1 Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
2 Department of Epidemiology Research, Danish Epidemiology Science Centre, Statens Serum Institut, Copenhagen, Denmark
3 Department of Oncology and Pathology, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden
4 Department of Genetics and Pathology, Uppsala University Hospital, Uppsala, Sweden
5 Department of Pathology and Cytology, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden
6 Department of Hematology, Aarhus University Hospital, Aarhus, Denmark
7 Department of Oncology, Radiology and Clinical Immunology, University of Uppsala, Uppsala, Sweden
Correspondence to Dr. Ellen T. Chang, Northern California Cancer Center, 2201 Walnut Avenue, Suite 300, Fremont, CA 94538-2334 (e-mail: ellen.chang{at}ki.se).
Received for publication February 8, 2005. Accepted for publication June 14, 2005.
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ABSTRACT |
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anti-bacterial agents; anti-inflammatory agents, non-steroidal; case-control studies; drug utilization; lymphoma
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INTRODUCTION |
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Of these medications, however, only strong immunosuppressive drugs have been consistently associated with increased NHL risk (9, 10
, 12
). Instead, perhaps just as many studies have detected no association or even an inverse association between risk of NHL and antibiotics (21
, 23
), NSAIDs and other analgesics (8
, 11
, 13
, 14
, 23
), corticosteroids (14
, 21
, 24
, 25
), histamine2-receptor antagonists (23
), estrogen (11
, 24
, 25
), antidepressants (11
, 14
), digitalis (11
), psychotropic drugs (11
, 14
, 25
, 26
), and anticonvulsants (11
, 14
, 21
, 27
, 28
), as well as progesterones (5
), antihistamines, blood pressure or cholesterol-lowering medications, and noninsulin drugs for diabetes (11
, 13
, 14
).
Adding to the confusion regarding the role of medications in lymphoma development is the fact that several medical conditions, including primary or acquired immunosuppression, autoimmune disorders, allergies, and infections, also appear to be associated with risk of NHL (3, 11
, 14
, 24
, 29
, 30
). Therefore, it is difficult to determine whether apparent associations between medications and lymphoma risk are due to the effects of the medications themselves or to the underlying disorder that the medication was intended to treat.
Some of the inconsistency in previous findings may be explained by the etiologic heterogeneity of NHL itself, which is classified into several distinct subtypes based on tumor histopathology (31). Epidemiologic studies suggest both differences and similarities in risk factors for histopathologic subtypes of NHL (4
, 11
, 14
, 19
, 32
, 33
), although most analyses have not distinguished among the subtypes. To tackle the challenge of clarifying the association between medication use and risk of NHL, we assembled the largest population-based case-control study of this subject known to date, with the unique strength that all cases were uniformly categorized according to the current World Health Organization classification of hematopoietic and lymphoid tumors (31
).
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MATERIALS AND METHODS |
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Eligible cases were all patients with a first, incident, and morphologically verified diagnosis of NHL, including chronic lymphocytic leukemia. Hodgkin's lymphoma cases were not included in the present analysis. Cases were identified through a rapid case ascertainment system organized for this study (33).
Controls were randomly sampled from the entire Danish and Swedish populations by using continuously updated, computerized population registers. A subset of controls was sampled every 6 months during the study period and was frequency matched to the expected distribution of cases in each country based on age (in 10-year intervals) and sex.
Of the eligible cases diagnosed with NHL, 81 percent (n = 3,122) consented to participate; the primary reason for nonparticipation was death (7 percent of all cases). The median time between diagnosis and interview was 2.8 months (range: 040 months). Among the potential controls, 71 percent (n =3,187) consented to participate. All participants granted informed consent prior to the interview. This study was approved by all regional ethics committees in Denmark and Sweden.
Exposure assessment
All study participants completed a telephone interview assessing a wide range of known and suspected risk factors for lymphoma. Use of most medications was evaluated in conjunction with history of particular medical conditions. Specifically, we inquired about use of corticosteroid injections among participants who reported a history of nasal or eye allergies; corticosteroid tablets or injections among persons diagnosed with asthma; corticosteroids among those who reported having rheumatoid arthritis, systemic lupus erythematosus, Sjögren's syndrome, psoriasis, sarcoidosis, other joint/muscle/connective tissue disorders, and/or other disorders (specified by the respondent; this question was open to all participants); cimetidine, ranatidine, nizatidine, or famotidine (histamine2-receptor antagonists) among persons with previous dyspepsia and/or gastroesophageal reflux; antibiotics among participants diagnosed with peptic ulcer by a physician; and phenytoin-containing drugs among those who had taken medication for epileptic seizures. Use of each medication was treated as a yes/no variable. For most medications, we also asked for the age at first use and/or duration (eight categories of months or years) of use. Immunosuppressive therapy was also evaluated among participants with autoimmune or other chronic inflammatory disorders, but these drugs were investigated in a separate analysis (K. Ekström Smedby et al., unpublished data).
