Pharmacologic and Nutritional Therapy for Mild Disease
5-Acetylsalicylic acid
Although oral 5-ASA preparations are commonly used, adult meta-analyses suggest that these preparations do not have a clinically important treatment effect on active Crohn disease and are not superior to placebo for the maintenance of remission in Crohn disease. [19] Topical 5-ASA therapy is available in suppository and enema forms for the treatment of distal colitis.
Antibiotics
A few small studies have shown the usefulness of antibiotic therapy in the treatment of Crohn disease. Metronidazole, as well as the combination of metronidazole and ciprofloxacin, is useful in the management of perianal disease and of small bowel and colonic disease.
Nutritional therapy
Nutritional therapy is another important modality for the treatment of disease, malnutrition, and growth failure in Crohn disease. [20] A dramatic reversal of malnutrition and a change in growth velocity can be expected in all children treated with adequate nutrition in conjunction with medical therapy to control symptoms of Crohn disease. Additionally, exclusive enteral nutrition has been shown to be as effective as corticosteroids for the induction of remission and might promote better GI tract mucosal healing. [21]
Because most patients have appetite suppression, overnight nasogastric feedings are often used. Although the exact mechanism of action is unknown, the beneficial effects of this approach could be due to alteration of the intestinal flora, a decrease in the antigen load, and reductions in inflammatory cytokine levels.
Corticosteroid and Immunomodulatory Therapy for More Severe Disease
Corticosteroids
Corticosteroids are the mainstay of therapy for acute exacerbations because they suppress acute inflammation, thereby providing rapid symptomatic relief. Systemic corticosteroids are not indicated for maintenance therapy. Enteric coated ileal-release preparations have been developed for the treatment of ileal and cecal Crohn disease; systemic effects are decreased with these formulations.
Immunomodulators
Immunomodulators have been used to induce and maintain long-term remission in chronically active, steroid-dependent or steroid-refractory, moderate-to-severe pediatric Crohn disease.
6-Mercaptopurine (6-MP) and its prodrug, azathioprine, are effective for the induction and maintenance of remission and the reduction of corticosteroid exposure in pediatric Crohn disease. Three months is often required to achieve therapeutic efficacy, although the onset of action varies.
Thiopurine methyltransferase (TPMT) activity should be measured before the initiation of therapy to identify patients predisposed to altered drug metabolism (which increases the risk of leukopenia). Measurement of 6-thioguanine nucleotide (6-TG) metabolites is helpful in assessing compliance and adjusting therapy.
MTX is effective in inducing and maintaining remission in chronic Crohn disease in adults and has been shown to be effective and well tolerated for maintenance of remission in children. [22, 23, 24, 25] MTX has a quicker onset of action than 6-MP does, and the once-weekly dosing is sometimes preferred. Whether oral therapy is as effective as parenteral administration is unclear.
Biologic Therapy for Unresponsive Disease
Infliximab (Remicade), a chimeric monoclonal antibody to tumor necrosis factor (TNF)-α, is effective in patients who have an inadequate response to conventional therapy and in patients who have fistulizing Crohn disease. [5] It has been approved for the treatment of pediatric Crohn disease. Current clinical practice is to give infliximab in an intravenous (IV) infusion of 5 mg/kg at 0 weeks, 2 weeks, and 6 weeks, followed by maintenance IV infusions every 8 weeks.
The most common adverse events to infliximab therapy are acute and delayed infusion reactions associated with the formation of antibodies to infliximab (ATI), which occur in 16-39% of children. Premedication does not seem to prevent infusion reactions; however, after an infusion reaction occurs, premedication may be indicated to prevent subsequent infusion reactions. [26]
Adalimumab (Humira), a fully humanized anti–TNF-α antibody, was approved by the US Food and Drug Administration (FDA) in September 2014 for children aged 6 years or older with moderately to severely active Crohn disease who have had an inadequate response to corticosteroids or immunomodulators (eg, azathioprine, 6-mercaptopurine, methotrexate). It is also a safe and effective substitute for patients who are allergic to infliximab or who develop high titers of human antichimeric antibodies (HACA). [6] Its approval was based on a prospective multicenter study in children with a Pediatric Crohn's Disease Activity Index (PCDAI) score of more than 30 for whom conventional treatment was unsuccessful (n= 192). The study demonstrated that adalimumab is effective for induction and maintenance of remission for pediatric Crohn disease and is well tolerated by children. [27, 28]
Adalimumab drug is already approved for the treatment of moderately to severely active Crohn's disease in adults.
A study by Dziechciarz et al assessed the published evidence on the efficacy and safety of adalimumab for Crohn's disease in children. The study found that there was only low-quality evidence based mainly on case series that showed that approximately half of children with Crohn's disease on adalimumab therapy achieve remission during the first year of the therapy with reasonable safety profile. [29, 30]
One area of concern with the use of these medications is that multiple patients have been reported to develop a rare hepatosplenic T-cell lymphoma when treated with dual therapy consisting of 6-MP or azathioprine with a TNF-α inhibitor. Although this has been a rare complication, all reported cases have been in adolescents and young adults.
Data from the observational RISK study has been published. The study included children from 28 pediatric gastroenterology centers in North America. Results showed that in newly diagnosed children with comparably severe Crohn disease, early monotherapy with and anti-TNF-alpha agents produced better overall clinical and growth outcomes at 1 year than early monotherapy with an immunomodulator. Further investigation is needed to identify which children are most likely to benefit from early anti-TNF-alpha therapy. [31]
A study examined changes in bone density and structure in children and adolescents with Crohn's disease following initiation of anti-tumor necrosis factor (TNF)-alpha inhibitors therapy. The study concluded that anti-TNF-α therapy was associated with improvements in trabecular bone mineral density and cortical structure. Improvements were greater in younger and growing participants, suggesting a window of opportunity for treatment of bone deficits. [32, 33]
