CLINICAL AND SYSTEMATIC REVIEWS
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Association Between Thiopurine Use and Nonmelanoma Skin Cancers in Patients With Inflammatory Bowel Disease: A Meta-Analysis Jonathan Ariyaratnam, MB, BChir1,2 and Venkataraman Subramanian, MD, DM, MRCP (UK)1,2 OBJECTIVES:
Thiopurines are the mainstay of treatment for patients with inflammatory bowel disease (IBD). Thiopurine therapy increases the risk of nonmelanoma skin cancers (NMSCs) in organ transplant patients. The data on NMSC in patients with IBD on thiopurines is conflicting.
METHODS:
We searched electronic databases for full journal articles reporting on the risk of developing NMSC in patients with IBD on thiopurine and hand searched the reference lists of all retrieved articles. Pooled adjusted hazard ratios and 95% confidence intervals (CIs) were determined using a random-effects model. Publication bias was assessed using Funnel plots and Egger’s test. Heterogeneity was assessed using Cochran’s Q and the I2 statistic.
RESULTS:
Eight studies involving 60,351 patients provided data on the risk of developing NMSC in patients with IBD on thiopurines. The pooled adjusted hazards ratio of developing NMSC after exposure to thiopurines in patients with IBD was 2.28 (95% CI: 1.50 to 3.45). There was significant heterogeneity (I2 = 76%) between the studies but no evidence of publication bias. Meta regression analysis suggested that the population studied (hospital-based vs. population-based) and duration of follow-up contributed significantly to heterogeneity. Grouping studies based on population studied and duration showed higher hazard rations in hospital-based and shorter duration studies.
CONCLUSIONS: The risk of developing NMSC in patients with IBD on thiopurines is only modestly elevated. The dif-
ference in pooled risk between population-based and hospital-based studies suggests the possibility that ascertainment bias could have contributed to this increased risk. Am J Gastroenterol 2014; 109:163–169; doi:10.1038/ajg.2013.451; published online 14 January 2014
INTRODUCTION Inflammatory bowel diseases (IBD), comprising ulcerative colitis and Crohn’s disease, are chronic relapsing conditions of the gastrointestinal tract, with a significant burden of disease and disability, and lifetime costs comparable to heart disease and cancer (1). Currently there is no cure for these conditions and medical therapies aim to induce and maintain clinical remission (2). Thiopurines, including azathioprine and 6-mercaptopurine, have been shown to be effective in inducing remission in Crohn’s disease and maintaining remission in both ulcerative colitis and Crohn’s disease (3–7). These drugs are widely used as adjunctive therapy in patients with severe IBD, when first-line therapy with aminosalicylates, antibiotics, and corticosteroids has failed. However, the use of such immunosuppressant therapy is not without risk. There is evidence to suggest that immunosuppres-
sant therapy increases the risk of lymphoma (8) and skin cancers (both melanoma and nonmelanoma skin cancers (NMSCs)) (9,10) in solid organ transplant patients. Furthermore, thiopurine drugs such as azathioprine have been associated with the development of squamous cell carcinoma (SCC) in patients with rheumatoid arthritis (11). The cellular mechanism by which this increased skin cancer risk with thiopurine treatment is thought to arise has been described by O’Donovan et al. (12). They showed that the accumulation of 6thioguanine in DNA that occurs in thiopurine treatment leads to an increased sensitivity to biologically relevant doses of UVA, resulting in the formation of reactive oxygen species that are mutagenic. This results in an increased risk of both SCC (65-fold) and basal cell carcinoma (10-fold) following organ transplantation (10). NMSC is more common than all other cancers combined, and the annual incidence in the United States has been shown to be
1
Department of Molecular Gastroenterology, Leeds Institute of Biomedical and Clinical Sciences, St James University Hospital, Leeds, UK; 2Department of Gastroenterology, Leeds Teaching Hospitals NHS Trust, UK. Correspondence: Venkataraman Subramanian, MD, DM, MRCP (UK), Department of Molecular Gastroenterology, Leeds Institute of Biomedical and Clinical Sciences, St James University Hospital, Level 4, Bexley Wing, Leeds LS9 7TF, UK. E-mail: [email protected] Received 13 March 2013; accepted 5 November 2013 © 2014 by the American College of Gastroenterology
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over 3.5 million cases (13). As a result of the high incidence, the direct costs of these diseases are substantial. Although basal cell carcinoma is more common than SCC, SCCs generally carry a higher risk of metastasis. Treatment for both types can include local excision, destruction, or use of topical immunomodulators. The rate of recurrence within 5 years following standard excision is around 8% for SCC (14) and 5% for basal cell carcinoma (15). Clearly, therefore, NMSC is a significant clinical problem and drugs associated with an increased risk of NMSC must be used with care. Despite the clear risks of NMSC as a result of thiopurine use in solid-organ-transplant patients, the risks in IBD patients are less apparent. The aim of this study was to conduct a literature review and meta-analysis to determine the risk of NMSC, specifically in IBD patients treated with thiopurines.
METHODS Materials and methods
We followed a prespecified and peer-reviewed protocol; preferred reporting items for systematic reviews and meta-analyses statement, a 27-item checklist deemed essential for reporting of systematic reviews and meta-analyses of randomized controlled trials and observational studies (16). Search strategy
We searched multiple electronic databases, including PubMed (1965 to October 2012), OVID (1965 to October 2012), the Cochrane library, EMBASE (1974 to October 2012), and Cumulative index to nursing and allied health (1982 to October 2012). The search terms used were as follows: (Thiopurine or Azathioprine or Mercaptopurine or Purine), (Crohn’s or Ulcerative Colitis or Inflammatory Bowel Disease), and (Skin Cancer or Skin Malignancy or Basal Cell Carcinoma or Squamous Cell Carcinoma or Nonmelanoma Skin Cancer or Skin Neoplasm or Outcome). No limits or language restrictions were applied. Study selection
Studies were eligible for inclusion if they reported on risk of developing NMSC in patient with IBD on thiopurines compared with a control population. Studies published only in abstract form were not included. Two reviewers (J.A. and V.S.) independently screened titles and abstracts identified by the preliminary searches to identity potentially eligible studies. Both reviewers independently assessed the full text articles of potentially relevant studies for inclusion in the pooled analysis on the basis of the above inclusion criteria. Data from included studies were independently extracted by two investigators (J.A. and V.S.) using predefined criteria and a standardized profoma, and were entered into an Excel 2010 (Microsoft, Redmond, WA) spread sheet. Information was collected on characteristics of the study and outcomes. Agreement between the investigators was >95% and differences between the data sets were resolved by discussion.
