Adalimumab Biosimilar in Pediatric Inflammatory Bowel Disease: A Retrospective Study from the Sicilian Network for Inflammatory Bowel Disease (SN-IBD).

BACKGROUND: The utilization of anti-tumor necrosis factor-α (anti-TNF-α) biosimilars in inflammatory bowel disease (IBD) is constantly increasing. However, pediatric data are limited. This study aimed to assess the effectiveness and safety of adalimumab biosimilar (ADL-BioS) in pediatric IBD patients. METHODS: All consecutive pediatric IBD patients from the Sicilian Network for Inflammatory Bowel Disease cohort treated with ADL-BioS from 2019 to 2021 were recruited. Remission at weeks 14 and 52, treatment persistence, and adverse events were the endpoints of this study. Factors associated with clinical remission and treatment persistence were examined. RESULTS: There were 41 patients in total. Nine (22%) patients were switched from the reference product to ADL-BioS. Two patients had multiple switches. Eleven months was the median follow-up period. Clinical remission was attained by 70.7% and 72.0% of patients on weeks 14 and 52, respectively. Four (9.8%) adverse events occurred (10.1/100 person-year). Treatment persistence was 85.4% at 1 and 2 years. Patients with a longer duration of disease had a higher probability of stopping their treatment (p = 0.036). CONCLUSIONS: This is the first real-world study that particularly addresses the use of ADL-BioS in pediatric IBD. With high rates of treatment persistence and a low frequency of non-serious side effects, ADL-BioS seems to be effective.

Raman Spectroscopy and Cystic Fibrosis Disease: An Alternative Potential Tool for Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Modulator Response Differentiation-A Pilot Study Based on Serum Samples.

Cystic fibrosis (CF) is a genetic disorder that alters chloride transport in mucous membranes. Recent studies have demonstrated that treatment with modulators of the chloride channel reduces inflammatory markers, restoring, among others, the imbalance of lipids. In this study, we analyzed the serum samples of treated and non-treated patients with modulators with Raman spectroscopy. Nineteen (eight treated an eleven non-treated) patients were considered. The main difference between the two groups appeared in the 3020-2800 cm-1 range. A Voigt deconvolution fit was performed, and nine sub-bands were identified. To distinguish between treated and non-treated patients, the area ratio between the CH3 and CH2 vibration modes was calculated for each patient. The results were validated using statistical analyses. In particular, receiver operating characteristic (ROC) curves and Youden index (Y) were calculated (Area Under Curve (AUC): 0.977; Y: 3.30). An ROC curve represents the performance of the classification, illustrating the diagnostic ability of Raman spectroscopy. It was demonstrated that Raman spectroscopy is able to highlight peculiar differences between elexacaftor/tezacaftor/ivacaftor (ETI)-treated and non-treated patients, in relation with lipids biomarkers.

Factors that influence infliximab biosimilar trough levels in the pediatric inflammatory bowel disease population.

BACKGROUND: The pharmacokinetics and pharmacodynamics of biosimilar infliximab (IFX-BioS) in pediatric inflammatory bowel disease (IBD) are poorly investigated. The aim of this study was to investigate factors predicting IFX-BioS trough levels (TLs). RESEARCH DESIGN AND METHODS: IBD children with an indication to start IFX-BioS were included in this prospective observational study (January 2021-June 2022). TLs were measured at the 4th and 6th infusions and correlated with several covariates. RESULTS: A total of 110 TLs in 55 children were included. The multivariate linear regression model at the 4th infusion found a positive correlation between TLs and age at diagnosis (B:1.950, 95% CI: [0.019, 3.882], p = 0.048) and IFX-BioS dose/kg (B:1.962, 95% CI: [0.238, 3.687], p = 0.029), and a negative correlation with clinical scores (B:-0.401, 95% CI: [-0.738, -0.064], p = 0.023). At the 6th infusion, female gender (B:6.887, 95% CI: [0.861, 12.913], p = 0.029), hemoglobin (B:1.853, 95% CI: [0.501, 3.204], p = 0.011), and IFX-BioS dose/kg (B:1.792, 95% CI: [0.979, 2.605], p < 0.001) were found to be positively correlated to TLs. No association between combined clinical and biochemical remission and TLs was found. CONCLUSIONS: This study discovered some predictors for IFX-BioS TLs in IBD children. Knowledge of predictive factors could help physicians choose the best dosing regimen.

