible effects of treatment could not be separated from possible effects of the disease process itself. The same problem, i.e., an inability to distinguish therapy-related effects from effects of the disease, is encountered in case–control studies whose results have indicated increased lymphoma risks after treatment with nonsteroidal antiinflammatory drugs (NSAIDs) and aspirin (18, 19) and with corticosteroids (20, 21). Reports based on case series and comparisons with age-matched healthy population controls have also linked tumor necrosis factor (TNF) blockade treatment to increased lymphoma risk (8, 22–24). Importantly, though, none of the above studies has been able to pinpoint the specific effects of disease activity on lymphoma risk, let alone distinguish them from the effects of treatment.
Consequently, it is of clinical as well as of scientific importance to better identify which patients with RA are at high risk of developing lymphomas, and in particular to understand whether the increased lymphoma risk is disease driven and a result of suboptimal use of immunosuppressive treatment, or is an untoward effect of the very same treatment. From a drug safety point of view, knowledge of the baseline lymphoma risk is essential for the evaluation of new drugs, as illustrated by the current uncertainty of the benefits—or hazards—with respect to lymphoma risk following TNF blockade treatment in patients with RA or inflammatory bowel disease (22–24). To address this, we used data from longitudinal, population-based, high-quality registers and biobanks in Sweden, in a population-based case–control study of 378 patients with RA-associated lymphoma occurring between 1964 and 1995. We assessed the importance of RA disease activity, phenotype, and treatment on lymphoma risk overall and by lymphoma subtype.
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- SUBJECTS AND METHODS
In this large case–control study of malignant lymphomas complicating RA, we have made a series of new observations: 1) A relatively small proportion of all patients with RA—those with the highest degree of inflammatory disease activity—have a dramatically increased lymphoma risk. 2) Treatment with most common DMARDs or antiinflammatory drugs is not in itself a risk factor for RA-associated lymphomas, nor does treatment further increase the risk associated with high inflammatory activity. 3) Although most “excess” lymphomas in RA are of the aggressive DLBCL type, the association with high disease activity also applies to other subtypes. 4) The presence of EBV in RA-associated lymphomas is low.
The strength of this study is its setting and combination of data sources. The population-based Swedish health care data combined with unique personal identifiers, high-quality, population-based health and census registers, original medical records from in- and outpatient medical care, and biobanks at pathology departments all over the country enabled us to compile detailed data on exposure (the fluctuating disease activity typical of RA, and its treatments) and outcome (reclassified and EBV-tested lymphomas). The underlying cohort of patients hospitalized with RA between 1964 and 1994 provided a well-defined source population for selection of controls and a wide range of exposure with respect to disease activity and treatments. Today, treatment of RA is not only more intensive, but also more uniform, thereby reducing the ability to dissect the collinear association between disease and treatment. Our study design also minimized recall and information bias and provided a sample size that was 10-fold higher than populations in related studies previously reported in the literature (6, 7).
In our previous work (6), disease activity was linked to lymphoma risk in a nonlinear manner. Therefore, to classify each level of monthly disease activity in the cumulative disease activity score (inactive, low, medium, and high) as accurately as possible, we investigated the effect of each level of disease activity on lymphoma risk by conditional logistic regression, and used the estimates derived from this analysis for the scoring (0, 1, 5, or 8). Although this approach is not without limitations, it is an attempt to base the scoring on the actual situation rather than just using an arbitrary 0–3 score. We did, however, perform a comparison with scores of 0–3 and found somewhat different ORs, but still a striking association with cumulative disease activity (data not shown). Thus, irrespective of the measure of burden of disease activity (overall disease activity, functional class, cumulative disease activity, ESR, irreversible joint damage), the results indicate a clear association of lymphoma development with chronic inflammatory activity, thereby extending the results of our pilot study (6) to show that the risk of lymphoma among RA patients is indeed mostly limited to those with longstanding and high disease activity.
Although cases and controls were matched both by year of birth and by calendar year of first RA discharge, review of the medical records revealed a small difference in disease duration between cases and controls (due to longer duration from onset of RA until first hospitalization in cases than in controls). To assess the impact of this difference, we stratified patients by disease duration and investigated lymphoma risk linked to AUC. We found no significant differences, which supports the notion that cumulative disease activity, rather than the time taken for it to accrue, is the major determinant of lymphoma risk.
Since our study was based on data obtained from routine medical files, there was not sufficient information to calculate repeatedly obtained data included in standard measures of disease activity, e.g., the 28-joint Disease Activity Score (DAS28) (33). Assuming that the swollen joint count is generally equivalent to the tender joint count, our definition of high disease activity would, however, broadly correspond to a DAS28 of >5.7 and low activity to a DAS28 of <4.3.
