Jacques Sarles

Incidence of Autoimmune Diseases in Celiac Disease: Protective Effect of the Gluten-Free Diet

BACKGROUND & AIMS Celiac disease may be associated with autoimmune diseases. The aims of the present study were to determine in celiac patients which factors modulate the risk of autoimmune disease and to evaluate the effect of the gluten-free diet. METHODS The occurrence of autoimmune disease and compliance to gluten-free diet were specified retrospectively in 924 celiac patients recruited from 27 French pediatric and adult gastroenterology centers. RESULTS One or several autoimmune diseases had developed in 178 patients. The cumulative risk of autoimmune disease was 8.1% +/- 1% at age 15, and 15.7% +/- 1.5% at age 30. Factors associated with an increased risk were family history of autoimmunity (hazard ratio, 2.36; 95% confidence interval, 1.71-3.31) and diagnosis of celiac disease before 36 years of age (hazard ratio, 2.65; 95% confidence interval, 1.79-3.85). After diagnosis of celiac disease, 55 of 788 patients developed an autoimmune disease. The cumulative risk of subsequent autoimmune disease was lower in patients compliant to a gluten-free diet versus noncompliant patients (at 10 years, 6% +/- 2% vs 15.6% +/- 5.9%, respectively; P = .02). The incidence of autoimmune diseases was 5.4 per 1000 patient-years during adherence to a gluten-free diet versus 11.3 per 1000 patient-years during nonadherence to the diet (P = .002). Results were similar in both the pediatric and the adult populations. CONCLUSIONS Celiac patients most at risk for autoimmune disease are those diagnosed early in life and having a family history of autoimmunity. The gluten-free diet has a protective effect.

Interferon alfa therapy for chronic hepatitis B in children: A multinational randomized controlled trial

BACKGROUND & AIMS Treatment of chronic hepatitis B with interferon alfa is not approved in children. The aim of this study was to evaluate the safety and efficacy of interferon alfa (IFN-alpha) in children with chronic hepatitis B and increased transaminase levels. METHODS Children were given either IFN-alpha2b (6 megaunits/m2 thrice weekly for 24 weeks) or no treatment. Clearance of markers of viral replication was evaluated 24 weeks after therapy and after 48 weeks of observation in controls. RESULTS Of 149 children enrolled, 144 were evaluable (70 treated and 74 controls). Serum hepatitis B e antigen and viral DNA became negative in 26% of treated children and 11% of controls (P < 0.05). Serum aminotransferase levels normalized and liver histology improved among responders. Hepatitis B surface antigen became undetectable in 10% of treated patients and 1% of controls. Female gender and interferon treatment were the only significant predictors of response. Ethnic origin, baseline aminotransferase level, initial DNA levels, and histology did not correlate with response. Most adverse reactions were mild or moderate, and dose was reduced in 24% of children. CONCLUSIONS In children with chronic hepatitis B, INF-alpha promotes loss of viral replication markers and surface antigen and improves aminotransferases and histology.

Impact of age at Kasai operation on its results in late childhood and adolescence: a rational basis for biliary atresia screening

BACKGROUND. Increased age at surgery has a negative impact on results of the Kasai operation for biliary atresia in infancy and early childhood. It remained unclear if an age threshold exists and if this effect persists with extended follow-up. In this study we examined the relationship between increased age at surgery and its results in adolescence. METHODS. All patients with biliary atresia who were living in France and born between 1986 and 2002 were included. Median follow-up in survivors was 7 years. RESULTS. Included in the study were 743 patients with biliary atresia, 695 of whom underwent a Kasai operation; 2-, 5-, 10-, and 15-year survival rates with native liver were 57.1%, 37.9%, 32.4%, and 28.5%, respectively. Median age at Kasai operation was 60 days and was stable over the study period. Whatever the follow-up (2, 5, 10, or 15 years), survival rates with native liver decreased when age at surgery increased (≤30, 31–45, 46–60, 61–75, and 76–90 days). Accordingly, we estimated that if every patient with biliary atresia underwent the Kasai operation before 46 days of age, 5.7% of all liver transplantations performed annually in France in patients younger than 16 years could be spared. CONCLUSIONS. Increased age at surgery had a progressive and sustained deleterious effect on the results of the Kasai operation until adolescence. These findings indicate a rational basis for biliary atresia screening to reduce the need for liver transplantations in infancy and childhood.