Real-life experience of infliximab biosimilar in pediatric-onset inflammatory bowel disease: data from the Sicilian Network for Inflammatory Bowel Disease.

OBJECTIVE: To provide data on the use of infliximab biosimilars (IFX-BioS) in children with inflammatory bowel disease (IBD). METHODS: A multicenter, observational, retrospective study was performed among the cohort of the Sicilian Network for IBD. All consecutive IBD children who had at least completed the induction with IFX-BioS from its introduction in Sicily to January 2021 were enrolled. Clinical remission at weeks 14 and 52, treatment persistence, and adverse events were the study outcomes. RESULTS: Eighty-seven patients [Crohn's disease (CD): 57.5% and ulcerative colitis (UC): 42.5%] were included: 75 (86.2%) were antitumor necrosis factor-α (anti-TNF-α) agent naïve, while three (3.45%) were switched from the originator to IFX-BioS. Twenty (23%) patients were multiply switched from the biosimilar CT-P13 to SB2 or GP1111 or vice versa. The median follow-up time was 15 months. Clinical remission was achieved by 55.2 and 65.5% of patients at weeks 14 and 52, respectively, with no differences between CD and UC. Dose escalation was needed in 8.0 and 35.7% of patients during induction and maintenance, respectively. Nine adverse events occurred (incidence rate: 6.13/100 person-year). Treatment persistence was 90.8% at 1 year and 75.7% at 2 years (patients on IFX-BioS at 2 years, n = 28). The risk of treatment discontinuation was higher in patients with extraintestinal manifestations ( P = 0.018) and in those who were nonnaïve to anti-TNF-α ( P = 0.027). CONCLUSION: This is the largest cohort of pediatric IBD patients treated with IFX-BioS. Real-life data show that IFX-BioS is efficacious in IBD children, with high percentages of treatment persistence and a low incidence of nonserious adverse events.

Recognizing the Emergent and Submerged Iceberg of the Celiac Disease: ITAMA Project-Global Strategy Protocol.

Coeliac disease (CD) is frequently underdiagnosed with a consequent heavy burden in terms of morbidity and health care costs. Diagnosis of CD is based on the evaluation of symptoms and anti-transglutaminase antibodies IgA (TGA-IgA) levels, with values above a tenfold increase being the basis of the biopsy-free diagnostic approach suggested by present guidelines. This study showcased the largest screening project for CD carried out to date in school children (n=20,000) aimed at assessing the diagnostic accuracy of minimally invasive finger prick point-of-care tests (POCT) which, combined with conventional celiac serology and the aid of an artificial intelligence-based system, may eliminate the need for intestinal biopsy. Moreover, this study delves deeper into the "coeliac iceberg" in an attempt to identify people with disorders who may benefit from a gluten-free diet, even in the absence of gastrointestinal symptoms, abnormal serology and histology. This was achieved by looking for TGA-IgA mucosal deposits in duodenal biopsy. This large European multidisciplinary health project paves the way to an improved quality of life for patients by reducing the costs for diagnosis due to delayed findings of CD and to offer business opportunities in terms of diagnostic tools and support.

Vedolizumab-associated pulmonary manifestations in children with ulcerative colitis.