In additional questions unrelated to specific medical conditions, we asked participants whether they used NSAIDs regularly, defined as at least five times per month for at least 1 year. If so, we asked for the frequency (five possible categories of times per week or day) and duration (seven possible categories of total years) of use. We combined frequency and duration of regular NSAID use into cumulative use by grouping users into four categories based on low or high frequency (16 times/week or 16 times/day, respectively) and short or long duration (110 years or >10 years, respectively) of use.
We also asked how often (0, 12, 35, 610, 1120, 2130, 3140, or 41 times) participants had been treated with antibiotics over their entire adult lifetime. We grouped respondents into those who had used antibiotics five or fewer times and those who had used them six or more times based on the balance of the distribution among controls.
In this analysis, where possible, we counted medication use only more than 2 years before the date of diagnosis (for cases) or interview (for controls), allowing for a latency period between exposure and onset of disease; medication use within the preceding 2 years was excluded. Because we did not assess timing of use for total antibiotics and anticonvulsant medications, including phenytoin, we considered all use of these medications. Corticosteroid use was counted for systemic conditions only and was combined for all of the medical conditions evaluated. Those reporting use for treatment of local or superficial inflammation only, and cases who were treated for only their lymphoma, were considered nonusers.
Histopathology
The histopathologic review for cases has been described in detail elsewhere (33). Information for cases was reviewed either within the Danish Lymphoma Group Registry (LYFO) in Denmark or by study-appointed senior hematopathologists or cytologists in Sweden, and cases were subsequently categorized according to the current World Health Organization classification of hematopoietic and lymphoid tumors (31
). As specified by the World Health Organization system, small lymphocytic lymphoma was classified in the same subgroup as chronic lymphocytic leukemia (collectively referred to in this paper as "chronic lymphocytic leukemia"). Of the 3,122 cases in the study, 3,055 were classified as having NHL and 67 had unspecified lymphoma that could not be further classified.
Statistical analyses
Unconditional logistic regression was performed to estimate the odds ratios for NHL and its subtypes, as well as the corresponding 95 percent confidence intervals, associated with medication use. Because the questions about corticosteroid treatment for unspecified conditions were added to the questionnaire a few months after the study began, participants for whom data on corticosteroid use were missing were included in a separate category. All models were adjusted for age (with indicator variables for 5-year categories), sex, and country of residence; alternative models were also adjusted for medical history of allergy, any autoimmune disorder (including type I diabetes, rheumatoid arthritis, systemic lupus erythematosus, Sjögren's syndrome, psoriasis, sarcoidosis, and celiac disease), dyspepsia, or peptic ulcer, with each medical condition entered as a separate variable. Other potential confounders were considered based on prior knowledge of risk factors for NHL and on changes in estimates based on models with and without additional covariates (34). Heterogeneity of associations between strata was evaluated by using a likelihood ratio test for the significance of an interaction term between medication use and a potential modifier. Tests for linear trend in frequency or duration of medication use were conducted with medication use coded as an ordinal variable with values at the median of each category. All statistical tests were two sided. Analyses were performed by using SAS system software, release 8.2 (19992001; SAS Institute, Inc., Cary, North Carolina).
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RESULTS |
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Although data were not available for most drugs, we examined whether there was a dose-response trend between increasing frequency and/or duration of use of corticosteroids, total antibiotics, or NSAIDs and risk of NHL (table 3). After controlling for age, sex, and country of residence, or after controlling additionally for medical history, we found no apparent dose-response trends between duration or frequency of corticosteroid or NSAID use and increased risk of NHL. In contrast, there was a significant dose-response trend toward higher NHL risk with greater frequency of antibiotic use. Furthermore, there was a marginally significant positive association between the highest category of cumulative NSAID usethat is, use of NSAIDs at least once a day for more than 10 yearsand risk of NHL, with a positive dose-response trend. Among the controls, cumulative NSAID use was significantly associated with being female (p < 0.001) and having had an autoimmune disorder (p < 0.001). No appreciable changes occurred after further adjustment for the variables described above (data not shown).
