Cancer Risk in IBD Patients Treated with Thiopurines or Anti-TNF-α Therapy: A Meta- analysis of Population-Based Studies

Cancer Risk in IBD Patients Treated with Thiopurines or Anti-TNF-α Therapy: A Meta- analysis of Population-Based Studies | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Cancer Risk in IBD Patients Treated with Thiopurines or Anti-TNF-α Therapy: A Meta- analysis of Population-Based Studies Zhenzhi Wang, Yukun Chen, Xinyu Li, Li Lin, Bozhu Chen, Min Chen, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6904749/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Objective To evaluate the cancer risk in patients with IBD treated with thiopurines or anti-tumor necrosis factor-α (anti-TNF-α) therapy through a meta-analysis. Methods A systematic search of PubMed, Embase, and Web of Science identified 31 population-based cohort studies (718,472 IBD patients). Hazard ratios (HRs) with 95% confidence intervals (CIs) were pooled using random-effects models. Subgroup analyses (Crohn’s disease [CD] vs. ulcerative colitis [UC]), sensitivity analyses, and publication bias assessments were performed. Results Thiopurine use significantly increased the risk of overall malignancies (HR = 1.53, 95% CI:1.06–2.2), particularly melanoma (HR = 2.7, 1.91–3.83) and lymphoma (HR = 1.64, 1.33–2.02). Subgroup analyses revealed higher risks in CD than UC patients (lymphoma: HR = 2.00 vs. 1.75). Conversely, thiopurines were associated with a potential reduction in colorectal cancer risk (HR = 0.56, 0.32–0.99), though this did not reach statistical significance ( P = 0.234). Anti-TNF-α monotherapy showed no significant overall cancer risk, but combination therapy with thiopurines elevated lymphoma risk (HR = 3.7). Limited evidence suggested associations with urinary tract (HR = 2.82, 1.04–7.68) and hematologic cancers (HR = 2.41, 1.04–4.76). Conclusion Thiopurines are linked to increased risks of specific cancers but may mitigate colorectal cancer risk via anti-inflammatory effects. Clinicians should balance immunosuppressive benefits against oncological risks and enhance cancer surveillance in long-term users. Future studies should explore dose-response relationships and safety profiles of newer biologics. Inflammatory bowel disease Thiopurines Anti-TNF-α therapy Cancer risk Meta-analysis Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Introduction Inflammatory bowel disease (IBD), encompassing Crohn’s disease (CD) and ulcerative colitis (UC), is a chronic immune-mediated disorder characterized by relapsing gastrointestinal inflammation 1 . Globally, IBD affects approximately 10 million individuals, with rising incidence rates in developing nations 2 , 3 . While genetic predisposition, dysbiosis, and environmental triggers contribute to pathogenesis, persistent immune dysregulation drives mucosal damage and complications such as strictures, fistulae, and colorectal cancer 3 , 4 . Current therapies, including thiopurines (azathioprine, 6-mercaptopurine) and anti-tumor necrosis factor-alpha (anti-TNF-α) agents, aim to control inflammation and improve quality of life. However, their immunosuppressive mechanisms raise concerns about long-term cancer risks 2 , 5 , 6 . Thiopurines inhibit lymphocyte proliferation by disrupting DNA synthesis, while anti-TNF-α agents neutralize pro-inflammatory cytokines. Although effective, these therapies are associated with dose-dependent and duration-dependent risks of malignancies. Thiopurines, for instance, increase susceptibility to non-melanoma skin cancers (NMSC), lymphomas, and hepatosplenic T-cell lymphoma (HSCTL), particularly in combination with anti-TNF-α 2 , 7 , 8 . Mechanistically, thiopurine metabolites induce DNA damage, impair immune surveillance, and reactivate oncogenic viruses like Epstein-Barr virus (EBV) 9 . Anti-TNF-α monotherapy has a more debated carcinogenic profile, though synergistic risks emerge when combined with thiopurines 3 , 6 , 10 . For example, a meta-analysis reported a 3.7-fold higher lymphoma risk with combination therapy compared to monotherapy 3 . Existing evidence on cancer risks remains heterogeneous. Observational studies suggest thiopurines elevate NMSC incidence (adjusted hazard ratio [aHR] 1.3–1.7) 5 , 11 , while anti-TNF-α alone shows no significant overall cancer risk 9 , 10 . However, specific malignancies—such as colorectal cancer in UC or hepatobiliary cancers in primary sclerosing cholangitis (PSC)—may be influenced by disease-specific inflammation rather than therapy 2 , 5 . Notably, population-based cohort studies in China and Denmark highlight elevated standardized incidence ratios for gastrointestinal, thyroid, and hematologic cancers in IBD patients, independent of treatment 12 , 13 . This meta-analysis has combined data from recent population-based studies to assess the cancer risks linked to thiopurines and anti-TNF-α treatments in IBD patients. The analysis aims to offer practical, stratified risk assessments to help guide treatment decisions for clinicians and patients. Methods This systematic review is presented following the guidelines set forth by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 14 . Search Strategy We searched multiple electronic databases, including PubMed, Embase, and Web of Science. The search terms used were as follows: (Thiopurine, Azathioprine, Mercaptopurine, Thioguanine, Anti-TNF-α, Tumor Necrosis Factor-alpha), (Inflammatory Bowel Disease, IBD, Crohn’s Disease, Ulcerative Colitis), and (Cancer, Malignancy, Neoplasm, Lymphoma, Colorectal Cancer, Skin Cancer, Nonmelanoma Skin Cancer). A more detailed list of search terms has been provided in the supplementary table S1 . The search was performed without any limits on publication date or language to maximize the comprehensiveness of the search. Study Selection Studies were included if they were population-based cohort studies focusing on patients with IBD who were treated with thiopurines (azathioprine, 6-mercaptopurine) or anti-tumor necrosis factor-alpha (anti-TNF-α) agents, and provided hazard ratios (HRs) with 95% confidence intervals (CIs) comparing cancer risk in exposed versus non-exposed groups, such as non-exposed IBD patients, the general population, or 5-ASA users. Studies were also expected to report detailed patient demographics, IBD subtype, disease duration, and other key covariates relevant to cancer risk. Exclusion criteria included non-population-based cohort studies, studies without standardized cancer outcome assessments or insufficient data for HR calculation, and those that did not specifically report on the cancer risks of interest, such as melanoma, lymphoma, or colorectal cancer. We excluded studies involving patients with pre-existing malignancies or immunodeficiency disorders unrelated to IBD, which might confound the relationship between thiopurine/anti-TNF-α use and cancer risk. Additionally, case reports, case series, narrative reviews without comparative data, and studies that combined thiopurines or anti-TNF-α with other non-traditional or experimental treatments in a way that made it impossible to isolate their effects were excluded. Data extraction Data extraction was performed independently by two researchers for all included studies. Any discrepancies were resolved through discussion or by consulting a third expert. Microsoft Excel was utilized with pre-designed templates to streamline the process. Extracted data included study characteristics such as first author details, publication year, and study duration, as well as exposure definitions, including specific thiopurine and anti-TNF-α agents and their dosages. Outcomes data focused on cancer incidence, with variables related to the association between these therapies and malignancies also extracted. Quality Assessment The quality of the included studies was evaluated by two authors using the Newcastle-Ottawa Scale (NOS) specifically designed for assessing the quality of non-randomized studies in meta-analyses. This scale consists of eight items, addressing three broad perspectives: the selection of study groups, the comparability of the groups, and the assessment of outcomes. Each item is scored with a maximum of one star, except for the comparability item, which can yield a maximum of two stars. The total score ranges from zero to nine, with higher scores indicating better quality. Studies scoring seven or above are considered high quality, those scoring four to six are regarded as moderate quality, and studies with scores below four are deemed low quality. The quality assessment was conducted independently by two researchers. Any disagreements were resolved through discussion, and if necessary, a third researcher made the final judgment. Statistical analysis This study adopted a systematic literature retrieval strategy in line with Cochrane Collaboration standards and pooled hazard ratios (HRs) using both the DerSimonian-Laird random effects model and the Mantel Haenszel fixed effects model. Model selection depended on heterogeneity assessment. We evaluated between study heterogeneity via Cochran’s Q test and I²statistics, adopting random effects models when significant heterogeneity (I²>50%) was detected. Sensitivity analyses involved leave-one-out sequential exclusion to gauge each study’s impact on pooled estimates and trim-and-fill adjustments to tackle potential publication bias. Funnel plot asymmetry and Egger’s linear regression (with a significance threshold of P < 0.10) were used in tandem to measure publication bias. Subgroup analyses, which calculated subgroup specific HRs with 95% confidence intervals, were stratified by cancer category (colorectal cancer, lymphoma, non-melanoma skin cancer, and other malignancies). Interaction tests (Wald test) assessed differences between subgroups. All statistical analyses were performed using Stata 17.0. Results Literature search Studies were independently screened and selected by two reviewers based on predefined inclusion and exclusion criteria. Initial searches yielded a total of 6,654 citations. After removing duplicates, 1,573 titles and abstracts were screened, resulting in the exclusion of 1,231 studies that did not meet the inclusion criteria. Full-text reviews were conducted for the remaining 126 articles. Studies were excluded if they were not population-based, lacked data on cancer risk, or evaluated non-traditional thiopurine or anti-TNF-α therapies. Ultimately, 31 studies were included in the final analysis. Characteristics of Selected Studies The included studies comprised a diverse collection of 31 investigations examining the association between thiopurines/anti-TNF therapy and cancer risk in patients with IBD. Figure 1 outlines the fate of the selected articles, which feature various study designs including retrospective cohort 15 – 26 (n = 11), prospective cohort 27 – 29 (n = 3), cohort 30 – 33 (n = 4),population-based cohort 34 – 39 (n = 6), case-control 40 , 41 (n = 2), and multicenter studies 42 , 43 (n = 2) and others 44,45 (n = 2), conducted across multiple countries, with the United States 17,20,21,24,28,33,46 (n = 7) and France 27 – 29 , 31 , 35 (n = 5) being the most represented regions. These studies encompassed a wide range of sample sizes, from smaller cohorts like Florian Beigel 25 (2014) with 666 participants to large-scale investigations such as Jingru Yu 39 (2023) involving 131,492 patients, with median follow-up durations spanning 3 to 14.5 years and study populations predominantly consisting of adults aged 31–68 years. The exposures of interest primarily included thiopurines (azathioprine, 6-mercaptopurine) and anti-TNF agents (infliximab, adalimumab), which were compared against non-exposed IBD patients, the general population, or 5-ASA users in various studies. The most frequently reported outcomes were lymphoma 17 , 25 , 31 , 33 , 38 , 42 , 45 , non-melanoma skin cancer 18 – 20 , 28 , 46 , 47 , and colorectal cancer 29 , 34 , 41 , 43 , with analyses consistently adjusted for key covariates including age, sex, IBD subtype, and disease duration. Table 1 presents the included studies along with their characteristics. The quality of included studies was assessed using the Newcastle-Ottawa Scale (NOS), with only high-quality studies (NOS score ≥ 6) included. The study selection process is outlined in a PRISMA flow diagram provided in the supplementary material. Supplementary Table S2 shows the quality scores of these studies based on the Newcastle Ottawa scale. Table 1 Main characteristics of the included studies Study, year Design Country Sources of participants No. (M/F) Mean/Median age years thiopurines or anti-TNF alpha antibodies description Reference category definition Exposure duration(mean, years) Follow up (CP/control)(years) Diagnosis of Cancer Tumor type HR 95%LL 95%UL Beigel 24 , 2014 Retrospective cohort Germany University Hospital Munich-Grosshadern 666 (439/227) 35 (TP group), 38 (TNF + group) TP group: treated with thiopurines alone; TNF + group: exposed to anti-TNF antibodies with no, discontinued, or continued thiopurine therapy TP group: never exposed to anti-TNF antibodies; TNF + group: exposed to anti-TNF antibodies TP group: 1.58 (median 19 months), TNF + group: 1 (median 12 months) TP group: 1.3 (median 68 weeks), TNF + group: 2.7 (median 140 weeks) NA malignancies 4.15 1.82 9.44 Khan 16 , 2013 Retrospective cohort USA Veterans Affairs (VA) health care system 36,891 (34,424/2,467) 60 (median) Patients with UC treated with thiopurines (azathioprine and 6-mercaptopurine) or not treated with thiopurines Patients who were not treated with thiopurines 0.97 (median) 6.7 (median) ICD-9 codes Lymphoma 4.2 2.5 6.8 Abbas 19 , 2014 Retrospective cohort USA Veterans Affairs (VA) health care system 14,527 (13,674/853) 59 (median) Patients with UC treated with thiopurines (azathioprine and 6-mercaptopurine) or not treated with thiopurines Patients who were not treated with thiopurines 1.6 (median) 8.1 (median) ICD-9 codes Non-melanoma skin cancer (NMSC) and Melanoma skin cancer (MSC) 2.1 1.6 2.6 Wewer 29 , 2024 Nationwide Cohort Denmark Danish national registers 43,419 (Not specified) 38.7 (median) Patients with IBD treated with thiopurines (azathioprine and mercaptopurine) Patients not exposed to thiopurines NA 8.2 (median) ICD-8/10 codes malignancies 1.36 1.17 1.57 Lemaitre 30 , 2017 Nationwide cohort France French National Health Insurance databases 189,289 (86,506/102,783) 43 (median) Patients with IBD treated with thiopurines (azathioprine and 6-mercaptopurine) or anti-TNF agents (infliximab and adalimumab) Patients not exposed to thiopurines or anti-TNF agents NA 6.7 (median) ICD-10 codes Lymphoma 2.6 1.96 3.44 Khan 23 , 2019 Retrospective cohort USA Veterans Affairs Healthcare System 54,919 (Not specified) 68.2 (median) Patients with IBD treated with thiopurines (azathioprine and 6-mercaptopurine) Patients treated with 5-ASA only and no prior exposure to thiopurines or anti-TNF agents NA From the time of incident SCC diagnosis until death or last recorded date in the health system ICD-9-CM, ICD-10-CM Squamous cell carcinoma (SCC) 8 2 32.8 Setshedi 17 , 2012 Retrospective cohort South Africa IBD patients attending a specialist IBD clinic at Groote Schuur Hospital, Cape Town 1084 (423M/661F) 34 (median) Thiopurines (azathioprine and 6-mercaptopurine) Patients who did not receive thiopurines 24 (azathioprine), 16 (6-mercaptopurine) 9.9 (mean follow-up) Clinical and pathology records Non-melanoma skin cancer (NMSC) 5.1 1.1 22.8 van den Heuvel 33 , 2016 Population-based cohort Netherlands Dutch population-based IBDSL cohort CD: 1,157 (430M/727F), UC: 1,644 (891M/753F) Median age at diagnosis: CD: 34.3 years, UC: 45.0 years Thiopurines (azathioprine, 6-mercaptopurine, thioguanine) and anti-TNFα antibodies (infliximab, adalimumab, golimumab) No immunosuppression exposure NA Median follow-up: CD: 8.1 years, UC: 8.8 years ICD-O malignancies 1.48 1.11 1.95 Colorectal cancer 2.97 1.08 6.46 hematologic cancer 2.41 1.04 4.76 skin cancer (including SCC and BCC) 1.55 1.06 2.19 melanoma na na na Cheddani. 