The Long-Term Effect of Early Anti-Tumor Necrosis Factor on Restoration of Growth in Pediatric Crohn’s Disease

Impairment of growth is one of the major complications in pediatric Crohn’s disease (CD). This is a distinctive feature compared to adult CD, and it may affect later health in adulthood. Impairment of growth at diagnosis has been reported in 4% to 38% of children with CD, and growth velocity may be reduced in up to 88% of these children. In a recent study, growth failure was present in 8% of patients at diagnosis and still in 5% of patients at final height. Children with CD have multiple risk factors for impaired growth, including, impaired bone modeling, delayed puberty, malnutrition, decreased muscle mass, and decreased physical activity. Insufficient food intake related to loss of appetite, intestinal malabsorption due to small bowel involvement of the disease, increased nutritional losses including protein losing enteropathy, iron, and zinc losses, and increased energy requirements may contribute to growth failure. A recent Korean study revealed that low vitamin D levels affect growth outcome in children with CD. Children with long-term use of steroids are at risk for growth failure. Moreover, children with CD with uncontrolled inflammation showed a lower growth velocity. Tumor necrosis factor  (TNF-) has direct negative effects on bone metabolism and plays an important role in CD pathogenesis. Numerous studies have reported the effect of anti-TNF- agents on growth restoration. The REACH study revealed improvement of height z-score (0.5) at week 54 with infliximab therapy, while initial bone age was delayed at least 1-year (zscore of –1.5). The REACH open-label extension study showed that the median height z-score had improved by 1.56 at the end of 3 years of infliximab therapy. In a study of children with CD with a median 43-month follow-up, increases in lean massheight z-score and fat mass-height z-score were associated with infliximab therapy. Height-z score was not improved during this study period. Another study showed that 1 year of anti-TNF- therapy was associated with improvements in trabecular bone mineral density and cortical structure. Several studies have considered early infliximab administration, before the use of corticosteroids. The recent guidelines of the European Crohn’s and Colitis Organization and European Society for Pediatric Gastroenterology, Hepatology, and Nutrition state that infliximab may be considered as a primary induction regimen in selected children with high risks, which include marked growth retardation of >–2.5 height z-score. There is lack of data to evaluate the efficacy of early use of infliximab in relation to growth restoration. Recently Church et al. reported that children with height was normalized (mean z-score 0) by 3 years in children with Tanner stage 1 to 2 for whom infliximab was initiated early, within 18 months of diagnosis, whereas those for whom infliximab was initiated after a longer duration remained shorter than healthy children. In this issue of Gut and Liver, the article “Early infliximab yields superior long-term effects on linear growth in pediatric Crohn’s disease patients” by Choi et al. investigated the efficacy of early combined immunosuppression on restoration of growth compared to conventional “step-up” therapy for a long-term period of 3 years. This retrospective study included 33 children with moderate to severe CD who had sustained