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Participants who used NSAIDs at high frequency for a long period of time (one to six per day for >10 years) were at increased risk of diffuse large B-cell lymphoma but no other NHL subtype examined. Ever versus never regular use of NSAIDs was not associated with risk of any NHL subtype, nor was there any independent association between frequency or duration of NSAID use and risk of any major NHL subtype (data not shown).
The only other statistically significant association was between phenytoin use and increased risk of T-cell lymphoma. Corticosteroid use was also nonsignificantly associated with increased risk of T-cell lymphoma and marginal zone lymphoma. However, we found no significant trend between increasing duration of corticosteroid use and risk of T-cell lymphoma (ptrend = 0.09) or marginal zone lymphoma (ptrend = 0.48).
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DISCUSSION |
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We also detected a suggestive positive association between high cumulative use of NSAIDs and risk of overall NHL and diffuse large B-cell NHL. However, no other major NHL subtype was associated with cumulative NSAID use, and we observed no association between ever versus never regular NSAID use, nor frequency or duration of use, and risk of NHL or any common subtype. A positive association between NSAID use and NHL risk has been reported previously (3, 6
, 7
), although other studies have found no association (8
, 11
, 23
) or an inverse association (13
, 14
). The diversity of findings could be explained largely by differences in the definition and classification of NSAID usethat is, inclusion or not of aspirin or non-NSAID analgesics, and consideration of timing, frequency, and duration of useespecially given that we detected no association with any measures other than cumulative intake. Positive findings could also result from confounding by indication.
We did not detect any significant association between use of corticosteroids, histamine2-receptor antagonists, analgesics, or anticonvulsants, including those containing phenytoin, and risk of overall NHL or most subtypes examined. This finding contrasts with reports of positive associations with corticosteroids (3, 6
, 11
), histamine2-receptor antagonists (13
, 14
), and anticonvulsant drugs (16
18
), although other studies have refuted these findings (21
, 23
25
, 27
, 28
). To our knowledge, no other studies have reported a positive association between use of phenytoin and risk of T-cell lymphoma.
Not all other studies have controlled for medical history when investigating associations with medication use. However, when we adjusted for medical history, we found no appreciable changes in the estimates of association with medication use. It is unclear whether adjusting for medical history enabled us to disentangle the medication completely from the disease, since use of many medications was assessed among only those persons who reported specific diseases. As a result, we cannot rule out the possibility of confounding by indicationthat is, that the underlying disorder that prompted medication use is in itself related to the risk of NHL, and that the disease rather than its treatment is responsible for any observed association with the outcome. Nevertheless, we observed no associations between most medications and risk of NHL, suggesting that neither the drugs nor their indications for treatment were related to lymphoma development.
In contrast, we lacked any information about indications for using antibiotics, analgesics, or NSAIDs. Therefore, we were unable to attempt to differentiate between medications and the medical conditions, such as infections and/or inflammatory disorders, that may have prompted use of these drugs. In light of the finding that regular NSAID users were not at higher risk of NHL than were nonusers and that neither frequency nor duration of use alone was associated with lymphoma risk, it is unlikely that NSAIDs themselves increase the risk of NHL, despite the fact that they can modulate lymphocyte activity and immune function (35). Rather, high cumulative use of NSAIDs, based on both high frequency and long duration of regular NSAID use, is most likely a surrogate for underlying chronic inflammationan assertion supported by the fact that high-cumulative-NSAID users were more likely to be women, who are more susceptible to chronic inflammatory diseases (36
), and among persons with a previous autoimmune disorder. Long-standing inflammation, in turn, may promote the development of lymphoma by stimulating B- and T-cell proliferation, suppressing cell-mediated immunity, preventing apoptosis, and promoting angiogenesis (37
, 38
). Indeed, some chronic inflammatory conditions, such as rheumatoid arthritis and celiac disease, are known to increase risk of NHL (39
42
) (K. Ekström Smedby et al., unpublished data) and of diffuse large B-cell lymphoma in particular (41
, 43
46
; K. Ekström Smedby et al., unpublished data).