34 , 2016 Population-based cohort France French population-based cohort CD: 370 (38% male/62% female), UC: 474 (62% male/38% female) Median age at diagnosis: CD: 70 years, UC: 69 years Thiopurines (azathioprine, 6-mercaptopurine, thioguanine) and anti-TNFα antibodies (infliximab, adalimumab) No immunosuppression exposure NA Median follow-up: 6 years NA malignancies 0.91 0.45 1.82 A. Bourrier 26 , 2016 Prospective observational cohort France 680 French gastroenterologists 19,486 (45.1% male) 37.0 (median, SD 14.3) Thiopurines (azathioprine and mercaptopurine) Never received thiopurines NA 35 months (median) Histologically proven Urinary tract cancers 2.82 1.04 7.68 Zheng 47 , 2020 Territory-wide Hong Kong, China Hospital Authority's Clinical Data Analysis and Reporting System (CDARS) 7452 (2712 male, 4740 female) 47.0 (median, IQR 36.0–57.0) Thiopurines (azathioprine and mercaptopurine) Non-users of thiopurines in the same diagnosis category 6.2 (IQR 2.0–10.8) 11.2 (median) Based on pathological confirmation All malignancies 2.3 2.13 2.48 Jess 35 , 2013 Population-based cohort Denmark North Jutland County, Denmark UC: 1437 (730 male, 707 female); CD: 774 (333 male, 441 female) UC: 20–39 years (45%); CD: 20–39 years (47%) Thiopurines (azathioprine) General population UC: 15 years; CD: 14 years UC: 22,582 person-years; CD: 11,261 person-years ICD-10 codes All malignancies 1.55 1.29 1.84 1.12 0.97 1.28 Peyrin-Biroulet 27 , 2011 Prospective observational cohort France CESAME study group 19,486 (45.1% male) 37.0 (median, SD 14.3) Thiopurines (azathioprine and mercaptopurine) Never received thiopurines 8.2 (SD 8.0) 35 months ICD-10 codes Nonmelanoma skin cancer (NMSC) 5.9 2.1 16.4 Clowry 18 , 2016 Retrospective single centre cohort Ireland St Vincent’s University Hospital, Dublin 2053 (1050 male, 1003 female) 31.1 (median, range 2.4–80.6) Thiopurines (azathioprine and 6-mercaptopurine) and TNFα inhibitors (adalimumab, infliximab, certolizumab pegol) Non-immunosuppressed patients 9.8 (range 1 month to 19.6 years) Over 20,000 patient-years ICD-10 codes Non-melanoma skin cancer (NMSC) 6.45 2.69 15.95 Beaugerie 28 , 2013 Prospective observational cohort France CESAME study group 19,486 (45.1% male) 40.3 (median, SD 15.6) Thiopurines (azathioprine and 6-mercaptopurine) Never received thiopurines 8.2 (SD 8.2) 35 months Based on histological confirmation Colorectal cancer (CRC) 0.28 0.09 0.89 Long 45 , 2012 Retrospective cohort and nested case-control USA LifeLink Health Plan Claims Database (1997–2009) IBD: 108,579 (M/F not specified); non-IBD: 434,233 (M/F not specified) IBD: 43 (31–52); non-IBD: 43 (31–52) Thiopurines (e.g., azathioprine, 6-mercaptopurine) and biologic anti-TNF medications (e.g., infliximab, adalimumab, certolizumab pegol) No use of thiopurines or biologic anti-TNF medications NA IBD cohort: median 24 months (range 1–138); non-IBD: median 21 months (range 10–39) Melanoma: ICD-9 code 172.0–172.9 with pathology and excision codes; NMSC: ICD-9 code 173.0–173.9 or 232.0–232.9 with procedure codes Nonmelanoma Skin Cancer (NMSC) 1.85 1.66 2.05 Kopylov 39 , 2015 Nested case-control study Canada (Québec) RAMQ/MedECHO database 19,582 (M/F not specified) 42.5 ± 19.3 Thiopurines (e.g., azathioprine, 6-mercaptopurine) and biologic anti-TNF agents (e.g., infliximab, adalimumab, certolizumab pegol) Never use of thiopurines or biologics NA NA NMSC: ICD-9/10 codes with procedure codes; Lymphoma, CRC, Melanoma: ICD-9/10 codes NMSC 1.78 1.25 2.54 Lymphoma 0.87 0.53 1.41 Scott 20 , 2016 Retrospective cohort study USA Medicare 9460 (M/F not specified) 42.5 thiopurines (azathioprine, 6-mercaptopurine), anti-TNF agents (infliximab, adalimumab, certolizumab, golimumab, etanercept) Non-use of thiopurines, or anti-TNF agents NA NA ICD-9/10 codes Nonmelanoma Skin Cancer (NMSC) 1.49 0.98 2.27 1.36 0.76 2.44 Long, 2010 Retrospective cohort and nested case-control USA PharMetrics Patient Centric Database 53,377 IBD patients (M/F not specified) 39.1 (CD), 41.5 (UC) Thiopurines (azathioprine, 6-mercaptopurine) and biologic anti-TNF agents (infliximab, adalimumab) Non-use of thiopurines or biologic anti-TNF agents NA NA ICD-9 codes and CPT-4 codes Nonmelanoma Skin Cancer (NMSC) 4.27 3.08 5.92 Kobayashi 25 , 2019 Retrospective cohort Japan Medical Data Vision (MDV) database 75,673 (M/F not specified) 45.7 Thiopurines (azathioprine, 6-mercaptopurine) and biologic anti-TNF agents (infliximab, adalimumab) Non-use of thiopurines or biologic anti-TNF agents NA NA ICD-10 codes Nonmelanoma Skin Cancer (NMSC) and Non-Hodgkin Lymphoma (NHL) NA NA NA Singh 31 , 2011 Historical cohort study Canada Manitoba Health administrative databases and Manitoba Cancer Registry IBD: 9618 (45808 M/55188 F) Controls: 91,378 (45808 M/55188 F) Median: 36 (IQR: 25–50) Thiopurines (azathioprine/6-mercaptopurine) and anti-TNF alpha antibodies (not analyzed separately) No exposure to immunosuppressant medications or corticosteroids NA IBD: 11.7 years Controls: 11.5 years Manitoba Cancer Registry NMSC (BCC and SCC) 1.2 1.03 1.4 Kobayashi 21 , 2022 Retrospective study Japan Medical Data Vision (MDV) claims database (17.8 million patients; April 2008–January 2018) IBD: 75,673 (F not specified) NA Thiopurines (azathioprine or 6-mercaptopurine) and anti-TNF alpha antibodies (infliximab or adalimumab) No prescription of thiopurine or anti-TNF alpha antibodies NA NA MDV database Non-Hodgkin lymphoma (NHL) 1.88 1 3.46 Herrinton 32 , 2011 Cohort study USA Kaiser Permanente IBD Registry and Kaiser Permanente Cancer Registry (1996–2009) IBD: 16,023 (M: 43, F: 15,980) NA Thiopurines (azathioprine and 6-mercaptopurine) and anti-TNF alpha antibodies (infliximab and adalimumab) No prescription or dispensing of thiopurine or anti-TNF alpha antibodies NA Average 5.8 years Kaiser Permanente Cancer Registry Lymphoma 1.4 1.2 1.7 Vos 44 , 2011 Nationwide study Netherlands Dutch National Database of PALGA IBD: 17,834 (M: 7,850, F: 9,984) Median: 56.5 (21–79) Thiopurines (azathioprine and 6-mercaptopurine) and anti-TNF alpha antibodies (not specified) No prescription or use of thiopurine or anti-TNF alpha antibodies NA 8 years PALGA database Lymphoma 1.27 0.92 1.68 Tassone 22 , 2023 Retrospective analysis Australia St Vincent’s Hospital Melbourne, single tertiary referral centre IBD: 549 (M: 269, F: 280) Median: 39 (IQR: 29.5–52) Thiopurines (azathioprine and 6-mercaptopurine) and anti-TNF alpha antibodies (infliximab and adalimumab) No prescription or use of thiopurine or anti-TNF alpha antibodies NA Median 11 years Electronic medical records malignancies 1.08 1.03 1.13 Park 41 , 2015 Multicenter study Korea Three tertiary referral centers in Seoul, Korea (Asan Medical Center, Seoul National University Hospital, and Samsung Medical Center) IBD: 6585 (M: 3957, F: 2628) Median: 43 (33 to 70) Thiopurines (azathioprine and 6-mercaptopurine) and anti-TNF alpha antibodies (not specified) No prescription or use of thiopurine or anti-TNF alpha antibodies NA Median 5.4 years Korea Central Cancer Registry Lymphoma 2.03 0.81 4.18 Gordillo 42 , 2015 Multicenter study Spain ENEIDA Registry (Spanish nationwide database of IBD patients) IBD: 831 (M: 415, F: 416) Median: 59.4 (range: 23–80) Thiopurines (azathioprine and 6-mercaptopurine) and anti-TNF alpha antibodies (not specified) No use of thiopurine or anti-TNF alpha antibodies 5.6 ± 2.6 Median 14.5 years Histological diagnosis reports Colorectal neoplasia (CRC and HGD) 0.21 0.06 0.76 Nieminen 40 , 2013 Case-control Finland Hospital patient registry and pathology database 183 cases (114 M/69 F); 370 controls (227 M/143 F) Cases: 44.9 (SD 15.5); Controls: 42.7 (SD 15.4) Use of thiopurines (azathioprine or mercaptopurine) Non-use of thiopurines Not explicitly stated Cases: 1996–2008; Controls: matched by diagnosis date Histopathology Colorectal carcinoma (CRC) 0.09 0.02 0.33 Lakatos 37 , 2013 Population-based cohort study Hungary Veszprém province database UC: 479/435; CD: 251/255 UC: 36.5; CD: 28.5 se of azathioprine (AZA) and anti-TNF agents (Infliximab) No use of thiopurines or anti-TNFs AZA: 3649 patient-years 1977–2010 Standardized incidence ratio (SIR) Lymphoma (CLL, NHL) 1.37 0.44 4.26 Yu 38 , 2023 Population-based cohort study Norway and Sweden Public hospitals and registries 131,492 (67,601 M/63,891 F) NA Use of thiopurines (azathioprine, 6-mercaptopurine) and anti-TNF-α therapy (Infliximab, Adalimumab, Certolizumab) No use of thiopurines or anti-TNF-α therapy Median follow-up: 9.6 years 1987/1993–2015/2016 ICD-9/10 codes Non-Hodgkin’s lymphoma (NHL) 1.3 1.1 1.5 Hodgkin’s lymphoma (HL) 1.5 1.1 2.1 Cumulative risk of developing malignancies in IBD patients exposed to thiopurines or anti-TNF-α Seven studies with 57,168 patients with IBD provided data on adjusted risks of developing malignancies after exposure to thiopurines. The pooled adjusted hazards ratio of developing malignancies after exposure to thiopurines in patients with IBD was 1.53 (95% CI:1.06–2.2; P = 0.022) (Fig. 2 ). A random-effects model was chosen, as the heterogeneity between the studies was high (P [heterogeneity] <0.001, I 2 = 97.9% ). For the IBD subtypes, the results were as follows. In CD subgroup analysis, the pooled results showed a HR of CD1.43 (95% CI: 1.25–1.65), P <0.001. Heterogeneity was also assessed (I²=0.0%, P [heterogeneity] = 0.388). In contrast, the results for UC subgroup showed a HR of 1.08 (95% CI: 0.96–1.22), P = 0.216. The heterogeneity was I²=0.0%, P [heterogeneity] = 0.821(Supplementary Table S3). Sensitivity analysis and evaluation for publication bias Cumulative risk of developing melanoma in IBD patients exposed to thiopurines or anti-TNF-α Eight relevant studies, encompassing 718,472 patients with IBD (IBD), offered data on the adjusted risks of malignancies following thiopurine exposure. The pooled adjusted hazard ratio for malignancy development post-thiopurine exposure in IBD patients was 2.7 (95% CI: 1.91–3.83; P <0.001) (Fig. 3 ). A random-effects model was selected due to significant heterogeneity among the studies (P [heterogeneity] <0.001, I² = 84.6%).For the IBD subtypes, it should be noted that only one study reported the separate results for UC and CD. The HR for CD was 3.87 (95% CI: 2.88–5.21). Whereas for UC, the HR was 3.09 (95% CI: 2.10–4.54). Sensitivity analysis and evaluation for publication bias Cumulative risk of developing Lymphoma in IBD patients exposed to thiopurines or anti-TNF-α A total of nine studies, involving 271,601 IBD patients, provided adjusted risk data for malignancies after thiopurine use. The combined adjusted hazard ratio for malignancies in IBD patients exposed to thiopurines was 1.64 (95% CI: 1.33–2.02; P <0.001) (Fig. 4 ). Given the high heterogeneity between studies (P [heterogeneity] <0.001, I² = 80.7%), a random-effects model was employed. In CD subgroup analysis, the pooled results revealed a significantly increased HR of 2.00 for Lymphoma (95% CI: 1.18–3.41, P <0.05). Heterogeneity assessment indicated no significant heterogeneity (I²=0.0%, P [heterogeneity] = 0.312). In contrast, the UC subgroup analysis showed a HR of 1.75 for Lymphoma (95% CI: 0.98–3.14, P = 0.000), with no significant heterogeneity observed (I²=0.0%, P [heterogeneity] = 0.701) (Supplementary Table S4). Sensitivity analysis and evaluation for publication bias Cumulative risk of developing Colorectal cancer in IBD patients exposed to thiopurines or anti-TNF-α Four studies, including 23,671 patients with IBD, contributed data on the adjusted risk of malignancies associated with thiopurine exposure. The pooled adjusted hazard ratio for malignancies in thiopurine-exposed IBD patients was 0.56 (95% CI: 0.32–0.99; P = 0.234) (Fig. 5 ). Although this association did not reach statistical significance, the point estimate suggests a potential protective effect of thiopurines against malignancies in IBD patients. Due to substantial heterogeneity across the studies (P [heterogeneity] <0.001, I² = 87.3%), a random-effects model was utilized. In the CD subgroup, two studies indicated a significant HR of 2.55 for colorectal cancer (95% CI: 1.67–3.88, P < 0.001) via a fixed-effects model, with no significant heterogeneity (I²= 0.0%, P [heterogeneity] = 0.704). In the UC subgroup, two studies found a nonsignificant HR of 1.19 (95% CI: 0.45–3.19, P = 0.726), also with no heterogeneity (I²= 0.0%, P [heterogeneity] = 0.011) (Supplementary Table S5). Sensitivity analysis and evaluation for publication bias Cumulative risk of developing other cancers in IBD patients exposed to thiopurines or anti-TNF-α When it comes to the cumulative risk of developing urinary tract cancer in IBD patients exposed to thiopurines or anti-TNF-α, evidence from an isolated study indicates a cumulative risk of urinary tract cancers of 82% (HR = 2.82, 95% CI: 1.04–7.68) among thiopurine-exposed patients. For hematologic cancer, one study indicated a cumulative risk of 2.41 (95% CI: 1.04–4.76) for thiopurine-exposed patients. However, due to the limited data available, further analysis of these associations is not feasible. Discussion Principal findings Our meta-analysis of population-based studies reveals several key findings regarding the risk of malignancies in IBD patients treated with thiopurines or anti-TNF-α therapy. We found a significantly increased risk of overall malignancies in patients exposed to thiopurines, with a pooled adjusted HR of 1.53 (95% CI:1.06–2.2; P = 0.022). This risk appeared to be consistent across studies, as evidenced by the stability of results in sensitivity analyses where the exclusion of any single study did not affect the overall conclusion. Furthermore, thiopurine use was associated with a higher risk of melanoma (HR = 2.7, 95% CI: 1.91–3.83) and lymphoma (HR = 1.74, 95% CI: 1.21–2.5). However, a reduced risk of colorectal cancer was observed in thiopurine-exposed patients (HR = 0.56, 95% CI: 0.32–0.99). For other cancers, such as urinary tract and hematologic cancers, the evidence was limited but suggested potential associations. Effects of Thiopurine and Anti-TNF-α Therapy on Cancer Risk Our analysis shows how thiopurine or anti-TNF-α exposure affects cancer risk in IBD patients. Thiopurines, known for their immunosuppressive effects, are linked to a higher risk of overall malignancies, melanoma, and lymphoma, which is consistent with previous studies 25 , 49 , 11 . Notably, our meta-analysis found no significant association between thiopurine use and colorectal cancer (CRC) risk in IBD patients, which contrasts with the well-established link between chronic inflammation and CRC 50 . While some studies propose that thiopurines’ anti-inflammatory properties may attenuate inflammation-driven carcinogenesis 29 , 41 , 43 , our null association suggests alternative explanations. A key mechanistic hypothesis is surveillance bias. Thiopurine-treated patients often undergo intensified gastroenterological monitoring due to their perceived higher risk of neoplasia—a consequence of both prolonged immunosuppression and existing clinical guidelines recommending enhanced surveillance for immunomodulator users 51 , 52 . Thiopurines, while effective for treating IBD, may theoretically impair immune-mediated tumor surveillance, prompting stricter colonoscopy protocols 53 – 55 . This could lead to earlier detection and resection of precancerous lesions (e.g., dysplasia via EMR), which may artificially reduce CRC incidence in observational studies 56 . Our meta-analysis might not have fully accounted for such surveillance heterogeneity across studies. For instance, retrospective cohorts often lack detailed data on endoscopic surveillance frequency or technique, potentially leading to residual confounding. Thus, the null association between thiopurines and CRC could reflect a balance between their modest chemoprotective anti-inflammatory effects and immunosuppression-related risks, further diluted by surveillance bias. Anti-tumor necrosis factor (TNF)-α agents, while effective in controlling inflammation, may also increase the risk of cancer, especially when used in combination with thiopurines. The combination of these therapies may enhance immunosuppression and increase susceptibility to cancer development 30 . However, the evidence for certain cancers, such as urinary tract and hematologic malignancies, is limited and requires further investigation 27 , 34 . These findings emphasize the need for a balanced approach in IBD treatment, considering both the therapeutic benefits and potential oncological risks of these medications. Comparison with Other Reviews Compared to other reviews in the field, our meta-analysis provides a more comprehensive and updated assessment of cancer risks associated with thiopurines and anti-TNF-α therapies in IBD patients. Previous reviews have highlighted the elevated risks of non-melanoma skin cancer and lymphoma with thiopurine use, which is consistent with our findings. However, our study further elucidates the potential protective effect of thiopurines on colorectal cancer risk, a finding that has not been thoroughly explored in prior reviews. Additionally, by incorporating recent population-based studies from diverse regions, our analysis offers a broader perspective on the cancer risk landscape in IBD patients across different populations. This strengthens the generalizability of our results and provides more robust evidence for clinicians to consider in treatment decision-making. Recommendations for Research and Clinical Practice For future research, there is a compelling need for large-scale, long-term studies to further investigate the dose-response relationships and the impact of treatment duration on cancer risk 57 . Additionally, more research is warranted to explore the cancer risks associated with newer biologic agents and combination therapies, as well as to clarify the underlying mechanisms linking these therapies to specific malignancies. In terms of clinical practice, clinicians should carefully weigh the benefits and risks of thiopurines and anti-TNF-alpha therapies when managing IBD patients 48 . For patients on these therapies, especially those with prolonged exposure, enhanced cancer surveillance and prevention strategies should be considered. This may include regular skin examinations for non-melanoma skin cancer, monitoring for signs of lymphoma, and appropriate colorectal cancer screening protocols. Furthermore, patient education on cancer prevention and early detection is crucial to improve outcomes in this high-risk population. Limitations of the Current Analysis To the best of our knowledge, this is the first comprehensive meta-analysis to systematically assess the cancer risks associated with thiopurine and anti-TNF-α therapies in IBD patients, utilizing population-based studies; however, several limitations necessitate cautious interpretation of the findings. The inherent observational nature of the included studies restricts the ability to establish definitive causal relationships between these therapies and cancer outcomes, as residual confounding by unmeasured or incompletely adjusted factors—such as disease severity, lifestyle variables (e.g., smoking), and comorbid conditions—may persist despite statistical adjustments, potentially biasing the risk estimates. Additionally, significant heterogeneity across studies introduces potential biases, encompassing variability in study designs (case-control vs. cohort), sample sizes, and operational definitions of IBD diagnoses, while cancer ascertainment methods also differed substantially: whereas some studies validated diagnoses through clinical or histopathological records, others relied solely on administrative coding systems (e.g., ICD-8/9/10), any of these variations could potentially have biased the results.. Furthermore, limited statistical power emerged in subgroup analyses of specific malignancies, as for rare cancers such as urinary tract and hematologic malignancies, the small number of contributing studies reduced precision, potentially obscuring true associations or inflating type II error rates. Lastly, clinical heterogeneity in treatment protocols poses challenges to generalizability, as variations in thiopurine dosing strategies, anti-TNF-α treatment durations, and combination therapy regimens across studies complicate efforts to disentangle dose-dependent or duration-dependent effects, and consequently, our findings may not be uniformly applicable to all IBD populations receiving these therapies. Conclusion In conclusion, our meta-analysis provides valuable insights into the cancer risks associated with thiopurine and anti-TNF-α therapies in IBD patients. While these therapies are effective in controlling inflammation and improving quality of life, they may increase the risk of certain