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

HLA-DP on Epithelial Cells Enables Tissue Damage by NKp44+ Natural Killer Cells in Ulcerative Colitis

Background & aims: Ulcerative colitis (UC) is characterized by severe inflammation and destruction of the intestinal epithelium, and is associated with specific risk single nucleotide polymorphisms in HLA class II. Given the recently discovered interactions between subsets of HLA-DP molecules and the activating natural killer (NK) cell receptor NKp44, genetic associations of UC and HLA-DP haplotypes and their functional implications were investigated.Methods: HLA-DP haplotype and UC risk association analyses were performed (UC: n = 13,927; control: n = 26,764). Expression levels of HLA-DP on intestinal epithelial cells (IECs) in individuals with and without UC were quantified. Human intestinal 3-dimensional (3D) organoid cocultures with human NK cells were used to determine functional consequences of interactions between HLA-DP and NKp44.Results: These studies identified HLA-DPA1∗01:03-DPB1∗04:01 (HLA-DP401) as a risk haplotype and HLA-DPA1∗01:03-DPB1∗03:01 (HLA-DP301) as a protective haplotype for UC in European populations. HLA-DP expression was significantly higher on IECs of individuals with UC compared with controls. IECs in human intestinal 3D organoids derived from HLA-DP401pos individuals showed significantly stronger binding of NKp44 compared with HLA-DP301pos IECs. HLA-DP401pos IECs in organoids triggered increased degranulation and tumor necrosis factor production by NKp44+ NK cells in cocultures, resulting in enhanced epithelial cell death compared with HLA-DP301pos organoids. Blocking of HLA-DP401-NKp44 interactions (anti-NKp44) abrogated NK cell activity in cocultures.Conclusions: We identified an UC risk HLA-DP haplotype that engages NKp44 and activates NKp44+ NK cells, mediating damage to intestinal epithelial cells in an HLA-DP haplotype-dependent manner. The molecular interaction between NKp44 and HLA-DP401 in UC can be targeted by therapeutic interventions to reduce NKp44+ NK cell-mediated destruction of the intestinal epithelium in UC

Withdrawal of infliximab or concomitant immunosuppressant therapy in patients with Crohn's disease on combination therapy (SPARE): a multicentre, open-label, randomised controlled trial.