WHAT IS KNOWN AND OBJECTIVE: The off-label use of vedolizumab (VDZ) for inflammatory bowel disease in children is increasing. We report on possibly the first case of VDZ-associated pulmonary manifestations in paediatrics. CASE SUMMARY: This report details the case of a 13-year-old child with ulcerative colitis who was initiated on VDZ due to persistent active disease. After the first three doses, he developed a persistent and productive cough. Microbiological work-up was normal. VDZ discontinuation led to the resolution of symptoms. WHAT IS NEW AND CONCLUSION: To our knowledge, this is the first case report of VDZ-associated pulmonary manifestations in paediatrics. A direct, pro-inflammatory effect of VDZ has been hypothesized, but further studies are warranted.

Raman Spectroscopy Technique: A Non-Invasive Tool in Celiac Disease Diagnosis.

Celiac disease (CD) is diagnosed by a combination of specific serology and typical duodenal lesions. The histological confirmation of CD, mandatory in the majority of patients with suspected CD, is based on invasive and poorly tolerated procedures, such as upper gastrointestinal endoscopy. In this study we propose an alternative and non-invasive methodology able to confirm the diagnosis of CD based on the analysis of serum samples using the Raman spectroscopy technique. Three different bands centered at 1650, 1450 and 1003 cm-1 have been considered and the A1450/A1003 and A1650/A1003 ratios have been computed to discriminate between CD and non-CD subjects. The reliability of the methodology was validated by statistical analysis using receiver operating characteristic (ROC) curves. The Youden index was also determined to obtain optimal cut-off points. The obtained results highlighted that the proposed methodology was able to distinguish between CD and non-CD subjects with 98% accuracy. The optimal cut-off points revealed, for both the A1450/A1003 and A1650/A1003 ratios, high values of sensitivity and specificity (>95.0% and >92.0% respectively), confirming that Raman spectroscopy may be considered a valid alternative to duodenal biopsy and demonstrates spectral changes in the secondary structures of the protein network.

Functional constipation masked as irritable bowel syndrome.

BACKGROUND: Rome IV criteria for functional gastrointestinal disorders state that children suspected of having Irritable Bowel Syndrome (IBS) with Constipation (IBS-C) should be preliminarily treated for constipation. We aimed at verifying if functional constipation may indeed lead to an erroneous diagnosis of IBS with diarrhea (IBS-D) or IBS with mixed pattern of diarrhea and constipation (IBS-M). METHODS: We prospectively enrolled in an unblinded fashion 10 and 16 consecutive children referred to our center who met Rome IV criteria for a diagnosis of IBS-D and IBS-M, respectively. Patients who fulfilled criteria for suspect "occult constipation" were then given a bowel cleaning regimen with Polyethylene glycol 3350, re-evaluated at 2 months and followed up for at least 6 months. Sixteen additional patients with IBS with Constipation (IBS-C) referred in the same period served as control. The endpoints were: 1) a decrease of more than 50% in abdominal pain intensity and frequency scores; and 2) for patients with IBS-D and IBS-M: resolution of diarrhea. RESULTS: The endpoints were met by 8 (80%) and 14 (87%) of the patients with IBS-D and IBS-M, respectively, with decrease of abdominal pain and resolution of "diarrhea". The response was not significantly different from that observed in 15 (93%) of the IBS-C control group. CONCLUSION: Acknowledging the limitations of the small number of patients and of the uncontrolled nature of the study, we suggest that a possibly large number of patients labeled as IBS-D or IBS-M may actually simply present functional constipation and should be managed as such.

Effectiveness and safety of biologics in pediatric inflammatory boweldisease: Real-life data from the Sicilian Network.