malignancies. Clinicians should consider these risks when developing treatment plans for IBD patients and implement appropriate cancer surveillance strategies. Future research should focus on clarifying the mechanisms underlying these risks and identifying strategies to mitigate them. Declarations We declare that the research was conducted in the absence of any commercial or financial relationships. Availability of data and materials The original contributions presented in the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding author/s. Competing interests All authors certify that they have no affiliations with or involvement in any organization or entity with any financial interest or non-financial interest in the subject matter or materials discussed in this manuscript. Funding NA. Authors’ Contributions Zhenzhi Wang, Yukun Chen developed the protocol, participated in the literature search, extracted data, and drafted the manuscript; Xinyu Li, Li Lin, Bozhu Chen was responsible for the analysis and interpretation of the data; Min Chen, Hui Zheng was the critical revision of the manuscript for important intellectual content. All authors contributed to the article and approved the submitted version. Compliance with Ethical Standards Not applicable Ethical approval Not applicable Informed consent Not applicable Acknowledgments None. References Adolph, T. E. et al. The metabolic nature of inflammatory bowel diseases. Nat Rev Gastroenterol Hepatol 19, 753–767 (2022). N, K., P, J., A, S., P, S. & N, T. Advances in the colon-targeted chitosan based multiunit drug delivery systems for the treatment of inflammatory bowel disease. Carbohydrate polymers 288, (2022). Shelton, E. et al. Cancer Recurrence Following Immune-suppressive Therapies in Patients With Immune-mediated Diseases: a Systematic Review and Meta-analysis. Gastroenterology 151, 97 (2016). Kim, D. H. & Cheon, J. H. Pathogenesis of Inflammatory Bowel Disease and Recent Advances in Biologic Therapies. Immune Network 17, 25 (2017). Axelrad, J. E., Lichtiger, S. & Yajnik, V. Inflammatory bowel disease and cancer: The role of inflammation, immunosuppression, and cancer treatment. World J Gastroenterol 22, 4794–4801 (2016). Thomsen, S. B. et al. Impact of thiopurine discontinuation at anti-tumour necrosis factor initiation in inflammatory bowel disease treatment: a nationwide Danish cohort study. Aliment Pharmacol Ther 55, 1128–1138 (2022). Thiopurines and the Risk of Cancer in Patients With Inflammatory Bowel Disease and Reference Individuals Without Inflammatory Bowel Disease - A Danish Nationwide Cohort Study (1996–2018) - PubMed. https://pubmed.ncbi.nlm.nih.gov/39209201/ . Narous, M., Nugent, Z., Singh, H. & Bernstein, C. N. Risks of Melanoma and Nonmelanoma Skin Cancers Pre- and Post-Inflammatory Bowel Disease Diagnosis. Inflamm Bowel Dis 29, 1047–1056 (2023). Mansilla-Polo, M. & Morgado-Carrasco, D. Biologics Versus JAK Inhibitors. Part I: Cancer Risk. A Narrative Review. Dermatology and Therapy 14, 1389 (2024). K, H. et al. Tumor necrosis factor α inhibitor therapy and cancer risk in chronic immune-mediated diseases. Arthritis and rheumatism 65, (2013). Narous, M., Nugent, Z., Singh, H. & Bernstein, C. N. Risks of Melanoma and Nonmelanoma Skin Cancers Pre- and Post-Inflammatory Bowel Disease Diagnosis. Inflamm Bowel Dis 29, 1047–1056 (2023). Meyer, A. et al. Risks of 75 major congenital malformations after in utero exposure to thiopurines and anti-TNF for maternal inflammatory bowel disease. Clin Gastroenterol Hepatol S1542-3565(25)00147–8 (2025) doi: 10.1016/j.cgh.2025.01.008 . Lo, B., Zhao, M., Vind, I. & Burisch, J. The Risk of Extraintestinal Cancer in Inflammatory Bowel Disease: A Systematic Review and Meta-analysis of Population-based Cohort Studies. Clin Gastroenterol Hepatol 19, 1117–1138.e19 (2021). Liberati, A. et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration. BMJ 339, b2700 (2009). Risk of malignancy in patients with inflammatory bowel disease: A population-based cohort study from China - PubMed. https://pubmed.ncbi.nlm.nih.gov/35037241/ . Ariyaratnam, J. & Subramanian, V. Association between thiopurine use and nonmelanoma skin cancers in patients with inflammatory bowel disease: a meta-analysis. Am J Gastroenterol 109, 163–169 (2014). N, K., Am, A., Gr, L., Ev, L. & La, B. Risk of lymphoma in patients with ulcerative colitis treated with thiopurines: a nationwide retrospective cohort study. Gastroenterology 145, (2013). 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 - PubMed. https://pubmed.ncbi.nlm.nih.gov/21793904/ . J, C. et al. Increased non-melanoma skin cancer risk in young patients with inflammatory bowel disease on immunomodulatory therapy: a retrospective single-centre cohort study. Journal of the European Academy of Dermatology and Venereology : JEADV 31, (2017). Am, A., Rm, A., Ev, L., Gr, L. & N, K. Risk of melanoma and non-melanoma skin cancer in ulcerative colitis patients treated with thiopurines: a nationwide retrospective cohort. The American journal of gastroenterology 109, (2014). Scott, F. I. et al. Risk of Nonmelanoma Skin Cancer Associated With the Use of Immunosuppressant and Biologic Agents in Patients With a History of Autoimmune Disease and Nonmelanoma Skin Cancer. JAMA Dermatol 152, 164–172 (2016). Kobayashi, T., Udagawa, E. & Hibi, T. Lack of Increased Risk of Lymphoma with Thiopurine Therapy Regardless of Dose and Duration of Treatment in Japanese Patients with Inflammatory Bowel Diseases. Digestion 103, 169–173 (2022). Tassone, D. et al. Risk factors for malignancy and serious infection in patients with inflammatory bowel disease: a retrospective analysis. Intern Med J 54, 446–454 (2024). Mortality Associated With Development of Squamous Cell Cancer in Patients With Inflammatory Bowel Diseases Receiving Treatment With Thiopurines - PubMed. https://pubmed.ncbi.nlm.nih.gov/30853615/ . Beigel, F. et al. Risk of malignancies in patients with inflammatory bowel disease treated with thiopurines or anti-TNF alpha antibodies. Pharmacoepidemiol Drug Saf 23, 735–744 (2014). Lack of Increased Risk of Lymphoma by Thiopurines or Biologics in Japanese Patients with Inflammatory Bowel Disease: A Large-Scale Administrative Database Analysis - PubMed. https://pubmed.ncbi.nlm.nih.gov/31867632/ . Bourrier, A. et al. Excess risk of urinary tract cancers in patients receiving thiopurines for inflammatory bowel disease: a prospective observational cohort study. Aliment Pharmacol Ther 43, 252–261 (2016). Increased risk for nonmelanoma skin cancers in patients who receive thiopurines for inflammatory bowel disease - PubMed. https://pubmed.ncbi.nlm.nih.gov/21708105/ . Beaugerie, L. et al. Risk of colorectal high-grade dysplasia and cancer in a prospective observational cohort of patients with inflammatory bowel disease. Gastroenterology 145, 166–175.e8 (2013). Thiopurines and the Risk of Cancer in Patients With Inflammatory Bowel Disease and Reference Individuals Without Inflammatory Bowel Disease - A Danish Nationwide Cohort Study (1996–2018) - PubMed. https://pubmed.ncbi.nlm.nih.gov/39209201/ . Lemaitre, M. et al. Association Between Use of Thiopurines or Tumor Necrosis Factor Antagonists Alone or in Combination and Risk of Lymphoma in Patients With Inflammatory Bowel Disease. JAMA 318, 1679–1686 (2017). Singh, H., Nugent, Z., Demers, A. A. & Bernstein, C. N. Increased risk of nonmelanoma skin cancers among individuals with inflammatory bowel disease. Gastroenterology 141, 1612–1620 (2011). Role of thiopurine and anti-TNF therapy in lymphoma in inflammatory bowel disease - PubMed. https://pubmed.ncbi.nlm.nih.gov/22031357/ . van den Heuvel, T. R. A. et al. Inflammatory bowel disease, cancer and medication: Cancer risk in the Dutch population-based IBDSL cohort. Int J Cancer 139, 1270–1280 (2016). Cancer in Elderly Onset Inflammatory Bowel Disease: A Population-Based Study - PubMed. https://pubmed.ncbi.nlm.nih.gov/27481308/ . Jess, T., Horváth-Puhó, E., Fallingborg, J., Rasmussen, H. H. & Jacobsen, B. A. Cancer risk in inflammatory bowel disease according to patient phenotype and treatment: a Danish population-based cohort study. Am J Gastroenterol 108, 1869–1876 (2013). C, R. et al. Inflammatory bowel disease and cervical neoplasia: a population-based nationwide cohort study. Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association 13, (2015). The risk of lymphoma and immunomodulators in patients with inflammatory bowel diseases: results from a population-based cohort in Eastern Europe - PubMed. https://pubmed.ncbi.nlm.nih.gov/22766526/ . Risk of malignant lymphomas in patients with inflammatory bowel disease: a population-based cohort study - PubMed. https://pubmed.ncbi.nlm.nih.gov/37142293/ . Kopylov, U. et al. Risk of Lymphoma, Colorectal and Skin Cancer in Patients with IBD Treated with Immunomodulators and Biologics: A Quebec Claims Database Study. Inflamm Bowel Dis 21, 1847–1853 (2015). Inflammation and disease duration have a cumulative effect on the risk of dysplasia and carcinoma in IBD: a case-control observational study based on registry data - PubMed. https://pubmed.ncbi.nlm.nih.gov/23797639/ . Risk and clinical characteristics of lymphoma in Korean patients with inflammatory bowel diseases: a multicenter study - PubMed. https://pubmed.ncbi.nlm.nih.gov/24705089/ . J, G. et al. Thiopurine Therapy Reduces the Incidence of Colorectal Neoplasia in Patients with Ulcerative Colitis. Data from the ENEIDA Registry. Journal of Crohn’s & colitis 9, (2015). Risk of malignancies in patients with inflammatory bowel disease who used thiopurines as compared with other indications: a territory-wide study - PubMed. https://pubmed.ncbi.nlm.nih.gov/33281936/ . Risk of malignant lymphoma in patients with inflammatory bowel diseases: a Dutch nationwide study - PubMed. https://pubmed.ncbi.nlm.nih.gov/21830262/ . Risk of melanoma and nonmelanoma skin cancer among patients with inflammatory bowel disease - PubMed. https://pubmed.ncbi.nlm.nih.gov/22584081/ . Md, L. et al. Increased risk for non-melanoma skin cancer in patients with inflammatory bowel disease. Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association 8, (2010). Zheng, K. Y. C. et al. Risk of malignancies in patients with inflammatory bowel disease who used thiopurines as compared with other indications: a territory-wide study. Therap Adv Gastroenterol 13, 1756284820967275 (2020). Chupin, A. et al. Systematic review with meta-analysis: comparative risk of lymphoma with anti-tumour necrosis factor agents and/or thiopurines in patients with inflammatory bowel disease. Aliment Pharmacol Ther 52, 1289–1297 (2020). Shah, S. C. & Itzkowitz, S. H. Colorectal Cancer in Inflammatory Bowel Disease: Mechanisms and Management. Gastroenterology 162, 715–730.e3 (2022). Singh, A. et al. Use of thiopurines in inflammatory bowel disease: an update. Intest Res 20, 11–30 (2022). Use of thiopurines in inflammatory bowel disease: Safety issues - PubMed. https://pubmed.ncbi.nlm.nih.gov/24868487/ . Thiopurine use associated with reduced B and natural killer cells in inflammatory bowel disease - PubMed. https://pubmed.ncbi.nlm.nih.gov/28566883/ . Thiopurines and inflammatory bowel disease: Current evidence and a historical perspective - PubMed. https://pubmed.ncbi.nlm.nih.gov/28028358/ . Karran, P. & Attard, N. Thiopurines in current medical practice: molecular mechanisms and contributions to therapy-related cancer. Nat Rev Cancer 8, 24–36 (2008). Chapman, C. G. & Rubin, D. T. The potential for medical therapy to reduce the risk of colorectal cancer and optimize surveillance in inflammatory bowel disease. Gastrointest Endosc Clin N Am 24, 353–365 (2014). Singh, A. et al. Use of thiopurines in inflammatory bowel disease: an update. Intest Res 20, 11–30 (2022). Additional Declarations No competing interests reported. Supplementary Files SupplementaryTables.docx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6904749","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":474539630,"identity":"793d94b3-40be-4215-8c77-babf9141bc63","order_by":0,"name":"Zhenzhi Wang","email":"","orcid":"","institution":"Hospital of Chengdu University of Traditional Chinese Medicine","correspondingAuthor":false,"prefix":"","firstName":"Zhenzhi","middleName":"","lastName":"Wang","suffix":""},{"id":474539631,"identity":"f3b1923b-a56f-4f73-8476-fcf4488f22ce","order_by":1,"name":"Yukun Chen","email":"","orcid":"","institution":"Beijing University of Chinese 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melanoma\u003c/p\u003e","description":"","filename":"Fig3.png","url":"https://assets-eu.researchsquare.com/files/rs-6904749/v1/dffd5925c3ba12565eac4267.png"},{"id":85390647,"identity":"7a580066-25d0-448e-ac0c-7288a6c31351","added_by":"auto","created_at":"2025-06-25 10:24:50","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":1602269,"visible":true,"origin":"","legend":"\u003cp\u003eForest plot and Sensitivity analysis of the association between IBD patients exposed to thiopurines or anti-TNF-α and risk of Lymphoma\u003c/p\u003e","description":"","filename":"Fig4.png","url":"https://assets-eu.researchsquare.com/files/rs-6904749/v1/8869dc70cb8c9b452175b901.png"},{"id":85390654,"identity":"d3d22efb-5bf2-4407-b23e-b37dda7d38a5","added_by":"auto","created_at":"2025-06-25 10:24:50","extension":"png","order_by":5,"title":"Figure 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10:24:49","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":29303,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryTables.docx","url":"https://assets-eu.researchsquare.com/files/rs-6904749/v1/eae795b0bbe737d2741a392c.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Cancer Risk in IBD Patients Treated with Thiopurines or Anti-TNF-α Therapy: A Meta- analysis of Population-Based Studies","fulltext":[{"header":"Introduction","content":"\u003cp\u003eInflammatory bowel disease (IBD), encompassing Crohn\u0026rsquo;s disease (CD) and ulcerative colitis (UC), is a chronic immune-mediated disorder characterized by relapsing gastrointestinal inflammation\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e. Globally, IBD affects approximately 10\u0026nbsp;million individuals, with rising incidence rates in developing nations\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e,\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e. While genetic predisposition, dysbiosis, and environmental triggers contribute to pathogenesis, persistent immune dysregulation drives mucosal damage and complications such as strictures, fistulae, and colorectal cancer\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e,\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e. Current therapies, including thiopurines (azathioprine, 6-mercaptopurine) and anti-tumor necrosis factor-alpha (anti-TNF-α) agents, aim to control inflammation and improve quality of life. However, their immunosuppressive mechanisms raise concerns about long-term cancer risks\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e,\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e,\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eThiopurines inhibit lymphocyte proliferation by disrupting DNA synthesis, while anti-TNF-α agents neutralize pro-inflammatory cytokines. Although effective, these therapies are associated with dose-dependent and duration-dependent risks of malignancies. Thiopurines, for instance, increase susceptibility to non-melanoma skin cancers (NMSC), lymphomas, and hepatosplenic T-cell lymphoma (HSCTL), particularly in combination with anti-TNF-α\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e,\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e,\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e. Mechanistically, thiopurine metabolites induce DNA damage, impair immune surveillance, and reactivate oncogenic viruses like Epstein-Barr virus (EBV)\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e. Anti-TNF-α monotherapy has a more debated carcinogenic profile, though synergistic risks emerge when combined with thiopurines\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e,\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e,\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e. For example, a meta-analysis reported a 3.7-fold higher lymphoma risk with combination therapy compared to monotherapy\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eExisting evidence on cancer risks remains heterogeneous. Observational studies suggest thiopurines elevate NMSC incidence (adjusted hazard ratio [aHR] 1.3\u0026ndash;1.7)\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e,\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e, while anti-TNF-α alone shows no significant overall cancer risk\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e,\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e. However, specific malignancies\u0026mdash;such as colorectal cancer in UC or hepatobiliary cancers in primary sclerosing cholangitis (PSC)\u0026mdash;may be influenced by disease-specific inflammation rather than therapy\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e,\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e. Notably, population-based cohort studies in China and Denmark highlight elevated standardized incidence ratios for gastrointestinal, thyroid, and hematologic cancers in IBD patients, independent of treatment\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e,\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e. This meta-analysis has combined data from recent population-based studies to assess the cancer risks linked to thiopurines and anti-TNF-α treatments in IBD patients. The analysis aims to offer practical, stratified risk assessments to help guide treatment decisions for clinicians and patients.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eThis systematic review is presented following the guidelines set forth by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)\u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eSearch Strategy\u003c/h2\u003e \u003cp\u003eWe searched multiple electronic databases, including PubMed, Embase, and Web of Science. The search terms used were as follows: (Thiopurine, Azathioprine, Mercaptopurine, Thioguanine, Anti-TNF-α, Tumor Necrosis Factor-alpha), (Inflammatory Bowel Disease, IBD, Crohn\u0026rsquo;s Disease, Ulcerative Colitis), and (Cancer, Malignancy, Neoplasm, Lymphoma, Colorectal Cancer, Skin Cancer, Nonmelanoma Skin Cancer). A more detailed list of search terms has been provided in the supplementary table \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e. The search was performed without any limits on publication date or language to maximize the comprehensiveness of the search.