NTBC treatment in tyrosinaemia type I: Long-term outcome in French patients

SummaryWe describe a retrospective study of long-term outcome of 46 patients treated and regularly followed in France with 2-(2-nitro-4-trifluoromethylbenzoyl)-1, 3-cyclohexanedione (NTBC) for tyrosinaemia type I. Most had initial good response with normalization of liver function and metabolic parameters. Only one infant had no response to treatment and required liver transplantation. Among the 45 long-term treated patients, three underwent secondary liver transplantation: one for cirrhosis and two because of hepatocellular carcinoma. One of the latter died of transplantation complications, so that the overall survival rate was 97.5%. However, 17 of 45 showed persistent abnormal liver imaging (heterogeneous liver) and 6 had cirrhosis. Furthermore, 15 had persistently elevated levels of alpha-fetoprotein, highlighting the question of the persistent risk of carcinoma. Quality of life was usually good but compliance problems were frequent, mainly regarding the low phenylalanine–tyrosine diet. Few adverse effects were observed. A main concern was the high frequency of cognitive impairment causing schooling problems, which may be related to persistent chronic hypertyrosinaemia. In conclusion, this series confirms that NTBC treatment has clearly improved the vital prognosis and quality of life of tyrosinaemia type I patients but that many late complications persist. Long-term studies are necessary to determine whether this drug may prevent or only delay liver complications, andto survey the possible risks of the drug. A more restricted diet could be necessary to prevent the neurological impact of the disease.

Management of patients with biliary atresia in France: Results of a decentralized policy 1986-2002†‡§

This study analyzed the results of the decentralized management of biliary atresia (BA) in France, where an improved collaboration between centers has been promoted since 1997. Results were compared to those obtained in England and Wales, where BA patients have been centralized in three designated centers since 1999. According to their birth dates, BA patients were divided into two cohorts: cohort A, with patients born between 1986 and 1996, had 472 patients; and cohort B, with patients born between 1997 and 2002, had 271 patients. Survival rates were calculated according to the Kaplan‐Meier method and compared by using the log rank test and the Cox model. Four‐year overall BA patient survival was 73.6% (95% CI 69.5%‐77.7%) and 87.1% (CI 82.6%‐91.6%) in cohorts A and B, respectively (P < .001). Median age at time of the Kasai operation was 61 and 57 days in cohorts A and B, respectively (NS). Four‐year survival with native liver after the Kasai operation was 40.1% and 42.7% in cohorts A and B, respectively (NS): 33.9% (cohort A) and 33.4% (cohort B) in the centers with two or fewer caseloads a year, 30.9% (cohort A) and 44.5% (cohort B) in the centers with 3‐5 cases/year, 47.8% (cohort A) and 47.7% (cohort B) in the center with more than 20 caseloads a year. In cohorts A and B, 74 (15.7%) and 19 (7%) patients, respectively, died without liver transplantation (LT). Four‐year survival after LT was 75.1% and 88.8% in cohorts A and B, respectively (P = .006). In conclusion, BA patients currently have the same chance of survival in France as in England and Wales. The early success rate of the Kasai operation remains inferior in the centers with limited caseloads in France, leading to a greater need for LTs in infancy and early childhood. (HEPATOLOGY 2006;44:75–84.)

Anakinra is safe and effective in controlling hyperimmunoglobulinaemia D syndrome-associated febrile crisis

SummaryHyper-IgD and periodic fever syndrome (HIDS) is a hereditary autoinflammatory syndrome, characterized by recurrent inflammatory attacks. Treatment of HIDS is difficult. Recently, the IL-1ra analogue anakinra was reported to be successful in aborting the IgD inflammatory attacks in a vaccination model. We report a clinical case of spectacular reduction of febrile attacks in a severe HIDS patient.

Efficacy of Infliximab in Pediatric Crohn's Disease : A Randomized Multicenter Open-label Trial Comparing Scheduled to On Demand Maintenance Therapy

Background: Infliximab (IFX) is efficacious in inducing remission in severe forms of pediatric Crohns disease (CD). Adult studies indicate that IFX is also safe and well tolerated as maintenance therapy. The present study aimed to evaluate in a prospective manner the efficacy and safety of IFX as maintenance therapy of severe pediatric CD comparing scheduled and “on demand” treatment strategies. Methods: Forty children with CD (nonpenetrating, nonstricturing as well as penetrating forms, mean age: 13.9 ± 2.2 years) with a severe flare‐up (Harvey–Bradshaw Index [HBI] ≥5, erythrocyte sedimentation rate [ESR] >20 mm/h) despite well‐conducted immunomodulator therapy (n = 36 azathioprine, n = 1 mercaptopurine, n = 3 methotrexate) combined with steroids were included in this randomized, multicenter, open‐label study. Three IFX infusions (5 mg/kg) were administered at week (W)0/W2/W6. At W10, clinical remission (HBI <5) and steroid withdrawal were analyzed and IFX responders were randomized to maintenance therapy over 1 year: group A, scheduled every 2 months; group B, “on demand” on relapse. Results: In all, 34/40 children came into remission during IFX induction therapy (HBI: 6.7 ± 2.5 (WO) vs. 1.1 ± 1.5 (W10); P < 0.001). At the end of phase 2, 15/18 (83%) patients were in remission in group A compared to 8/13 (61%) children in group B (P < 0.01), with a mean HBI of 0.5 versus 3.2 points (group A versus B, P = 0.011). In group A, 3/13 (23.1%) children experienced a relapse compared to 11/12 (92%) children in group B. No severe adverse event occurred during this trial. Conclusions: IFX is well tolerated and safe as maintenance therapy for pediatric CD, with a clear advantage when used on a scheduled 2‐month basis compared to an “on demand” basis.