BACKGROUND: Biological therapies have modified the disease course of pediatric inflammatory bowel disease (IBD) and are routinely used in clinical practice. Our observational study aims to evaluate effectiveness and safety of biologics in IBD. METHOD: Clinical benefit and safety data of 93 children with IBD, receiving biologics (Infliximab - IFX, Adalimumab - ADA, Golimumab - GOL) from January 2013 to December 2017, were extracted from the cohort of the Sicilian Network of IBD. RESULTS: Among 87 children aged 7-17 years (63 Crohn's disease [CD], 24 Ulcerative colitis [UC]), 101 out of 108 biologic treatments were considered. Evaluation of 74 biologic treatments in CD patients at 26, 52, 104 weeks showed clinical benefit rates of 84.2%, 93.3%, 66.7% with IFX (n= 38) and 88.9%, 84.4%, 65.2% with ADA (n= 36). Biologic treatments (n=27) evaluated in the UC group at 26, 52, 104 weeks, led to clinical benefit rates of 85.7%, 83.3%, 50% in IFX subgroup (n=21) and 40%, 50%, 33% in the ADA subgroup (n=5), respectively. One patient treated with GOL showed 100% clinical benefit at 26 and 52 weeks. Overall adverse events (AEs) rate was 9.25%. Six younger children, <6 years, receiving 8 treatments (4 ADA, 4 IFX) presented a clinical remission rate of 75% at 12 weeks and 25% at 52 weeks. AEs rate was 25% in this group. CONCLUSION: Our data show that biologic therapy in children, even at a younger age, is effective in allowing long-term remission with a good safety profile.

Diagnostic Yield of 2 Strategies for Adult Celiac Disease Identification in Primary Care.

GOALS: To compare the diagnostic yield and cost-consequences of 2 strategies, screening regardless of symptoms versus case finding (CF), using a point-of-care test (POCT), for the detection of celiac disease (CD) in primary care, to bridge the diagnostic gap of CD in adults. MATERIALS AND METHODS: All subjects under 75 years of age who consecutively went to their general practitioners' offices were offered POCT for anti-transglutaminase immunoglobulin A antibodies. The POCT was performed on all subjects who agreed, and then a systematic search for symptoms or conditions associated with higher risk for CD was performed, immediately after the test but before knowing the test results. The 2 resulting groups were: (a) POCT positive and (b) symptomatic subject at CF. Subjects were defined as symptomatic at CF in the presence of 1 or more symptoms. All POCT-positive or symptomatic subjects at CF were referred to the CD Centers for confirmation of CD. Data on resource consumption were gathered from patients' charts. Cost of examinations, and diagnostic and laboratory tests were estimated with regional outpatient tariffs (Sicily), and a price of &OV0556;2.5 was used for each POCT. RESULTS: Of a total of 2197 subjects who agreed to participate in the study, 36 (1.6%) and 671 (30.5%) were POCT positive and symptomatic at CF, respectively. The yield from the screening and CF was 5 new celiac patients. The total cost and mean cost for each new CD case were &OV0556;7497.35 and &OV0556;1499.47 for the POCT screening strategy, and &OV0556;9855.14 and &OV0556;1971.03 for the CF strategy, respectively. Assuming consecutive use of both strategies, performing POCT only in symptomatic subjects at CF, the calculated yield would be 4 new diagnoses with a total cost of &OV0556;2345.84 and a mean cost of &OV0556;586.46 for each newly diagnosed patient. Only 1 patient was celiac despite a negative POCT. CONCLUSIONS: Testing symptomatic subjects at CF only by POCT seems the most cost-effective strategy to bridge the diagnostic gap of adult CD in primary care.

Case report on pathogenetic link between gluten and IgA nephropathy.

BACKGROUND: A relationship between IgA nephropathy (IgAN) and celiac disease (CD) has been reported. We show the pathogenetic link for the first time. CASE PRESENTATION: A 39-year-old man with cystic fibrosis (CF) and CF-related diabetes started to present gross hematuria, back pain and headache. At admission, laboratory analysis showed increase in serum creatinine of 1.5 mg/dl, together with hematuria and mild proteinuria (1 g/24 h). He underwent a renal biopsy to investigate the cause of hematuria and renal failure. Biopsy was consistent with IgAN. In view of patient reported dyspepsia, an upper gastrointestinal endoscopy with duodenal biopsies was undertaken and was normal. We looked for mucosal deposits of tTG-2 in the duodenum and the renal mesangium. tTG-2 deposits were found both in the duodenum and in renal biopsies, where they topographically replicated mesangial IgA deposits. After one year on a continued gluten containing diet, the patient developed a Marsh 2 type duodenal pathology. CONCLUSIONS: Our findings suggest a connection between CD and IgAN in terms of an immune-mediated gluten-induced pathogenesis even in the absence of villous atrophy and serum celiac autoantibodies.