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eStudy Selection\u003c/h3\u003e\n\u003cp\u003eStudies were included if they were population-based cohort studies focusing on patients with IBD who were treated with thiopurines (azathioprine, 6-mercaptopurine) or anti-tumor necrosis factor-alpha (anti-TNF-α) agents, and provided hazard ratios (HRs) with 95% confidence intervals (CIs) comparing cancer risk in exposed versus non-exposed groups, such as non-exposed IBD patients, the general population, or 5-ASA users. Studies were also expected to report detailed patient demographics, IBD subtype, disease duration, and other key covariates relevant to cancer risk.\u003c/p\u003e \u003cp\u003eExclusion criteria included non-population-based cohort studies, studies without standardized cancer outcome assessments or insufficient data for HR calculation, and those that did not specifically report on the cancer risks of interest, such as melanoma, lymphoma, or colorectal cancer. We excluded studies involving patients with pre-existing malignancies or immunodeficiency disorders unrelated to IBD, which might confound the relationship between thiopurine/anti-TNF-α use and cancer risk. Additionally, case reports, case series, narrative reviews without comparative data, and studies that combined thiopurines or anti-TNF-α with other non-traditional or experimental treatments in a way that made it impossible to isolate their effects were excluded.\u003c/p\u003e\n\u003ch3\u003eData extraction\u003c/h3\u003e\n\u003cp\u003eData extraction was performed independently by two researchers for all included studies. Any discrepancies were resolved through discussion or by consulting a third expert. Microsoft Excel was utilized with pre-designed templates to streamline the process. Extracted data included study characteristics such as first author details, publication year, and study duration, as well as exposure definitions, including specific thiopurine and anti-TNF-α agents and their dosages. Outcomes data focused on cancer incidence, with variables related to the association between these therapies and malignancies also extracted.\u003c/p\u003e\n\u003ch3\u003eQuality Assessment\u003c/h3\u003e\n\u003cp\u003eThe quality of the included studies was evaluated by two authors using the Newcastle-Ottawa Scale (NOS) specifically designed for assessing the quality of non-randomized studies in meta-analyses. This scale consists of eight items, addressing three broad perspectives: the selection of study groups, the comparability of the groups, and the assessment of outcomes. Each item is scored with a maximum of one star, except for the comparability item, which can yield a maximum of two stars. The total score ranges from zero to nine, with higher scores indicating better quality. Studies scoring seven or above are considered high quality, those scoring four to six are regarded as moderate quality, and studies with scores below four are deemed low quality. The quality assessment was conducted independently by two researchers. Any disagreements were resolved through discussion, and if necessary, a third researcher made the final judgment.\u003c/p\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eThis study adopted a systematic literature retrieval strategy in line with Cochrane Collaboration standards and pooled hazard ratios (HRs) using both the DerSimonian-Laird random effects model and the Mantel Haenszel fixed effects model. Model selection depended on heterogeneity assessment. We evaluated between study heterogeneity via Cochran\u0026rsquo;s Q test and I\u0026sup2;statistics, adopting random effects models when significant heterogeneity (I\u0026sup2;\u0026gt;50%) was detected. Sensitivity analyses involved leave-one-out sequential exclusion to gauge each study\u0026rsquo;s impact on pooled estimates and trim-and-fill adjustments to tackle potential publication bias. Funnel plot asymmetry and Egger\u0026rsquo;s linear regression (with a significance threshold of P\u0026thinsp;\u0026lt;\u0026thinsp;0.10) were used in tandem to measure publication bias. Subgroup analyses, which calculated subgroup specific HRs with 95% confidence intervals, were stratified by cancer category (colorectal cancer, lymphoma, non-melanoma skin cancer, and other malignancies). Interaction tests (Wald test) assessed differences between subgroups. All statistical analyses were performed using Stata 17.0.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eLiterature search\u003c/h2\u003e \u003cp\u003eStudies were independently screened and selected by two reviewers based on predefined inclusion and exclusion criteria. Initial searches yielded a total of 6,654 citations. After removing duplicates, 1,573 titles and abstracts were screened, resulting in the exclusion of 1,231 studies that did not meet the inclusion criteria. Full-text reviews were conducted for the remaining 126 articles. Studies were excluded if they were not population-based, lacked data on cancer risk, or evaluated non-traditional thiopurine or anti-TNF-α therapies. Ultimately, 31 studies were included in the final analysis.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eCharacteristics of Selected Studies\u003c/h3\u003e\n\u003cp\u003eThe included studies comprised a diverse collection of 31 investigations examining the association between thiopurines/anti-TNF therapy and cancer risk in patients with IBD. Figure\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e outlines the fate of the selected articles, which feature various study designs including retrospective cohort\u003csup\u003e\u003cspan additionalcitationids=\"CR16 CR17 CR18 CR19 CR20 CR21 CR22 CR23 CR24 CR25\" citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u003c/sup\u003e (n\u0026thinsp;=\u0026thinsp;11), prospective cohort\u003csup\u003e\u003cspan additionalcitationids=\"CR28\" citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u003c/sup\u003e (n\u0026thinsp;=\u0026thinsp;3), cohort\u003csup\u003e\u003cspan additionalcitationids=\"CR31 CR32\" citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e\u003c/sup\u003e (n\u0026thinsp;=\u0026thinsp;4),population-based cohort\u003csup\u003e\u003cspan additionalcitationids=\"CR35 CR36 CR37 CR38\" citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e\u003c/sup\u003e (n\u0026thinsp;=\u0026thinsp;6), case-control\u003csup\u003e\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e,\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e\u003c/sup\u003e (n\u0026thinsp;=\u0026thinsp;2), and multicenter studies\u003csup\u003e\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e,\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e\u003c/sup\u003e (n\u0026thinsp;=\u0026thinsp;2) and others \u003csup\u003e44,45\u003c/sup\u003e(n\u0026thinsp;=\u0026thinsp;2), conducted across multiple countries, with the United States \u003csup\u003e17,20,21,24,28,33,46\u003c/sup\u003e(n\u0026thinsp;=\u0026thinsp;7) and France\u003csup\u003e\u003cspan additionalcitationids=\"CR28\" citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e,\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e,\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e\u003c/sup\u003e (n\u0026thinsp;=\u0026thinsp;5) being the most represented regions. These studies encompassed a wide range of sample sizes, from smaller cohorts like Florian Beigel \u003csup\u003e\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u003c/sup\u003e(2014) with 666 participants to large-scale investigations such as Jingru Yu\u003csup\u003e\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e\u003c/sup\u003e (2023) involving 131,492 patients, with median follow-up durations spanning 3 to 14.5 years and study populations predominantly consisting of adults aged 31\u0026ndash;68 years. The exposures of interest primarily included thiopurines (azathioprine, 6-mercaptopurine) and anti-TNF agents (infliximab, adalimumab), which were compared against non-exposed IBD patients, the general population, or 5-ASA users in various studies. The most frequently reported outcomes were lymphoma\u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e,\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e,\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e,\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e,\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e,\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e,\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e\u003c/sup\u003e, non-melanoma skin cancer\u003csup\u003e\u003cspan additionalcitationids=\"CR19\" citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e,\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e,\u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e,\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e\u003c/sup\u003e, and colorectal cancer\u003csup\u003e\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e,\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e,\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e,\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e\u003c/sup\u003e, with analyses consistently adjusted for key covariates including age, sex, IBD subtype, and disease duration. Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e presents the included studies along with their characteristics. The quality of included studies was assessed using the Newcastle-Ottawa Scale (NOS), with only high-quality studies (NOS score\u0026thinsp;\u0026ge;\u0026thinsp;6) included. The study selection process is outlined in a PRISMA flow diagram provided in the supplementary material. Supplementary Table S2 shows the quality scores of these studies based on the Newcastle Ottawa scale.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eMain characteristics of the included studies\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"15\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c11\" colnum=\"11\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c12\" colnum=\"12\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c13\" colnum=\"13\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c14\" colnum=\"14\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c15\" colnum=\"15\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStudy, year\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDesign\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCountry\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eSources of participants\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNo. (M/F)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eMean/Median age years\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003ethiopurines or anti-TNF alpha antibodies description\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003eReference category definition\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c9\"\u003e \u003cp\u003eExposure duration(mean, years)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c10\"\u003e \u003cp\u003eFollow up (CP/control)(years)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c11\"\u003e \u003cp\u003eDiagnosis of Cancer\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c12\"\u003e \u003cp\u003eTumor type\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c13\"\u003e \u003cp\u003eHR\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c14\"\u003e \u003cp\u003e95%LL\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c15\"\u003e \u003cp\u003e95%UL\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eBeigel\u003c/b\u003e\u003csup\u003e\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e ,\u003cb\u003e2014\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRetrospective cohort\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eGermany\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eUniversity Hospital Munich-Grosshadern\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e666 (439/227)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e35 (TP group), 38 (TNF\u0026thinsp;+\u0026thinsp;group)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eTP group: treated with thiopurines alone; TNF\u0026thinsp;+\u0026thinsp;group: exposed to anti-TNF antibodies with no, discontinued, or continued thiopurine therapy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eTP group: never exposed to anti-TNF antibodies; TNF\u0026thinsp;+\u0026thinsp;group: exposed to anti-TNF antibodies\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eTP group: 1.58 (median 19 months), TNF\u0026thinsp;+\u0026thinsp;group: 1 (median 12 months)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eTP group: 1.3 (median 68 weeks), TNF\u0026thinsp;+\u0026thinsp;group: 2.7 (median 140 weeks)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003emalignancies\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e4.15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e1.82\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c15\"\u003e \u003cp\u003e9.44\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eKhan\u003c/b\u003e\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e, \u003cb\u003e2013\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRetrospective cohort\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eUSA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eVeterans Affairs (VA) health care system\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e36,891 (34,424/2,467)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e60 (median)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003ePatients with UC treated with thiopurines (azathioprine and 6-mercaptopurine) or not treated with thiopurines\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003ePatients who were not treated with thiopurines\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.97 (median)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e6.7 (median)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eICD-9 codes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003eLymphoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e4.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e2.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c15\"\u003e \u003cp\u003e6.8\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAbbas\u003c/b\u003e\u003csup\u003e\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e, \u003cb\u003e2014\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRetrospective cohort\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eUSA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eVeterans Affairs (VA) health care system\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e14,527 (13,674/853)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e59 (median)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003ePatients with UC treated with thiopurines (azathioprine and 6-mercaptopurine) or not treated with thiopurines\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003ePatients who were not treated with thiopurines\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e1.6 (median)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e8.1 (median)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eICD-9 codes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003eNon-melanoma skin cancer (NMSC) and Melanoma skin cancer (MSC)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e2.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e1.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c15\"\u003e \u003cp\u003e2.6\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eWewer\u003c/b\u003e\u003csup\u003e\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u003c/sup\u003e, \u003cb\u003e2024\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNationwide Cohort\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eDenmark\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eDanish national registers\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e43,419 (Not specified)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e38.7 (median)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003ePatients with IBD treated with thiopurines (azathioprine and mercaptopurine)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003ePatients not exposed to thiopurines\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e8.2 (median)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eICD-8/10 codes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003emalignancies\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e1.36\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e1.17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c15\"\u003e \u003cp\u003e1.57\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eLemaitre\u003c/b\u003e\u003csup\u003e\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u003c/sup\u003e, \u003cb\u003e2017\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNationwide cohort\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eFrance\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eFrench National Health Insurance databases\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e189,289 (86,506/102,783)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e43 (median)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003ePatients with IBD treated with thiopurines (azathioprine and 6-mercaptopurine) or anti-TNF agents (infliximab and adalimumab)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003ePatients not exposed to thiopurines or anti-TNF agents\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e6.7 (median)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eICD-10 codes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003eLymphoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e2.