controls were either extracted from the study or calculated from the data provided. If possible, the hazard ratio and associated variance were obtained directly from each trial publication or from individual patient data. Hazard ratios not reported were calculated by the methods of Parmer et al. (17). These methods use information, such as P-values and numbers of deaths, to estimate the hazard ratio and variance, and they account for the censoring associated with varying follow-up times. When insufficient data had been published, we contacted the study authors. As randomization and blinding is not possible in observational studies and baseline differences between the groups can confound the results, we used the authors odds or hazard ratios with adjustment for potential confounding factors. Hazard ratios and 95% CIs were obtained for each study, and the pooled estimate was calculated from an inverse-variance-weighted average of the individual studies (18). A fixed-effects model was used unless there was significant heterogeneity, in which case the DerSimonian–Laird random-effects model was used (19). Comprehensive Meta Analysis version 2.2 (Biostat, Englewood, NJ) statistical package was used for the data analysis. Heterogeneity and sensitivity analysis
We used the Cochran’s Q to test heterogeneity among pooled estimates (20). Statistical heterogeneity was also measured by the I2 statistic that quantifies the proportion of inconsistency in individual studies that cannot be explained by chance (21). Values of I2 = 25, 50, and 75% represent low, moderate, and high heterogeneity, respectively. Finally, in order to exclude an excessive influence of any one study we evaluated whether exclusion of each study substantially affected the magnitude or statistical significance of the summary odds ratio. To test for publication bias, we used a test for asymmetry of the funnel plot proposed by Egger et al. (22). This test detects funnel plot asymmetry by determining whether the intercept deviates significantly from zero in a regression of the normalized effect estimate (estimate divided by the s.e.) again precision (reciprocal of the s.e. of the estimate) weighted by the reciprocal of the variance of the estimate. The quality of the primary studies assessing the risk of bias was evaluated using the Newcastle-Ottawa Scale (23). The influence of the following factors on the trial outcome and on the heterogeneity of the analyses was assessed with meta-regression analysis (24) where sufficient data were available: (a) study design used (nested case–control or cohort), (b) the population studied (population based or hospital based), (c) definition of drug exposure (ever user or prolonged exposure), (d) mean duration of follow-up (>6 years or < 3 years), (e) average UVA radiation for the country from which study (http://www.who. int/uv/intersunprogramme/activities/uv_index/en/index3.html and (f) the average latitude of the country of origin of the study (https://docs.google.com/spreadsheet/ccc?key=0At92oU3FPZ4Q dEIwVV8tZGJHRmV6VXV3LWpfQThiUnc&hl=en#gid=0).
RESULTS Statistical analysis
Characteristics of selected studies
Hazard with 95% confidence intervals (CIs) of developing of NMSC in patients with IBD on thiopurines compared with
Our PubMed search retrieved 10 potentially relevant articles of which 2 did not provide any data on NMSCs (25,26). Figure 1
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Thiopurine Use and Nonmelanoma Skin Cancers
CINAHL Search: 635articles
196 review articles
744 articles retained
Embase search: 3035 articles
102 review articles 24 editorials 36 case reports
473 articles retained
734 articles discarded after reading title and abstract
833 review articles 230 conference abstracts 114 conference papers 43 editorials 74 notes 40 short surveys 164 letters 6 books
1531 articles retained
2 articles discarded after reading full text (did not provide data on NMSC)
469 articles discarded after reading title and abstract
1523 articles discarded after reading title and abstract
8 articles retained from all three databases
Figure 1. Flowchart showing the fate of articles selected from the search strategy.
outlines the fate of the selected articles. A total of 8 studies (27–34) involving 60,351 participants with a diagnosis of IBD were included in the final meta-analysis. Four studies were nested case–control studies from insurance claims databases and four were retrospective cohort studies. No additional articles were retrieved from the other research strategies. Table 1 lists all the included studies and their characteristics and Table 2 the quality scores of these studies based on the Newcastle-Ottawa scale. Of the eight included studies, five were population-based studies (data derived from insurance claims databases or primary care databases) and three were based on hospital databases. All of the case– control studies were nested within a larger cohort of patients with IBD. The cases were patients with IBD, who developed NMSC during the follow-up period, and controls were patients with IBD, who did not develop NMSC. We obtained further data of the risk of NMSC with azathioprine use from the authors of the Armstrong et al. study (27). One study (34) was published as a letter to the editor but did include information on the risk of NMSC in IBD patients with thiopurine exposure and was therefore included in the final analysis. Cumulative risk of developing NMSC in IBD patients exposed to thiopurines
Eight studies with 60,351 patients with IBD provided data on adjusted risks of developing NMSC after exposure to thiopurines. The pooled adjusted hazards ratio of developing NMSC after exposure to thiopurines in patients with IBD was 2.28 (95% CI: 1.50–3.45; Figure 2). A random-effects model was chosen, as the heterogeneity between the studies was high (Cochran’s Q = 30.3, P = 0.001, and I2 = 76%). © 2014 by the American College of Gastroenterology
Sensitivity analysis and publication bias
Exclusion of each of the studies in turn did not alter the significance of the summary statistic. Mixed-effects meta-regression analysis using an unrestricted maximum likelihood model showed that the population studied (hospital-based studies vs. population-based databases) and mean duration of follow-up (either < 3 years or > 6 years) were significant predictors of heterogeneity (Table 3). When the studies were grouped according to the type of population studied, the pooled adjusted hazard ratio of developing NMSC in patients exposed to thiopurines using a random-effects model from hospital-based studies was 7.22 (95% CI: 3.08–16.90) and in population-based studies was 1.83 (95% CI: 1.2–2.80). There was no heterogeneity among hospital-based studies (Cochran’s Q = 0.66, P = 0.72) but significant heterogeneity between population-based studies (Cochran’s Q = 22.6, P = 0.001). Using mixed-effects analysis, tests for difference between the subgroups was significant (Cochran’s Q = 8.01, P = 0.005). When the studies were grouped according to the duration of follow-up, the pooled adjusted hazard ratio of developing NMSC from studies with shorter duration of follow-up ( < 3 years) was 2.87 (95% CI: 2.02–4.08) and in studies with longer duration of follow-up ( > 6 years) was 1.88 (95% CI: 0.87–4.06). There was significant heterogeneity among studies with short ( < 3 years) followup (Cochran’s Q = 5.91, P = 0.05) as well as studies with longer ( > 6 years) follow-up (Cochran’s Q = 13.32, P = 0.01). Using mixed-effects analysis tests for differences between the subgroups was not significant (Cochran’s Q = 0.964, P = 0.326). There was some funnel plot asymmetry compatible with publication bias (Figure 3); however Egger’s regression asymmetry test (P = 0.15, The American Journal of GASTROENTEROLOGY
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Table 1. Characteristics of included studies
Author (ref)
Year
Country
Type of study
Drug
Definition of exposure
No. of cases
No. of controls
Mean duration of followup (years)
Variables adjusted for in-risk estimates
Variables matched for (case–control studies only)
1
Long et al. (31)
2010
USA
Case– control
AZA/6MP
Recent thiopurine use of by ≥1 prescription < 90 days from NMSC diagnosis
742
2,968
1.32
Health care utilization, comorbidities, any use of 5-ASA/biologics
Age, sex, geographic region, disease type, duration of follow-up
2
Armstrong et al. (29)
2010
UK
Case–control
AZA
> 1 prescription
43
15,398
6.4
Age group, smoking
NA
3
Singh et al. (35)
2011
Canada
Case–control
AZA/6MP
2 Prescriptions in the study period
170
680
11.7
Average annual number of ambulatory physician visits, socioeconomic status
Age, sex, disease type (UC/CD), time since diagnosis of IBD.
