Massimo Maschio

Effect of Thalidomide on Clinical Remission in Children and Adolescents With Refractory Crohn Disease: A Randomized Clinical Trial

IMPORTANCE Pediatric-onset Crohn disease is more aggressive than adult-onset disease, has high rates of resistance to existing drugs, and can lead to permanent impairments. Few trials have evaluated new drugs for refractory Crohn disease in children. OBJECTIVE To determine whether thalidomide is effective in inducing remission in refractory pediatric Crohn disease. DESIGN, SETTING, AND PATIENTS Multicenter, double-blind, placebo-controlled, randomized clinical trial of 56 children with active Crohn disease despite immunosuppressive treatment, conducted August 2008-September 2012 in 6 pediatric tertiary care centers in Italy. INTERVENTIONS Thalidomide, 1.5 to 2.5 mg/kg per day, or placebo once daily for 8 weeks. In an open-label extension, nonresponders to placebo received thalidomide for an additional 8 weeks. All responders continued to receive thalidomide for an additional minimum 52 weeks. MAIN OUTCOMES AND MEASURES Primary outcomes were clinical remission at week 8, measured by Pediatric Crohn Disease Activity Index (PCDAI) score and reduction in PCDAI by ≥25% or ≥75% at weeks 4 and 8. Primary outcomes during the open-label follow-up were clinical remission and 75% response. RESULTS Twenty-eight children were randomized to thalidomide and 26 to placebo. Clinical remission was achieved by significantly more children treated with thalidomide (13/28 [46.4%] vs 3/26 [11.5%]; risk ratio [RR], 4.0 [95% CI, 1.2-12.5]; P = .01; number needed to treat [NNT], 2.86). Responses were not different at 4 weeks, but greater improvement was observed at 8 weeks in the thalidomide group (75% response, 13/28 [46.4%] vs 3/26 [11.5%]; RR, 4.0 [95% CI, 1.2-12.5]; NNT = 2.86; P = .01; and 25% response, 18/28 [64.2%] vs 8/26 [30.8%]; RR, 2.1 [95% CI, 1.1-3.9]; NNT = 2.99; P = .01). Of the nonresponders to placebo who began receiving thalidomide, 11 of 21 (52.4%) subsequently reached remission at week 8 (RR, 4.5 [95% CI, 1.4-14.1]; NNT = 2.45; P = .01). Overall, 31 of 49 children treated with thalidomide (63.3%) achieved clinical remission, and 32 of 49 (65.3%) achieved 75% response. Mean duration of clinical remission in the thalidomide group was 181.1 weeks (95% CI, 144.53-217.76) vs 6.3 weeks (95% CI, 3.51-9.15) in the placebo group (P < .001). Cumulative incidence of severe adverse events was 2.1 per 1000 patient-weeks, with peripheral neuropathy the most frequent severe adverse event. CONCLUSIONS AND RELEVANCE In children and adolescents with refractory Crohn disease, thalidomide compared with placebo resulted in improved clinical remission at 8 weeks of treatment and longer-term maintenance of remission in an open-label follow-up. These findings require replication to definitively determine clinical utility of this treatment. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00720538.

Thromboembolism in pediatric inflammatory bowel disease: Systematic review

Background: Several studies suggest an increased risk of venous and arterial thromboembolism (TE) in adults with inflammatory bowel disease (IBD) compared to the general population. We performed a systematic review of studies on incidence and characteristic of TE in children with IBD. Methods: We searched Medline, LILACS, EMBASE, POPLINE, CINHAL, and reference lists of identified articles, without language restrictions, in August 2010. Results: Population studies suggest that there is an increased risk of TE in children with IBD compared to controls. TE occurred in children with IBD in all age ranges, mostly (82.8%) during active disease, and more frequently in children with ulcerative colitis (odds ratio [OR] 3.7, 95% confidence interval [CI] 1.8–7.6). At least one specific risk factor for TE was recognized in 50% of cases; two risk factors were present in 24%. Out of 92 published cases of TE in children with IBD, 54.3% occurred in cerebral site, 26% in the limbs, 13% in the abdominal vessels, and the remaining in the retina and lungs. After a first episode of TE, an early recurrence was observed in 11.4% of children, a late recurrence in 10%. A number of different therapeutic schemes were used. Overall mortality was 5.7% and was mostly associated with cerebral TE. Conclusions: Population studies are needed to clarify the risk of TE in children with IBD, the relative weight of other risk factors, the characteristics of the events, and to define guidelines of therapy and prophylaxis. (Inflamm Bowel Dis 2010)

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 Crohns 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.

