Rheumatology Advance Access originally published online on December 5, 2006
Rheumatology 2007 46(4):690-694; doi:10.1093/rheumatology/kel396
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Non-Hodgkin's lymphoma—meta-analyses of the effects of corticosteroids and non-steroidal anti-inflammatories
Division of Clinical Epidemiology, McGill University Health Centre, Montreal, Canada.
Correspondence to: Dr Sasha Bernatsky, Division of Clinical Epidemiology, McGill University Health Centre (MUHC), 687 Pine Avenue West, V Building, Montreal, Quebec H3A 1A1, Canada. E-mail: sasha.bernatsky{at}mail.mcgill.ca
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Abstract |
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Objective. Recent research has focused on the effects of corticosteroids and non-steroidal anti-inflammatory drugs/agents (NSAIDs) on non-Hodgkin's lymphoma (NHL) risk, with inconclusive results. We conducted meta-analyses of data published to date, to ascertain the over-all association between NHL and corticosteroid use, and between NHL and NSAID use.
Methods. Literature searches were performed to find studies assessing the effects of corticosteroids and/or NSAIDs on NHL risk. We analysed nine case-control studies and one cohort study of the effect of corticosteroids and/or NSAIDs on NHL risk. We performed a formal meta-analysis using summary measures from these studies.
Results. The studies contributed 6897 NHL cases and 8881 controls for the corticosteroid analyses, and 5794 NHL cases and 34 707 controls for the NSAID analyses. There was no heterogeneity of the odds ratio (OR) estimates. The overall OR for the effect of corticosteroid exposure on NHL occurrence was not suggestive of an increased risk [OR 1.09, 95% confidence interval (CI) 0.96–1.24]. Similarly, the OR for the effect of NSAIDs on NHL occurrence did not support an increased risk (OR 0.93, 95% CI 0.74–1.14).
Conclusions. Our meta-analyses suggest little evidence that corticosteroid or NSAID exposures are themselves risk factors for NHL. Early data linking corticosteroids and/or NSAIDs with NHL may reflect an underlying increased risk of lymphoma in patient populations that use these medications (i.e. autoimmune diseases such as rheumatoid arthritis), and may point to the importance of disease activity in driving NHL risk in these populations.
KEY WORDS: Non-Hodgkin's lymphoma, NHL, corticosteroids, NSAID, meta-analysis
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Introduction |
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The possibility of an increased risk of non-Hodgkin's lymphoma (NHL) after exposure to corticosteroid and/or non-steroidal anti-inflammatory drugs/agents (NSAIDs) has been examined by several groups in the last 15 yrs, but study results have been inconclusive. Some have suggested a potentially increased risk of lymphoma associated with corticosteroid use or NSAIDs, although others indicated a possible inverse correlation, or no relationship. We thus conducted meta-analyses of published case-control studies to ascertain the over-all association between NHL and corticosteroid use, and between NHL and NSAID use.
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Methods |
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We conducted a systematic literature search to identify studies of NHL risk associated with corticosteroid and/or NSAID use. For our computerized search, we used the text-based search and retrieval system of the National Center for Biotechnology Information, accessing over 16 million citations from MEDLINE as well as other life science journal citations. Our search strategy employed the following terms: non-Hodgkin's lymphoma, NHL, corticosteroid, steroid, NSAIDs, non-steroidal. In addition, a search was conducted of abstracts presented between 2002 and 2006 at the annual meetings of the American Society of Clinical Oncologists, the American Society of Hematology, the American Rheumatology Association and the European League against Rheumatism. Finally, a manual review of references from primary or review articles was performed, to identify any additional relevant studies. All potentially relevant articles were reviewed; to be included in our meta-analysis, studies had to be a research study in humans, designed to assess the effect of medication exposures (corticosteroids and/or NSAIDs) on the incidence of NHL. We assessed the quality of each study's design (including case ascertainment and data collection methods), and constructed study summaries and funnel plots [a plot of the odds ratio (OR) and the precision (the inverse of the OR standard error)].
To assess NSAIDs and corticosteroids, we conducted two separate meta-analyses of the relevant studies, computing the pooled ORs and 95% confidence intervals (CIs) using a random-effects model. The overall effect of each of the two agents on NHL risk was estimated using the model proposed by DerSimonian and Laird [1]. A weighted mean of the adjusted OR was calculated, with the weights being the inverse of the total variance obtained from adding the within-study and between-studies variances. The consistency of the treatment effect across the studies was assessed using a chi-squared test for heterogeneity. Statistical analyses were performed using S-PLUS version 6 for Windows.
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Results |
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In the analyses for the effects of corticosteroids, we included eight population-based case-control studies that contained summary data for adjusted and/or unadjusted OR effects; eight case-control studies and one cohort study were considered for inclusion in the analyses for the effects of NSAIDs (Tables 1 and 2, Figs 1–3
) [2–12]. The studies were completed between 1992 and 2006. One study (Smedby et al. [9]) was excluded because it studied the same population as an earlier study already included in our meta-analysis (Chang et al. [13]). Two other case-control studies of lymphoma risk were not included as they considered only aspirin use and not other NSAIDs [13, 14]. The rationale for not including these two studies was that aspirin use over the past two decades has been primarily at low doses (for its anti-platelet effect) as opposed to higher doses where the agent has appreciable anti-inflammatory effects (i.e. has characteristics of an NSAID) [15].
