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Evaluation of effect of empirical attack-preventive immunotherapies in neuromyelitis optica spectrum disorders: An update systematic review and meta -analysis.
Ma, J, Yu, H, Wang, H, Zhang, X, Feng, K
Journal of neuroimmunology. 2022;:577790
Abstract
BACKGROUND Neuromyelitis optica spectrum disorder (NMOSD) is an inflammatory disease of the central nervous system, which mainly involves the optic nerve and spinal cord. Frequent relapse can accumulate the degree of disability. At present, the main treatment options are immunosuppressants and blood purification. The first-line immunosuppressants for NMOSD are mainly rituximab (RTX), mycophenolate mofetil (MMF) and azathioprine (AZA). Therefore, we designed this systematic review and meta-analysis to evaluate the safety and effect of the above three drugs in the treatment of NMOSD patients. METHODS The following Medical Subject Heading (MeSH) and related entry terms are used to search English literature in PubMed, MEDLINE and CENTRAL databases, respectively. MeSH include: Neuromyelitis optic and Rituximab or Azathioprine or Mycophenolate Mofetil; entry terms include: NMO Spectrum Disorder, NMO Spectrum Disorders, Neuromyelitis Optica (NMO) Spectrum Disorder, Neuromyelitis Optica Spectrum Disorders, Devic Neuromyelitis Optica, Neuromyelitis Optica, Devic, Devic's Disease, Devic Syndrome, Devic's Neuromyelitis Optica, Neuromyelitis Optica (NMO) Spectrum Disorders, CD20 Antibody, Rituximab CD20 Antibody, Mabthera, IDEC-C2B8 Antibody, GP2013, Rituxan, Mycophenolate Mofetil, Mofetil, Mycophenolate, Mycophenolic Acid, Morpholinoethyl Ester, Cellcept, Mycophenolate Sodium, Myfortic, Mycophenolate Mofetil Hydrochloride, Mofetil Hydrochloride, Mycophenolate, RS 61443, RS-61443, RS61443, azathioprine sodium, azathioprine sulfate (note: literature retrieval operators "AND" "OR" "NOT" are used to link MeSH with Entry Terms.) The literature search found a total of 3058 articles about rituximab, mycophenolate mofetil and azathioprine in the treatment of NMOSD, 63 of which were included in this study after a series of screening. RESULTS 930,933,732 patients with NMOSD were enrolled, who had been treated with MMF, AZA and RTX, respectively. The pooled standardized mean difference (SMD) of EDSS before and after RTX treated was -0.58 (95%CI: -0.72, -0.44) (I2 = 0%, p = 0.477), before and after MMF treated was -0.47 (95%CI: -0.73, -0.21) (I2 = 85.6%, p<0.001), before and after AZA treated was -0.41 (95%CI: -0.60, -0.23) (I2 = 65.4%, p<0.001). there was no significant difference in the effect of the three drugs on reducing EDSS scores (RTX vs MMF, p = 0.522; RTX vs AZA, p = 0.214; MMF vs AZA, p = 0.732). The pooled standardized mean difference (SMD) of ARR before and after RTX treated was -1.45 (95%CI: -1.72, -1.18) (I2 = 72.4%, p<0.001), before and after MMF treated was -1.14 (95%CI: -1.31, -0.97) (I2 = 54.5%, p<0.001), before and after AZA treated was -1.11 (95%CI: -1.39, -0.83) (I2 = 83.4%, p<0.001). RTX significantly reduced ARR compared with the other two drugs (RTX vs MMF, p = 0.039; RTX vs AZA, p = 0.049; MMF vs AZA, p = 0.436). CONCLUSION The results of this systematic review and meta-analysis showed that the treatment of NMOSD patients with RTX, MMF and AZA is associated with decreased number of relapses and disability improvement as well, and there was no significant difference in the effect of the three drugs on reducing EDSS scores, but RTX significantly reduced ARR compared with the other two drugs.
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Enteral immunonutrition versus enteral nutrition for patients undergoing oesophagectomy: a systematic review and meta-analysis.