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e1.96\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c15\"\u003e \u003cp\u003e3.44\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eKhan\u003c/b\u003e\u003csup\u003e\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e, \u003cb\u003e2019\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRetrospective cohort\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eUSA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eVeterans Affairs Healthcare System\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e54,919 (Not specified)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e68.2 (median)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003ePatients with IBD treated with thiopurines (azathioprine and 6-mercaptopurine)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003ePatients treated with 5-ASA only and no prior exposure to thiopurines or anti-TNF agents\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eFrom the time of incident SCC diagnosis until death or last recorded date in the health system\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eICD-9-CM, ICD-10-CM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003eSquamous cell carcinoma (SCC)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c15\"\u003e \u003cp\u003e32.8\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSetshedi\u003c/b\u003e\u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e, \u003cb\u003e2012\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRetrospective cohort\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSouth Africa\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eIBD patients attending a specialist IBD clinic at Groote Schuur Hospital, Cape Town\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1084 (423M/661F)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e34 (median)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eThiopurines (azathioprine and 6-mercaptopurine)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003ePatients who did not receive thiopurines\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e24 (azathioprine), 16 (6-mercaptopurine)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e9.9 (mean follow-up)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eClinical and pathology records\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003eNon-melanoma skin cancer (NMSC)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e5.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e1.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c15\"\u003e \u003cp\u003e22.8\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"4\" rowspan=\"5\"\u003e \u003cp\u003e\u003cb\u003evan den Heuvel\u003c/b\u003e\u003csup\u003e\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e\u003c/sup\u003e, \u003cb\u003e2016\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\" morerows=\"4\" rowspan=\"5\"\u003e \u003cp\u003ePopulation-based cohort\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\" morerows=\"4\" rowspan=\"5\"\u003e \u003cp\u003eNetherlands\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\" morerows=\"4\" rowspan=\"5\"\u003e \u003cp\u003eDutch population-based IBDSL cohort\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\" morerows=\"4\" rowspan=\"5\"\u003e \u003cp\u003eCD: 1,157 (430M/727F), UC: 1,644 (891M/753F)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\" morerows=\"4\" rowspan=\"5\"\u003e \u003cp\u003eMedian age at diagnosis: CD: 34.3 years, UC: 45.0 years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\" morerows=\"4\" rowspan=\"5\"\u003e \u003cp\u003eThiopurines (azathioprine, 6-mercaptopurine, thioguanine) and anti-TNFα antibodies (infliximab, adalimumab, golimumab)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\" morerows=\"4\" rowspan=\"5\"\u003e \u003cp\u003eNo immunosuppression exposure\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\" morerows=\"4\" rowspan=\"5\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\" morerows=\"4\" rowspan=\"5\"\u003e \u003cp\u003eMedian follow-up: CD: 8.1 years, UC: 8.8 years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\" morerows=\"4\" rowspan=\"5\"\u003e \u003cp\u003eICD-O\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003emalignancies\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e1.48\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e1.11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c15\"\u003e \u003cp\u003e1.95\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003eColorectal cancer\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e2.97\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e1.08\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c15\"\u003e \u003cp\u003e6.46\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003ehematologic cancer\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e2.41\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e1.04\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c15\"\u003e \u003cp\u003e4.76\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003eskin cancer (including SCC and BCC)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e1.55\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e1.06\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c15\"\u003e \u003cp\u003e2.19\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003emelanoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003ena\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003ena\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c15\"\u003e \u003cp\u003ena\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eCheddani.\u003c/b\u003e\u003csup\u003e\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e\u003c/sup\u003e, \u003cb\u003e2016\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePopulation-based cohort\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eFrance\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eFrench population-based cohort\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eCD: 370 (38% male/62% female), UC: 474 (62% male/38% female)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eMedian age at diagnosis: CD: 70 years, UC: 69 years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eThiopurines (azathioprine, 6-mercaptopurine, thioguanine) and anti-TNFα antibodies (infliximab, adalimumab)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eNo immunosuppression exposure\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eMedian follow-up: 6 years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003emalignancies\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e0.91\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e0.45\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c15\"\u003e \u003cp\u003e1.82\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eA. Bourrier\u003c/b\u003e\u003csup\u003e\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u003c/sup\u003e, \u003cb\u003e2016\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eProspective observational cohort\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eFrance\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e680 French gastroenterologists\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e19,486 (45.1% male)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e37.0 (median, SD 14.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eThiopurines (azathioprine and mercaptopurine)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eNever received thiopurines\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e35 months (median)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eHistologically proven\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003eUrinary tract cancers\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e2.82\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e1.04\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c15\"\u003e \u003cp\u003e7.68\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eZheng\u003c/b\u003e\u003csup\u003e\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e\u003c/sup\u003e, \u003cb\u003e2020\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTerritory-wide\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eHong Kong, China\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eHospital Authority's Clinical Data Analysis and Reporting System (CDARS)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e7452 (2712 male, 4740 female)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e47.0 (median, IQR 36.0\u0026ndash;57.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eThiopurines (azathioprine and mercaptopurine)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eNon-users of thiopurines in the same diagnosis category\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e6.2 (IQR 2.0\u0026ndash;10.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e11.2 (median)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eBased on pathological confirmation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003eAll malignancies\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e2.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e2.13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c15\"\u003e \u003cp\u003e2.48\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e\u003cb\u003eJess\u003c/b\u003e\u003csup\u003e\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e\u003c/sup\u003e, \u003cb\u003e2013\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003ePopulation-based cohort\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eDenmark\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eNorth Jutland County, Denmark\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eUC: 1437 (730 male, 707 female); CD: 774 (333 male, 441 female)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eUC: 20\u0026ndash;39 years (45%); CD: 20\u0026ndash;39 years (47%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eThiopurines (azathioprine)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eGeneral population\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eUC: 15 years; CD: 14 years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eUC: 22,582 person-years; CD: 11,261 person-years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eICD-10 codes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eAll malignancies\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e1.55\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e1.29\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c15\"\u003e \u003cp\u003e1.84\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e1.12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e0.97\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c15\"\u003e \u003cp\u003e1.28\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePeyrin-Biroulet\u003c/b\u003e\u003csup\u003e\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u003c/sup\u003e, \u003cb\u003e2011\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eProspective observational cohort\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eFrance\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eCESAME study group\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e19,486 (45.1% male)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e37.0 (median, SD 14.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eThiopurines (azathioprine and mercaptopurine)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eNever received thiopurines\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e8.2 (SD 8.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e35 months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eICD-10 codes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003eNonmelanoma skin cancer (NMSC)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e5.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e2.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c15\"\u003e \u003cp\u003e16.4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eClowry\u003c/b\u003e\u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e, \u003cb\u003e2016\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRetrospective single centre cohort\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eIreland\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eSt Vincent\u0026rsquo;s University Hospital, Dublin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2053 (1050 male, 1003 female)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e31.1 (median, range 2.4\u0026ndash;80.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eThiopurines (azathioprine and 6-mercaptopurine) and TNFα inhibitors (adalimumab, infliximab, certolizumab pegol)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eNon-immunosuppressed patients\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e9.8 (range 1 month to 19.6 years)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eOver 20,000 patient-years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eICD-10 codes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003eNon-melanoma skin cancer (NMSC)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e6.45\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e2.69\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c15\"\u003e \u003cp\u003e15.95\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eBeaugerie\u003c/b\u003e\u003csup\u003e\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u003c/sup\u003e, \u003cb\u003e2013\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eProspective observational cohort\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eFrance\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eCESAME study group\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e19,486 (45.1% male)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e40.3 (median, SD 15.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eThiopurines (azathioprine and 6-mercaptopurine)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eNever received thiopurines\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e8.2 (SD 8.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e35 months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eBased on histological confirmation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003eColorectal cancer (CRC)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e0.28\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e0.09\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c15\"\u003e \u003cp\u003e0.89\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eLong\u003c/b\u003e\u003csup\u003e\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e\u003c/sup\u003e, \u003cb\u003e2012\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRetrospective cohort and nested case-control\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eUSA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eLifeLink Health Plan Claims Database (1997\u0026ndash;2009)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eIBD: 108,579 (M/F not specified); non-IBD: 434,233 (M/F not specified)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eIBD: 43 (31\u0026ndash;52); non-IBD: 43 (31\u0026ndash;52)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eThiopurines (e.g., azathioprine, 6-mercaptopurine) and biologic anti-TNF medications (e.g., infliximab, adalimumab, certolizumab pegol)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eNo use of thiopurines or biologic anti-TNF medications\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eIBD cohort: median 24 months (range 1\u0026ndash;138); non-IBD: median 21 months (range 10\u0026ndash;39)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eMelanoma: ICD-9 code 172.0\u0026ndash;172.9 with pathology and excision codes; NMSC: ICD-9 code 173.0\u0026ndash;173.9 or 232.0\u0026ndash;232.9 with procedure codes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003eNonmelanoma Skin Cancer (NMSC)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e1.85\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e1.66\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c15\"\u003e \u003cp\u003e2.05\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e\u003cb\u003eKopylov\u003c/b\u003e\u003csup\u003e\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e\u003c/sup\u003e, \u003cb\u003e2015\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eNested case-control study\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eCanada (Qu\u0026eacute;bec)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eRAMQ/MedECHO database\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e19,582 (M/F not specified)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e42.5\u0026thinsp;\u0026plusmn;\u0026thinsp;19.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eThiopurines (e.g., azathioprine, 6-mercaptopurine) and biologic anti-TNF agents (e.g., infliximab, adalimumab, certolizumab pegol)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eNever use of thiopurines or biologics\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eNMSC: ICD-9/10 codes with procedure codes; Lymphoma, CRC, Melanoma: ICD-9/10 codes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003eNMSC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e1.78\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e1.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c15\"\u003e \u003cp\u003e2.54\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003eLymphoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e0.87\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e0.53\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c15\"\u003e \u003cp\u003e1.41\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e\u003cb\u003eScott\u003c/b\u003e\u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e, \u003cb\u003e2016\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eRetrospective cohort study\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eUSA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eMedicare\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e9460 (M/F not specified)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e42.