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Table 2 and Figs 1 and 2 outline the summary data from each of the studies, which together provided 6897 NHL cases and 8881 controls for the corticosteroid analyses, as well as 5794 NHL cases and 34 707 controls for the NSAID analyses. Regarding design and methodology (particularly related to methods of case and exposure ascertainment), study quality was uniformly high across the studies. As can be seen from Table 1, cancer ascertainment was primarily performed through linkage with tumour registries. Figure 3 presents the funnel plots, which are the classic pictorial representation of the study OR and precision estimates. Accounting for the relatively limited number of studies, the desired ‘inverted funnel’ shape is suggested, which indicates non-biased study representation.
Our analyses demonstrated no heterogeneity of the ORs. The summary OR for the effect of corticosteroid exposure on NHL occurrence was not suggestive of an increased risk (unadjusted OR 1.09, 95% CI 0.96–1.24; adjusted OR 1.13, 95% CI 0.99–1.29). Similarly, the summary OR for the effect of NSAIDs on NHL occurrence did not support an increased risk (unadjusted OR 0.93, 95% CI 0.74 – 1.14; adjusted OR 1.11, 95% CI 0.98 – 1.25).
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Discussion |
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Our meta-analyses confirm that there is little evidence that either corticosteroid or NSAID exposures are risk factors for the development of NHL.
The question of why NSAIDs and corticosteroids might have been linked to NHL in earlier studies may reflect an underlying increased risk of NHL in patient populations that use these medications. Smedby et al. [9] examined NHL risk considering underlying medical conditions. They confirmed what has been shown in previous studies, that NHL is increased in persons with rheumatoid arthritis (RA) (OR 1.5, 95% CI 1.1–1.9), systemic lupus erythematosus (OR 4.6, 95% CI 1.0–22) and other autoimmune disorders. When Smedby et al. [9] looked at the effect of NSAIDs, corticosteroids and selected immunosuppressants on the risk of NHL specifically in RA subjects, they found an increased risk of NHL that was not apparent in non-RA subjects. (In contrast, however, Cerhan et al.'s [5] work suggested similar effects regarding NSAIDs and increased NHL risk in both RA and non-RA populations.)
This may reflect effect modification, but more likely it represents a confounding effect. That is, new evidence points to the importance of disease severity in driving NHL risk in autoimmune diseases such as RA. A recent nested case-control study of RA patients provides the strongest evidence for this association; high inflammatory activity itself (compared with low activity) conferred a huge relative risk (RR) of 71 (95% CI 24–211) for NHL risk in RA (Baecklund et al. [11]). Disease-modifying anti-rheumatic medications (DMARDs) were not associated with lymphoma in that study. Other studies have suggested that, with adjustment for disease severity, possible associations between RA medications and lymphoma risk become less apparent. Setoguchi et al. [16] reported that, after adjustment for RA severity, the rate ratios of haematological cancers in patients receiving either anti-tumour necrosis factor (TNF) agents or methotrexate were comparable. Askling et al. [17], in his post-marketing cohort of RA patients treated with anti-TNF agents, arrived at similar conclusions, although some recent analyses suggest the data may still point towards increased lymphoma risk with anti-TNF exposures [18].
Regarding the prevalence of indications for the use of corticosteroids and NSAIDs in the studies included in the meta-analysis, unfortunately this explicit data is lacking, except for Baecklund et al. [11] (who only studied RA patients) and Engels et al. [12]. In the latter study population, the following potential indications were identified: RA (prevalence 6.1%), inflammatory bowel disease (2.0%), Sjögren's syndrome (0.7%), polymyalgia rheumatica (0.4%), sarcoidosis (0.4%), systemic lupus erythematosus (0.3%), receipt of an organ transplant (0.3%), multiple sclerosis (0.3%), uveitis (0.2%) and myasthenia gravis (0.1%). It should be noted that these diagnoses were self-reported and not necessarily clinically confirmed.
One limitation of our study was that exposure to NSAIDs and corticosteroids were categorized as ‘ever-never’, since not all studies had data on duration of exposure. If risk was present but dose-dependent, in theory this may have contributed towards an over-all effect towards the null. We believe that our results are considerably robust, since sensitivity analyses, limiting the inclusion of studies according to the date of publication or the size of the study, produced results nearly identical to the primary result. In fact, as noted earlier, regarding design and methodology (particularly related to methods of case and exposure ascertainment), quality was uniformly high across the studies.
In summary, our meta-analyses confirm that there is little evidence that corticosteroid or NSAID exposures are risk factors for the development of NHL. We believe that early data suggesting links between NSAIDs and/or corticosteroids may reflect an underlying increased risk of NHL in patient populations that use these medications (i.e. autoimmune diseases such as RA), and the importance of disease activity in driving NHL risk in these populations.
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Acknowledgements |
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S. B. is a recipient of investigator awards from the Canadian Institute of Health Research and Fonds de la Recherche en Santé du Québec and is a Canadian Arthritis Network Scholar. She receives support from the McGill University Health Centre Research Institute and Department of Medicine. E. R. is a research scholar funded by The Arthritis Society. She has received grants and consultant fees from Merck & Co., Inc., the previous manufacturer of rofecoxib, from Pfizer, Inc., the manufacturer of celecoxib and from Boehringer Ingelheim, the manufacturer of meloxicam.
E.R. has received grants and consultancies from Merck & Co., Inc., Pfizer, Inc. and Boehringer Ingelheim in the course of other studies unrelated to the one described in this article.
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References |
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