Li, XK, Zhou, H, Xu, Y, Cong, ZZ, Wu, WJ, Luo, J, Jiang, ZS, Shen, Y
Interactive cardiovascular and thoracic surgery. 2020;(6):854-862
Abstract
OBJECTIVES According to retrospective studies, oesophageal carcinoma is the second deadliest gastrointestinal cancer after gastric cancer. Enteral immunonutrition (EIN) has been increasingly used to enhance host immunity and relieve the inflammatory response of patients undergoing oesophagectomy; however, conclusions across studies remain unclear. We aimed to evaluate the effect of EIN on the clinical and immunological outcomes of patients undergoing oesophagectomy. METHODS Four electronic databases (MEDLINE, Embase, Web of Science and Cochrane Library) were used to search articles in peer-reviewed, English-language journals. The mean difference, relative risk or standard mean difference with 95% confidence interval were calculated. Heterogeneity was assessed by the Cochran's Q test and I2 statistic combined with the corresponding P-value. The analysis was carried out with RevMan 5.3. RESULTS Six articles were finally included, with a total of 320 patients with oesophageal cancer. The meta-analysis results showed that EIN did not improve clinical outcomes (such as infectious complications, pneumonia, surgical site infection, anastomotic leak and postoperative hospital stay) or immune indices [referring to C-reactive protein, interleukin (IL)-6, IL-8, tumour necrosis factor-α]. Descriptive analysis suggested that EIN also increased the serum concentrations of IgG and the percentage of the B-cell fraction. Thus, its impact on IL-8 and IL-6 remains inconsistent. CONCLUSIONS The early-stage impact of EIN on immunological status in patients undergoing oesophagectomy is still unclear. According to the results of this meta-analysis, whether EIN could improve the clinical outcomes or biological status after oesophagectomy compared to standard enteral nutrition is uncertain. Since the impact of EIN is unclear, current guidelines that strongly advise the use of EIN should be changed, as the utility of EIN is very uncertain. More appropriately powered clinical studies are warranted to confirm its effectiveness.
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Systematic review with meta-analysis: high prevalence and cost of continued aminosalicylate use in patients with ulcerative colitis escalated to immunosuppressive and biological therapies.
Ma, C, Guizzetti, L, Cipriano, LE, Parker, CE, Nguyen, TM, Gregor, JC, Chande, N, Feagan, BG, Jairath, V
Alimentary pharmacology & therapeutics. 2019;(4):364-374
Abstract
BACKGROUND Aminosalicylates are the most frequently prescribed treatment for ulcerative colitis (UC). In the absence of empirical evidence, clinicians are uncertain whether to continue aminosalicylates in patients with UC after escalating therapy. AIMS To quantify concomitant aminosalicylate use in UC randomised clinical trials (RCTs), identify factors associated with their use, and estimate treatment costs of concomitant aminosalicylate therapy. METHODS MEDLINE, Embase, and CENTRAL were searched from inception to 1 March 2017 for placebo-controlled RCTs of immunosuppressants, biologics, or oral small molecules in adults with UC. The proportion of patients prescribed concomitant aminosalicylates at trial entry was pooled using a random-effects model. Meta-regression was performed to assess trial-level factors associated with aminosalicylate use. Treatment costs were estimated using 2018 formulary data from five Canadian provinces. RESULTS Thirty-two trials were included (23 induction only, nine induction, and maintenance trials). The pooled proportion of patients co-prescribed aminosalicylates was 80.7% (95% CI 75.5%-85.1%), with considerable observed heterogeneity (I2 = 95%). In univariable meta-regression, aminosalicylate use was not associated with trial design, setting, year of publication, disease severity, disease duration, or drug class. The estimated direct annual treatment cost of concomitant aminosalicylates is ~$20 million for the Canadian UC population, assuming conservative estimates of UC prevalence, aminosalicylate use and dose, and the lowest cost formulation. CONCLUSIONS Approximately 80% of UC patients entering clinical trials of immunosuppressants, biologics, or oral small molecules continue to use aminosalicylates. An RCT is needed to inform the benefits and harms of continuing vs stopping aminosalicylates in patients escalating therapy.