4
Van Schaik et al. (36)
2011
Holland
Cohort
AZA/6MP
At least 50 mg AZA/6MP for 6 months
819
2,068
6.46
Age, sex, type of IBD, duration of IBD
NA
5
Setshedi et al. (34)
2011
South Africa
Cohort
AZA/6MP
Treated (not defined)
123
691
9.9
Not adjusted
NA
6
PeyrinBiroulet et al. (33)
2011
France
Cohort
AZA/6MP
Ongoing (not defined)
8,676
10,810
2.55
Age, sex
NA
7
Long et al. (32)
2012
USA
Case–control
AZA/6MP
At least 1 pharmacy claim
3,288
12,945
2
Other classes of IBD medication, Medicaid insurance status
Age (within 2 years), sex, region, disease type, month of the case’s diagnosis
8
Camus et al. (30)
2012
France
Cohort
AZA
2.25 mg/kg AZA—1 year
220
440
12.17
Age, gender, ethnicity, area of residence, socioeconomic status, family history of IBD, extra-intestinal manifestations, prior appendectomy, smoking status, disease duration, site and behavior of disease, perianal disease, prior intestinal surgery.
Sex, age (boxes of 5 years), date of IBD diagnosis (boxes of 5 years)
5-ASA: 5-aminosalicylcates; AZA, azathioprine; CD, Crohn’s disease; IBD, inflammatory bowel disease; 6MP, 6-meraptopurine; NA, not applicable; NMSC, nonmelanoma skin cancer; UC, ulcerative colitis.
intercept = − 6.7, and 95% CI: − 17.2 to 3.7) was nonsignificant. The regression asymmetry test is probably underpowered, as there are only eight studies included in the meta-analysis.
DISCUSSION Principle findings
Given the evidence to date that use of immunosuppressive thiopurines in solid-organ-transplant patients is associated with NMSC, it is important to determine the risk in IBD patients who are also The American Journal of GASTROENTEROLOGY
prescribed thiopurines. The results of this meta-analysis suggest that the risk of developing NMSC following treatment with thiopurines for IBD is only modestly elevated and loses significance when studies with < 3 years follow-up are excluded. Immune deregulation has been hypothesized to be the reason behind an increased risk of NMSC in all patients with IBD (35), and this meta-analysis suggests that thiopurine use can magnify this risk about two fold. There was significant heterogeneity between studies for this analysis mainly due to differences in the type of population VOLUME 109 | FEBRUARY 2014 www.amjgastro.com
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Table 2. Newcastle Ottawa scale scores of the included studies
Selection Author (reference) Long et al. (31) Armstrong et al. (29) Singh et al. (35) Long et al. (32)
Exposure
Case definition
Representativeness
Selection of controls
Definition of controls
Comparability
Ascertainment
Same method for cases/controls
Nonresponse
3
3
3
3
33
3
3
3
3
3
3
3
3
3
3
3
3
3
3
33
3
3
3
3
3
3
33
3
3
3
3 Cohort studies
Selection
Author
Representativeness
Selection of unexposed cohort
Ascertainment of exposure
3
3
3
3
3
3
33
3
3
3
3
33
3
3
3
3
33
Van Schaik et al. (36) Setshedi et al. (34) Peyrin-Biroulet et al. (33) Camus et al. (30)
Outcome Outcome not present at start
studied and differing duration of follow-up. When the analysis was re-run grouping the studies according to type of population, hospital-based studies showed a much greater pooled adjusted hazard ratio compared with population-based studies. Ascertainment bias could explain some of the differences in risk noted between hospital-based and population-based studies. Patients who were on thiopurines during the follow-up period would have been more likely to attend hospital and be seen by a medical professional than those not on thiopurines. Surveillance bias could also account for this increased risk, as medical professionals aware of the association between thiopurine use and NMSC may be more likely to diagnose NMSCs and biopsy any suspicious skin lesions in thiopurineexposed patients than in those unexposed to the drug. We also found that studies with shorter duration of follow-up ( < 3 years) reported higher risks of developing NMSCs in thiopurine-exposed patients. Conversely, when studies with longer mean follow-up duration ( > 6 years) were grouped, there was a nonsignificant rise in the risk of developing NMSCs with thiopurine exposure. It has been suggested earlier (36) that studies with shorter duration of follow-up could have had more intensive regimes and therefore resulted in greater risks of developing NMSCs. On the other hand, it is also likely that most of these NMSCs were detected early on in the course of therapy, which could explain why with longer duration of follow-up the risk reduces. Ascertainment bias could once again explain the differences noted as intensive scrutiny by medical professionals, whereas monitoring thiopurine therapy could © 2014 by the American College of Gastroenterology
Assessment of outcome
Sufficient duration of follow-up
Adequacy of follow-up
3
3
3
3
3
3
3
3
3
3
3
Comparability
result in increased detection of pre-existing skin lesions that might have been attributed to the use of thiopurines. Limitations of the study
As with any meta-analysis, there are possible limitations in combining the results of multiple separate studies. The types of population studied (population-based vs. hospital-based), and duration and follow-up were major contributory factors in the heterogeneity noted between studies. In addition, the eight studies used in this meta-analysis were taken from six different countries resulting in inherent, unavoidable differences between sample populations such as amount of UV light exposure, prevalence of smoking, and race (skin color). These risk factors are all likely to have been different across these differing populations. Only Setshedi et al. (32) considered race in their analysis, showing that odds of developing NMSC in IBD when on thiopurines were far greater in white Caucasian patients than those of other races. Further variations between studies include sample size and type of study (nested case–control vs. cohort studies). Some of the studies included in this meta-analysis included small samples, which could result in selection bias. The definitions used to determine patients with IBD also varied between studies. One study (33) used histologically confirmed IBD patients and others used physician contacts/hospitalizations/pharmacy claims for IBD as their definitions. Furthermore, although the majority of these studies used histological confirmation as evidence of NMSC outcome (28–30,32), The American Journal of GASTROENTEROLOGY
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Funnel plot of s.e. by log hazard ratio
Hazard ratio and 95% Cl
Hazard Lower Upper ratio limit limit 29 2.28 1.86 Long et al. 2.79 27 1.02 0.41 Armstrong et al. 2.51 33 2.17 1.24 3.80 Singh et al. 34 0.85 0.51 Van Schaik et al. 1.41 7.81 0.85 71.68 Setshedi et al.32 26 5.90 2.11 Peyrin-Biroulet et al. 16.49 3.16 2.38 Long et al.30 4.19 Camus et al.28 15.36 1.92 122.86 2.28 1.50 3.45 Pooled
0.0
0.5
s.e.
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Study name
0.01 0.1 Protects
1
10
100
1.0
1.5
Increases risk 2.0
Figure 2. Forest plot showing the pooled adjusted hazards ratio of developing nonmelanoma skin cancer (NMSC) after exposure to thiopurines in patients with inflammatory bowel disease (IBD).
