Analysis of Genes Associated With Monogenic Primary Immunodeficiency Identifies Rare Variants in XIAP in Patients With Crohn's Disease.

BACKGROUND & AIMS: A few rare monogenic primary immunodeficiencies (PIDs) are characterized by chronic intestinal inflammation that resembles Crohn's disease (CD). We investigated whether 23 genes associated with 10 of these monogenic disorders contain common, low-frequency, or rare variants that increase risk for CD. METHODS: Common and low frequency variants in 1 Mb loci centered on the candidate genes were analyzed using meta-data corresponding to genotypes of approximately 17,000 patients with CD or without CD (controls) in Europe. The contribution of rare variants was assessed by high-throughput sequencing of 4750 individuals, including 660 early-onset and/or familial cases among the 2390 patients with CD. Variants were expressed from vectors in SW480 or HeLa cells and functions of their products were analyzed in immunofluorescence, luciferase, immunoprecipitation, and immunoblot assays. RESULTS: We reproduced the association of the interleukin 10 locus with CD (P = .007), although none of the significantly associated variants modified the coding sequence of interleukin 10. We found XIAP to be significantly enriched for rare coding mutations in patients with CD vs controls (P = .02). We identified 4 previously unreported missense variants associated with CD. Variants in XIAP cause the PID X-linked lymphoproliferative disease type 2, yet none of the carriers of these variants had all the clinical features of X-linked lymphoproliferative disease type 2. Identified XIAP variants S123N, R233Q, and P257A were associated with an impaired activation of NOD2 signaling after muramyl dipeptide stimulation. CONCLUSIONS: In a systematic analysis of variants in 23 PID-associated genes, we confirmed the association of variants in XIAP with CD. Further screenings for CD-associated variants and analyses of their functions could increase our understanding of the relationship between PID-associated genes and CD pathogenesis.

Consecutive fecal calprotectin measurements to predict relapse in patients with ulcerative colitis receiving infliximab maintenance therapy.

BACKGROUND: This study examined whether fecal calprotectin can be used in daily practice as a marker to monitor patients with ulcerative colitis (UC) receiving infliximab maintenance therapy. METHODS: This prospective multicenter study enrolled adult patients with UC in clinical remission under infliximab maintenance therapy. Fecal calprotectin levels were measured every 4 weeks. Sigmoidoscopies were performed at inclusion and at study end. Relapse was defined as a clinical need for change in treatment or an endoscopic Mayo subscore of ≥2 at week 52. Sustained deep remission was defined as a partial Mayo score <3 at all points and an endoscopic Mayo score 0 at week 52. RESULTS: Full analysis was possible for 87 of 113 included patients with UC (77%). Of these patients, 30 (34.4%) were considered to be in sustained deep remission and 13 (14.9%) to have relapsed. Calprotectin levels in patients with sustained deep remission remained very low (median < 40 mg/kg at all time points). Patients who flared had significantly higher calprotectin levels (median > 300 mg/kg) already 3 months before the flare. Further receiver operator curve analysis suggested that a calprotectin level >300 mg/kg had a reasonable sensitivity (58.3%) and specificity (93.3%) to model flare. Two consecutive calprotectin measurements of >300 mg/kg with 1-month interval were identified as the best predictor of flare (61.5% sensitivity and 100% specificity). CONCLUSIONS: Fecal calprotectin can be used in daily practice to monitor patients with UC receiving infliximab maintenance therapy. Two consecutive measurements >300 mg/kg is more specific than a single measurement for predicting relapse.

Acute upper gastrointestinal bleeding in cirrhosis: changes and advances over the past two decades.

BACKGROUND AND AIMS: Few studies have compared two or more cohorts of cirrhotic patients admitted for upper gastrointestinal bleeding (UGIB) several decades apart. Our aim was to compare epidemiological, clinical, therapeutic and prognostic characteristics of UGIB (whatever the source) in two cohorts of cirrhotic patients admitted to the emergency room of the same general hospital 2 decades apart. METHODS: One-hundred cases of UGIB in cirrhotic patients consecutively admitted between 1984 and 1990 (cohort A) were compared with 100 similar cases admitted between 2004 and 2009 (cohort B). RESULTS: The sex ratio (M/F: 2/1), mean age (approximately 55Y) and the proportion of patients with alcoholic cirrhosis (approximately 80%) did not change. Mean Child-Pugh score and the proportion of patients in Child-Pugh stage C increased from 7.6 and 19% in cohort A to 8.8 and 35% in cohort B (p < 0.001). Therapeutic intervention was performed during initial endoscopy in 13 cases from cohort A and 50 from cohort B (p < 0.001), respectively. The number of transfused patients (85 in cohort A, 58 in cohort B) and the number of red blood cell units administered on the first day (median: 4 in cohort A, 2 in cohort B) were significantly decreased in cohort B (p < 0.001). The rate of rebleeding (45 in cohort A, 11 in cohort B), the need for rescue surgery (8 in cohort A, 0 in cohort B) and the in-hospital mortality (24 in cohort A, 9 in cohort B) significantly decreased in the more recent cohort (p < 0.005). CONCLUSION: This study demonstrated that several characteristics of cirrhotic patients admitted with UGIB have changed over the past 2 decades. Above all, outcome has improved despite an increase in the severity of cirrhosis.

[Screening for hepatocarcinoma in a cohort with cirrhosis mainly of alcoholic origin]. / Dépistage du carcinome hépatocellulaire dans une cohorte de malades porteurs d'une cirrhose d'origine principalement alcoolique.

OBJECTIVES: To assess the feasibility and efficiency of the screening for hepatocarcinoma in a cohort of cirrhoseis mainly of alcoholic origin. PATIENTS AND METHODS: 293 patients with cirrhosis, among them 186 (63.5%) from alcoholic origin, were included in a surveillance programme for hepatocarcinoma by carrying out liver ultrasonography and alpha-foetoprotein dosage every 6 months. Results were analyzed with a mean follow-up of 60 months. Seventeen hepatocarcinoma discovered through the surveillance programme ("screened HCC") were compared with 40 hepatocarcinoma discovered outside the surveillance programme during the same period ("incidental HCC"). RESULTS: The alcoholic origin of the cirrhosis was a predictive factor of poor compliance to the surveillance programme. Among the 186 patients with alcoholic cirrhosis, 129 (69%) were lost during the surveillance programme due to lack of compliance (97 cases) or death (32 cases). By comparison, among the 65 patients with hepatitis C-related cirrhosis, 18 were lost by lack of compliance (11 cases) or death (7 cases) (P<0.001). Moreover, sustained or relapsing alcohol abuse after inclusion in the surveillance programme were also related to the quality of the compliance. Seventeen hepatocarcinoma were discovered through the surveillance giving an annual incidence of 2% for the emergence of hepatocarcinoma. The comparison between screened (n=17) and incidental (n=40) hepatocarcinoma showed that screened HCC were more often asymptomatic (P<0.01), were more often a solitary nodule less than 5 cms (P<0.001) and underwent more often curative treatment (P=0.02). However, the survival between screened and incidental hepatocarcinoma was not different. CONCLUSIONS: Screening for hepatocarcinoma in patients with alcoholic cirrhosis is a difficult task due to poor compliance and early death. According to our results, a surveillance every 6 months is sufficient to detect early lesions accessible to curative treatment by surgical resection or transcutaneous ablation.