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Interventions to Prevent Nonmelanoma Skin Cancers in Recipients of a Solid Organ Transplant: Systematic Review of Randomized Controlled Trials.
Chung, EYM, Palmer, SC, Strippoli, GFM
Transplantation. 2019;(6):1206-1215
Abstract
BACKGROUND Organ transplant recipients are at high risk of developing skin cancer. The benefits and harms of interventions to prevent nonmelanoma skin cancer in solid organ transplant recipients have not been summarized. METHODS We searched MEDLINE, Embase, and CENTRAL through April 2018. Risk of bias was assessed using the Cochrane tool, and evidence certainty was evaluated using the Grades of Recommendation, Assessment, Development, and Evaluation process. Prespecified outcomes were nonmelanoma skin cancer, clearance and prevention of keratotic skin lesions, and intervention-specific adverse events. RESULTS Ninety-two trials (20 012 participants) were included. The evaluated treatments were cancer-specific interventions (acitretin, imiquimod, photodynamic therapy, nicotinamide, topical diclofenac, and selenium) and immunosuppression regimes (azathioprine, mycophenolate mofetil, calcineurin inhibitors, mammalian target of rapamycin [mTOR] inhibitors, belatacept, induction agents, and withdrawal of calcineurin inhibitors or corticosteroids). Effects on nonmelanoma skin cancer were uncertain for photodynamic therapy (3 trials, 93 participants, risk ratio [RR] 1.42 [95% confidence interval (CI), 0.65-3.11]; low certainty evidence), nicotinamide (2 trials, 60 participants), acitretin (2 trials, 61 participants), and imiquimod (1 trial, 20 participants) compared to control. mTOR inhibitors probably reduced skin cancer compared to calcineurin inhibitors (12 trials, 2225 participants, RR 0.62 [95% CI, 0.45-0.85]; moderate certainty evidence). Photodynamic therapy may cause pain at the treatment site (4 trials, 95 patients, RR 17.09 [95% CI, 4.22-69.26]; low certainty evidence). CONCLUSIONS There is limited evidence for the efficacy and safety of specific treatments to prevent nonmelanoma skin cancers among solid organ transplant recipients.
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A PRISMA-compliant systematic review and network meta-analysis on the efficacy between different regimens based on Tripterygium wilfordii Hook F in patients with primary nephrotic syndrome.
Wang, XB, Dai, EL, Xue, GZ, Ma, RL
Medicine. 2018;(27):e11282
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Abstract
BACKGROUND The present study aims to comprehensively determine the efficacy of different therapy regimens based on Tripterygium wilfordii Hook F (TwHF) for patients with primary nephrotic syndrome (PNS) using network meta-analysis method. METHODS Seven electronic databases were searched to identify randomized controlled trials (RCTs) that compared the differences between different therapy regimens based on TwHF for patients with PNS. The risk of bias in included RCTs was evaluated according to the Cochrane Handbook version 5.2.0. Network meta-analysis was performed to compare different regimens. Primary outcomes were complete remission rate and total remission rate. The secondary outcomes were hr urinary protein excretion, serum albumin, serum creatinine, and urea nitrogen. Data analysis was performed using R software. RESULTS A total of 40 studies involving 2846 patients with PNS were included. Compared with prednisone, the improvement in total remission rate and complete remission rate was associated with TwHF alone (odds ratio [OR] = 4.80, 95% credible intervals [CrI]: 2.20-10.00; OR = 6.30, 95% CrI: 2.90-13.00, respectively), TwHF+prednisone (OR = 2.10, 95% CrI: 1.30-3.50; OR = 2.40, 95% CrI: 1.50-3.80, respectively), TwHF+CPA (OR = 12.00, 95% CrI: 1.10-150.00; OR = 16.00, 95% CrI: 1.60-170.00, respectively), and TwHF+Cyclosporine A (OR = 28.00, 95% CrI: 3.20-250.00; OR = 35.00, 95% CrI: 4.50-270.00, respectively). Compared with TwHF alone, TwHF+prednisone showed less benefit in improving total remission rate and complete remission rate (OR = 0.44, 95% CrI: 0.21-0.91; OR = 0.38, 95% CrI: 0.19-0.77, respectively). TwHF alone, TwHF+prednisone could significantly reduce hr urinary protein excretion (MD = -0.69, 95% CrI: -1.30 to -0.14; MD = -1.00, 95% CrI: -1.90 to -0.14, respectively) and increase serum albumin (MD = 5.90, 95% CrI: 2.50-9.30; MD = 3.40, 95% CrI: 1.30-5.50, respectively) when compared to prednisone alone. TwHF alone showed significant reduction in serum creatinine when compared to CPA (MD = -19.00, 95% CrI: -37.00 to -0.56). CONCLUSIONS TwHF alone, the addition TwHF to prednisone showed more benefit in improving total and complete remission rate, hr urinary protein excretion, serum albumin, and serum creatinine.
