1 Division of Cancer Epidemiology and Genetics, National Cancer Institute, Department of Health and Human Services, Rockville, MD
2 Department of Health Sciences Research, Mayo Clinic College of Medicine, Rochester, MN
3 Department of Preventative Medicine, Norris Comprehensive Cancer Center, University of Southern California School of Medicine, Los Angeles, CA
4 Program in Epidemiology, Fred Hutchinson Cancer Research Center, Seattle, WA
5 Department of Family Medicine and Karmanos Cancer Institute, Wayne State University, Detroit, MI
Correspondence to Dr. Eric A. Engels, Viral Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, DHHS, 6120 Executive Boulevard, EPS 8010, Rockville, MD 20852 (e-mail: engelse{at}exchange.nih.gov).
Received for publication March 4, 2005. Accepted for publication July 18, 2005.
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ABSTRACT |
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autoimmune diseases; case-control studies; immunosuppression; lymphoma, non-Hodgkin; methotrexate; organ transplantation; risk factors; Sjogren's syndrome
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INTRODUCTION |
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Autoimmune conditions have attracted substantial attention as possible predisposing conditions for NHL. These idiopathic diseases are characterized by disregulated lymphocyte reactivity against self-antigens and the production of autoantibodies, leading to damage of the targeted tissues (e.g., joints, skin) (3). By analogy with what is observed in immunosuppressed states, the ongoing abnormal lymphocyte activation present in autoimmune disorders could predispose to NHL. Indeed, cohort studies of individuals with systemic lupus erythematosus (SLE), rheumatoid arthritis, and rarer conditions such as Sjögren's syndrome have provided evidence that these individuals have an increased risk of NHL (4
11
). Still, cohort studies have usually followed up only those individuals with a single autoimmune condition, often with especially severe manifestations. In addition, cohort studies have generally observed few NHL outcomes, which have not always been well characterized. A case-control study of NHL offers a complementary approach. Several case-control studies of NHL have examined the associations with the more common autoimmune conditions (e.g., rheumatoid arthritis) or all autoimmune conditions taken together, but they have not provided detailed data that would allow a systematic evaluation of NHL risk in relation to the full spectrum of autoimmune conditions (12
15
).
In the present analysis, we used data from a large, population-based US case-control study of NHL to examine the associations of various immune-related conditions (i.e., autoimmune conditions and receipt of an organ transplant) with NHL. We also studied whether NHL risk was elevated for individuals who received selected immune-modulating medications or had a family history of autoimmune conditions. Finally, we sought to characterize whether these factors were related to particular NHL subtypes defined by histology or anatomic site.
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MATERIALS AND METHODS |
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Eligible cases were individuals with incident NHL (aged 2074 years) identified by the SEER registries (18). Of 2,248 potentially eligible cases, 320 (14 percent) died before we could conduct an interview, 127 (6 percent) could not be located, 16 (1 percent) had moved out of the area, and, for 57 (3 percent), the physician refused participation. We attempted to contact the remaining 1,728; 1,321 (76 percent) participated. Controls were selected from the general population in the four areas, stratified by age, sex, and race, and were identified by using random digit dialing (aged 2064 years) or Medicare eligibility files (aged 6574 years). Of 2,409 potential controls selected, 28 (1 percent) died before we could contact them, 311 (13 percent) could not be located, and 24 (1 percent) had moved out of the area. We attempted to contact the remaining 2,046 subjects; 1,057 (52 percent) participated. Response rates were higher for some demographic subgroups, including women (17
).
Study subjects completed a computer-assisted personal interview in their home and provided a blood or buccal cell sample (16). In the interview, the 1-year period prior to interview was excluded from medical history questions to avoid confusion with symptoms possibly related to incipient NHL. All subjects were asked about a history of specific medical conditions, including immune-related disorders ("Were you ever told by a doctor or other health professional that you had CONDITION?"), and use of corticosteroids ("Before one year ago, did you ever take corticosteroids, such as cortisone or prednisone?"). Subjects who answered in the affirmative were then asked to specify the age at diagnosis or (for corticosteroids) age at first use. Because of the length and complexity of the overall interview, by design some questionnaire components were administered to only half of the subjects. "Questionnaire A," which included an especially detailed medical history and a family history, was given to all African-American subjects and, by random selection, to half of the other subjects. Family history questions inquired whether first-degree relatives (specified separately as father, mother, siblings, children) had any of the autoimmune conditions of interest. Questionnaire A also contained questions regarding use of methotrexate and gold injections. Remaining subjects answered "questionnaire B," which did not include information on family history.
