Biologic Treatment of Pediatric Inflammatory Bowel Disease

Drug development in children and adolescents occasionally is hindered by a hesitance to expose young patients to experimental and untested therapies. A case in point is the application of biologic agents in the management of pediatric patients with inflammatory bowel disease (IBD). The degree of acceptance of antitumor necrosis factor (TNF) agents after their introduction as a novel treatment option has ranged from initial enthusiasm to caution resulting from fear of complications such as hepatosplenic T-cell lymphoma (HSTCL) to approval as part of standard management. In fact, as we gather additional experience and evidence, a trend toward the use of biologic agents as a first-line treatment has emerged.
For this introductory e-book, we selected articles from JPGN that represent seminal work on the application, safety, and efficacy of the 2 leading anti-TNF agents, infliximab and adalimumab, in the treatment of pediatric patients with chronic IBD. Several NASPGHAN and ESPGHAN clinical research articles document the role of these medications in the management of specific patients with complicated IBD. We also present several notable case reports, including one of the first documented cases of HSTCL (Thayu et al).
Anti-TNF medications were aimed at initially Crohn disease, following postulated involvement of TNF in T-helper cell 1 disorders. The excitement overanti-TNF therapy in Crohn disease was stimulated in particular by emerging evidence that mucosal healing could be achieved for the first time. Extending the application of anti-TNF agents in IBD, Mamula and colleagues’ article reported the successful application of infliximab in pediatric patients with ulcerative colitis, with a corresponding review by Fuss.
Early enthusiasm for infliximab therapy waned in light of reports of an association between anti-TNF therapy and the development of HSTCL. JPGN published one of the first cases in 2005, and the Food and Drug Administration’s Adverse Event Reporting System followed with several case reports of this association. In 2006, the Food and Drug Administration mandated a black box warning directed at anti-TNF agents. Subsequent evidence has implicated immunomodulator agents, primarily azathioprine and mercaptopurine, rather than anti-TNF agents, in this rare but serious complication. Nevertheless, apprehension that anti-TNF agents may induce HSTCL has been slow to dissipate, and several longitudinal surveillance studies have been launched to address this issue.
deRidder et al documented the advantages of repeated dosing rather than intermittent or “as needed” application of anti-TNF agents. The accompanying editorial by F.M. Ruemmele discussed the findings of deRidder et al and their potential complications, including infections and 1 fatality presumed to have been the result of sepsis. Newer research has further documented the efficacy of infliximab, with a few additional reports about HSTCL. Reports by Ruemmele et al, followed by Wynands et al, and, most recently, by Nuti et al, document the safety and efficacy of repeated infusions of anti-TNF therapies. In addition, previous work by Miele et al showed that human anti-chimeric antibody formation associated with infusion reactions could be tempered with the concomitant use of immunomodulators. Although pediatric gastroenterologists agree in general on dosing schedules, other practitioners (Adler et al) continue to use a variety of dosing regimens. As noted by Falaive et al, the commonly applied dosage regimens may be inadequate for patients with severe ulcerative or Crohn colitis.
The complexity of the immune system is evidenced by paradoxical reports implicating anti-TNF agents in the development of diseases that are typically treated with these medications. In addition to the well-recognized complication of psoriasis, development of Crohn disease in a patient treated with etanercept for juvenile idiopathic arthritis (Ruemmele et al) is documented in this series of articles.
The need for more data on the natural history of IBD in childhood was highlighted by Hyams and Markowitz in their 2005 review and followed by other reports. These articles, including several reproduced in this e-book, have laid the groundwork for new clinical trials. The Crohn’s and Colitis Foundation of America, along with the National Institutes of Health and other funding sources, have taken an important lead in supporting multinational projects designed to explore these issues.
NASPGHAN and ESPGHAN have issued clinical observations and guidelines for pediatric IBD. Two publications included here (Pfefferkorn et al and de Zoeten et al) suggest using biologic agents as treatment regimens in pediatric patients with IBD.
It is hoped that this collection of research papers, case reports, and critical reviews will assist our readers in considering treatment options and further advances in the care of young patients with chronic IBD.