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003ethiopurines (azathioprine, 6-mercaptopurine), anti-TNF agents (infliximab, adalimumab, certolizumab, golimumab, etanercept)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eNon-use of thiopurines, or anti-TNF agents\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eICD-9/10 codes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eNonmelanoma Skin Cancer (NMSC)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e1.49\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e0.98\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c15\"\u003e \u003cp\u003e2.27\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e1.36\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e0.76\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c15\"\u003e \u003cp\u003e2.44\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eLong, 2010\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRetrospective cohort and nested case-control\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eUSA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ePharMetrics Patient Centric Database\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e53,377 IBD patients (M/F not specified)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e39.1 (CD), 41.5 (UC)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eThiopurines (azathioprine, 6-mercaptopurine) and biologic anti-TNF agents (infliximab, adalimumab)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eNon-use of thiopurines or biologic anti-TNF agents\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eICD-9 codes and CPT-4 codes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003eNonmelanoma Skin Cancer (NMSC)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e4.27\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e3.08\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c15\"\u003e \u003cp\u003e5.92\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eKobayashi\u003c/b\u003e\u003csup\u003e\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u003c/sup\u003e, \u003cb\u003e2019\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRetrospective cohort\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eJapan\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMedical Data Vision (MDV) database\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e75,673 (M/F not specified)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e45.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eThiopurines (azathioprine, 6-mercaptopurine) and biologic anti-TNF agents (infliximab, adalimumab)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eNon-use of thiopurines or biologic anti-TNF agents\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eICD-10 codes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003eNonmelanoma Skin Cancer (NMSC) and Non-Hodgkin Lymphoma (NHL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c15\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSingh\u003c/b\u003e\u003csup\u003e\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e\u003c/sup\u003e, \u003cb\u003e2011\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHistorical cohort study\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCanada\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eManitoba Health administrative databases and Manitoba Cancer Registry\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eIBD: 9618 (45808 M/55188 F)\u0026thinsp;\u0026lt;\u0026thinsp;br\u0026thinsp;\u0026gt;\u0026thinsp;Controls: 91,378 (45808 M/55188 F)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eMedian: 36 (IQR: 25\u0026ndash;50)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eThiopurines (azathioprine/6-mercaptopurine) and anti-TNF alpha antibodies (not analyzed separately)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eNo exposure to immunosuppressant medications or corticosteroids\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eIBD: 11.7 years\u0026thinsp;\u0026lt;\u0026thinsp;br\u0026thinsp;\u0026gt;\u0026thinsp;Controls: 11.5 years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eManitoba Cancer Registry\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003eNMSC (BCC and SCC)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e1.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e1.03\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c15\"\u003e \u003cp\u003e1.4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eKobayashi\u003c/b\u003e\u003csup\u003e\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e, \u003cb\u003e2022\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRetrospective study\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eJapan\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMedical Data Vision (MDV) claims database (17.8\u0026nbsp;million patients; April 2008\u0026ndash;January 2018)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eIBD: 75,673 (F not specified)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eThiopurines (azathioprine or 6-mercaptopurine) and anti-TNF alpha antibodies (infliximab or adalimumab)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eNo prescription of thiopurine or anti-TNF alpha antibodies\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eMDV database\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003eNon-Hodgkin lymphoma (NHL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e1.88\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c15\"\u003e \u003cp\u003e3.46\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eHerrinton\u003c/b\u003e\u003csup\u003e\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e\u003c/sup\u003e, \u003cb\u003e2011\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCohort study\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eUSA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eKaiser Permanente IBD Registry and Kaiser Permanente Cancer Registry (1996\u0026ndash;2009)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eIBD: 16,023 (M: 43, F: 15,980)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eThiopurines (azathioprine and 6-mercaptopurine) and anti-TNF alpha antibodies (infliximab and adalimumab)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eNo prescription or dispensing of thiopurine or anti-TNF alpha antibodies\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eAverage 5.8 years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eKaiser Permanente Cancer Registry\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003eLymphoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e1.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e1.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c15\"\u003e \u003cp\u003e1.7\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eVos\u003c/b\u003e\u003csup\u003e\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e\u003c/sup\u003e, \u003cb\u003e2011\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNationwide study\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNetherlands\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eDutch National Database of PALGA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eIBD: 17,834 (M: 7,850, F: 9,984)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eMedian: 56.5 (21\u0026ndash;79)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eThiopurines (azathioprine and 6-mercaptopurine) and anti-TNF alpha antibodies (not specified)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eNo prescription or use of thiopurine or anti-TNF alpha antibodies\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e8 years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003ePALGA database\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003eLymphoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e1.27\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e0.92\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c15\"\u003e \u003cp\u003e1.68\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eTassone\u003c/b\u003e\u003csup\u003e\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e,\u003cb\u003e2023\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRetrospective analysis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAustralia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eSt Vincent\u0026rsquo;s Hospital Melbourne, single tertiary referral centre\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eIBD: 549 (M: 269, F: 280)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eMedian: 39 (IQR: 29.5\u0026ndash;52)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eThiopurines (azathioprine and 6-mercaptopurine) and anti-TNF alpha antibodies (infliximab and adalimumab)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eNo prescription or use of thiopurine or anti-TNF alpha antibodies\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eMedian 11 years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eElectronic medical records\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003emalignancies\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e1.08\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e1.03\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c15\"\u003e \u003cp\u003e1.13\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePark\u003c/b\u003e\u003csup\u003e\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e\u003c/sup\u003e, \u003cb\u003e2015\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMulticenter study\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eKorea\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eThree tertiary referral centers in Seoul, Korea (Asan Medical Center, Seoul National University Hospital, and Samsung Medical Center)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eIBD: 6585 (M: 3957, F: 2628)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eMedian: 43 (33 to 70)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eThiopurines (azathioprine and 6-mercaptopurine) and anti-TNF alpha antibodies (not specified)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eNo prescription or use of thiopurine or anti-TNF alpha antibodies\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eMedian 5.4 years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eKorea Central Cancer Registry\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003eLymphoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e2.03\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e0.81\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c15\"\u003e \u003cp\u003e4.18\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eGordillo\u003c/b\u003e\u003csup\u003e\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e\u003c/sup\u003e, \u003cb\u003e2015\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMulticenter study\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSpain\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eENEIDA Registry (Spanish nationwide database of IBD patients)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eIBD: 831 (M: 415, F: 416)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eMedian: 59.4 (range: 23\u0026ndash;80)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eThiopurines (azathioprine and 6-mercaptopurine) and anti-TNF alpha antibodies (not specified)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eNo use of thiopurine or anti-TNF alpha antibodies\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e5.6\u0026thinsp;\u0026plusmn;\u0026thinsp;2.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eMedian 14.5 years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eHistological diagnosis reports\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003eColorectal neoplasia (CRC and HGD)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e0.21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e0.06\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c15\"\u003e \u003cp\u003e0.76\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eNieminen\u003c/b\u003e\u003csup\u003e\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e\u003c/sup\u003e, \u003cb\u003e2013\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCase-control\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eFinland\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eHospital patient registry and pathology database\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e183 cases (114 M/69 F); 370 controls (227 M/143 F)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eCases: 44.9 (SD 15.5); Controls: 42.7 (SD 15.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eUse of thiopurines (azathioprine or mercaptopurine)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eNon-use of thiopurines\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eNot explicitly stated\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eCases: 1996\u0026ndash;2008; Controls: matched by diagnosis date\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eHistopathology\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003eColorectal carcinoma (CRC)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e0.09\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e0.02\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c15\"\u003e \u003cp\u003e0.33\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eLakatos\u003c/b\u003e\u003csup\u003e\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e\u003c/sup\u003e, \u003cb\u003e2013\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePopulation-based cohort study\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eHungary\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eVeszpr\u0026eacute;m province database\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eUC: 479/435; CD: 251/255\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eUC: 36.5; CD: 28.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003ese of azathioprine (AZA) and anti-TNF agents (Infliximab)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eNo use of thiopurines or anti-TNFs\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eAZA: 3649 patient-years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e1977\u0026ndash;2010\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eStandardized incidence ratio (SIR)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003eLymphoma (CLL, NHL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e1.37\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e0.44\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c15\"\u003e \u003cp\u003e4.26\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e\u003cb\u003eYu\u003c/b\u003e\u003csup\u003e\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e\u003c/sup\u003e,\u003cb\u003e2023\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003ePopulation-based cohort study\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eNorway and Sweden\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003ePublic hospitals and registries\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e131,492 (67,601 M/63,891 F)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eUse of thiopurines (azathioprine, 6-mercaptopurine) and anti-TNF-α therapy (Infliximab, Adalimumab, Certolizumab)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eNo use of thiopurines or anti-TNF-α therapy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eMedian follow-up: 9.6 years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e1987/1993\u0026ndash;2015/2016\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eICD-9/10 codes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003eNon-Hodgkin\u0026rsquo;s lymphoma (NHL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e1.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e1.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c15\"\u003e \u003cp\u003e1.5\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003eHodgkin\u0026rsquo;s lymphoma (HL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e1.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e1.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c15\"\u003e \u003cp\u003e2.1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eCumulative risk of developing malignancies in IBD patients exposed to thiopurines or anti-TNF-α\u003c/h2\u003e \u003cp\u003eSeven studies with 57,168 patients with IBD provided data on adjusted risks of developing malignancies after exposure to thiopurines. The pooled adjusted hazards ratio of developing malignancies after exposure to thiopurines in patients with IBD was 1.53 (95% CI:1.06\u0026ndash;2.2; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.022) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). A random-effects model was chosen, as the heterogeneity between the studies was high (P \u003csub\u003e[heterogeneity]\u003c/sub\u003e\u0026lt;0.001, I \u003csup\u003e2\u003c/sup\u003e= 97.9% ). For the IBD subtypes, the results were as follows. In CD subgroup analysis, the pooled results showed a HR of CD1.43 (95% CI: 1.25\u0026ndash;1.65), \u003cem\u003eP\u003c/em\u003e\u0026lt;0.001. Heterogeneity was also assessed (I\u0026sup2;=0.0%, P\u003csub\u003e[heterogeneity]\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;0.388). In contrast, the results for UC subgroup showed a HR of 1.08 (95% CI: 0.96\u0026ndash;1.22), \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.216. The heterogeneity was I\u0026sup2;=0.0%, P\u003csub\u003e[heterogeneity]\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;0.821(Supplementary Table S3).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eSensitivity analysis and evaluation for publication bias\u003c/h2\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eCumulative risk of developing melanoma in IBD patients exposed to thiopurines or anti-TNF-α\u003c/h2\u003e \u003cp\u003eEight relevant studies, encompassing 718,472 patients with IBD (IBD), offered data on the adjusted risks of malignancies following thiopurine exposure. The pooled adjusted hazard ratio for malignancy development post-thiopurine exposure in IBD patients was 2.7 (95% CI: 1.91\u0026ndash;3.83; \u003cem\u003eP\u003c/em\u003e\u0026lt;0.001) (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). A random-effects model was selected due to significant heterogeneity among the studies (P \u003csub\u003e[heterogeneity]\u003c/sub\u003e\u0026lt;0.001, I\u0026sup2; = 84.6%).For the IBD subtypes, it should be noted that only one study reported the separate results for UC and CD. The HR for CD was 3.87 (95% CI: 2.88\u0026ndash;5.21). Whereas for UC, the HR was 3.09 (95% CI: 2.10\u0026ndash;4.54).