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.

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.

Impact of JC virus antibody testing in patients with Crohn's disease with loss of response to infliximab: a Markov model.

BACKGROUND: The optimal treatment strategy for patients with Crohn's disease who have loss of response to the anti-tumor necrosis factor α medication infliximab is uncertain. Natalizumab has an alternative mechanism of action, but its use has been limited by the risk of progressive multifocal leukoencephalopathy. In this study, we performed a decision analysis assessing the impact of JC virus (JCV) antibody testing and natalizumab utilization for loss of response to infliximab. METHODS: We constructed a Markov model to assess the difference between unscreened natalizumab use (option 1), JCV antibody testing with natalizumab when appropriate (option 2), and second anti-tumor necrosis factor α use (option 3). The base case was a 35-year-old man with severe Crohn's disease with loss of response to infliximab. The time horizon was 3 years. Results are reported in quality-adjusted life years (QALYs). Deterministic and probabilistic analyses were conducted. Markov analysis using a cohort of 5000 individuals was performed. The impact of JCV antibody status on outcomes in this model was assessed. RESULTS: Option 2 was the preferred strategy (2.0880 QALYs), followed by option 1 (2.0875 QALYs) and option 3 (2.0808 QALYs). Patients in option 2 required fewer surgeries compared with option 3. Previous JCV infection was associated with reduced QALYs with all options that allowed for natalizumab use. CONCLUSIONS: JCV antibody testing and subsequent treatment selection yield improved outcomes over natalizumab without testing or using only a second anti-tumor necrosis factor α in all patients.

Prevention of flare recurrences in childhood-refractory chronic uveitis: an open-label comparative study of adalimumab versus infliximab.

OBJECTIVE: To compare the efficacy and safety of adalimumab versus infliximab in an open-label prospective, comparative, multicenter cohort study of childhood noninfectious chronic uveitis. METHODS: Thirty-three patients (22 females, 11 males, median age 9.17 years) with refractory, vision-threatening, noninfectious active uveitis were enrolled, and received for at least 1 year infliximab (5 mg/kg at weeks 0, 2, and 6, and then every 6-8 weeks) or adalimumab (24 mg/m2 every 2 weeks). The primary outcome was to assess, once remission was achieved, the time of a first relapse. Time to remission, time to steroid discontinuation, and the number of relapses were also considered. RESULTS: Sixteen children (12 with juvenile idiopathic arthritis [JIA], 3 with idiopathic uveitis, and 1 with Behçet's disease) were recruited in the adalimumab cohort and 17 children (10 with JIA, 5 with idiopathic uveitis, 1 with early-onset sarcoidosis, and 1 with Behçet's disease) were recruited in the infliximab group. Cox regression analysis did not show statistically significant differences between the two groups with regard to time to achieve remission and time to steroid discontinuation, whereas a higher probability of uveitis remission on adalimumab during the time of treatment was shown (Mantel-Cox χ2=6.83, P<0.001). At 40 months of followup, 9 (60%) of 15 children receiving adalimumab compared to 3 (18.8%) of 16 children receiving infliximab were still in remission on therapy (P<0.02). CONCLUSION: Even if limited to a relatively small group, our study suggests that over 3 years of treatment, adalimumab is more efficacious than infliximab in maintaining remission of chronic childhood uveitis.

Current therapeutic approaches to autoimmune chronic uveitis in children.

Uveitis is an inflammatory disorder involving inflammation of the uveal tract. It is classified as anterior, intermediate, posterior or panuveitis, depending on the part of eye affected by the inflammatory process. In children, non-infectious, chronic uveitis is a relatively uncommon but serious disease, with the potential for significant long-term complications and possible blindness. Although frequently associated with an underlying systemic disease, e.g. juvenile idiopathic arthritis (JIA), a significant number of cases in children show no associated signs or symptoms, and are labelled as idiopathic. Taking into account this evidence, an anti-inflammatory therapy based on an immuno-modulatory approach seems a reasonable strategy for non-infectious chronic uveitis, in children as well as in adults. Due to a lack of controlled studies regarding uveitis in children, immunosuppressive drugs are supported only at evidence level III. The aim of this review is to report currently available medical strategies for treatment of childhood sight-threatening chronic uveitis; in addition, a step-by-step approach to the use of immunosuppressants in this context is suggested.

[Efficacy of meloxicam in juvenile polyposis syndrome. A case report]. / Poliposi giovanile in un caso clinico in cui e risultata efficace la terapia con meloxicam.

The Authors present a case of a 11 year-old patient with a history of Juvenile Polyposis Syndrome (JPS), a condition characterized by the occurrence of multiple hamartomatous polyps in the gastrointestinal tract. Patients with JPS are traditionally treated by repeated endoscopic polypectomies and elective surgery. Recent studies reported up-regulation of cyclo-ossigenase 2 (COX-2) in colorectal polyps. Specific COX-2 inhibitors have been withdrown from the market for tromboembolic side effects. However efficacy and safety of preferential selective COX-2 inhibitor has been reported as antiinflammatory drugs also in children. In this patient meloxicam treatment, a preferential selective COX-2 inhibitor, leaded to a significant reduction in the number of colorectal polyps during 3 years follow up.