Crohn's disease and Takayasu's arteritis: an uncommon association.

Takayasus arteritis (TA) and Crohns disease (CD) are two rare autoimmune disorders; however some reports describe the presence of both diseases in the same patient. This finding has suggested the possibility that both diseases could share some common etiologic origin. We describe a case of a 13-year-old male affected by CD characterized by fever, diarrhea, weight loss, abdominal pain and elevation of inflammatory markers. Clinical and histological features from colonic specimens were consistent with CD. Treatment with steroids and azathioprine was started, however disease flared every time steroids were tapered. One year later, while still on treatment, he came back to our attention for dyspnea at rest and at night, tiredness and weakness. At physical examination a diastolic heart murmur was found as well as a left carotid artery bruit. A transthoracic echocardiography showed mild aortic valve insufficiency, left ventricular hypertrophy and a dilated ascending aorta with same findings at the aortic arch. A computed tomography scan showed abdominal aorta thickening, dilated thoracic aorta and the presence of a thoracic aortic aneurysm. TA associated with CD was diagnosed and medical treatment with cyclophosphamide, steroids and aminosalicylic acid was started, with good clinical response at 6 mo follow-up. We discuss the presence of possible common causes for the two diseases and the importance of differential diagnosis in those patients characterized for intractable disease.

Serum Anti-Tissue Transglutaminase Antibodies Detected during Febrile Illness May Not Be Produced by the Intestinal Mucosa

Anti-transglutaminase antibodies are the diagnostic marker of celiac disease, and are considered to be synthesized only by intestinal B-lymphocytes. During an infectious disease, these antibodies are transiently detected in serum. We show that these infection-triggered antibodies may not originate in the intestinal mucosa and are not an indication of celiac disease.

Giant cell hepatitis with Coombs-positive haemolytic anaemia: steroid sparing with high-dose intravenous immunoglobulin and cyclosporine.

Giant cell hepatitis (GCH) with Coombs-positive autoimmune haemolytic anaemia (AIHA) is a rare clinicopathological entity with early age onset and severe clinical course for which an autoimmune origin has been hypothesized. Aggressive immunosuppressive treatment may control disease progression but should be carried on for at least 5 years as relapse is frequent after early discontinuation and carries a poor prognosis. Different immunosuppressive drugs have been tried with varying degrees of benefit and several side effects, but due to few reported cases, no univocal data exist on which therapy might be the most effective. We describe a patient with GCH with AIHA who initially responded to the association of prednisone, cyclosporine and intravenous immunoglobulin (IVIg) but developed severe steroid side effects. Early tapering of steroid was successfully managed with the association of cyclosporine and monthly infusion of high-dose IVIg. A 8-month-old male infant presented to the Emergency Department for hyporeactivity and marked pallor. He had been well until 1 month before admission when pallor and progressive irritability were noted. On physical examination he was pale and unresponsive. Liver and spleen were not palpable. His initial laboratory evaluation revealed a leukocyte count of 14.790/mm, haemoglobin 2.8 g/dL, platelets 604.000/mm, haptoglobin 3 mg/dl (normal range 34–200), serum alanine aminotransferase (ALT) 700 IU/L, serum aspartate aminotransferase (AST) 439 IU/L, total bilirubin 3.9 mg/dL (normal range 0.0–0.1), conjugated bilirubin of 1.38 mg/dL (normal range 0.00–0.20), International Normalized Ratio 1.04, activated partial thromboplastin time 0.28 sec. Evaluation of the anaemia revealed a positive direct and indirect Coombs test with warm antibody (IgG and anti-C3d). Microbiologic and molecular examinations were negative for hepatitis viruses A, B and C, cytomegalovirus, parvovirus B19 and herpes virus 6. Serology for Epstein–Barr (EBV) revealed low titer (<1/20) IgM antibodies against EBV virus capsid antigen (VCA) with positive IgG-VCA (>1/256) antibodies suggestive of recent primary infection. Antinuclear antibody, anti-smooth muscle and anti-liver/ kidney microsomal antibody tests were negative. Total immunoglobulin G level was within normal range. Liver histology revealed GCH with multinucleated giant hepathocytes, mild increase in inflammatory infiltrate and activation of Kupffer cells. He was initially treated with intravenous methylprednisolone 3 mg/kg/day followed by oral prednisone and cyclosporine 4 mg/kg/day. At the same time, the first infusion of IVIg was administered at a dose of 2 g/kg. Liver enzymes progressively decreased but the patient developed severe steroid-related side effects (hypertension, high intraocular pressure, cushingoid appearance with prominent cheeks and difficulty breathing and aggressive behaviour); for this reason, after 1 month of treatment, an attempt to reduce steroid dosage was made and prednisone was tapered to 2 mg/kg over 2 weeks. This was followed by a striking raise in aminotranserase levels. Cyclosporine dose was then increased to 5 mg/kg/day to reach serum levels between 150 and 200 ng/mL, and a second dose of IVIg was administered. Prednisone was replaced with betamethasone at an equivalent dose. Normalization of liver enzymes was obtained and treatment was subsequently continued with monthly infusions of IVIg of 2 g/kg, cyclosporine and betamethasone (Fig. 1). The former was adjusted to keep serum levels of 100–150 ng/mL, while betamethasone was slowly tapered over 4 months and maintained at a dose of 0.04 mg/kg/day with good control of hepatic and hematologic disease. After 6 months of treatment, aminotransferase persist within normal range; direct Coombs test continues to be positive but without evidence of haemolysis. Giant cell hepatitis with Coombs-positive AIHA is a rare entity characterized by severe liver disease that can rapidly progress to cirrhosis and hepatic failure (1–4). The mechanism of disease is not completely understood but the presence of Coombs positive haemolytic anaemia, the efficacy of immunosuppressive treatment and the occurrence of relapses when treatment doses are reduced strongly point to an autoimmune origin. In the present case, viral serology was suggestive of a recent EBV infection. This association has been reported previously (1); whether this is an incidental finding or EBV could act by triggering a genetic susceptibility to autoimmunity has not been established so far. The diagnosis of GCH with Coombs-positive AIHA should always be the first thought in a young child (after neonatal period) with a positive Coombs test of the IgG + C type and acute liver disease.