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003eSensitivity analysis and evaluation for publication bias\u003c/h2\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003e\u003cb\u003eCumulative risk of developing Lymphoma in IBD patients exposed to thiopurines or anti-TNF-α\u003c/b\u003e\u003c/h2\u003e \u003cp\u003eA total of nine studies, involving 271,601 IBD patients, provided adjusted risk data for malignancies after thiopurine use. The combined adjusted hazard ratio for malignancies in IBD patients exposed to thiopurines was 1.64 (95% CI: 1.33\u0026ndash;2.02; \u003cem\u003eP\u003c/em\u003e\u0026lt;0.001) (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). Given the high heterogeneity between studies (P \u003csub\u003e[heterogeneity]\u003c/sub\u003e\u0026lt;0.001, I\u0026sup2; = 80.7%), a random-effects model was employed. In CD subgroup analysis, the pooled results revealed a significantly increased HR of 2.00 for Lymphoma (95% CI: 1.18\u0026ndash;3.41, \u003cem\u003eP\u003c/em\u003e\u0026lt;0.05). Heterogeneity assessment indicated no significant heterogeneity (I\u0026sup2;=0.0%, P\u003csub\u003e[heterogeneity]\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;0.312). In contrast, the UC subgroup analysis showed a HR of 1.75 for Lymphoma (95% CI: 0.98\u0026ndash;3.14, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.000), with no significant heterogeneity observed (I\u0026sup2;=0.0%, P\u003csub\u003e[heterogeneity]\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;0.701) (Supplementary Table S4).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec16\" class=\"Section2\"\u003e \u003ch2\u003eSensitivity analysis and evaluation for publication bias\u003c/h2\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec17\" class=\"Section2\"\u003e \u003ch2\u003e\u003cb\u003eCumulative risk of developing Colorectal cancer in IBD patients exposed to thiopurines or anti-TNF-α\u003c/b\u003e\u003c/h2\u003e \u003cp\u003eFour studies, including 23,671 patients with IBD, contributed data on the adjusted risk of malignancies associated with thiopurine exposure. The pooled adjusted hazard ratio for malignancies in thiopurine-exposed IBD patients was 0.56 (95% CI: 0.32\u0026ndash;0.99; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.234) (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e). Although this association did not reach statistical significance, the point estimate suggests a potential protective effect of thiopurines against malignancies in IBD patients. Due to substantial heterogeneity across the studies (P \u003csub\u003e[heterogeneity]\u003c/sub\u003e\u0026lt;0.001, I\u0026sup2; = 87.3%), a random-effects model was utilized. In the CD subgroup, two studies indicated a significant HR of 2.55 for colorectal cancer (95% CI: 1.67\u0026ndash;3.88, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001) via a fixed-effects model, with no significant heterogeneity (I\u0026sup2;= 0.0%, P \u003csub\u003e[heterogeneity]\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;0.704). In the UC subgroup, two studies found a nonsignificant HR of 1.19 (95% CI: 0.45\u0026ndash;3.19, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.726), also with no heterogeneity (I\u0026sup2;= 0.0%, P \u003csub\u003e[heterogeneity]\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;0.011) (Supplementary Table S5).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec18\" class=\"Section2\"\u003e \u003ch2\u003eSensitivity analysis and evaluation for publication bias\u003c/h2\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec19\" class=\"Section2\"\u003e \u003ch2\u003eCumulative risk of developing other cancers in IBD patients exposed to thiopurines or anti-TNF-α\u003c/h2\u003e \u003cp\u003eWhen it comes to the cumulative risk of developing urinary tract cancer in IBD patients exposed to thiopurines or anti-TNF-α, evidence from an isolated study indicates a cumulative risk of urinary tract cancers of 82% (HR\u0026thinsp;=\u0026thinsp;2.82, 95% CI: 1.04\u0026ndash;7.68) among thiopurine-exposed patients. For hematologic cancer, one study indicated a cumulative risk of 2.41 (95% CI: 1.04\u0026ndash;4.76) for thiopurine-exposed patients. However, due to the limited data available, further analysis of these associations is not feasible.\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cdiv id=\"Sec21\" class=\"Section2\"\u003e \u003ch2\u003ePrincipal findings\u003c/h2\u003e \u003cp\u003eOur meta-analysis of population-based studies reveals several key findings regarding the risk of malignancies in IBD patients treated with thiopurines or anti-TNF-α therapy. We found a significantly increased risk of overall malignancies in patients exposed to thiopurines, with a pooled adjusted HR of 1.53 (95% CI:1.06\u0026ndash;2.2; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.022). This risk appeared to be consistent across studies, as evidenced by the stability of results in sensitivity analyses where the exclusion of any single study did not affect the overall conclusion. Furthermore, thiopurine use was associated with a higher risk of melanoma (HR\u0026thinsp;=\u0026thinsp;2.7, 95% CI: 1.91\u0026ndash;3.83) and lymphoma (HR\u0026thinsp;=\u0026thinsp;1.74, 95% CI: 1.21\u0026ndash;2.5). However, a reduced risk of colorectal cancer was observed in thiopurine-exposed patients (HR\u0026thinsp;=\u0026thinsp;0.56, 95% CI: 0.32\u0026ndash;0.99). For other cancers, such as urinary tract and hematologic cancers, the evidence was limited but suggested potential associations.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec22\" class=\"Section2\"\u003e \u003ch2\u003eEffects of Thiopurine and Anti-TNF-α Therapy on Cancer Risk\u003c/h2\u003e \u003cp\u003eOur analysis shows how thiopurine or anti-TNF-α exposure affects cancer risk in IBD patients. Thiopurines, known for their immunosuppressive effects, are linked to a higher risk of overall malignancies, melanoma, and lymphoma, which is consistent with previous studies\u003csup\u003e\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e,\u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e,\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eNotably, our meta-analysis found no significant association between thiopurine use and colorectal cancer (CRC) risk in IBD patients, which contrasts with the well-established link between chronic inflammation and CRC\u003csup\u003e\u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e\u003c/sup\u003e. While some studies propose that thiopurines\u0026rsquo; anti-inflammatory properties may attenuate inflammation-driven carcinogenesis \u003csup\u003e\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e,\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e,\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e\u003c/sup\u003e, our null association suggests alternative explanations. A key mechanistic hypothesis is surveillance bias. Thiopurine-treated patients often undergo intensified gastroenterological monitoring due to their perceived higher risk of neoplasia\u0026mdash;a consequence of both prolonged immunosuppression and existing clinical guidelines recommending enhanced surveillance for immunomodulator users\u003csup\u003e\u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e,\u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e52\u003c/span\u003e\u003c/sup\u003e. Thiopurines, while effective for treating IBD, may theoretically impair immune-mediated tumor surveillance, prompting stricter colonoscopy protocols\u003csup\u003e\u003cspan additionalcitationids=\"CR54\" citationid=\"CR53\" class=\"CitationRef\"\u003e53\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR55\" class=\"CitationRef\"\u003e55\u003c/span\u003e\u003c/sup\u003e. This could lead to earlier detection and resection of precancerous lesions (e.g., dysplasia via EMR), which may artificially reduce CRC incidence in observational studies\u003csup\u003e\u003cspan citationid=\"CR56\" class=\"CitationRef\"\u003e56\u003c/span\u003e\u003c/sup\u003e. Our meta-analysis might not have fully accounted for such surveillance heterogeneity across studies. For instance, retrospective cohorts often lack detailed data on endoscopic surveillance frequency or technique, potentially leading to residual confounding. Thus, the null association between thiopurines and CRC could reflect a balance between their modest chemoprotective anti-inflammatory effects and immunosuppression-related risks, further diluted by surveillance bias. Anti-tumor necrosis factor (TNF)-α agents, while effective in controlling inflammation, may also increase the risk of cancer, especially when used in combination with thiopurines. The combination of these therapies may enhance immunosuppression and increase susceptibility to cancer development \u003csup\u003e\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u003c/sup\u003e. However, the evidence for certain cancers, such as urinary tract and hematologic malignancies, is limited and requires further investigation\u003csup\u003e\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e,\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e\u003c/sup\u003e. These findings emphasize the need for a balanced approach in IBD treatment, considering both the therapeutic benefits and potential oncological risks of these medications.\u003c/p\u003e \u003cdiv id=\"Sec23\" class=\"Section3\"\u003e \u003ch2\u003eComparison with Other Reviews\u003c/h2\u003e \u003cp\u003eCompared to other reviews in the field, our meta-analysis provides a more comprehensive and updated assessment of cancer risks associated with thiopurines and anti-TNF-α therapies in IBD patients. Previous reviews have highlighted the elevated risks of non-melanoma skin cancer and lymphoma with thiopurine use, which is consistent with our findings. However, our study further elucidates the potential protective effect of thiopurines on colorectal cancer risk, a finding that has not been thoroughly explored in prior reviews. Additionally, by incorporating recent population-based studies from diverse regions, our analysis offers a broader perspective on the cancer risk landscape in IBD patients across different populations. This strengthens the generalizability of our results and provides more robust evidence for clinicians to consider in treatment decision-making.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec24\" class=\"Section2\"\u003e \u003ch2\u003eRecommendations for Research and Clinical Practice\u003c/h2\u003e \u003cp\u003eFor future research, there is a compelling need for large-scale, long-term studies to further investigate the dose-response relationships and the impact of treatment duration on cancer risk\u003csup\u003e\u003cspan citationid=\"CR57\" class=\"CitationRef\"\u003e57\u003c/span\u003e\u003c/sup\u003e. Additionally, more research is warranted to explore the cancer risks associated with newer biologic agents and combination therapies, as well as to clarify the underlying mechanisms linking these therapies to specific malignancies. In terms of clinical practice, clinicians should carefully weigh the benefits and risks of thiopurines and anti-TNF-alpha therapies when managing IBD patients\u003csup\u003e\u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e\u003c/sup\u003e. For patients on these therapies, especially those with prolonged exposure, enhanced cancer surveillance and prevention strategies should be considered. This may include regular skin examinations for non-melanoma skin cancer, monitoring for signs of lymphoma, and appropriate colorectal cancer screening protocols. Furthermore, patient education on cancer prevention and early detection is crucial to improve outcomes in this high-risk population.\u003c/p\u003e \u003cdiv id=\"Sec25\" class=\"Section3\"\u003e \u003ch2\u003eLimitations of the Current Analysis\u003c/h2\u003e \u003cp\u003eTo the best of our knowledge, this is the first comprehensive meta-analysis to systematically assess the cancer risks associated with thiopurine and anti-TNF-α therapies in IBD patients, utilizing population-based studies; however, several limitations necessitate cautious interpretation of the findings. The inherent observational nature of the included studies restricts the ability to establish definitive causal relationships between these therapies and cancer outcomes, as residual confounding by unmeasured or incompletely adjusted factors\u0026mdash;such as disease severity, lifestyle variables (e.g., smoking), and comorbid conditions\u0026mdash;may persist despite statistical adjustments, potentially biasing the risk estimates. Additionally, significant heterogeneity across studies introduces potential biases, encompassing variability in study designs (case-control vs. cohort), sample sizes, and operational definitions of IBD diagnoses, while cancer ascertainment methods also differed substantially: whereas some studies validated diagnoses through clinical or histopathological records, others relied solely on administrative coding systems (e.g., ICD-8/9/10), any of these variations could potentially have biased the results.. Furthermore, limited statistical power emerged in subgroup analyses of specific malignancies, as for rare cancers such as urinary tract and hematologic malignancies, the small number of contributing studies reduced precision, potentially obscuring true associations or inflating type II error rates. Lastly, clinical heterogeneity in treatment protocols poses challenges to generalizability, as variations in thiopurine dosing strategies, anti-TNF-α treatment durations, and combination therapy regimens across studies complicate efforts to disentangle dose-dependent or duration-dependent effects, and consequently, our findings may not be uniformly applicable to all IBD populations receiving these therapies.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn conclusion, our meta-analysis provides valuable insights into the cancer risks associated with thiopurine and anti-TNF-α therapies in IBD patients. While these therapies are effective in controlling inflammation and improving quality of life, they may increase the risk of certain malignancies. Clinicians should consider these risks when developing treatment plans for IBD patients and implement appropriate cancer surveillance strategies. Future research should focus on clarifying the mechanisms underlying these risks and identifying strategies to mitigate them.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eWe declare that the research was conducted in the absence of any commercial or financial relationships.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe original contributions presented in the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding author/s.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors certify that they have no affiliations with or involvement in any organization or entity with any financial interest or non-financial interest in the subject matter or materials discussed in this manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNA.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors’ Contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eZhenzhi Wang, Yukun Chen developed the protocol, participated in the literature search, extracted data, and drafted the manuscript; Xinyu Li, Li Lin, Bozhu Chen was responsible for the analysis and interpretation of the data; Min Chen, Hui Zheng was the critical revision of the manuscript for important intellectual content. All authors contributed to the article and approved the submitted version.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompliance with Ethical Standards\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthical approval\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInformed consent\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNone.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eAdolph, T. E. \u003cem\u003eet al.\u003c/em\u003e The metabolic nature of inflammatory bowel diseases. \u003cem\u003eNat Rev Gastroenterol Hepatol\u003c/em\u003e 19, 753\u0026ndash;767 (2022).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eN, K., P, J., A, S., P, S. \u0026amp; N, T. Advances in the colon-targeted chitosan based multiunit drug delivery systems for the treatment of inflammatory bowel disease. \u003cem\u003eCarbohydrate polymers\u003c/em\u003e 288, (2022).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eShelton, E. \u003cem\u003eet al.\u003c/em\u003e Cancer Recurrence Following Immune-suppressive Therapies in Patients With Immune-mediated Diseases: a Systematic Review and Meta-analysis. \u003cem\u003eGastroenterology\u003c/em\u003e 151, 97 (2016).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKim, D. H. \u0026amp; Cheon, J. H. Pathogenesis of Inflammatory Bowel Disease and Recent Advances in Biologic Therapies. \u003cem\u003eImmune Network\u003c/em\u003e 17, 25 (2017).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAxelrad, J. E., Lichtiger, S. \u0026amp; Yajnik, V. Inflammatory bowel disease and cancer: The role of inflammation, immunosuppression, and cancer treatment. \u003cem\u003eWorld J Gastroenterol\u003c/em\u003e 22, 4794\u0026ndash;4801 (2016).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eThomsen, S. B. \u003cem\u003eet al.\u003c/em\u003e Impact of thiopurine discontinuation at anti-tumour necrosis factor initiation in inflammatory bowel disease treatment: a nationwide Danish cohort study. \u003cem\u003eAliment Pharmacol Ther\u003c/em\u003e 55, 1128\u0026ndash;1138 (2022).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eThiopurines and the Risk of Cancer in Patients With Inflammatory Bowel Disease and Reference Individuals Without Inflammatory Bowel Disease - A Danish Nationwide Cohort Study (1996\u0026ndash;2018) - PubMed. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://pubmed.ncbi.nlm.nih.gov/39209201/\u003c/span\u003e\u003cspan address=\"https://pubmed.ncbi.nlm.nih.gov/39209201/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNarous, M., Nugent, Z., Singh, H. \u0026amp; Bernstein, C. N. Risks of Melanoma and Nonmelanoma Skin Cancers Pre- and Post-Inflammatory Bowel Disease Diagnosis. \u003cem\u003eInflamm Bowel Dis\u003c/em\u003e 29, 1047\u0026ndash;1056 (2023).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMansilla-Polo, M. \u0026amp; Morgado-Carrasco, D. Biologics Versus JAK Inhibitors. Part I: Cancer Risk. A Narrative Review. \u003cem\u003eDermatology and Therapy\u003c/em\u003e 14, 1389 (2024).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eK, H. \u003cem\u003eet al.