The positive association between antibiotic use and risk of NHL may also be explained in several ways. In both Denmark and Sweden, the most common reason for antibiotic treatment is respiratory tract infection, followed by urinary tract infection and skin/soft tissue infection (4749
). Common infections, such as Streptococcus strains, Staphylococcus aureus, Escherichia coli, and Haemophilus influenzae, have prompted the majority of antibiotic prescriptions in these populations. It is probable that frequent antibiotic use is a marker for repeated or prolonged infections; these infections, or susceptibility to infections, could be associated with an increased risk of NHL. Continuous immunologic stimulation by infectious agents can cause chronic inflammation, which, as explained above, may advance lymphomagenesis. Infection and inflammation can also trigger the production of DNA-damaging free radicals (50
), and some bacteria themselves may produce carcinogenic metabolites (51
). Furthermore, individual genetic variation in immunityfor example, polymorphisms in genes that encode cytokines or their receptorscan affect the degree and nature of the inflammatory response to infection (52
) and hence possibly influence NHL risk as well.
Alternatively, persons who frequently use antibiotics could be more susceptible to infections because of subclinical immune impairment. It is well known that strong immune suppression, as in congenital or acquired immunodeficiency disorders or post-transplantation drug treatment, increases the risk of NHL (17, 53
56
). Therefore, it is also conceivable that less profound immune dysfunction, as manifested by increased susceptibility to common bacterial and viral infections, could contribute to increased lymphoma risk.
On the other hand, there could also be a direct pathogenetic effect of antibiotics on lymphoma development. Some, albeit not most (57), types of antibiotics can cause genotoxicity (57
, 58
), cytotoxicity (59
, 60
), or leukopenia (61
63
), any or all of which could play a role in lymphomagenesis. Because we did not have information on the type of antibiotics used, we were not able to conduct subanalyses by class or type of antibiotic. One case-control study on antibiotics and NHL found that only penicillins were associated with an increased risk of NHL, suggesting that the positive association was not explained by a general cytotoxic effect of antibiotics, since penicillins are not known to cause cytotoxicity (4
).
The positive association between antibiotic use and risk of lymphoma could also be explained by reverse causality; that is, antibiotic use could have been prompted by symptoms of lymphoma that resembled an infectious disease. However, the positive association between use of antibiotics more than 10 times (the highest category) and risk of lymphoma is unlikely to be explained by the onset of symptoms, since it is improbable that any person would have used antibiotics more than 10 times during the interval between the development of symptoms and the time of interview. In addition, the association persisted when cases were limited to those interviewed within 45 days of diagnosis, making it unlikely that the association was due to postdiagnosis antibiotic treatment. Regular NSAID use was considered only if it occurred more than 2 years before the interview, ruling out the possibility of reverse causality.
Chance and uncontrolled or residual confounding, which may produce unpredictable results, must be considered possible explanations for any of our observations. This possibility applies especially to the marginal associations with risk of individual NHL subtypes, since we tested many associations. Selection bias may have occurred if potential controls with a history of medication use were more or less likely than cases to participate in the study, leading to falsely deflated or inflated odds ratios, respectively. However, the relatively high participation rates reduced the probability of selection bias. Recall bias could have similarly affected our findings if controls and cases differed in their tendency to over- or underreport previous medication use. However, there is little public awareness of hypothesized associations between use of medications and risk of NHL, and evidence in the literature points to both positive and negative associations. Because reporting accuracy was most likely nondifferential between cases and controls, any recall bias should have attenuated odds ratios toward the null.
In summary, our findings suggest that frequent use of antibiotics and high cumulative use of NSAIDs are associated with a higher risk of NHL. If antibiotics themselves increase the risk of lymphoma, the escalating use of antibiotics worldwide in the second half of the 20th century (64) could explain part of the rise in the incidence of NHL during the same time period (1
, 2
). However, our data were insufficient to determine whether antibiotic use and frequent, long-term NSAID use are independent risk factors for NHL, apart from inflammation, infections, or susceptibility to infections. Biologic data more strongly support the hypothesis that antibiotic use is an indicator of infection and consequent inflammation, which may increase the risk of NHL, and that high cumulative NSAID use is a marker of chronic inflammation. Reassuringly, our results suggest that many commonly used medications do not increase the risk of NHL.
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ACKNOWLEDGMENTS |
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The authors thank project coordinator Charlotte Appel (Statens Serum Institut), project coordinator Leila Nyrén (Karolinska Institutet), and secretariat Kirsten Ehlers (LYFO). They also thank pathologists Dr. Göran Roos (Umeå University Hospital), Dr. Måns Åkerman (Lund University Hospital), and Dr. Åke Öst (Medilab, Stockholm) for reviewing the tumor material for the study. Finally, they are grateful to all of the contact physicians and nurses in Denmark and Sweden who participated in the network for rapid case ascertainment.
Conflict of interest: none declared.
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References |
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