All NHLs were confirmed histologically. Information on NHL histology and anatomic site was obtained from reports supplied to the SEER registries. Histologic diagnoses were coded by using the International Classification of Diseases for Oncology, Second Edition (19) and were subsequently translated to categories of the World Health Organization classification (20
).
Statistical methods
We calculated odds ratios to assess the association between various immune-related medical conditions and NHL. Similarly, we measured associations between NHL and variables describing medication use and family history (summarized as any vs. no first-degree relative with the condition). Odds ratios were adjusted with logistic regression for the variables used in control sampling (age, sex, race, study site), unless there were too few subjects with the condition of interest for the model to converge, in which instance we calculated an unadjusted odds ratio. We did not calculate any odds ratio when the number of subjects with the condition was five or fewer. In this paper, we present 95 percent confidence intervals using the Wald method. We also present p values derived by using a score test, which is more accurate than the Wald statistic for sparse data, although we note that the Wald p value was generally close to the score test p value. For comparisons in which no odds ratio could be calculated (zero cases or controls with the condition), we report the Fisher's exact test p value. All p values are two sided.
For the minority of subjects who were administered a given questionnaire but did not respond to a specific question or did not know the answer, we considered them as not having the condition of interest (analyses in which these subjects were excluded produced similar results). We also conducted more detailed analyses for some conditions, as suggested by an overall positive association with NHL in the present study or prior reports. We characterized the duration of the immune-related condition or use of medication among cases and, when possible, examined the relation between duration and NHL risk. In this paper, we also describe the distribution of NHL subtypes by histology and site among cases with specific conditions of interest, medication history, or family history.
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RESULTS |
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Associations of NHL with immune-related medical conditions
Receipt of an organ transplant was associated with a twofold increased risk of NHL, although this increase was not significant (table 2). Transplanted organs included the kidney (n = 3), kidney and pancreas (n = 1), liver (n = 2), and heart (n = 1). NHL developed a median of 10 years after transplantation (range, 122 years). Four NHLs in transplant recipients were diffuse large B cell, and one was a Burkitt's. By site, four NHLs were nodal and one arose in the small intestine.
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Individuals with lupus experienced a fourfold increased risk of NHL (table 2). Approximately half of lupus patients specifically described SLE (n = 8), while the remainder largely reported poorly specified subtypes: discoid (n = 2), drug induced (n = 1), early/incompletely diagnosed (n = 2), or unspecified (n = 4). NHL was not significantly associated with SLE but was strongly associated with other/unknown lupus subtypes (table 2). The most common histologic subtype of NHL was follicular (n = 5), followed by marginal zone (n = 3), diffuse large B cell (n = 2), and other/unspecified (n = 4) subtypes. Among cases with lupus, 10 NHLs were nodal and four were extranodal or of unknown site. Two cases had both lupus and Sjögren's syndrome. The median duration of lupus was 19 years (range, 348 years) among eight NHL cases who provided data.
NHL was not significantly associated with a history of rheumatoid arthritis (OR = 1.3, table 2) or with duration of rheumatoid arthritis (not shown; median duration, 12 years; range, 151 years among cases). For cases with rheumatoid arthritis, NHLs were classified histologically as diffuse large B cell (n = 14), marginal zone (n = 10), follicular (n = 8), small lymphocytic (n = 6), lymphoplasmacytic (n = 2), T cell (n = 4), or other/unspecified (n = 4) subtype. Twenty-five NHLs were nodal and 23 were extranodal. Seven cases with rheumatoid arthritis also had Sjögren's syndrome. Four cases with rheumatoid arthritis had salivary gland NHL, but only one of them also had Sjögren's syndrome.
Associations of NHL with immune-modulating medications
Among both cases and controls, prior use of corticosteroids was common, but use of these medications was unrelated to NHL risk, both overall and when duration of use was considered (table 3). Reasons for corticosteroid use were specified for only 21 percent of the subjects and varied widely (not shown). Among subjects who had Sjögren's syndrome, lupus, or rheumatoid arthritis, corticosteroid use was reported by 63 percent, 76 percent, and 52 percent, respectively (although reasons for use were mostly unspecified). For subjects with these autoimmune conditions, there was a nonsignificantly increased risk of NHL with corticosteroid use (unadjusted OR = 1.7, 95 percent CI: 0.7, 3.7; p = 0.22). Among subjects not known to have these conditions, corticosteroid use was not associated with NHL risk (unadjusted OR = 0.9, 95 percent CI: 0.8, 1.1; p = 0.48).