Table 3. Results of mixed effects meta-regression analysis using an unrestricted maximum likelihood model Regression co-efficient (s.e)
P value
Tau-squareda
Definition of drug exposure
0.23 (0.54)
0.66
0.27
Study design
− 0.28 (0.53)
0.59
0.33
Population studied
− 1.41 (0.55)
0.01
0.15
Duration of follow-up
− 0.62 (0.19)
0.001
0.15
Latitude (midpoint) of the country from which study originated
− 0.03 (0.02)
0.09
0.16
Mean reported UV radiation according to country of origin
0.25 (0.10)
0.15
0.13
Variable
a
Tau-squared is the between-studies variance calculated using the unrestricted maximum-likelihood method.
other studies did not specify how the diagnosis of NMSC was confirmed. Any of these variations could potentially have biased the results. The definition of exposure to thiopurines and duration of follow-up to determine development of NMSC were also diverse across the eight studies. Although most studies defined exposure as simply one or more pharmacy claims (28,29,32) for thiopurine medication, others either defined a specific dosage and duration of treatment (25,27) or did not specify dosage or duration (30,31). In addition, some studies followed patients for 1–3 years (28–30), whereas others continued to assess patients for NMSC development for 6–12 years (27,31–33). The definition of exposure to thiopurine however was not a significant predictor of heterogeneity in our analysis. Clinical implications
Clinical guidelines for management of IBD in the United Kingdom emphasize the risk of NMSC in patients treated with thiopurines (37). This meta-analysis has shown that the risk of developing NMSCs with thiopurine use in patients with IBD is just over 2-fold and is only 1.8-fold when population-based studies are included, The American Journal of GASTROENTEROLOGY
–3
–2
–1
0
1
2
3
log hazard ratio Figure 3. Funnel plot for publication bias on studies included in the metaanalysis. The x axis (measure of effect size) represents the hazard ratio of developing nonmelanoma skin cancer (NMSC) after thiopurine exposure and the y axis (measure of study precision) represents a measure of the size of the study. The center line represents summary statistic—that is, the pooled adjusted hazard ratio of developing NMSC after thiopurine exposure. The two-side lines represent 95% confidence intervals.
and there was a nonsignificant increase in risk of NMSCs when studies with longer ( > 6 years) duration of follow-up were pooled. Some of this increased risk could be the result of ascertainment bias and although thiopurines should continue to be used with care in patients with IBD, the risk of NMSC as a result of this therapy in this population should not be overstated. We agree that patients taking thiopurines for the treatment of IBD, particularly White Caucasian patients, should avoid excessive sun exposure and use high-strength sun block. In addition, gastroenterologists and primary care doctors should continue to stay vigilant and investigate suspicious skin lesions thoroughly in these patients. However, thiopurines have been shown to be hugely effective in the management of both ulcerative colitis and Crohn’s disease . Thiopurines have become the mainstay of treatment in steroid-dependent IBD and their use should not be limited by the minimally increased risk of NMSC. The magnitude of the risk has to take into account the fact that NMSC is fairly common in the general population with an estimated 3.5 million annual cases affecting over 2 million people in the United States (13). The overall annual incidence of NMSC in the IBD population in a North American study was found to be 733 per 100,000 compared with 447 per 100,000 in the general population (29). A small increase in risk could therefore result in a reasonably large number of extra cases of NMSC. Further work should investigate the effects of long-term treatment with thiopurines. To date, there are only two studies that have investigated prolonged exposure to thiopurine use ( > 365 days), both of which have shown increased odds of developing NMSC compared with shorter treatment regimens (25,29). However, many patients with IBD are treated with thiopurines for several years and there is a paucity of data to inform us of the risk of developing NMSC in these patients. In addition, prospective studies need to evaluate the risk to benefit ratio of thiopurines in IBD with respect to development of NMSCs. VOLUME 109 | FEBRUARY 2014 www.amjgastro.com
CONFLICT OF INTEREST
Guarantor of the article: Venkataraman Subramanian, MD, DM, MRCP (UK). Specific author contributions: J.A.: study design, data collection, and wrote first draft of paper. V.S.: study conception, study design, data collection, data analysis, and edited the paper. Financial support: J.A. was awarded a NIHR Academic Foundation Trainee fellowship from the National Institute of Health Research, UK. Potential competing interests: None.
Study Highlights WHAT IS CURRENT KNOWLEDGE
3Thiopurines are currently the mainstay of treatment in steroid-dependent inflammatory bowel disease (IBD). 3Thiopurines use is associated with an increased risk of nonmelanoma skin cancer (NMSC) in solid-organ-transplant
patients. Risk of developing NMSCs in IBD patients on thiopurines is unclear.
WHAT IS NEW HERE
3Risk of developing NMSC as a result of thiopurine treatment for IBD is modestly elevated. 3Risk of developing NMSC may be overestimated in these studies due to ascertainment bias. 3There is not enough evidence to suggest that the increased risk of NMSC outweighs the benefit of thiopurines in IBD.
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© 2014 by the American College of Gastroenterology
13. Rogers HW, Weinstock MA, Harris AR et al. Incidence estimate of nonmelanoma skin cancer in the United States, 2006. Arch Dermatol 2010;146:283. 14. Brodland DG, Zitelli JA. Surgical margins for excision of primary cutaneous squamous cell carcinoma. J Am Acad Dermatol 1992; 27:241–8. 15. Wolf DJ, Zitelli JA. Surgical margins for basal cell carcinoma. Arch Dermatol 1987;123:340. 16. Moher D, Liberati A, Tetzlaff J et al. preferred reporting items for systematic reviews and meta-analyses: The PRISMA Statement. J Clin Epidemiol 2009;62:1006–12. 17. Parmar MKB, Torri V, Stewart L. Extracting summary statistics to perform meta-analyses of the published literature for survival endpoints. Stat Med 1998;17:2815–34. 18. Yusuf S, Peto R, Lewis J et al. Beta blockade during and after myocardial infarction: an overview of the randomized trials. Prog Cardiovasc Dis 1985;27:335. 19. DerSimonian R, Laird N. Meta-analysis in clinical trials. Controlled Clin Trials 1986;7:177–88. 20. Cochran WG. The combination of estimates from different experiments. Biometrics 1954;10:101–29. 21. Higgins J, Thompson SG, Deeks JJ et al. Measuring inconsistency in metaanalyses. BMJ 2003;327:557–60. 22. Egger M, Smith GD, Schneider M et al. Bias in meta-analysis detected by a simple, graphical test. BMJ 1997;315:629–34. 23 . Wells G , Shea B, O’connell D et al. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in metaanalyses . In: 3rd Symposium on Systematic Reviews: Beyond the Basics, Oxford, 2000 . 24. Thompson SG, Higgins J. How should meta-regression analyses be undertaken and interpreted? Stat Med 2002;21:1559–73. 25. Lichtenstein GR, Rutgeerts P, Sandborn WJ et al. A pooled analysis of infections, malignancy, and mortality in infliximab- and immunomodulator-treated adult patients with inflammatory bowel disease. Am J Gastroenterol 2012;107:1051–63. 