BACKGROUND: The combination of infliximab and immunosuppressant therapy is a standard management strategy for patients with Crohn's disease. Concerns regarding the implications of long-term combination therapy provided the rationale for a formal clinical trial of treatment de-escalation. Our aim was to compare the relapse rate and the time spent in remission over 2 years between patients continuing combination therapy and those stopping infliximab or immunosuppressant therapy. METHODS: This multicentre, open-label, randomised controlled trial was performed in 64 hospitals in seven countries in Europe and Australia. Adult patients with Crohn's disease in steroid-free clinical remission for more than 6 months, on combination therapy of infliximab and immunosuppressant therapy for at least 8 months were randomly assigned (1:1:1) to either continue combination therapy (combination group), discontinue infliximab (infliximab withdrawal group), or discontinue immunosuppressant therapy (immunosuppressant withdrawal group). Randomisation was stratified according to disease duration before start of first anti-TNF treatment (≤2 or >2 years), failure of immunosuppressant therapy before start of infliximab, and presence of ulcers at baseline endoscopy. The patient number and group of each stratum were assigned by a central online randomisation website. Treatment was optimised or resumed in case of relapse in all groups. Participants, those assessing outcomes, and those analysing the data were not masked to group assignment. The coprimary endpoints were the relapse rate (superiority analysis) and time in remission over 2 years (non-inferiority analysis, non-inferiority margin 35 days). Analyses were done on an intention-to-treat basis. This study is registered with ClinicalTrials.gov, NCT02177071, and with EU Clinical Trials Register, EUDRACT 2014-002311-41. The trial was completed in April, 2021. FINDINGS: Between Nov 2, 2015, and April 24, 2019, 254 patients were screened. Of these, 211 were randomised and 207 were included in the final analysis (n=67 in the combination group, n=71 in the infliximab withdrawal group, and n=69 in the immunosuppressant withdrawal group). 39 patients had a relapse (eight [12%] of 67 in the combination group, 25 [35%] of 71 in the infliximab withdrawal group, six [9%] of 69 in the immunosuppressant withdrawal group). 2-year relapse rates were 14% (95% CI 4-23) in the combination group, 36% (24-47) in the infliximab withdrawal group, and 10% (2-18) in the immunosuppressant withdrawal group (hazard ratio [HR] 3·45 [95% CI 1·56-7·69], p=0·003, for infliximab withdrawal vs combination, and 4·76 [1·92-11·11], p=0·0004, for infliximab withdrawal vs immunosuppressant withdrawal). Of 28 patients who had a relapse and were retreated or optimised according to protocol, remission was achieved in 25 patients (one of two in the combination group, 22 of 23 in the infliximab withdrawal group, and two of three in the immunosuppressant withdrawal group). The mean time spent in remission over 2 years was 698 days (95% CI 668-727) in the combination group, 684 days (651-717) in the infliximab withdrawal group, and 706 days (682-730) in the immunosuppressant withdrawal group. The difference in restricted mean survival time in remission was -14 days (95% CI -56 to 27) between the infliximab withdrawal group and the combination group and -22 days (-62 to 16) between the infliximab withdrawal group and the immunosuppressant withdrawal group. The 95% CIs contained the non-inferiority threshold (-35 days). We recorded 31 serious adverse events, in 20 patients, with no difference in frequency between groups. The most frequent serious adverse events were infections (four in the combination group, two in the infliximab withdrawal group, and one in the immunosuppressant withdrawal group) and Crohn's disease exacerbation (three in the combination group, four in the infliximab withdrawal group, and one in the immunosuppressant withdrawal group). No death nor malignancy was recorded. INTERPRETATION: In patients with Crohn's disease in sustained steroid-free remission under combination therapy with infliximab and immunosuppressant therapy, withdrawal of infliximab should only be considered after careful assessment of risks and benefits for each patient, whereas withdrawal of immunosuppressant therapy could generally represent a preferable strategy when considering treatment de-escalation. FUNDING: European Union's Horizon 2020

Management of IBD Patients with Current Immunosuppressive Therapy and Concurrent Infections.

In an era of increasing use of immunomodulator therapy and biologics, opportunistic infections (OI) have emerged as a pivotal safety issue in patients with inflammatory bowel disease (IBD). Clinical studies, registries and case reports warn about the increased risk for infections, particularly OIs. Today, the challenge for a physician is not only to manage IBD, but also to recognize, prevent and treat common and uncommon infections. The 2014 European Crohn's and Colitis Organisation (ECCO) guidelines on the management and prevention of OIs in patients with IBD provide clinicians with guidance on the prevention, detection and management of OIs. Proposals may appear radical, potentially changing the current practice, but we believe that the recommendations will help optimize patient outcomes by reducing the morbidity and mortality related to OIs. In this ongoing process, prevention is by far the first and most important step. Prevention of OIs relies on recognition of risk factors for infection, the use of primary or secondary chemoprophylaxis, careful monitoring (clinical and laboratory work-up) before and during the use of immunomodulators, vaccination and education of the patient. Special recommendations should also be given to patients before and after travel

