Prédicteurs de première lésion néoplasique colique chez les patients surveillés par coloscopies itératives pour maladie inflammatoire chronique intestinale

Introduction: Little is known about risk factors of first colorectal neoplasia (CRN) in inflammatory bowel diseases (IBD) patients after a surveillance colonoscopy without dysplasia. The aims of our study were to assess the risk for first CRN in this population and to search for protective and risk factors for CRN.Methods: All consecutive patients who have undergone at least 2 colonoscopies at Saint Antoine Hospital between 01/01/1996 and 31/03/2015 and whose first procedure was a surveillance colonoscopy were included. A nested case-cohort study was performed to assess risk factors of CRN developed in inflamed mucosa.Results: 404 patients with a total of 1236 colonoscopies were included. The cumulative risk of CRN was 22.6% at 10 years. 38 patients with CRN developed in inflamed mucosa and 92 controls were included in the nested case control study. In multivariate analysis, primary sclerosing cholangitis (PSC) (Odds ratio (OR), 6.26; CI 95% 1.07-36.8; p=0.04), neutrophils or cryptic abscess present on over half of colonoscopies (OR, 8.77; CI 95% 1.71-45; p=0.009) and glandular distortions present on over half of colonoscopies (OR, 8.09; CI 95% 1.21-54.3 ; p=0.03) were positively associated with CRN, whereas thiopurines (OR, 0.18; CI 95% 0.047-0.698; p=0.01) and aminosalicylates (OR, 0.27; CI 95% 0.084-0.876; p=0.03) reduced the risk for CRN.Conclusion: Occurrence of first CRN was associated with PSC, persistence of acute and chronic inflammation. Administration of thiopurines and aminosalicylates reduced risk of first CRN. Surveillance colonoscopy intervals after a surveillance colonoscopy without dysplasia should take into account these parameters.Objectif: Les déterminants du risque de néoplasie colique ne sont pas connus chez les patients atteints de maladies inflammatoires chroniques intestinales (MICI) ayant réalisé une coloscopie de surveillance sans néoplasie identifiée. Notre objectif était de mettre en évidence les déterminants de première néoplasie colique dans cette population.Méthodes: Tous les patients consécutifs ayant eu au moins 2 coloscopies à l’hôpital Saint Antoine entre le 01/01/1996 et le 31/03/2015, dont la première avec un protocole de biopsies à la recherche de dysplasie, ont été inclus. Une étude cas-témoins nichée a été réalisée pour étudier les déterminants d’une première néoplasie en territoire inflammatoire.Résultats: 404 patients ayant eu au total 1236 coloscopies ont été inclus dans la cohorte. 38 cas avec première néoplasie en territoire inflammatoire et 92 témoins ont été inclus dans l’analyse. Le risque de première néoplasie colique était augmenté en cas de cholangite sclérosante primitive (CSP) (OR: 6,26; p=0,04) de polynucléaires neutrophiles (OR: 8,77; p=0,009) et distorsions glandulaires (OR: 8,09; p=0,03) sur plus de la moitié des coloscopies antérieures, alors qu’un effet protecteur était associé à un traitement par 5-aminosalicylés (OR: 0,27; p=0,03) et thiopurines (OR: 0,18; p=0,01).Conclusion: Le risque de première néoplasie colique était associé à la présence d’une CSP, la persistance d’une inflammation aigue et résiduelle. L’exposition aux 5-aminosalicylés et aux thiopurines était associée à une diminution du risque. Le choix des intervalles entre 2 coloscopies de surveillance après une coloscopie de surveillance sans dysplasie pourrait tenir compte de ces paramètres

Impact on Life Expectancy of Withdrawing Thiopurines in Patients with Crohn’s Disease in Sustained Clinical Remission: A Lifetime Risk-Benefit Analysis