Cystic Fibrosis: A Risk Condition for Renal Disease.

OBJECTIVE: Cystic fibrosis (CF) is the most common autosomal recessive disease affecting the Caucasian population, with a birth incidence ranging between 1:2,500 and 1:1,800. It is caused by mutations in the CF transmembrane regulator gene which is localized on 7 chromosomes. Renal disease is reported as a relatively rare complication in adult patient with CF. We evaluated proteinuria and chronic renal failure (CRF) in a population of patients with CF. METHODS: A retrospective study was carried out in a referral center for CF at University of Messina in Italy. We identified all patients with renal disease, characterized by proteinuria and/or CRF, during the period 2007 to 2012 and reviewed their medical records to assess influence on renal disease of genotype, number of pulmonary exacerbation, pancreatic insufficiency, pulmonary function, CF-related diabetes, and antibiotics courses. RESULTS: From a population of 77 adult patients with CF, we identified 9 patients with proteinuria (11.7%), and 11 patients (14.28%) with CRF. Mean age was 35.6 (+5.1 standard deviation) years, 55% were female and 33% had diabetes mellitus. Renal biopsy was performed in 3 patients because of nephrotic syndrome in 1 patient and proteinuria with renal failure in the other 2 patients. Renal amyloidosis was disclosed in 2, whereas IgA nephropathy in 1 patient. The ΔF508 mutation in homozygosis was present in 44% of patients with proteinuria (vs. 27% of our CF population, relative risk 2.07), whereas genotype ΔF508/N1303K in 22%. ΔF508 allele mutation was present in 77.7% of proteinuric patients. CONCLUSIONS: Our study shows a higher prevalence of renal disease in patients with CF, than was previously described. The main reason may be related to increased life expectancy because of better management. Moreover, patients with ΔF508 homozygosis had higher risk of proteinuria.

Risk Factors and Outcomes of Thalidomide-induced Peripheral Neuropathy in a Pediatric Inflammatory Bowel Disease Cohort.

BACKGROUND: Thalidomide is an effective therapy in children with inflammatory bowel disease refractory to standard treatments, but thalidomide-induced peripheral neuropathy (TiPN) limits its long-term use. We aimed to investigate the risk factors and the outcome of TiPN in children with inflammatory bowel disease. METHODS: Within a retrospective multicenter cohort study, we evaluated prevalence and evolution of TiPN. Clinical data and candidate genetic profiles of patients with and without TiPN were compared with detect predisposing factors. RESULTS: One hundred forty-two patients were identified. TiPN was found in 72.5% of patients (38.7% clinical and instrumental alterations, 26.8% exclusive electrophysiological anomalies, and 7.0% exclusive neurological symptoms). Median TiPN-free period of treatment was 16.5 months; percentage of TiPN-free patients was 70.0% and 35.6% at 12 and 24 months of treatment, respectively. The risk of TiPN increased depending on the mean daily dose (50-99 mg/d adjusted hazard ratio 2.62; 95% confidence interval [CI], 1.31-5.21; 100-149 mg/d adjusted hazard ratio 6.16; 95% CI, 20.9-13.06; >150 mg/d adjusted hazard ratio 9.57; 95% CI, 2.6-35.2). Single nucleotide polymorphisms in ICAM1 (rs1799969) and SERPINB2 (rs6103) genes were found to be protective against TiPN (odds ratio 0.15; 95% CI, 0.03-0.82 and 0.36; 95% CI, 0.14-0.88, respectively). TiPN was the cause of drug suspension in 41.8% of patients. Clinical symptoms resolved in 89.2% of cases, whereas instrumental alteration persisted in more than half of the patients during a short follow-up. CONCLUSIONS: In children with inflammatory bowel disease, TiPN is common but mild and generally reversible. Cumulative dose seems to be the most relevant risk factor, whereas polymorphisms in genes involved in neuronal inflammation may be protective.