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Associations of NHL with family history of autoimmune conditions
Table 4 shows associations between NHL and subjects' family history of specific autoimmune conditions. NHL was significantly related to family history of dermatomyositis (seven cases vs. 0 controls, p = 0.02). NHLs associated with a family history of dermatomyositis were of the follicular (n = 3), diffuse large B cell (n = 3), or marginal zone (n = 1) subtype. Four were nodal and three were extranodal. In addition, NHL was marginally associated with family history of celiac disease (table 4). One such NHL arose in the ileum (diffuse large B cell subtype), while the others were nodal.
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DISCUSSION |
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Sjögren's syndrome is an autoimmune condition of unknown etiology that affects mostly women. It is characterized clinically by the variable presence of parotid gland enlargement, xerostomia, and keratoconjunctivitis sicca and pathologically by the infiltration of lymphocytes into salivary and lacrimal glands (21). Kassan et al. (11
) first described a markedly excess risk of lymphoma in Sjögren's syndrome (standardized incidence ratio = 44 compared with the general population). Lymphoma risk in Sjögren's syndrome increases with the severity of inflammation, as indicated by parotid gland enlargement, decreased complement levels, or cutaneous vasculitis (11
, 22
). We observed extraordinarily elevated risks of salivary gland NHL, marginal zone NHL, and, specifically, marginal zone NHL of the salivary gland for Sjögren's syndrome patients (OR = 290, OR = 75, and OR = 880, respectively). Others have previously noted a relation between Sjögren's syndrome and marginal zone NHL of the salivary gland (23
25
). The high risk of these lymphomas suggests that they originate locally as a consequence of chronic lymphocyte activation related to the autoimmune disease process itself. This mechanism could be especially likely for marginal zone NHLs, for which the site of involvement frequently reflects a preceding localized immune response (26
).
Somewhat unexpectedly, we found only a nonsignificant, twofold elevation in NHL risk for organ transplant recipients, substantially lower than observed in cohort studies of transplant recipients, which have reported standardized incident ratios for NHL of 640 (2730
). The difference between our finding and previous results may be due to several factors. First, NHL represents only one end of a spectrum of posttransplant lymphoproliferative disorder, which also includes more benign reactive hyperplasia and polymorphic lymphoproliferations (20
). Because classification of posttransplant lymphoproliferative disorder has changed over time, and because SEER captures only those cases considered to be NHL, we might have included fewer cases than previous studies did. Second, although the overall risk of posttransplant lymphoproliferative disorder has remained constant during the last 15 years (31
), changes in organ transplantation practices or immunosuppression regimens could have affected the spectrum of posttransplant lymphoproliferative disorder. Third, our estimate of the association with NHL was imprecise, and the upper limit of our confidence interval for the odds ratio is consistent with prior standardized incidence ratio estimates.
Previous cohort studies have found that individuals with lupus and rheumatoid arthritis are at increased risk of NHL (standardized incidence ratios = 35 for lupus and 23 for rheumatoid arthritis) (410
, 32
, 33
). We found a similar association between lupus and NHL (OR = 4.2), but this association appeared limited to the heterogeneous group of individuals with lupus subtypes other than SLE. Nonetheless, given the small number of individuals with a history of SLE and lack of documentation regarding lupus diagnoses, we cannot rule out an association between SLE and NHL. Some cohort studies of individuals with rheumatoid arthritis (7
, 9
, 10
), though not all (8
, 33
), have included only hospitalized patients, who presumably had especially severe arthritis. By contrast, our study evaluated NHL risk related to any history of rheumatoid arthritis. Our modest odds ratio estimate for rheumatoid arthritis is in accord with estimates from prior case-control studies (13
15
), suggesting that NHL risk might be increased for only those individuals with especially severe rheumatoid arthritis (34
).