Children under 5 years are at risk for tuberculosis after occasional contact with highly contagious patients: outbreak from a smear-positive healthcare worker

The World Health Organization (WHO), jointly with experts from tuberculosis (TB) low-incidence countries, developed a framework for TB elimination [1, 2]. Children under 5 years of age are at risk for tuberculosis after occasional contact with highly contagious patients http://ow.ly/RqAn30fKdGk

To GERD or not to GERD, this is the question

To the Editor: We appreciate the comments of Tornese et al on our study, and also appreciate that they agree with us that proton pump inhibitors (PPIs) should not be used in infants to treat symptoms of gastroesophageal reflux disease (GERD) not known to be due to acid reflux. Major concerns of Tornese et al are the diagnostic validity of the I-GERQ score, along with the broader and more clinically important question of whether symptoms can be used clinically to diagnose acid-mediated GERD in infants. We agree with them that our findings indicate that symptoms, and thus symptom-based questionnaires, cannot be used reliably to diagnose acid-mediated GERD. Note, however, that no questionnaires were used to diagnose the infants in our study. Selection for inclusion was based on clinician diagnosis and on a particular amount of persistent feeding-related crying despite nonpharmacologic management. An adaptation of the I-GERQ Score, the I-GERQ-MH, was used only post hoc to illustrate the comparability of the symptom burden in participating infants to that of other infants diagnosed in routine clinical practice. The I-GERQ Score itself was originally validated in infants in whom acid-mediated GERD had been identified using the gold standards of esophageal pH monitoring (EpHM) and histology. But only asymptomatic controls were used in the validation process; no symptomatic controls with normal EpHM and biopsy were included. This leaves undefined the questionnaire’s ability to distinguish such symptomatic infants without acid-mediated GERD from those with acidmediated GERD. Once symptomatic infants have been confirmed to have acid-mediated GERD, however, a revised version of the I-GERQ Score (the I-GERQ-R), which has demonstrated validity in tracking symptoms over time, can allow the rigorous tracking of symptomatic response to interventions or to time. We emphasize acid-mediated GERD here, because that is the type of GERD that PPIs should effectively treat. But PPI-unresponsive symptoms also can be due to non–acidmediated GERD, that is, troublesome symptoms due to nonacid reflux (eg, aspiration, pain due to volume reflux or to PPI-unresponsive nonerosive reflux disease). Because crying was the main symptom quantified in our patients, the relationship between reflux and crying in

A novel approach based on low-field NMR for the detection of the pathological components of sputum in cystic fibrosis patients

Development of a reliable, simple method to monitor lung condition in cystic fibrosis (CF) patients. Lung functionality assessment in CF patients is relevant, as most of them still die of respiratory failure. In lung mucus (sputum) of CF patients, components such as proteins, biopolymers, DNA, bacteria, and mucin are pathologically increased. As lung functionality is related to the amount of the pathological components in the sputum, their determination can help clinicians in monitoring lung condition and planning therapy.

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).