Berenice Study GroupInternational audienceObjectiveLong-term treatment with thiopurines is associated with a decreased risk of Crohn’s disease (CD) flare but an increased risk of various cancers depending on gender, age, and presence of extensive colitis. We evaluated risks and benefits of withdrawing thiopurines in patients with CD in prolonged remission.MethodsWe developed a Markov model assessing risks and benefits of withdrawing thiopurines compared to continuing thiopurines in a lifetime horizon. The model was stratified by age (35 and 65 years old at thiopurine withdrawal), gender and presence of extensive colitis. Parameter estimates were taken from French cohorts and hospital databases, cancer and death national registries and published literature. Life expectancy, rates of relapse, serious adverse events, and causes-of-death were evaluated.ResultsIn patients without extensive colitis, continuing thiopurines increased life expectancy up to 0.03 years for 35 year-old men and women but decreased life expectancy down to 0.07 years for 65 year-old men and women. Withdrawal strategy became the preferred strategy at 40.6 years for men, and 45.7 years for women without extensive colitis. In patients with extensive colitis, continuation strategy was the preferred strategy regardless of age. Risk-benefit analysis was not modified by duration of CD activity.ConclusionsFactors determining life expectancy associated with withdrawal or continuation of thiopurines in patients with CD and in sustained clinical remission vary substantially according to gender, age and presence of extensive colitis. Individual decisions to continue or withdraw thiopurines in patients with CD in sustained remission should take into account these parameters

Risk of first ischaemic stroke and use of antidopaminergic antiemetics: nationwide case-time-control study

OBJECTIVE: To estimate the risk of ischaemic stroke associated with antidopaminergic antiemetic (ADA) use. DESIGN: Case-time-control study. SETTING: Data from the nationwide French reimbursement healthcare system database Système National des Données de Santé (SNDS). PARTICIPANTS: Eligible participants were ≥18 years with a first ischaemic stroke between 2012 and 2016 and at least one reimbursement for any ADA in the 70 days before stroke. Frequencies of ADA reimbursements were compared for a risk period (days -14 to -1 before stroke) and three matched reference periods (days -70 to -57, -56 to -43, and -42 to -29) for each patient. Time trend of ADA use was controlled by using a control group of 21 859 randomly selected people free of the event who were individually matched to patients with stroke according to age, sex, and risk factors of ischaemic stroke. MAIN OUTCOME MEASURES: Association between ADA use and risk of ischaemic stroke was assessed by estimating the ratio of the odds ratios of exposure evaluated in patients with stroke and in controls. Analyses were adjusted for time varying confounders (anticoagulants, antiplatelets, and prothrombotic or vasoconstrictive drugs). RESULTS: Among the 2612 patients identified with incident stroke, 1250 received an ADA in the risk period and 1060 in the reference periods. The comparison with the 5128 and 13 165 controls who received an ADA in the same periods yielded a ratio of adjusted odds ratios of 3.12 (95% confidence interval 2.85 to 3.42). Analyses stratified by age, sex, and history of dementia showed similar results. Ratio of adjusted odds ratios for analyses stratified by ADA was 2.51 (2.18 to 2.88) for domperidone, 3.62 (3.11 to 4.23) for metopimazine, and 3.53 (2.62 to 4.76) for metoclopramide. Sensitivity analyses suggested the risk would be higher in the first days of use. CONCLUSIONS: Using French nationwide exhaustive reimbursement data, this self-controlled study reported an increased risk of ischaemic stroke with recent ADA use. The highest increase was found for metopimazine and metoclopramide

I-CARE, a European prospective cohort study assessing safety and effectiveness of biologics in inflammatory bowel disease