Lymphatic vessels and lymphangiogenesis in inflammatory bowel disease

Anomalies in the lymphatic vasculature were identified in the initial descriptions of Crohn's disease on surgical specimens that had not been subjected to different drug treatments. However, it is unclear whether these morphological anomalies were early events, possibly primary, or whether these alterations were secondary to chronic inflammation. First, we mapped the lymphatic vasculature in Crohn's disease and ulcerative colitis. We therefore showed the growth of lymphatic vessels (lymphangiogenesis) in different segments of intestine, not only in inflammatory zones but also in areas devoid of inflammatory infiltrate and this feature was observed both in Crohn's disease and ulcerative colitis. We revealed that significant remodeling of lymphatic vasculature precedes the appearance of histological lesions. The mechanism causing the proliferation of lymphatic vessels in healthy zone remains poorly understood because no growth factors generally recognized as responsible for lymphangiogenesis have been found in these areas. We further found that in Crohn's disease, the degree of lymphangiogenesis in non-inflamed sections is highly variable from one patient to another. In a second step, we investigated whether this lymphangiogenesis was a sign of an early lymphatic dysfunction or if, on the contrary, it was an appropriate and adequate response found in some individuals. Using postoperative recurrence model in Crohn's disease, we showed that early lymphan-giogenesis decreased the recurrence in ileal disease. Thus, patients with low lymphatic density in non-inflamed ileal resection margin tend to have recurrence on neo terminal ileum more severely than those with high lymphatic density. It is therefore likely that in the "gut wall", lymphatic function is not initially affected. However, it appears that early alterations of lymphatics exist in the mesentery and it will be important in future works to study in parallel lymphatic alterations in the "gut wall" and in the mesentery.(BIFA - Sciences biomédicales et pharmaceutiques) -- UCL, 201

Prevention and management of infectious complications in IBD.

In an era of increasing use of immunomodulating therapy and biologics, opportunistic infections have emerged as a pivotal safety concern for patients with IBD. Clinical studies, registries and case reports warn of the increased risk of infection, particularly opportunistic infections. The current challenge to physicians lies not only in managing IBD, but also in recognizing, preventing and treating common and uncommon infections. The European Crohn's and Colitis Organization (ECCO) guidelines on the management and prevention of opportunistic infections in patients with IBD provide clinicians with guidance on the prevention, detection and management of such infections. The proposals therein may appear radical, potentially changing current practice, but we believe that these recommendations will help optimize patient outcome by reducing the morbidity and mortality related to these infections. In this ongoing process, prevention is by far the most important step; this relies on the recognition of risk factors for infection, the use of primary or secondary chemoprophylaxis, careful monitoring (clinical and laboratory work-up) before and during use of immunomodulators and the vaccination and education of the patient. Special recommendations should also be given to patients before and after travelling. Management of infection in IBD patients is case-dependent. Severe infection should be treated according to advice from infectious-disease experts

Eruptions psoriasiformes et eczématiformes chez les malades traités par anti-TNF pour une maladie inflammatoire du tube digestif (étude rétrospective multicentrique)

LILLE2-BU Santé-Recherche (593502101) / SudocSudocFranceF

Severe acute cholestatic hepatitis with prolonged cholestasis and bile-duct injury following atorvastatin therapy: a case report.

We report the case of a patient who exhibited severe acute hepatitis with symptomatic cholestasis for more than 3 months and bile duct injury following the prescription of atorvastatin. After withdrawal the drug, the patient's wellbeing slowly improves and biological features normalize in 4 months. Therapy aimed at treating severe liver steatosis and hypercholesterolemia. Atorvastatin is a highly effective 3-hydroxy-3 methylglutamyl- coenzyme A reductase (statin) used to lower low-density lipoprotein. Reported frequent adverse events of the medication include nausea, depression, myalgia, abdominal pain and abnormal liver function tests. Although abnormal liver function tests is not an uncommon side effect of the medication, more serious liver injury is rare. In a recent literature review, about ten cases of serious hepatotoxicity have been documented. In the typical presentation, the duration of exposure prior to hepatic toxicity is variable. Liver injury is generally of the mixed type. A prolonged cholestasis for more than 3 months has been seldom reported. Morphological changes includes canalicular cholestasis, feathery degeneration but no cholangiolitis nor cholangitis under the form of cytological and inflammatory changes at the level of interlobular bile ducts. This case report provides further evidence that among statins, atorvastatin may be implicated in drug-induced liver injury and indicates for the first time that such liver injury may be followed by prolonged cholestasis and interlobular bile duct injury. Atorvastatin has thus to be added to the list of medication potentially responsible for bile duct injury