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Drug Treatment of Idiopathic Pulmonary Fibrosis: Systematic Review and Network Meta-Analysis.
Canestaro, WJ, Forrester, SH, Raghu, G, Ho, L, Devine, BE
Chest. 2016;(3):756-66
Abstract
BACKGROUND Idiopathic pulmonary fibrosis (IPF) is a form of chronic progressive fibrosing interstitial lung disease of unknown origin. Recently, nintedanib and pirfenidone demonstrated efficacy in slowing disease progression and were approved by the US Food and Drug Administration. Although numerous treatments have been evaluated in IPF, none have shown significant decreases in mortality. The objective of this study was to identify all pharmacologic treatments evaluated for IPF and analyze their efficacy via Bayesian network meta-analysis and pairwise indirect treatment comparisons. This review did not evaluate the effect of steroid therapy. METHODS We searched MEDLINE, Embase, and the Cochrane Library for studies published on or before August 2014. Studies were required to contain a randomized evaluation of nonsteroidal drug therapy for treatment of IPF and be published in English. Key outcomes of interest for this analysis were pulmonary function as measured by FVC as well as all-cause and respiratory-specific death. All outcomes were analyzed via a Bayesian framework. RESULTS Our review identified 30 eligible studies that evaluated 16 unique treatments. Under both the fixed-effect and random-effect models for respiratory-specific mortality, no treatments performed better than placebo. For all-cause mortality, pirfenidone and nintedanib had effects approaching significance with credible intervals slightly crossing the null under a fixed-effect model. Notably, for respiratory-specific mortality, all-cause mortality, and decline in percent predicted FVC, nintedanib and pirfenidone were virtually indistinguishable and no clear advantage was detected. CONCLUSIONS Although two treatments have been approved for IPF on the basis of reduced decline in pulmonary function, neither one has a clear advantage on mortality outcomes.
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Rituximab shows no effect on remission in patients with refractory nephrotic syndrome: A MOOSE-compliant meta-analysis.
Yin, S, He, T, Li, Y, Wang, J, Zeng, W, Tang, S, Zhao, J
Medicine. 2016;(50):e5320
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To assess the efficacy of rituximab in treatment of refractory nephrotic syndrome (NS) compared with other agents.Studies were searched from Web of Science, PubMed, and CNKI up to April 2016. The standardized mean difference or relative risk or odds ratio and 95% confidence intervals were used to assess the efficacy of rituximab treatment compared with other agents in refractory NS.Totally, 8 studies were included. The present study showed that there was a significant higher relapse-free survival rate in rituximab group than that in the other agents group. Compared with other agents, rituximab did not significantly improve the complete and overall remission rate, serum albumin levels. Rituximab also did not decrease the serum creatinine, urinary protein, and serum cholesterol levels. However, compared with other agents, the adult patients had a higher serum cholesterol levels after treatment with rituximab.Rituximab promised to be a new agent in the treatment of refractory NS; it also could be used as an alternative to conventional immunosuppressive drugs-dependent or drugs-resistant. However, more high-quality, large sample, and multicenter randomized controlled trials are needed to further confirm the efficacy of rituximab in treatment of refractory NS.
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Methotrexate for maintenance of remission in ulcerative colitis.