Although the excess risk of NHL seen for individuals with autoimmune conditions might be due to the immune disregulation characteristic of the condition itself, at least two other explanations have been proposed. First, increased NHL risk may be partly due to treatment with immune-modulating medications (35). Kamel et al. (36
) described the occurrence of Epstein-Barr-virus-positive lymphomas in patients receiving methotrexate for rheumatoid arthritis or dermatomyositis, which resolved upon discontinuation of the methotrexate. Of interest, in addition to having immunosuppressing effects, methotrexate can act directly to activate Epstein-Barr virus replication (37
). In our study, even though duration of use was generally brief, methotrexate was marginally associated with increased NHL risk. Existing data regarding corticosteroid use have been inconclusive, with several studies finding modestly increased NHL risk related to corticosteroid use (ORs or standardized incidence ratios = 1.21.7) (15
, 38
40
). We did not find strong evidence for an association with corticosteroid use, but we did not have information on specific corticosteroid medications, doses, or routes of administration. Unfortunately, we could not completely separate the effects of these medications from those of the autoimmune conditions. Indeed, we found evidence for increased NHL risk associated with corticosteroids when we restricted analysis to those individuals with Sjögren's syndrome, lupus, or rheumatoid arthritis, suggesting that use of corticosteroid might have been a marker for severity of the underlying autoimmune disease. Likewise, the majority of methotrexate users were individuals with these same autoimmune conditions. Finally, there is substantial interest in whether new agents for the treatment of rheumatoid arthritis, which block tumor necrosis factor, increase NHL risk (32
, 41
). Because these medications have been introduced only recently, we could not examine their potential association with NHL.
Second, the associations might be explained by an underlying genetic predisposition to both the autoimmune condition and NHL. If so, NHL should be associated with a family history of the autoimmune condition. Our data, although somewhat limited by small numbers, do not support this hypothesis. A family history of dermatomyositis was present solely among cases, but the NHL subtypes in these individuals varied substantially, and no case himself had dermatomyositis. Similarly, although we observed a nonsignificant association between NHL and family history of celiac disease, no NHL case had celiac disease. Our null finding regarding a family history of rheumatoid arthritis confirms the results of a prior registry-based linkage study in Sweden (9).
Several study limitations should be acknowledged. First, most immune-related conditions are uncommon. Thus, although our study was relatively large, it lacked statistical power to identify associations for the least common autoimmune conditions, and our estimates of risk related to these conditions, especially for specific NHL subtypes, were unstable. We were similarly limited in our ability to explore associations with methotrexate use or specific family histories. A related problem due to the sparseness of the data was that regression models adjusting for the study matching factors did not converge for a few conditions; while we present unadjusted odds ratios and tests of significance in these instances, these results could have been biased by the original matching (42). Second, the participation rates were somewhat low, although they were similar to those reported in other recent population-based case-control studies with in-home interviews. The impact of these low rates on our results is difficult to evaluate. It is unlikely, for instance, that the strong association between Sjögren's syndrome and specific NHL subtypes was due solely to a bias introduced by nonparticipation. Indeed, participation rates must differ systematically and substantially between cases and controls for observed associations to be appreciably affected. Third, medical conditions and medication use were self-reported. Because we did not review medical records, we could have misclassified autoimmune conditions, which can resemble one another clinically. This misclassification may have been true especially for rheumatoid arthritis, since the prevalence among our controls (5.8 percent) was somewhat higher than the 0.9 percent prevalence estimated for the general US population based on published studies (43
). We suspect that this difference partly reflects inaccurate reporting of rheumatoid arthritis diagnoses by our subjects and partly that previous prevalence estimates may have missed mild arthritis cases. If some of our study subjects reporting rheumatoid arthritis actually had other conditions (e.g., osteoarthritis), our odds ratio estimate could have been biased.
On the other hand, our study had several strengths. Its population-based case-control design enabled us to study a representative sample of NHL cases and the general population. We also had detailed data on the histologic subtypes and anatomic sites of these NHLs.
In conclusion, our results indicate that several immune-related conditions are associated with an increased risk of NHL. Further investigations into the relation between autoimmune conditions and NHL appear warranted. Additional information regarding associations of NHL with rarer autoimmune conditions may derive from pooling data from multiple case-control studies.
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ACKNOWLEDGMENTS |
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The authors gratefully acknowledge the contributions of the SEER centers of Detroit, Iowa, Los Angeles, and Seattle for rapid identification of cases; the Centers for Medicare and Medicaid Services for selection of older controls; Carol Haines (Westat, Rockville, Maryland) for development of study materials and procedures, selection of younger controls, and study coordination; Peter Hui and Michael Stagner (Information Management Services, Silver Spring, Maryland) for computer programming support; and Geoffrey Tobias (National Cancer Institute) for research assistance.
Conflict of interest: none declared.
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References |
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