There is a need to evaluate the benefit-risk ratio of current therapies in inflammatory bowel disease (IBD) patients to provide the best quality of care. The primary objective of I-CARE was to assess prospectively safety concerns in IBD, with specific focus on the risk of cancer/lymphoma and serious infections in patients treated with for anti-tumor necrosis factor and other biologics monotherapy as well as in combination with immunomodulators.I-CARE was designed as a European prospective longitudinal observational multicenter cohort study, to include patients with a diagnosis of Crohn's disease, ulcerative colitis or IBD unclassified established at least 3 months prior to enrollment.A total of 10,206 patients were enrolled between March 2016 and April 2019, including 6,169 (60.4%) patients with Crohn's disease, 3,853 (37.8%) with ulcerative colitis, and 184 (1.8%) with a diagnosis of IBD unclassified. Thirty-two percent of patients were receiving AZA/thiopurines, 4.6% 6-mercaptopurine, and 3.2% methotrexate at study entry. At inclusion, 47.3% of patients were treated with an anti-tumor necrosis factor agent, 8.8% with vedolizumab, and 3.4% with ustekinumab. Roughly one quarter of patients (26.8%) underwent prior IBD related surgery. Sixty-six % of patients had been previously treated with systemic steroids. Three percent of patients had a medical history of cancer prior to inclusion, and 1.1% had a history of colonic, esophageal or uterine cervix high-grade dysplasia.I-CARE is an ongoing investigator-initiated observational European prospective cohort study that will provide unique information on the long-term benefits and risks of biological therapies in IBD patients

Risque d'accident artériel aigu chez les patients atteints de maladie inflammatoire chronique intestinale et impact des traitements sur le risque : analyse des bases de données médico administratives françaises PMSI et SNIIRAM

The risk of acute arterial events in inflammatory bowel disease (IBD) remains unclear. The objectives of this thesis are to assemble a nationwide cohort of IBD patients based on the French administrative health databases, in order to assess the risk of acute arterial events in IBD and the impact of immunosuppressive treatment on the risk. Disease course and therapeutic management of IBD were first studied, in order to validate the coding diagnosis of IBD in the databases. Treatment exposure, hospitalisation, and surgery rates are similar to current standard of care and incidence rates are in the range of those reported in other populations. Patients with Crohn’s disease (CD) and ulcerative colitis (UC) have an increased risk of acute arterial events compared with the general population. The highest risk is observed in patients under the age of 55 years. Disease activity is an independent risk factor of acute arterial events, with a similar magnitude of risk in CD and UC. Exposure to thiopurine and anti-TNF monotherapies, and combination therapy are all numerically associated with a decreased risk of acute arterial events compared to unexposed patients, although the difference is only statistically significant for patients exposed to combination therapy. The magnitude in risk reduction is highest in men with CD exposed to combination therapy. These studies support the concept that a tight control of inflammation is crucial in patients with IBD to avoid IBD-related systemic complications. Prevention of acute arterial events should be considered in the benefit-risk balance assessment of thiopurines and anti-TNFs treatment in IBD patients, according to age, sex and IBD subtype.Le risque d’accidents artériels aigus chez les patients atteints de maladie inflammatoire chronique intestinale (MICI) reste incertain. L’objectif de cette thèse est d’évaluer le risque d’accident artériel aigu chez les patients atteints de MICI et l’impact des traitements sur le risque à partir des bases de données médico administratives françaises PMSI et SNIIRAM. La prise en charge thérapeutique des patients atteints de MICI a été initialement étudiée afin de valider le code diagnostique dans les bases de données. L’exposition au traitement, les taux d’hospitalisation et de chirurgie sont similaires à ceux attendus et les taux d’incidence sont comparables à ceux rapportés dans d’autres populations. Les patients atteints de maladie de Crohn (MC) et rectocolite hémorragique (RCH) ont un surrisque d’accident artériel aigu comparé à la population générale. Le risque le plus élevé est observé chez les patients de moins de 55 ans. L’activité de la MICI est un facteur de risque indépendant d’accident artériel aigu, avec une magnitude d’effet similaire dans la MC et la RCH. Comparés aux patients non exposés, les patients exposés à la monothérapie thiopurines, anti-TNFs et combothérapie ont un risque moins élevé d’accident artériel aigu, mais cette différence est seulement significative chez les patients exposés à la combothérapie. La diminution du risque est la plus importante chez les hommes atteints de MC exposés à la combothérapie. La modulation du risque d’accident artériel aigu devrait être prise en compte dans la balance bénéfice-risque des traitements par thiopurines et anti-TNFs chez les patients atteints de MICI

Prédicteurs de première lésion néoplasique colique chez les patients surveillés par coloscopies itératives pour maladie inflammatoire chronique intestinale