Exposure to DMARDs was less common than would be expected from current guidelines for treatment of RA, but fully reasonable considering treatment practices during the study period. Of all the medical treatments assessed, we observed increased risks associated only with AZA, which is consistent with the results of some previous studies (13, 14, 34) but discordant with the results of others (35). However, we noted no differences in the proportion of EBV-positive lymphomas or the distribution of lymphoma subtypes among the patients who had been treated with AZA. AZA has not been regarded as a traditional DMARD for RA and is sparsely used in RA today.
Case reports and case series have linked MTX treatment to lymphomas, often EBV positive, that are characterized by spontaneous regression once MTX is withdrawn (10, 11, 36, 37). Investigators in France (17) recently reported on the heretofore largest number of studied RA patients who developed lymphoma and had been treated with MTX (n = 25). Although the definition of the underlying cohort hampers our ability to draw inferences from that study, no overall association between lymphoma risk and MTX treatment was observed, but 3 of the 25 lymphomas remitted after MTX was stopped (although 2 subsequently relapsed). Based on 19 cases of lymphoma occurring in MTX-treated RA patients in our well-defined population-based cohort, we did not observe any increase in lymphoma risk associated with MTX, nor did we find an increased occurrence of EBV-positive lymphomas, or any EBV-positive lymphoma that regressed spontaneously. Our results therefore suggest that although MTX might be associated with lymphomas that can regress upon treatment withdrawal, such lymphomas are likely to constitute a small minority of all lymphomas that occur in RA patients exposed to MTX, and MTX does not appear to increase overall lymphoma risk.
We found no risks linked to duration of DMARD treatment. However, for some of the individual DMARDs, analyses were based on only a few patients in each interval of treatment duration, and results should be interpreted with some caution.
By and large, our results suggest that treatment with traditional DMARDs, including MTX, is not a risk factor for malignant lymphoma in RA and does not further increase the elevated lymphoma risk in patients with high disease activity. Since DMARDs act to reduce inflammatory activity, which exhibited a strong association with lymphoma risk, and since several of the drug-specific relative risk estimates were below, rather than above, 1.0, DMARD treatment may in reality be associated with a reduction in lymphoma risk.
We found risk estimates below 1.0 to also be linked to corticosteroid use, which suggests a lymphoma-protective effect of this treatment as well. Of interest, lymphoma risk was particularly low in patients who had received frequent intraarticular corticosteroid injections in inflamed joints. A lymphoma-protective role of corticosteroids is theoretically possible; apart from being potent antiinflammatory drugs, corticosteroids are included in antilymphoma treatment and exert their effects through many mechanisms, one being apoptosis of hematologic cells (38).
Besides the association between degree of inflammatory disease and DLBCLs, we observed a 5-fold risk gradient with other lymphoma subtypes, suggesting that the lymphomagenic potential of inflammation either may be nonspecific or may exert its influence on pathways common to several lymphoma types. The fact that the proportion of lymphomas that were EBV positive (common in immunocompromised individuals ) was not high indirectly supports our conclusion that immunostimulation, rather than immunosuppression, is the driving force in inflammation-associated lymphomas.
The restriction of our case and control subjects to those whose RA ever required hospitalization may have led to selection of individuals with more severe RA, but does not explain the association with disease activity. The underlying cohort was population based, and we estimate that it covers >50% of all patients with RA in Sweden during the study period, so this restriction is unlikely to have substantially affected generalizability of the results. The inclusion of patients discharged with RA as either the main or a contributory diagnosis increased the number of cases and controls who were in the hospital for reasons other than severe RA. This study spanned many years, and to avoid possible calendar period–related differences in threshold for hospitalization, register coverage, and treatment type and intensity, patients were matched for the year of first RA discharge and county of residence.
The comparatively high proportion of males in our study (45%) must be interpreted in light of the higher lymphoma incidence among males (5, 28). There were, however, no significant differences in results between men and women when analyses of disease activity were stratified by sex.
We did not exclude patients with lymphoma diagnosed within the first year after the first discharge for which RA was listed. This may have led to the inclusion of some RA patients who were hospitalized due to the emerging lymphoma (confounding by indication), but allowed us to achieve a more complete study that encompassed all RA-related lymphomas that could be identified with the register-based approach. High cumulative disease activity was characteristic of the patients with lymphoma diagnosis soon after the first discharge for RA.
Given the many uncertainties regarding the link between malignant lymphomas and chronic inflammatory diseases, and the difficulties in judging the lymphoma risks associated with new therapies, the implications of the present results are substantial. The association between lymphoma risk and very high and/or longstanding disease activity indicates that most patients with RA will never have any clinically relevant increased lymphoma risk. In contrast, those who do may have highly increased risks, but can be readily identified based on their accrued inflammatory burden. Conventional medical treatment to suppress and alleviate disease activity is not by itself a risk factor for lymphoma. Rather, it is possible that aggressive treatment may reduce lymphoma risk by reducing cumulative inflammation. From a drug safety perspective, our results provide background data that should be considered essential for the evaluation of lymphoma risk following therapy with TNF blockers, for example, as well as other new drugs.