26. Peyrin-Biroulet L, Chevaux JB, Bouvier AM et al. Risk of melanoma in patients who receive thiopurines for inflammatory bowel disease is not increased. Am J Gastroenterol 2012;107:1443–4. 27. Armstrong RG, West J, Card TR. Risk of cancer in inflammatory bowel disease treated with azathioprine: a UK population-based case–control study. Am J Gastroenterol 2010;105:1604–9. 28. Camus M, Seksik P, Bourrier A et al. Long-term outcome of patients with Crohn’s disease that responds to Azathioprine. Clin Gastroenterol Hepatol 2013;11:389–94. 29. Long MD, Herfarth HH, Pipkin CA et al. Increased risk for non-melanoma skin cancer in patients with inflammatory bowel disease. Clin Gastroenterol Hepatol 2010;8:268–74. 30. Long MD, Martin C, Pipkin CA et al. Risk of melanoma and non-melanoma skin cancer among patients with inflammatory bowel disease. Gastroenterology 2012;143:390–399.e1. 31. Peyrin–Biroulet L, Khosrotehrani K, Carrat F et al. Increased risk for nonmelanoma skin cancers in patients who receive thiopurines for inflammatory bowel disease. Gastroenterology 2011;141:1621–1628.e5. 32. Setshedi M, Epstein D, Winter TA et al. Use of thiopurines in the treatment of inflammatory bowel disease is associated with an increased risk of non-melanoma skin cancer in an at-risk population: a cohort study. J Gastroenterol Hepatol 2012;27:385–9. 33. Singh H, Nugent Z, Demers AA et al. Increased risk of nonmelanoma skin cancers among individuals with inflammatory bowel disease. Gastroenterology 2011;141:1612–20. 34. van Schaik FDM, van Oijen MGH, Smeets HM et al. Risk of nonmelanoma skin cancer in patients with inflammatory bowel disease who use thiopurines is not increased. Clin Gastroenterol Hepatol 2011;9:449–450.e1. 35. Pedersen N, Duricova D, Elkjaer M et al. Risk of extra-intestinal cancer in inflammatory bowel disease: meta-analysis of population-based cohort studies. Am J Gastroenterol 2010;105:1480–7. 36. Jess T. Thiopurines for inflammatory bowel disease: time to engage with dermatologists? Gastroenterology 2011;141:1549–51. 37. Mowat C, Cole A, Windsor A et al. Guidelines for the management of inflammatory bowel disease in adults. Gut 2011;60:571–607.
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Association Between Thiopurine Use and Nonmelanoma Skin Cancers in Patients With Inflammatory Bowel Disease: A Meta-Analysis Jonathan Ariyaratnam, MB, BChir1,2 and Venkataraman Subramanian, MD, DM, MRCP (UK)1,2 OBJECTIVES:
Thiopurines are the mainstay of treatment for patients with inflammatory bowel disease (IBD). Thiopurine therapy increases the risk of nonmelanoma skin cancers (NMSCs) in organ transplant patients. The data on NMSC in patients with IBD on thiopurines is conflicting.
METHODS:
We searched electronic databases for full journal articles reporting on the risk of developing NMSC in patients with IBD on thiopurine and hand searched the reference lists of all retrieved articles. Pooled adjusted hazard ratios and 95% confidence intervals (CIs) were determined using a random-effects model. Publication bias was assessed using Funnel plots and Egger’s test. Heterogeneity was assessed using Cochran’s Q and the I2 statistic.
RESULTS:
Eight studies involving 60,351 patients provided data on the risk of developing NMSC in patients with IBD on thiopurines. The pooled adjusted hazards ratio of developing NMSC after exposure to thiopurines in patients with IBD was 2.28 (95% CI: 1.50 to 3.45). There was significant heterogeneity (I2 = 76%) between the studies but no evidence of publication bias. Meta regression analysis suggested that the population studied (hospital-based vs. population-based) and duration of follow-up contributed significantly to heterogeneity. Grouping studies based on population studied and duration showed higher hazard rations in hospital-based and shorter duration studies.
CONCLUSIONS: The risk of developing NMSC in patients with IBD on thiopurines is only modestly elevated. The dif-
ference in pooled risk between population-based and hospital-based studies suggests the possibility that ascertainment bias could have contributed to this increased risk. Am J Gastroenterol 2014; 109:163–169; doi:10.1038/ajg.2013.451; published online 14 January 2014
INTRODUCTION Inflammatory bowel diseases (IBD), comprising ulcerative colitis and Crohn’s disease, are chronic relapsing conditions of the gastrointestinal tract, with a significant burden of disease and disability, and lifetime costs comparable to heart disease and cancer (1). Currently there is no cure for these conditions and medical therapies aim to induce and maintain clinical remission (2). Thiopurines, including azathioprine and 6-mercaptopurine, have been shown to be effective in inducing remission in Crohn’s disease and maintaining remission in both ulcerative colitis and Crohn’s disease (3–7). These drugs are widely used as adjunctive therapy in patients with severe IBD, when first-line therapy with aminosalicylates, antibiotics, and corticosteroids has failed. However, the use of such immunosuppressant therapy is not without risk. There is evidence to suggest that immunosuppres-
sant therapy increases the risk of lymphoma (8) and skin cancers (both melanoma and nonmelanoma skin cancers (NMSCs)) (9,10) in solid organ transplant patients. Furthermore, thiopurine drugs such as azathioprine have been associated with the development of squamous cell carcinoma (SCC) in patients with rheumatoid arthritis (11). The cellular mechanism by which this increased skin cancer risk with thiopurine treatment is thought to arise has been described by O’Donovan et al. (12). They showed that the accumulation of 6thioguanine in DNA that occurs in thiopurine treatment leads to an increased sensitivity to biologically relevant doses of UVA, resulting in the formation of reactive oxygen species that are mutagenic. This results in an increased risk of both SCC (65-fold) and basal cell carcinoma (10-fold) following organ transplantation (10). NMSC is more common than all other cancers combined, and the annual incidence in the United States has been shown to be
1
Department of Molecular Gastroenterology, Leeds Institute of Biomedical and Clinical Sciences, St James University Hospital, Leeds, UK; 2Department of Gastroenterology, Leeds Teaching Hospitals NHS Trust, UK. Correspondence: Venkataraman Subramanian, MD, DM, MRCP (UK), Department of Molecular Gastroenterology, Leeds Institute of Biomedical and Clinical Sciences, St James University Hospital, Level 4, Bexley Wing, Leeds LS9 7TF, UK. E-mail: [email protected] Received 13 March 2013; accepted 5 November 2013 © 2014 by the American College of Gastroenterology
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over 3.5 million cases (13). As a result of the high incidence, the direct costs of these diseases are substantial. Although basal cell carcinoma is more common than SCC, SCCs generally carry a higher risk of metastasis. Treatment for both types can include local excision, destruction, or use of topical immunomodulators. The rate of recurrence within 5 years following standard excision is around 8% for SCC (14) and 5% for basal cell carcinoma (15). Clearly, therefore, NMSC is a significant clinical problem and drugs associated with an increased risk of NMSC must be used with care. Despite the clear risks of NMSC as a result of thiopurine use in solid-organ-transplant patients, the risks in IBD patients are less apparent. The aim of this study was to conduct a literature review and meta-analysis to determine the risk of NMSC, specifically in IBD patients treated with thiopurines.