Introduction: Little is known about risk factors of first colorectal neoplasia (CRN) in inflammatory bowel diseases (IBD) patients after a surveillance colonoscopy without dysplasia. The aims of our study were to assess the risk for first CRN in this population and to search for protective and risk factors for CRN.Methods: All consecutive patients who have undergone at least 2 colonoscopies at Saint Antoine Hospital between 01/01/1996 and 31/03/2015 and whose first procedure was a surveillance colonoscopy were included. A nested case-cohort study was performed to assess risk factors of CRN developed in inflamed mucosa.Results: 404 patients with a total of 1236 colonoscopies were included. The cumulative risk of CRN was 22.6% at 10 years. 38 patients with CRN developed in inflamed mucosa and 92 controls were included in the nested case control study. In multivariate analysis, primary sclerosing cholangitis (PSC) (Odds ratio (OR), 6.26; CI 95% 1.07-36.8; p=0.04), neutrophils or cryptic abscess present on over half of colonoscopies (OR, 8.77; CI 95% 1.71-45; p=0.009) and glandular distortions present on over half of colonoscopies (OR, 8.09; CI 95% 1.21-54.3 ; p=0.03) were positively associated with CRN, whereas thiopurines (OR, 0.18; CI 95% 0.047-0.698; p=0.01) and aminosalicylates (OR, 0.27; CI 95% 0.084-0.876; p=0.03) reduced the risk for CRN.Conclusion: Occurrence of first CRN was associated with PSC, persistence of acute and chronic inflammation. Administration of thiopurines and aminosalicylates reduced risk of first CRN. Surveillance colonoscopy intervals after a surveillance colonoscopy without dysplasia should take into account these parameters.Objectif: Les déterminants du risque de néoplasie colique ne sont pas connus chez les patients atteints de maladies inflammatoires chroniques intestinales (MICI) ayant réalisé une coloscopie de surveillance sans néoplasie identifiée. Notre objectif était de mettre en évidence les déterminants de première néoplasie colique dans cette population.Méthodes: Tous les patients consécutifs ayant eu au moins 2 coloscopies à l’hôpital Saint Antoine entre le 01/01/1996 et le 31/03/2015, dont la première avec un protocole de biopsies à la recherche de dysplasie, ont été inclus. Une étude cas-témoins nichée a été réalisée pour étudier les déterminants d’une première néoplasie en territoire inflammatoire.Résultats: 404 patients ayant eu au total 1236 coloscopies ont été inclus dans la cohorte. 38 cas avec première néoplasie en territoire inflammatoire et 92 témoins ont été inclus dans l’analyse. Le risque de première néoplasie colique était augmenté en cas de cholangite sclérosante primitive (CSP) (OR: 6,26; p=0,04) de polynucléaires neutrophiles (OR: 8,77; p=0,009) et distorsions glandulaires (OR: 8,09; p=0,03) sur plus de la moitié des coloscopies antérieures, alors qu’un effet protecteur était associé à un traitement par 5-aminosalicylés (OR: 0,27; p=0,03) et thiopurines (OR: 0,18; p=0,01).Conclusion: Le risque de première néoplasie colique était associé à la présence d’une CSP, la persistance d’une inflammation aigue et résiduelle. L’exposition aux 5-aminosalicylés et aux thiopurines était associée à une diminution du risque. Le choix des intervalles entre 2 coloscopies de surveillance après une coloscopie de surveillance sans dysplasie pourrait tenir compte de ces paramètres

Risk of ischemic heart disease, cerebrovascular disease and peripheral artery disease in patients with inflammatory bowel disease and impact of medical treatment on these risks : analysis of the French administrative health databases PMSI and SNIIRAM