Endoscopic and Histologic Healing in Children With Inflammatory Bowel Diseases Treated With Thalidomide.

BACKGROUND & AIMS: Mucosal healing, determined by endoscopic evaluation, is one of the most important prognostic markers for patients with inflammatory bowel diseases. Findings from histologic evaluation, however, could complement findings from endoscopy in assessing mucosal responses to treatment. We analyzed long-term results of children treated with thalidomide to determine the association between clinical response and histology and endoscopy findings. METHODS: We collected data from 2 multicenter trials of 70 children with refractory Crohn's disease (CD) or ulcerative colitis (UC) (2-18 years old; ileocolonic or colonic disease) given thalidomide or placebo (NCT00720538). Clinical remission and clinical response at 8 weeks were defined as a pediatric CD activity index scores 10 points or lower and a decrease of at least 50% from baseline, respectively, for patients with CD; and as a pediatric UC activity index score below 10 and a decrease of at least 20 points from baseline, respectively, for patients with UC. Patients with a clinical response to 8 weeks' treatment with thalidomide underwent endoscopic examination with biopsy collection at study weeks 12 and 52. Severity of inflammation in patients with UC was assessed by Mayo score and in patients with CD by 4-grade system. Biopsies were assessed for signs of active inflammation, erosion or ulceration, and crypt abscesses and assigned a histologic score. RESULTS: Clinical remission was observed in 42 patients (60.0%) and clinical response in 45 patients (64.2%) at Week 8. At Week 52, a total of 38 patients (54.3%) were still in clinical remission or still had a clinical response; 29 patients (41.4%) had mucosal healing, defined as complete healing of erosions or ulcerations, and 20 patients (27.7%) had histologic healing, defined as complete absence of markers of inflammation. Of patients with clinical remission or clinical response, 75.3% also had mucosal healing and 52.6% also had histologic healing. The probability of achieving mucosal healing decreased significantly with increasing values of erythrocyte sedimentation rate (adjusted odds ratio, 0.96; 95% CI, 0.93-0.98; P = .006). CONCLUSIONS: In a long-term analysis of data from 2 clinical trials of pediatric patients with CD or UC, 52 weeks' treatment with thalidomide led to clinical remission in 54.3% of patients with ileocolonic or colonic disease; of these patients, 75.3% had mucosal healing and 52.6% also had histologic healing. Further studies are needed to determine how thalidomide therapy affects long-term progression of inflammatory bowel diseases. (ClinicalTrials.gov number NCT00720538).

Effect of Early Versus Late Azathioprine Therapy in Pediatric Ulcerative Colitis.

BACKGROUND: We aimed at describing the efficacy of azathioprine (AZA) in pediatric ulcerative colitis, comparing the outcomes of early (0-6 months) versus late (6-24 months) initiation of therapy. METHODS: Children with ulcerative colitis treated with AZA within 24 months of diagnosis were included. Corticosteroid (CS)-free remission and mucosal healing (MH), assessed by endoscopy or fecal calprotectin, at 12 months were the primary outcomes. Patients were also compared for CS-free remission and MH, need for treatment escalation or surgery, number of hospitalizations, and adverse events during a 24-month follow-up. RESULTS: A total of 121 children entered the study (median age 10.5 ± 4.0 years, 59% girls). Seventy-six (63%) started AZA between 0 and 6 months (early group) and 45 (37%) started between 6 and 24 months (late group). Seventy-five percent and 53% of patients in the early and late group, respectively, received CS at the diagnosis (P = 0.01). CS-free remission at 1 year was achieved by 30 (50%) of the early and 23 (57%) of the late patients (P = 0.54). MH occurred in 37 (37%) patients at 1 year, with no difference between the 2 groups (33% early, 42% late; P = 0.56). No difference was found for the other outcomes. CONCLUSIONS: Introduction of AZA within 6 months of diagnosis seems not more effective than later treatment to achieve CS-free remission in pediatric ulcerative colitis. MH does not depend on the timing of AZA initiation; however, because of the incomplete comparability of the 2 groups at the diagnosis and the use of fecal calprotectin as a surrogate marker of MH, our results should be further confirmed by prospective studies.