METHODS Materials and methods
We followed a prespecified and peer-reviewed protocol; preferred reporting items for systematic reviews and meta-analyses statement, a 27-item checklist deemed essential for reporting of systematic reviews and meta-analyses of randomized controlled trials and observational studies (16). Search strategy
We searched multiple electronic databases, including PubMed (1965 to October 2012), OVID (1965 to October 2012), the Cochrane library, EMBASE (1974 to October 2012), and Cumulative index to nursing and allied health (1982 to October 2012). The search terms used were as follows: (Thiopurine or Azathioprine or Mercaptopurine or Purine), (Crohn’s or Ulcerative Colitis or Inflammatory Bowel Disease), and (Skin Cancer or Skin Malignancy or Basal Cell Carcinoma or Squamous Cell Carcinoma or Nonmelanoma Skin Cancer or Skin Neoplasm or Outcome). No limits or language restrictions were applied. Study selection
Studies were eligible for inclusion if they reported on risk of developing NMSC in patient with IBD on thiopurines compared with a control population. Studies published only in abstract form were not included. Two reviewers (J.A. and V.S.) independently screened titles and abstracts identified by the preliminary searches to identity potentially eligible studies. Both reviewers independently assessed the full text articles of potentially relevant studies for inclusion in the pooled analysis on the basis of the above inclusion criteria. Data from included studies were independently extracted by two investigators (J.A. and V.S.) using predefined criteria and a standardized profoma, and were entered into an Excel 2010 (Microsoft, Redmond, WA) spread sheet. Information was collected on characteristics of the study and outcomes. Agreement between the investigators was >95% and differences between the data sets were resolved by discussion.
controls were either extracted from the study or calculated from the data provided. If possible, the hazard ratio and associated variance were obtained directly from each trial publication or from individual patient data. Hazard ratios not reported were calculated by the methods of Parmer et al. (17). These methods use information, such as P-values and numbers of deaths, to estimate the hazard ratio and variance, and they account for the censoring associated with varying follow-up times. When insufficient data had been published, we contacted the study authors. As randomization and blinding is not possible in observational studies and baseline differences between the groups can confound the results, we used the authors odds or hazard ratios with adjustment for potential confounding factors. Hazard ratios and 95% CIs were obtained for each study, and the pooled estimate was calculated from an inverse-variance-weighted average of the individual studies (18). A fixed-effects model was used unless there was significant heterogeneity, in which case the DerSimonian–Laird random-effects model was used (19). Comprehensive Meta Analysis version 2.2 (Biostat, Englewood, NJ) statistical package was used for the data analysis. Heterogeneity and sensitivity analysis
We used the Cochran’s Q to test heterogeneity among pooled estimates (20). Statistical heterogeneity was also measured by the I2 statistic that quantifies the proportion of inconsistency in individual studies that cannot be explained by chance (21). Values of I2 = 25, 50, and 75% represent low, moderate, and high heterogeneity, respectively. Finally, in order to exclude an excessive influence of any one study we evaluated whether exclusion of each study substantially affected the magnitude or statistical significance of the summary odds ratio. To test for publication bias, we used a test for asymmetry of the funnel plot proposed by Egger et al. (22). This test detects funnel plot asymmetry by determining whether the intercept deviates significantly from zero in a regression of the normalized effect estimate (estimate divided by the s.e.) again precision (reciprocal of the s.e. of the estimate) weighted by the reciprocal of the variance of the estimate. The quality of the primary studies assessing the risk of bias was evaluated using the Newcastle-Ottawa Scale (23). The influence of the following factors on the trial outcome and on the heterogeneity of the analyses was assessed with meta-regression analysis (24) where sufficient data were available: (a) study design used (nested case–control or cohort), (b) the population studied (population based or hospital based), (c) definition of drug exposure (ever user or prolonged exposure), (d) mean duration of follow-up (>6 years or < 3 years), (e) average UVA radiation for the country from which study (http://www.who. int/uv/intersunprogramme/activities/uv_index/en/index3.html and (f) the average latitude of the country of origin of the study (https://docs.google.com/spreadsheet/ccc?key=0At92oU3FPZ4Q dEIwVV8tZGJHRmV6VXV3LWpfQThiUnc&hl=en#gid=0).
RESULTS Statistical analysis
Characteristics of selected studies
Hazard with 95% confidence intervals (CIs) of developing of NMSC in patients with IBD on thiopurines compared with
Our PubMed search retrieved 10 potentially relevant articles of which 2 did not provide any data on NMSCs (25,26). Figure 1
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Thiopurine Use and Nonmelanoma Skin Cancers
CINAHL Search: 635articles
196 review articles
744 articles retained
Embase search: 3035 articles
102 review articles 24 editorials 36 case reports
473 articles retained
734 articles discarded after reading title and abstract
833 review articles 230 conference abstracts 114 conference papers 43 editorials 74 notes 40 short surveys 164 letters 6 books
1531 articles retained
2 articles discarded after reading full text (did not provide data on NMSC)
469 articles discarded after reading title and abstract
1523 articles discarded after reading title and abstract
8 articles retained from all three databases
Figure 1. Flowchart showing the fate of articles selected from the search strategy.