Le risque d’accidents artériels aigus chez les patients atteints de maladie inflammatoire chronique intestinale (MICI) reste incertain. L’objectif de cette thèse est d’évaluer le risque d’accident artériel aigu chez les patients atteints de MICI et l’impact des traitements sur le risque à partir des bases de données médico administratives françaises PMSI et SNIIRAM. La prise en charge thérapeutique des patients atteints de MICI a été initialement étudiée afin de valider le code diagnostique dans les bases de données. L’exposition au traitement, les taux d’hospitalisation et de chirurgie sont similaires à ceux attendus et les taux d’incidence sont comparables à ceux rapportés dans d’autres populations. Les patients atteints de maladie de Crohn (MC) et rectocolite hémorragique (RCH) ont un surrisque d’accident artériel aigu comparé à la population générale. Le risque le plus élevé est observé chez les patients de moins de 55 ans. L’activité de la MICI est un facteur de risque indépendant d’accident artériel aigu, avec une magnitude d’effet similaire dans la MC et la RCH. Comparés aux patients non exposés, les patients exposés à la monothérapie thiopurines, anti-TNFs et combothérapie ont un risque moins élevé d’accident artériel aigu, mais cette différence est seulement significative chez les patients exposés à la combothérapie. La diminution du risque est la plus importante chez les hommes atteints de MC exposés à la combothérapie. La modulation du risque d’accident artériel aigu devrait être prise en compte dans la balance bénéfice-risque des traitements par thiopurines et anti-TNFs chez les patients atteints de MICI.The risk of acute arterial events in inflammatory bowel disease (IBD) remains unclear. The objectives of this thesis are to assemble a nationwide cohort of IBD patients based on the French administrative health databases, in order to assess the risk of acute arterial events in IBD and the impact of immunosuppressive treatment on the risk. Disease course and therapeutic management of IBD were first studied, in order to validate the coding diagnosis of IBD in the databases. Treatment exposure, hospitalisation, and surgery rates are similar to current standard of care and incidence rates are in the range of those reported in other populations. Patients with Crohn’s disease (CD) and ulcerative colitis (UC) have an increased risk of acute arterial events compared with the general population. The highest risk is observed in patients under the age of 55 years. Disease activity is an independent risk factor of acute arterial events, with a similar magnitude of risk in CD and UC. Exposure to thiopurine and anti-TNF monotherapies, and combination therapy are all numerically associated with a decreased risk of acute arterial events compared to unexposed patients, although the difference is only statistically significant for patients exposed to combination therapy. The magnitude in risk reduction is highest in men with CD exposed to combination therapy. These studies support the concept that a tight control of inflammation is crucial in patients with IBD to avoid IBD-related systemic complications. Prevention of acute arterial events should be considered in the benefit-risk balance assessment of thiopurines and anti-TNFs treatment in IBD patients, according to age, sex and IBD subtype

Predicting, Preventing, and Managing Treatment-related Complications in Patients With Inflammatory Bowel Diseases.

Risk of complications from specific classes of drugs for inflammatory bowel diseases (IBD) can be kept low by respecting contra-indications. Patients with IBD frequently develop serious infections, due to the disease itself or its treatment. At the time of diagnosis, patients' vaccination calendars should be updated according to IBD guidelines-live vaccines should be postponed for patients receiving immunosuppressive drugs. Opportunistic infections should be detected and the vaccine against Pneumococcus should be given before patients begin immunosuppressive therapy. Thiopurines promote serious viral infections, in particular, whereas tumor necrosis factor (TNF) antagonists promote all types of serious and opportunistic infections. Severe forms of varicella can be prevented by vaccinating seronegative patients against varicella zoster virus. Detection and treatment of latent tuberculosis is mandatory before starting anti-TNF therapy and other new IBD drugs. Tofacitinib promotes herpes zoster infection in a dose- and age-dependent manner. Physicians should consider giving patients live vaccines against herpes zoster before they begin immunosuppressive therapy or a recombinant vaccine, when available, at any time point during treatment. Risk of thiopurine-induced lymphomas can be lowered by limiting the use of thiopurines in patients who are seronegative for Epstein-Barr virus (especially young men) and in older men. The risk of lymphoma related to monotherapy with anti-TNF agents is still unclear. There are no robust data on carcinogenic effects of recently developed IBD drugs. For patients with previous cancer at substantial risk of recurrence, physicians should try to implement a pause in the use of immunosuppressive therapy (except in patients with severe disease and no therapeutic alternative) and prioritize use of IBD drugs with lowest carcinogenic effects. Finally, sun protection and skin surveillance from the time of diagnosis are recommended