Difficulty in recruiting subjects who meet the inclusion/exclusion criteria

Crohn's disease (CD) is a life-long inflammatory bowel disease disease with an unknown pathogenesis. The ultimate goal of therapy is to modify the natural history of CD thus reducing complications. Thalidomide is a small molecule with immunomodulatory and anti-angiogenetic properties. It is currently approved for the treatment of erythema nodosum leprosum, an immunological complication of leprosy and multiple myeloma. It has also been used in several other inflammatory diseases of the skin and of the mucosal membranes, such as Behcet disease, oropharyngeal ulcers in AIDS, cutaneous lupus, and graft versus host disease. Many case series and one pediatric randomized controlled trial proved the efficacy of thalidomide in the treatment of children with CD refractory to standard treatments. In these patients, clinical remission was achieved in about 50% of the cases and was maintained for a mean time superior of 3 years. Mucosal healing after 52 weeks of treatment was observed in 40% of the patients in clinical remission. Moreover, thalidomide was found to have a steroid-sparing effect and to decrease the need for surgical interventions. The clinical and endoscopic efficacy of thalidomide was also observed in children with failure to respond or intolerance to anti-TNF biological drugs.

The aim of this multicentric prospective randomized controlled is to evaluate the efficacy and safety of thalidomide vs infliximab in changing the natural history of CD in patients with poor prognostic outcome. Moreover, the study will evaluate the immunological and genetical mechanisms of CD, the mechanisms of action thalidomide in CD and will the pharmacokinetics, metabolomics and pharmacogenomics of thalidomide, and their impact on thalidomide safety and effectiveness.

Inclusion Criteria:

• Age at diagnosis <18 years and >=6 years

• New diagnosis of CD based on Porto criteria

• CD with inflammatory phenotype (non-penetrating, non-fistulizing) and with no need for surgery except for perinal fistulas

• Presence of at least one of the following risk factors for poor prognosis:

  • fistulizing perianal disease
  • pan-enteric disease
  • disease extension > 60 cm
  • severe growth delay (height z-score < -2 DS)
  • severe osteoporosis (z score < -2 DS)
  • hypoalbuminemia (< 3g/dL) or high C-reactive protein (2 times higher the normal range)

• Acceptance of the Risk Evaluation and Mitigation Strategy (REMS) program for reducing the teratogenic risk.

Exclusion Criteria:

• ongoing pregnancy
• presence of peripheral neuropathy
• HIV
• patients with transplanted organs
• ongoing major infections or other severe diseases
• participation to other experimental studies.