Clinical Features and Risk Factors of Autoimmune Liver Involvement in Pediatric Inflammatory Bowel Disease.

OBJECTIVES: Autoimmune liver disease is reported in up to 7.8% of children with inflammatory bowel disease. A distinct inflammatory bowel disease phenotype has been suggested in adults and in small pediatric cohorts. The aim of the study was to evaluate the features of inflammatory bowel disease associated with autoimmune liver diseases and to analyze the characteristics of the liver disease. METHODS: Information on patients was obtained from the Italian Pediatric Inflammatory Bowel Disease Registry. Data of patients with and without autoimmune liver disease were compared. RESULTS: Autoimmune liver disease was detected in 6.8% of the 677 patients enrolled and was significantly associated with the diagnosis of ulcerative colitis (83%), with pancolonic involvement (84%), and with perinuclear antineutrophil cytoplasmic antibody positivity (41%) (all Ps < 0.05). Autoimmune liver disease was defined as sclerosing cholangitis in 61% of the patients and as an overlap syndrome in 33%. Concomitant intra- and extrahepatic biliary involvement was reported in 61% of cases, whereas exclusive extrahepatic lesions were reported in 21%. Hepatobiliary complications were observed in 9% of the patients during follow-up. CONCLUSIONS: Autoimmune liver disease, especially sclerosing cholangitis, was significantly more common in patients with extensive ulcerative colitis. Although complications are relatively rare in the pediatric age, monitoring is recommended.

Effect of Thalidomide on Clinical Remission in Children and Adolescents with Ulcerative Colitis Refractory to Other Immunosuppressives: Pilot Randomized Clinical Trial.

BACKGROUND: In a randomized controlled trial, thalidomide has shown to be effective in refractory Crohn's disease in children. This pilot study aimed at evaluating thalidomide in refractory pediatric ulcerative colitis (UC). METHODS: Double-blind, placebo-controlled randomized clinical trial on thalidomide 1.5 to 2.5 mg/kg/day in children with active UC despite multiple immunosuppressive treatments. In an open-label extension, nonresponders to placebo received thalidomide for an additional 8 weeks; all responders were followed up for a minimum of 52 weeks. RESULTS: Twenty-six children with refractory UC were randomized to thalidomide or placebo. Clinical remission at week 8 was achieved by significantly more children treated with thalidomide {10/12 (83.3%) versus 2/11 (18.8%); risk ratio, 4.5 (95% confidence interval [CI], 1.2-16.4); P = 0.005; number needed to treat, 1.5}. Of the nonresponders to placebo who were switched to thalidomide, 8 of 11 (72.7%) subsequently reached remission at week 8 (risk ratio, 4.0 [95% CI, 1.1-14.7]; number needed to treat, 2.45; P = 0.01). Clinical remission in the thalidomide group was 135.0 weeks (95% CI, 32-238), compared with 8.0 weeks (95% CI, 2.4-13.6) in the placebo group (P < 0.0001). Cumulative incidence of severe adverse events was 3.1 per 1000 patient-weeks. Peripheral neuropathy and amenorrhea were the most frequent adverse events. CONCLUSIONS: In this pilot randomized controlled trial on cases of UC refractory to immunosuppressive therapy, thalidomide compared with placebo resulted in improved clinical remission at 8 weeks of treatment and in longer term maintenance of remission. These findings require replication in larger clinical studies evaluating both thalidomide efficacy and safety.