outlines the fate of the selected articles. A total of 8 studies (27–34) involving 60,351 participants with a diagnosis of IBD were included in the final meta-analysis. Four studies were nested case–control studies from insurance claims databases and four were retrospective cohort studies. No additional articles were retrieved from the other research strategies. Table 1 lists all the included studies and their characteristics and Table 2 the quality scores of these studies based on the Newcastle-Ottawa scale. Of the eight included studies, five were population-based studies (data derived from insurance claims databases or primary care databases) and three were based on hospital databases. All of the case– control studies were nested within a larger cohort of patients with IBD. The cases were patients with IBD, who developed NMSC during the follow-up period, and controls were patients with IBD, who did not develop NMSC. We obtained further data of the risk of NMSC with azathioprine use from the authors of the Armstrong et al. study (27). One study (34) was published as a letter to the editor but did include information on the risk of NMSC in IBD patients with thiopurine exposure and was therefore included in the final analysis. Cumulative risk of developing NMSC in IBD patients exposed to thiopurines
Eight studies with 60,351 patients with IBD provided data on adjusted risks of developing NMSC after exposure to thiopurines. The pooled adjusted hazards ratio of developing NMSC after exposure to thiopurines in patients with IBD was 2.28 (95% CI: 1.50–3.45; Figure 2). A random-effects model was chosen, as the heterogeneity between the studies was high (Cochran’s Q = 30.3, P = 0.001, and I2 = 76%). © 2014 by the American College of Gastroenterology
Sensitivity analysis and publication bias
Exclusion of each of the studies in turn did not alter the significance of the summary statistic. Mixed-effects meta-regression analysis using an unrestricted maximum likelihood model showed that the population studied (hospital-based studies vs. population-based databases) and mean duration of follow-up (either < 3 years or > 6 years) were significant predictors of heterogeneity (Table 3). When the studies were grouped according to the type of population studied, the pooled adjusted hazard ratio of developing NMSC in patients exposed to thiopurines using a random-effects model from hospital-based studies was 7.22 (95% CI: 3.08–16.90) and in population-based studies was 1.83 (95% CI: 1.2–2.80). There was no heterogeneity among hospital-based studies (Cochran’s Q = 0.66, P = 0.72) but significant heterogeneity between population-based studies (Cochran’s Q = 22.6, P = 0.001). Using mixed-effects analysis, tests for difference between the subgroups was significant (Cochran’s Q = 8.01, P = 0.005). When the studies were grouped according to the duration of follow-up, the pooled adjusted hazard ratio of developing NMSC from studies with shorter duration of follow-up ( < 3 years) was 2.87 (95% CI: 2.02–4.08) and in studies with longer duration of follow-up ( > 6 years) was 1.88 (95% CI: 0.87–4.06). There was significant heterogeneity among studies with short ( < 3 years) followup (Cochran’s Q = 5.91, P = 0.05) as well as studies with longer ( > 6 years) follow-up (Cochran’s Q = 13.32, P = 0.01). Using mixed-effects analysis tests for differences between the subgroups was not significant (Cochran’s Q = 0.964, P = 0.326). There was some funnel plot asymmetry compatible with publication bias (Figure 3); however Egger’s regression asymmetry test (P = 0.15, The American Journal of GASTROENTEROLOGY
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Table 1. Characteristics of included studies
Author (ref)
Year
Country
Type of study
Drug
Definition of exposure
No. of cases
No. of controls
Mean duration of followup (years)
Variables adjusted for in-risk estimates
Variables matched for (case–control studies only)
1
Long et al. (31)
2010
USA
Case– control
AZA/6MP
Recent thiopurine use of by ≥1 prescription < 90 days from NMSC diagnosis
742
2,968
1.32
Health care utilization, comorbidities, any use of 5-ASA/biologics
Age, sex, geographic region, disease type, duration of follow-up
2
Armstrong et al. (29)
2010
UK
Case–control
AZA
> 1 prescription
43
15,398
6.4
Age group, smoking
NA
3
Singh et al. (35)
2011
Canada
Case–control
AZA/6MP
2 Prescriptions in the study period
170
680
11.7
Average annual number of ambulatory physician visits, socioeconomic status
Age, sex, disease type (UC/CD), time since diagnosis of IBD.
4
Van Schaik et al. (36)
2011
Holland
Cohort
AZA/6MP
At least 50 mg AZA/6MP for 6 months
819
2,068
6.46
Age, sex, type of IBD, duration of IBD
NA
5
Setshedi et al. (34)
2011
South Africa
Cohort
AZA/6MP
Treated (not defined)
123
691
9.9
Not adjusted
NA
6
PeyrinBiroulet et al. (33)
2011
France
Cohort
AZA/6MP
Ongoing (not defined)
8,676
10,810
2.55
Age, sex
NA
7
Long et al. (32)
2012
USA
Case–control
AZA/6MP
At least 1 pharmacy claim
3,288
12,945
2
Other classes of IBD medication, Medicaid insurance status
Age (within 2 years), sex, region, disease type, month of the case’s diagnosis
8
Camus et al. (30)
2012
France
Cohort
AZA
2.25 mg/kg AZA—1 year
220
440
12.17
Age, gender, ethnicity, area of residence, socioeconomic status, family history of IBD, extra-intestinal manifestations, prior appendectomy, smoking status, disease duration, site and behavior of disease, perianal disease, prior intestinal surgery.
Sex, age (boxes of 5 years), date of IBD diagnosis (boxes of 5 years)
5-ASA: 5-aminosalicylcates; AZA, azathioprine; CD, Crohn’s disease; IBD, inflammatory bowel disease; 6MP, 6-meraptopurine; NA, not applicable; NMSC, nonmelanoma skin cancer; UC, ulcerative colitis.
intercept = − 6.7, and 95% CI: − 17.2 to 3.7) was nonsignificant. The regression asymmetry test is probably underpowered, as there are only eight studies included in the meta-analysis.
DISCUSSION Principle findings
Given the evidence to date that use of immunosuppressive thiopurines in solid-organ-transplant patients is associated with NMSC, it is important to determine the risk in IBD patients who are also The American Journal of GASTROENTEROLOGY
prescribed thiopurines. The results of this meta-analysis suggest that the risk of developing NMSC following treatment with thiopurines for IBD is only modestly elevated and loses significance when studies with < 3 years follow-up are excluded. Immune deregulation has been hypothesized to be the reason behind an increased risk of NMSC in all patients with IBD (35), and this meta-analysis suggests that thiopurine use can magnify this risk about two fold. There was significant heterogeneity between studies for this analysis mainly due to differences in the type of population VOLUME 109 | FEBRUARY 2014 www.amjgastro.com
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Table 2. Newcastle Ottawa scale scores of the included studies
Selection Author (reference) Long et al. (31) Armstrong et al. (29) Singh et al. (35) Long et al. (32)
Exposure
Case definition
Representativeness
Selection of controls
Definition of controls
Comparability
Ascertainment
Same method for cases/controls
Nonresponse
3
3
3
3
33
3
3
3
3
3
3
3
3
3
3
3
3
3
3
33
3
3
3
3
3
3
33
3
3
3
3 Cohort studies
Selection
Author
Representativeness
Selection of unexposed cohort
Ascertainment of exposure
3
3
3
3
3
3
33
3
3
3
3
33
3
3
3
3
33
Van Schaik et al. (36) Setshedi et al. (34) Peyrin-Biroulet et al. (33) Camus et al. (30)
Outcome Outcome not present at start
studied and differing duration of follow-up. When the analysis was re-run grouping the studies according to type of population, hospital-based studies showed a much greater pooled adjusted hazard ratio compared with population-based studies. Ascertainment bias could explain some of the differences in risk noted between hospital-based and population-based studies. Patients who were on thiopurines during the follow-up period would have been more likely to attend hospital and be seen by a medical professional than those not on thiopurines. Surveillance bias could also account for this increased risk, as medical professionals aware of the association between thiopurine use and NMSC may be more likely to diagnose NMSCs and biopsy any suspicious skin lesions in thiopurineexposed patients than in those unexposed to the drug. We also found that studies with shorter duration of follow-up ( < 3 years) reported higher risks of developing NMSCs in thiopurine-exposed patients. Conversely, when studies with longer mean follow-up duration ( > 6 years) were grouped, there was a nonsignificant rise in the risk of developing NMSCs with thiopurine exposure. It has been suggested earlier (36) that studies with shorter duration of follow-up could have had more intensive regimes and therefore resulted in greater risks of developing NMSCs. On the other hand, it is also likely that most of these NMSCs were detected early on in the course of therapy, which could explain why with longer duration of follow-up the risk reduces. Ascertainment bias could once again explain the differences noted as intensive scrutiny by medical professionals, whereas monitoring thiopurine therapy could © 2014 by the American College of Gastroenterology
Assessment of outcome
Sufficient duration of follow-up
Adequacy of follow-up
3
3
3
3
3
3
3
3
3
3
3
Comparability
result in increased detection of pre-existing skin lesions that might have been attributed to the use of thiopurines. Limitations of the study
As with any meta-analysis, there are possible limitations in combining the results of multiple separate studies. The types of population studied (population-based vs. hospital-based), and duration and follow-up were major contributory factors in the heterogeneity noted between studies. In addition, the eight studies used in this meta-analysis were taken from six different countries resulting in inherent, unavoidable differences between sample populations such as amount of UV light exposure, prevalence of smoking, and race (skin color). These risk factors are all likely to have been different across these differing populations. Only Setshedi et al. (32) considered race in their analysis, showing that odds of developing NMSC in IBD when on thiopurines were far greater in white Caucasian patients than those of other races. Further variations between studies include sample size and type of study (nested case–control vs. cohort studies). Some of the studies included in this meta-analysis included small samples, which could result in selection bias. The definitions used to determine patients with IBD also varied between studies. One study (33) used histologically confirmed IBD patients and others used physician contacts/hospitalizations/pharmacy claims for IBD as their definitions. Furthermore, although the majority of these studies used histological confirmation as evidence of NMSC outcome (28–30,32), The American Journal of GASTROENTEROLOGY
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Funnel plot of s.e. by log hazard ratio
Hazard ratio and 95% Cl
Hazard Lower Upper ratio limit limit 29 2.28 1.86 Long et al. 2.79 27 1.02 0.41 Armstrong et al. 2.51 33 2.17 1.24 3.80 Singh et al. 34 0.85 0.51 Van Schaik et al. 1.41 7.81 0.85 71.68 Setshedi et al.32 26 5.90 2.11 Peyrin-Biroulet et al. 16.49 3.16 2.38 Long et al.30 4.19 Camus et al.28 15.36 1.92 122.86 2.28 1.50 3.45 Pooled
0.0
0.5
s.e.