Wang, Y, MacDonald, JK, Vandermeer, B, Griffiths, AM, El-Matary, W
The Cochrane database of systematic reviews. 2015;(8):CD007560
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BACKGROUND Methotrexate, a folate antagonist, is an immunosuppressant drug that is effective for treating several inflammatory disorders including Crohn's disease. Ulcerative colitis, a related chronic inflammatory bowel disease, can be challenging to treat. T his updated systematic review summarizes the current evidence on the use of methotrexate for induction maintenance of remission in ulcerative colitis. OBJECTIVES The objectives of this review were to assess the efficacy and safety of methotrexate for maintenance of remission in patients with ulcerative colitis. SEARCH METHODS We searched MEDLINE, EMBASE, CENTRAL and the Cochrane IBD/FBD group specialized trials register from inception to June 26, 2014. Study references and review papers were also searched for additional trials. Abstracts from major gastroenterological meetings were searched to identify research published in abstract form only. SELECTION CRITERIA Randomized controlled trials in which methotrexate was compared to placebo or an active comparator in patients with quiescent ulcerative were considered for inclusion. DATA COLLECTION AND ANALYSIS Two authors independently extracted data and assessed the risk of bias for each study. The primary outcome was the occurrence of clinical or endoscopic relapse as defined by the primary studies. Secondary outcomes included frequency and nature of adverse events, change of disease activity score and steroid-sparing effect. We calculated the risk ratio and corresponding 95% confidence interval for dichotomous outcomes. Data were analyzed on an intention-to-treat basis. The overall quality of the evidence supporting the outcomes was evaluated using the GRADE criteria. MAIN RESULTS Three trials (165 patients) fulfilled the inclusion criteria. One study compared oral methotrexate (12.5 mg/week) to placebo, another compared oral methotrexate (15 mg/week) to 6-mercaptopurine (6-MP, 1.5 mg/kg/day) or 5-aminosalicylic acid (5-ASA, 3 g/day) and the other compared methotrexate (15 mg/week) in combination sulfasalazine (3 g/day) to sulfasalazine. The placebo-controlled study was rated as low risk of bias. The study comparing methotrexate to 6-MP and 5-ASA was rated as high risk of bias and the study assessing methotrexate and sulfasalazine was rated as unclear risk of bias for sequence generation, allocation concealment and blinding. The placebo-controlled study found no statistically significant differences in the proportion of patients who maintained remission. At nine months, 36% (5/14) of methotrexate patients maintained remission compared to 54% (10/18) of placebo patients (RR 0.64, 95% CI 0.28 to 1.45). A GRADE analysis indicated that the overall quality of the evidence for this outcome was low due to very sparse data (15 events). The study comparing combination therapy to sulfasalazine found no statistically significant difference in the proportion of patients who maintained remission. At 12 months, 100% (14/14) of patients in the combination group maintained remission compared to 75% (9/12) of sulfasalazine patients (RR 1.32, 95% CI 0.94 to 0.86), A GRADE analysis indicated that the overall quality of the evidence for this outcome was very low due to unknown risk of bias and very sparse data (23 events). There were no statistically significant differences in maintenance of remission rates between methotrexate and 6-MP or between methotrexate and 5-ASA. At 76 weeks, 14% (1/7) of methotrexate patients maintained remission compared to 64% (7/11) of 6-MP patients (RR 0.22, 95% CI 0.03 to 1.45) and 0% (0/2) of 5-ASA patients (RR 1.13, 95% CI 0.06 to 20.71). A GRADE analysis indicated that the overall quality of the evidence from this study was very low due to high risk of bias and very sparse data. Adverse events reported in these studies included transient leucopenia, migraine, nausea and dyspepsia, mild alopecia, mild increase in aspartate aminotransferase levels, peritoneal abscess, hypoalbuminemia, severe rash and atypical pneumonia AUTHORS' CONCLUSIONS The results for efficacy and safety outcomes between methotrexate and placebo, methotrexate and sulfasalazine, methotrexate and 6-mercaptopurine and methotrexate and 5-aminosalicylic acid were uncertain. Whether a higher dose or parenteral administration of methotrexate would be effective in quiescent ulcerative colitis is unknown. At present there is no evidence supporting the use of methotrexate for maintenance of remission in ulcerative colitis. More studies are needed to determine the efficacy and safety of methotrexate maintenance therapy in patients with quiescent ulcerative colitis. Large scale methodologically rigorous randomized controlled trials are needed. These studies should investigate higher doses of methotrexate (e.g. 15 to 25 mg/week) and parenteral administration.