A point-of-care test for facing the burden of undiagnosed celiac disease in the Mediterranean area: a pragmatic design study.

BACKGROUND: We aimed at assessing the factors that can influence results of the dissemination of an already validated, new generation commercial Point-of-Care Test (POCT) for detecting celiac disease (CD), in the Mediterranean area, when used in settings where it was designed to be administered, especially in countries with poor resources. METHODS: Pragmatic study design. Family pediatricians at their offices in Italy, nurses and pediatricians in Slovenia and Turkey at pediatricians', schools and university primary care centers looked for CD in 3,559 (1-14 yrs), 1,480 (14-23 yrs) and 771 (1-18 yrs) asymptomatic subjects, respectively. A new generation POCT detecting IgA-tissue antitransglutaminase antibodies and IgA deficiency in a finger-tip blood drop was used. Subjects who tested positive and those suspected of having CD were referred to a Celiac Centre to undergo further investigations in order to confirm CD diagnosis. POCT Positive Predictive Value (PPV) at tertiary care (with Negative Predictive Value) and in primary care settings, and POCT and CD rates per thousand in primary care were estimated. RESULTS: At tertiary care setting, PPV of the POCT and 95% CI were 89.5 (81.3-94.3) and 90 (56-98.5) with Negative Predictive Value 98.5 (94.2-99.6) and 98.7% (92-99.8) in children and adults, respectively. In primary care settings of different countries where POCT was performed by a different number of personnel, PPV ranged from 16 to 33% and the CD and POCT rates per thousand ranged from 4.77 to 1.3 and from 31.18 to 2.59, respectively. CONCLUSIONS: Interpretation of POCT results by different personnel may influence the performance of POC but dissemination of POCT is an urgent priority to be implemented among people of countries with limited resources, such as rural populations and school children.

Introduction of gluten, HLA status, and the risk of celiac disease in children.

BACKGROUND: The relationship between the risk of celiac disease and both the age at which gluten is introduced to a child's diet and a child's early dietary pattern is unclear. METHODS: We randomly assigned 832 newborns who had a first-degree relative with celiac disease to the introduction of dietary gluten at 6 months (group A) or 12 months (group B). The HLA genotype was determined at 15 months of age, and serologic screening for celiac disease was evaluated at 15, 24, and 36 months and at 5, 8, and 10 years. Patients with positive serologic findings underwent intestinal biopsies. The primary outcome was the prevalence of celiac disease autoimmunity and of overt celiac disease among the children at 5 years of age. RESULTS: Of the 707 participants who remained in the trial at 36 months, 553 had a standard-risk or high-risk HLA genotype and completed the study. At 2 years of age, significantly higher proportions of children in group A than in group B had celiac disease autoimmunity (16% vs. 7%, P=0.002) and overt celiac disease (12% vs. 5%, P=0.01). At 5 years of age, the between-group differences were no longer significant for autoimmunity (21% in group A and 20% in group B, P=0.59) or overt disease (16% and 16%, P=0.78 by the log-rank test). At 10 years, the risk of celiac disease autoimmunity was far higher among children with high-risk HLA than among those with standard-risk HLA (38% vs. 19%, P=0.001), as was the risk of overt celiac disease (26% vs. 16%, P=0.05). Other variables, including breast-feeding, were not associated with the development of celiac disease. CONCLUSIONS: Neither the delayed introduction of gluten nor breast-feeding modified the risk of celiac disease among at-risk infants, although the later introduction of gluten was associated with a delayed onset of disease. A high-risk HLA genotype was an important predictor of disease. (Funded by the Fondazione Celiachia of the Italian Society for Celiac Disease; CELIPREV ClinicalTrials.gov number, NCT00639444.).