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Study name
0.01 0.1 Protects
1
10
100
1.0
1.5
Increases risk 2.0
Figure 2. Forest plot showing the pooled adjusted hazards ratio of developing nonmelanoma skin cancer (NMSC) after exposure to thiopurines in patients with inflammatory bowel disease (IBD).
Table 3. Results of mixed effects meta-regression analysis using an unrestricted maximum likelihood model Regression co-efficient (s.e)
P value
Tau-squareda
Definition of drug exposure
0.23 (0.54)
0.66
0.27
Study design
− 0.28 (0.53)
0.59
0.33
Population studied
− 1.41 (0.55)
0.01
0.15
Duration of follow-up
− 0.62 (0.19)
0.001
0.15
Latitude (midpoint) of the country from which study originated
− 0.03 (0.02)
0.09
0.16
Mean reported UV radiation according to country of origin
0.25 (0.10)
0.15
0.13
Variable
a
Tau-squared is the between-studies variance calculated using the unrestricted maximum-likelihood method.
other studies did not specify how the diagnosis of NMSC was confirmed. Any of these variations could potentially have biased the results. The definition of exposure to thiopurines and duration of follow-up to determine development of NMSC were also diverse across the eight studies. Although most studies defined exposure as simply one or more pharmacy claims (28,29,32) for thiopurine medication, others either defined a specific dosage and duration of treatment (25,27) or did not specify dosage or duration (30,31). In addition, some studies followed patients for 1–3 years (28–30), whereas others continued to assess patients for NMSC development for 6–12 years (27,31–33). The definition of exposure to thiopurine however was not a significant predictor of heterogeneity in our analysis. Clinical implications
Clinical guidelines for management of IBD in the United Kingdom emphasize the risk of NMSC in patients treated with thiopurines (37). This meta-analysis has shown that the risk of developing NMSCs with thiopurine use in patients with IBD is just over 2-fold and is only 1.8-fold when population-based studies are included, The American Journal of GASTROENTEROLOGY
–3
–2
–1
0
1
2
3
log hazard ratio Figure 3. Funnel plot for publication bias on studies included in the metaanalysis. The x axis (measure of effect size) represents the hazard ratio of developing nonmelanoma skin cancer (NMSC) after thiopurine exposure and the y axis (measure of study precision) represents a measure of the size of the study. The center line represents summary statistic—that is, the pooled adjusted hazard ratio of developing NMSC after thiopurine exposure. The two-side lines represent 95% confidence intervals.
and there was a nonsignificant increase in risk of NMSCs when studies with longer ( > 6 years) duration of follow-up were pooled. Some of this increased risk could be the result of ascertainment bias and although thiopurines should continue to be used with care in patients with IBD, the risk of NMSC as a result of this therapy in this population should not be overstated. We agree that patients taking thiopurines for the treatment of IBD, particularly White Caucasian patients, should avoid excessive sun exposure and use high-strength sun block. In addition, gastroenterologists and primary care doctors should continue to stay vigilant and investigate suspicious skin lesions thoroughly in these patients. However, thiopurines have been shown to be hugely effective in the management of both ulcerative colitis and Crohn’s disease . Thiopurines have become the mainstay of treatment in steroid-dependent IBD and their use should not be limited by the minimally increased risk of NMSC. The magnitude of the risk has to take into account the fact that NMSC is fairly common in the general population with an estimated 3.5 million annual cases affecting over 2 million people in the United States (13). The overall annual incidence of NMSC in the IBD population in a North American study was found to be 733 per 100,000 compared with 447 per 100,000 in the general population (29). A small increase in risk could therefore result in a reasonably large number of extra cases of NMSC. Further work should investigate the effects of long-term treatment with thiopurines. To date, there are only two studies that have investigated prolonged exposure to thiopurine use ( > 365 days), both of which have shown increased odds of developing NMSC compared with shorter treatment regimens (25,29). However, many patients with IBD are treated with thiopurines for several years and there is a paucity of data to inform us of the risk of developing NMSC in these patients. In addition, prospective studies need to evaluate the risk to benefit ratio of thiopurines in IBD with respect to development of NMSCs. VOLUME 109 | FEBRUARY 2014 www.amjgastro.com
CONFLICT OF INTEREST
Guarantor of the article: Venkataraman Subramanian, MD, DM, MRCP (UK). Specific author contributions: J.A.: study design, data collection, and wrote first draft of paper. V.S.: study conception, study design, data collection, data analysis, and edited the paper. Financial support: J.A. was awarded a NIHR Academic Foundation Trainee fellowship from the National Institute of Health Research, UK. Potential competing interests: None.
Study Highlights WHAT IS CURRENT KNOWLEDGE
3Thiopurines are currently the mainstay of treatment in steroid-dependent inflammatory bowel disease (IBD). 3Thiopurines use is associated with an increased risk of nonmelanoma skin cancer (NMSC) in solid-organ-transplant
patients. Risk of developing NMSCs in IBD patients on thiopurines is unclear.
WHAT IS NEW HERE
3Risk of developing NMSC as a result of thiopurine treatment for IBD is modestly elevated. 3Risk of developing NMSC may be overestimated in these studies due to ascertainment bias. 3There is not enough evidence to suggest that the increased risk of NMSC outweighs the benefit of thiopurines in IBD.
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REVIEW
Thiopurine Use and Nonmelanoma Skin Cancers