\u003c/em\u003e Tumor necrosis factor α inhibitor therapy and cancer risk in chronic immune-mediated diseases. \u003cem\u003eArthritis and rheumatism\u003c/em\u003e 65, (2013).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNarous, M., Nugent, Z., Singh, H. \u0026amp; Bernstein, C. N. Risks of Melanoma and Nonmelanoma Skin Cancers Pre- and Post-Inflammatory Bowel Disease Diagnosis. \u003cem\u003eInflamm Bowel Dis\u003c/em\u003e 29, 1047\u0026ndash;1056 (2023).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMeyer, A. \u003cem\u003eet al.\u003c/em\u003e Risks of 75 major congenital malformations after in utero exposure to thiopurines and anti-TNF for maternal inflammatory bowel disease. \u003cem\u003eClin Gastroenterol Hepatol\u003c/em\u003e S1542-3565(25)00147\u0026ndash;8 (2025) doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.cgh.2025.01.008\u003c/span\u003e\u003cspan address=\"10.1016/j.cgh.2025.01.008\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLo, B., Zhao, M., Vind, I. \u0026amp; Burisch, J. The Risk of Extraintestinal Cancer in Inflammatory Bowel Disease: A Systematic Review and Meta-analysis of Population-based Cohort Studies. \u003cem\u003eClin Gastroenterol Hepatol\u003c/em\u003e 19, 1117\u0026ndash;1138.e19 (2021).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLiberati, A. \u003cem\u003eet al.\u003c/em\u003e The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration. \u003cem\u003eBMJ\u003c/em\u003e 339, b2700 (2009).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRisk of malignancy in patients with inflammatory bowel disease: A population-based cohort study from China - PubMed. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://pubmed.ncbi.nlm.nih.gov/35037241/\u003c/span\u003e\u003cspan address=\"https://pubmed.ncbi.nlm.nih.gov/35037241/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAriyaratnam, J. \u0026amp; Subramanian, V. Association between thiopurine use and nonmelanoma skin cancers in patients with inflammatory bowel disease: a meta-analysis. \u003cem\u003eAm J Gastroenterol\u003c/em\u003e 109, 163\u0026ndash;169 (2014).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eN, K., Am, A., Gr, L., Ev, L. \u0026amp; La, B. Risk of lymphoma in patients with ulcerative colitis treated with thiopurines: a nationwide retrospective cohort study. \u003cem\u003eGastroenterology\u003c/em\u003e 145, (2013).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eUse 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 - PubMed. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://pubmed.ncbi.nlm.nih.gov/21793904/\u003c/span\u003e\u003cspan address=\"https://pubmed.ncbi.nlm.nih.gov/21793904/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJ, C. \u003cem\u003eet al.\u003c/em\u003e Increased non-melanoma skin cancer risk in young patients with inflammatory bowel disease on immunomodulatory therapy: a retrospective single-centre cohort study. \u003cem\u003eJournal of the European Academy of Dermatology and Venereology : JEADV\u003c/em\u003e 31, (2017).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAm, A., Rm, A., Ev, L., Gr, L. \u0026amp; N, K. Risk of melanoma and non-melanoma skin cancer in ulcerative colitis patients treated with thiopurines: a nationwide retrospective cohort. \u003cem\u003eThe American journal of gastroenterology\u003c/em\u003e 109, (2014).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eScott, F. I. \u003cem\u003eet al.\u003c/em\u003e Risk of Nonmelanoma Skin Cancer Associated With the Use of Immunosuppressant and Biologic Agents in Patients With a History of Autoimmune Disease and Nonmelanoma Skin Cancer. \u003cem\u003eJAMA Dermatol\u003c/em\u003e 152, 164\u0026ndash;172 (2016).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKobayashi, T., Udagawa, E. \u0026amp; Hibi, T. Lack of Increased Risk of Lymphoma with Thiopurine Therapy Regardless of Dose and Duration of Treatment in Japanese Patients with Inflammatory Bowel Diseases. \u003cem\u003eDigestion\u003c/em\u003e 103, 169\u0026ndash;173 (2022).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTassone, D. \u003cem\u003eet al.\u003c/em\u003e Risk factors for malignancy and serious infection in patients with inflammatory bowel disease: a retrospective analysis. \u003cem\u003eIntern Med J\u003c/em\u003e 54, 446\u0026ndash;454 (2024).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMortality Associated With Development of Squamous Cell Cancer in Patients With Inflammatory Bowel Diseases Receiving Treatment With Thiopurines - PubMed. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://pubmed.ncbi.nlm.nih.gov/30853615/\u003c/span\u003e\u003cspan address=\"https://pubmed.ncbi.nlm.nih.gov/30853615/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBeigel, F. \u003cem\u003eet al.\u003c/em\u003e Risk of malignancies in patients with inflammatory bowel disease treated with thiopurines or anti-TNF alpha antibodies. \u003cem\u003ePharmacoepidemiol Drug Saf\u003c/em\u003e 23, 735\u0026ndash;744 (2014).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLack of Increased Risk of Lymphoma by Thiopurines or Biologics in Japanese Patients with Inflammatory Bowel Disease: A Large-Scale Administrative Database Analysis - PubMed. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://pubmed.ncbi.nlm.nih.gov/31867632/\u003c/span\u003e\u003cspan address=\"https://pubmed.ncbi.nlm.nih.gov/31867632/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBourrier, A. \u003cem\u003eet al.\u003c/em\u003e Excess risk of urinary tract cancers in patients receiving thiopurines for inflammatory bowel disease: a prospective observational cohort study. \u003cem\u003eAliment Pharmacol Ther\u003c/em\u003e 43, 252\u0026ndash;261 (2016).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eIncreased risk for nonmelanoma skin cancers in patients who receive thiopurines for inflammatory bowel disease - PubMed. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://pubmed.ncbi.nlm.nih.gov/21708105/\u003c/span\u003e\u003cspan address=\"https://pubmed.ncbi.nlm.nih.gov/21708105/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBeaugerie, L. \u003cem\u003eet al.\u003c/em\u003e Risk of colorectal high-grade dysplasia and cancer in a prospective observational cohort of patients with inflammatory bowel disease. \u003cem\u003eGastroenterology\u003c/em\u003e 145, 166\u0026ndash;175.e8 (2013).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eThiopurines and the Risk of Cancer in Patients With Inflammatory Bowel Disease and Reference Individuals Without Inflammatory Bowel Disease - A Danish Nationwide Cohort Study (1996\u0026ndash;2018) - PubMed. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://pubmed.ncbi.nlm.nih.gov/39209201/\u003c/span\u003e\u003cspan address=\"https://pubmed.ncbi.nlm.nih.gov/39209201/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLemaitre, M. \u003cem\u003eet al.\u003c/em\u003e Association Between Use of Thiopurines or Tumor Necrosis Factor Antagonists Alone or in Combination and Risk of Lymphoma in Patients With Inflammatory Bowel Disease. \u003cem\u003eJAMA\u003c/em\u003e 318, 1679\u0026ndash;1686 (2017).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSingh, H., Nugent, Z., Demers, A. A. \u0026amp; Bernstein, C. N. Increased risk of nonmelanoma skin cancers among individuals with inflammatory bowel disease. \u003cem\u003eGastroenterology\u003c/em\u003e 141, 1612\u0026ndash;1620 (2011).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRole of thiopurine and anti-TNF therapy in lymphoma in inflammatory bowel disease - PubMed. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://pubmed.ncbi.nlm.nih.gov/22031357/\u003c/span\u003e\u003cspan address=\"https://pubmed.ncbi.nlm.nih.gov/22031357/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003evan den Heuvel, T. R. A. \u003cem\u003eet al.\u003c/em\u003e Inflammatory bowel disease, cancer and medication: Cancer risk in the Dutch population-based IBDSL cohort. \u003cem\u003eInt J Cancer\u003c/em\u003e 139, 1270\u0026ndash;1280 (2016).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCancer in Elderly Onset Inflammatory Bowel Disease: A Population-Based Study - PubMed. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://pubmed.ncbi.nlm.nih.gov/27481308/\u003c/span\u003e\u003cspan address=\"https://pubmed.ncbi.nlm.nih.gov/27481308/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJess, T., Horv\u0026aacute;th-Puh\u0026oacute;, E., Fallingborg, J., Rasmussen, H. H. \u0026amp; Jacobsen, B. A. Cancer risk in inflammatory bowel disease according to patient phenotype and treatment: a Danish population-based cohort study. \u003cem\u003eAm J Gastroenterol\u003c/em\u003e 108, 1869\u0026ndash;1876 (2013).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eC, R. \u003cem\u003eet al.\u003c/em\u003e Inflammatory bowel disease and cervical neoplasia: a population-based nationwide cohort study. \u003cem\u003eClinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association\u003c/em\u003e 13, (2015).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eThe risk of lymphoma and immunomodulators in patients with inflammatory bowel diseases: results from a population-based cohort in Eastern Europe - PubMed. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://pubmed.ncbi.nlm.nih.gov/22766526/\u003c/span\u003e\u003cspan address=\"https://pubmed.ncbi.nlm.nih.gov/22766526/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRisk of malignant lymphomas in patients with inflammatory bowel disease: a population-based cohort study - PubMed. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://pubmed.ncbi.nlm.nih.gov/37142293/\u003c/span\u003e\u003cspan address=\"https://pubmed.ncbi.nlm.nih.gov/37142293/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKopylov, U. \u003cem\u003eet al.\u003c/em\u003e Risk of Lymphoma, Colorectal and Skin Cancer in Patients with IBD Treated with Immunomodulators and Biologics: A Quebec Claims Database Study. \u003cem\u003eInflamm Bowel Dis\u003c/em\u003e 21, 1847\u0026ndash;1853 (2015).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eInflammation and disease duration have a cumulative effect on the risk of dysplasia and carcinoma in IBD: a case-control observational study based on registry data - PubMed. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://pubmed.ncbi.nlm.nih.gov/23797639/\u003c/span\u003e\u003cspan address=\"https://pubmed.ncbi.nlm.nih.gov/23797639/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRisk and clinical characteristics of lymphoma in Korean patients with inflammatory bowel diseases: a multicenter study - PubMed. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://pubmed.ncbi.nlm.nih.gov/24705089/\u003c/span\u003e\u003cspan address=\"https://pubmed.ncbi.nlm.nih.gov/24705089/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJ, G. \u003cem\u003eet al.\u003c/em\u003e Thiopurine Therapy Reduces the Incidence of Colorectal Neoplasia in Patients with Ulcerative Colitis. Data from the ENEIDA Registry. \u003cem\u003eJournal of Crohn\u0026rsquo;s \u0026amp; colitis\u003c/em\u003e 9, (2015).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRisk of malignancies in patients with inflammatory bowel disease who used thiopurines as compared with other indications: a territory-wide study - PubMed. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://pubmed.ncbi.nlm.nih.gov/33281936/\u003c/span\u003e\u003cspan address=\"https://pubmed.ncbi.nlm.nih.gov/33281936/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRisk of malignant lymphoma in patients with inflammatory bowel diseases: a Dutch nationwide study - PubMed. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://pubmed.ncbi.nlm.nih.gov/21830262/\u003c/span\u003e\u003cspan address=\"https://pubmed.ncbi.nlm.nih.gov/21830262/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRisk of melanoma and nonmelanoma skin cancer among patients with inflammatory bowel disease - PubMed. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://pubmed.ncbi.nlm.nih.gov/22584081/\u003c/span\u003e\u003cspan address=\"https://pubmed.ncbi.nlm.nih.gov/22584081/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMd, L. \u003cem\u003eet al.\u003c/em\u003e Increased risk for non-melanoma skin cancer in patients with inflammatory bowel disease. \u003cem\u003eClinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association\u003c/em\u003e 8, (2010).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZheng, K. Y. C. \u003cem\u003eet al.\u003c/em\u003e Risk of malignancies in patients with inflammatory bowel disease who used thiopurines as compared with other indications: a territory-wide study. \u003cem\u003eTherap Adv Gastroenterol\u003c/em\u003e 13, 1756284820967275 (2020).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChupin, A. \u003cem\u003eet al.\u003c/em\u003e Systematic review with meta-analysis: comparative risk of lymphoma with anti-tumour necrosis factor agents and/or thiopurines in patients with inflammatory bowel disease. \u003cem\u003eAliment Pharmacol Ther\u003c/em\u003e 52, 1289\u0026ndash;1297 (2020).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eShah, S. C. \u0026amp; Itzkowitz, S. H. Colorectal Cancer in Inflammatory Bowel Disease: Mechanisms and Management. \u003cem\u003eGastroenterology\u003c/em\u003e 162, 715\u0026ndash;730.e3 (2022).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSingh, A. \u003cem\u003eet al.\u003c/em\u003e Use of thiopurines in inflammatory bowel disease: an update. \u003cem\u003eIntest Res\u003c/em\u003e 20, 11\u0026ndash;30 (2022).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eUse of thiopurines in inflammatory bowel disease: Safety issues - PubMed. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://pubmed.ncbi.nlm.nih.gov/24868487/\u003c/span\u003e\u003cspan address=\"https://pubmed.ncbi.nlm.nih.gov/24868487/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eThiopurine use associated with reduced B and natural killer cells in inflammatory bowel disease - PubMed. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://pubmed.ncbi.nlm.nih.gov/28566883/\u003c/span\u003e\u003cspan address=\"https://pubmed.ncbi.nlm.nih.gov/28566883/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eThiopurines and inflammatory bowel disease: Current evidence and a historical perspective - PubMed. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://pubmed.ncbi.nlm.nih.gov/28028358/\u003c/span\u003e\u003cspan address=\"https://pubmed.ncbi.nlm.nih.gov/28028358/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKarran, P. \u0026amp; Attard, N. Thiopurines in current medical practice: molecular mechanisms and contributions to therapy-related cancer. \u003cem\u003eNat Rev Cancer\u003c/em\u003e 8, 24\u0026ndash;36 (2008).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChapman, C. G. \u0026amp; Rubin, D. T. The potential for medical therapy to reduce the risk of colorectal cancer and optimize surveillance in inflammatory bowel disease. \u003cem\u003eGastrointest Endosc Clin N Am\u003c/em\u003e 24, 353\u0026ndash;365 (2014).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSingh, A. \u003cem\u003eet al.\u003c/em\u003e Use of thiopurines in inflammatory bowel disease: an update. \u003cem\u003eIntest Res\u003c/em\u003e 20, 11\u0026ndash;30 (2022).\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Inflammatory bowel disease, Thiopurines, Anti-TNF-α therapy, Cancer risk, Meta-analysis","lastPublishedDoi":"10.21203/rs.3.rs-6904749/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6904749/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eObjective\u003c/h2\u003e \u003cp\u003eTo evaluate the cancer risk in patients with IBD treated with thiopurines or anti-tumor necrosis factor-α (anti-TNF-α) therapy through a meta-analysis.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eA systematic search of PubMed, Embase, and Web of Science identified 31 population-based cohort studies (718,472 IBD patients). Hazard ratios (HRs) with 95% confidence intervals (CIs) were pooled using random-effects models. Subgroup analyses (Crohn\u0026rsquo;s disease [CD] vs. ulcerative colitis [UC]), sensitivity analyses, and publication bias assessments were performed.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eThiopurine use significantly increased the risk of overall malignancies (HR\u0026thinsp;=\u0026thinsp;1.53, 95% CI:1.06\u0026ndash;2.2), particularly melanoma (HR\u0026thinsp;=\u0026thinsp;2.7, 1.91\u0026ndash;3.83) and lymphoma (HR\u0026thinsp;=\u0026thinsp;1.64, 1.33\u0026ndash;2.02). Subgroup analyses revealed higher risks in CD than UC patients (lymphoma: HR\u0026thinsp;=\u0026thinsp;2.00 vs. 1.75). Conversely, thiopurines were associated with a potential reduction in colorectal cancer risk (HR\u0026thinsp;=\u0026thinsp;0.56, 0.32\u0026ndash;0.99), though this did not reach statistical significance (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.234). Anti-TNF-α monotherapy showed no significant overall cancer risk, but combination therapy with thiopurines elevated lymphoma risk (HR\u0026thinsp;=\u0026thinsp;3.7). Limited evidence suggested associations with urinary tract (HR\u0026thinsp;=\u0026thinsp;2.82, 1.04\u0026ndash;7.68) and hematologic cancers (HR\u0026thinsp;=\u0026thinsp;2.41, 1.04\u0026ndash;4.76).\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eThiopurines are linked to increased risks of specific cancers but may mitigate colorectal cancer risk via anti-inflammatory effects. Clinicians should balance immunosuppressive benefits against oncological risks and enhance cancer surveillance in long-term users. Future studies should explore dose-response relationships and safety profiles of newer biologics.\u003c/p\u003e","manuscriptTitle":"Cancer Risk in IBD Patients Treated with Thiopurines or Anti-TNF-α Therapy: A Meta- analysis of Population-Based Studies","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-06-25 10:24:45","doi":"10.21203/rs.3.rs-6904749/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"4611eda0-deae-4da5-a7f4-8688fe2ed3f7","owner":[],"postedDate":"June 25th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-09-15T00:08:12+00:00","versionOfRecord":[],"versionCreatedAt":"2025-06-25 10:24:45","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6904749","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6904749","identity":"rs-6904749","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}