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Does belatacept improve outcomes for kidney transplant recipients? A systematic review.
Talawila, N, Pengel, LH
Transplant international : official journal of the European Society for Organ Transplantation. 2015;(11):1251-64
Abstract
BACKGROUND Belatacept was intended to provide better outcomes for kidney transplant (KT) recipients by allowing minimization/withdrawal of calcineurin inhibitors (CNI) and steroids. METHODS We searched for randomized controlled trials (RCTs) in adult KT comparing belatacept with CNIs. Methodological quality was assessed. Meta-analyses were performed to calculate odds ratios (OR) and mean differences (MD). RESULTS Six RCTs were included. Pooled analyses found no differences for acute rejection at any time point. Renal function [Calculated glomerular filtration rate (cGFR)] was better with belatacept at 12 and 24 months (MD = 11.7 and 13.7 ml/min/1.73 m(2) ). New onset diabetes after transplantation was lower with belatacept at 12 months (OR = 0.43). Systolic and diastolic blood pressures were lower at 12 months (MD -7.2 and -3.1 mmHg) as were triglycerides at 12 and 24 months (MD = -32.9 and -41.7 mg/dl). Total and low-density lipoprotein cholesterol were lower with belatacept at 24 months (MD = -19.8 and -10.6 mg/dl). There were no differences for other outcomes. CONCLUSION Limited available data suggest a potential benefit for belatacept by reducing the risk of CNI toxicity, especially renal function, without evidence of increased acute rejection. There were no safety issues apart from a possible risk of post-transplant lymphoproliferative disorder in Epstein-barr virus-seronegative recipients. Further studies are required to confirm this benefit.
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Thiopurines and risk of colorectal neoplasia in patients with inflammatory bowel disease: a meta-analysis.
Jess, T, Lopez, A, Andersson, M, Beaugerie, L, Peyrin-Biroulet, L
Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association. 2014;(11):1793-1800.e1
Abstract
BACKGROUND & AIMS Patients with inflammatory bowel disease (IBD) are at increased risk for developing colorectal neoplasia. Researchers have debated whether treatment of IBD with thiopurines reduces cancer risk. We performed a meta-analysis of thiopurine exposure and risk of colorectal dysplasia or cancer in patients with IBD. METHODS We used MEDLINE, EMBASE, and Cochrane search engines and abstract books from international conferences to identify relevant literature. We included studies on thiopurine exposure and risk of colorectal neoplasia in patients with ulcerative colitis or Crohn's disease. We calculated pooled odds ratios (ORs) with 95% confidence intervals (CIs) and performed a meta-regression analysis of the effect of year of publication. Various sensitivity analyses were conducted. RESULTS Fifteen studies fulfilled the inclusion criteria. Overall, we did not observe a significant effect of thiopurines on risk for colorectal neoplasia (dysplasia and/or cancer) in patients with IBD (OR, 0.87; 95% CI, 0.71-1.06). The estimate did not change markedly in separate assessments of the 2 population-based studies (OR, 0.87; 95% CI, 0.59-1.29), the 13 clinic-based studies (OR, 0.87; 95% CI, 0.59-1.09), the 7 cohort studies (OR, 0.93; 95% CI, 0.67-1.28), or the 8 case-control studies (OR, 0.83; 95% CI, 0.65-1.08). Studies that used neoplasia (dysplasia or cancer) as outcomes tended to show that thiopurines had protective effects (OR for neoplasia, 0.72; 95% CI, 0.50-1.05); these effects were not observed in studies of colorectal cancer (OR, 0.90; 95% CI, 0.72-1.12) or in studies published in recent years (meta-regression; P = .16). CONCLUSIONS In a meta-analysis, we did not find a significant protective effect of treatment with thiopurines on the risk of colorectal neoplasia in patients with IBD.