SKIV2L mutations cause syndromic diarrhea, or trichohepatoenteric syndrome.

Syndromic diarrhea (or trichohepatoenteric syndrome) is a rare congenital bowel disorder characterized by intractable diarrhea and woolly hair, and it has recently been associated with mutations in TTC37. Although databases report TTC37 as being the human ortholog of Ski3p, one of the yeast Ski-complex cofactors, this lead was not investigated in initial studies. The Ski complex is a multiprotein complex required for exosome-mediated RNA surveillance, including the regulation of normal mRNA and the decay of nonfunctional mRNA. Considering the fact that TTC37 is homologous to Ski3p, we explored a gene encoding another Ski-complex cofactor, SKIV2L, in six individuals presenting with typical syndromic diarrhea without variation in TTC37. We identified mutations in all six individuals. Our results show that mutations in genes encoding cofactors of the human Ski complex cause syndromic diarrhea, establishing a link between defects of the human exosome complex and a Mendelian disease.

Efficacy and tolerance of infliximab in children and adolescents with Crohn's disease.

Infliximab, a monoclonal antibody against tumor necrosis factor-alpha, has been shown to be effective for the treatment of refractory Crohn’s disease in adult patients, but experience in pediatrics is limited. This retrospective study included 88 children and adolescents, 39 girls and 49 boys, with a median age of 14 years (range 3.3–17.9). Infliximab was indicated for active disease (66%) and/or fistulas (42%) that were refractory to corticosteroids (70%), and/or other immunosuppressive (82%) agents, and/or parenteral nutrition (20%). Patients received 1 to 17 infusions (median 4) of 5 mg/kg (range 3.8–7.3) of infliximab during a median time period of 4 months (1–17 months). Infusion reaction was noted in 13 patients (15%), with a total of 16 reactions in 450 infusions (4%). At Day 90 after the first infusion of infliximab, symptoms improved in 49% of patients, whereas 29% of patients were in remission and 13% of patients relapsed. From Day 0 to Day 90, Harvey–Bradshaw score decreased from 7.5 to 2.8 (P < 0.001), C-reactive protein from 36 to 16 mg/L (P < 0.01), and 1-hour erythrocyte sedimentation rate from 35 to 17 mm (P < 0.01). Dosage of corticosteroids decreased from to 0.59 to 0.17 mg/kg/d (P < 0.001); 53% of patients could be weaned of corticosteroids and 92% of parenteral nutrition. Treatment with infliximab is well tolerated and effective in most children and adolescents with Crohn’s disease that is refractory to conventional immunosuppressive therapy. Nevertheless, long-term efficacy remains to be shown, and further studies are urgently needed to precisely determine the best modality of continuing treatment.

Impact of chronic hepatitis B and interferon-α therapy on growth of children

Interferon‐α (IFN) has been approved as treatment for children with chronic hepatitis B (CHB). The aims of this study were to assess the impact on children’s growth of the disease itself and of IFN treatment. The growth of 142 children with CHB (70 IFN‐treated, 72 untreated) was monitored for a minimum of one year. Regression analysis models were used to determine which of the variables most affected children’s growth. After adjusting for racial differences, the population of 142 children with CHB had a mean baseline height for age percentile of 39 and a mean baseline weight for age percentile of 38, which were significantly different (P < 0.0001) from the 50th percentiles of their respective reference populations. The height for age Z score of untreated children was inversely correlated with serum hepatitis B virus DNA and aspartate aminotransferase levels, and the weight for age Z score was inversely correlated with serum hepatitis B virus DNA levels. While undergoing IFN therapy, children displayed a ‘U‐shaped’ growth pattern, such that height for age and weight for age Z scores at 3 or 6 months were lower than scores at baseline or 12 months. In this study the average child with CHB showed compromised growth even in the absence of IFN therapy. During IFN therapy, children’s growth was temporarily disrupted.