Ustekinumab for Resistant Pediatric Crohn Disease

Abstract

Crohn disease (CD) is a chronic inflammatory bowel disease that, in the pediatric age group, tends to present with a more severe form than in adults and frequently takes a complicated course (1). Biological treatment is a therapeutic option in patients with CD who either do not respond to immunomodulators or present with extensive and penetrating disease. Biological therapies may also be used to reduce symptoms when immunomodulators are unsuitable or ineffective and to promote growth in stunted children (2). Anti–tumor necrosis factor-α (TNF-α) agents, infliximab and adalimumab, are the only biological agents approved for pediatric CD. One-year and 5-year response rates to infliximab in pediatric patients are approximately 89% and 50%, respectively (3). The difference between short- and long-term responses is attributed to the emergence of anti-TNF antibodies, among other factors, leading to a loss of response (4). Therapeutic options for pediatric patients with CD who fail anti-TNF treatment are scarce. Biological agents targeted against cytokines and integrins other than TNF have been studied with apparent efficacy in adult patients with CD (5). Ustekinumab is a human monoclonal antibody that targets the p40 subunit of both interleukin 12 (IL-12) and IL-23 and inhibits their activity. IL-12 and IL-23 have a key role in the differentiation and proliferation of TH1 and TH17 cell subsets. Indeed, ustekinumab is approved for psoriasis in adult patients (6), whereas pediatric data are limited to a single published case report (7). In CD, a recent randomized controlled trial (5) has demonstrated that ustekinumab is effective in achieving remission in patients with moderate-to-severe CD. Data regarding efficacy of ustekinumab in pediatric CD are lacking. PATIENT DESCRIPTION A 7-year-old Jewish boy was diagnosed as having inflammatory bowel disease during infancy. The child presented at the age 4 months with fever, failure to thrive, hypoalbuminemia, iron deficiency anemia, and bloody diarrhea unresponsive to a course of exclusive elemental diet. Ileocolonoscopy performed at the age 9 months demonstrated pancolitis with patchy mucosal involvement. Histological findings were compatible with chronic inflammation. Evaluation for primary immunodeficiency including immunoglobulin levels, lymphocyte count, and nitroblue tetrazolium assay did not demonstrate any abnormal findings. Evaluation of the IL-10 receptor axis was not performed, largely because of the absence of perianal disease. After failure of inducing remission with mesalamine, treatment with azathioprine and corticosteroid combination was initiated. On receiving this treatment, fever and bloody diarrhea resolved and the infant resumed weight gain. At 1 year of age, the child developed left ankle arthritis accompanied by fever and elevated inflammatory markers that did not respond to a local steroid injection. Recurrent episodes of arthritis and fever resulted in changing maintenance therapy from azathioprine to methotrexate. In face of failure to achieve remission, the child was put on a regimen of adalimumab and methotrexate. The child continued to experience recurrent episodes of bloody diarrhea and arthritis and required repeated courses of systemic corticosteroids. Adalimumab treatment was discontinued because of undetectable drug level with high titer of antibodies. An attempt to induce remission with infliximab resulted in an anaphylactic reaction. Thus, the patient was placed under salazopyrin combined with alternate-day prednisolone. Reevaluation at 6 years of age including gastroscopy, colonoscopy, capsule endoscopy, and computed tomography enterography demonstrated patchy colitis with ulcers and pseudopolyps from the ascending colon to the cecum, without involvement of the small bowel. In light of active colonic disease, chronic arthritis, and failure to respond to all of the approved therapies for pediatric CD, we decided upon an attempt to induce remission with ustekinumab based on adult CD literature (5). The child received 3 subcutaneous doses of ustekinumab (22.5 mg = 1.3 mg/kg) at months 0, 1, and 3. The treatment resulted in complete clinical and biochemical remission with no observed adverse events. Remarkable clinical response was achieved within the first 2 months of treatment, including resolution of diarrhea and arthritis, and a reduction of pediatric CD activity index to zero. Furthermore, 1 year after the induction, a weight gain of 3 kg and growth of 8 cm were noted. In addition, inflammatory blood markers (C-reactive protein, erythrocyte sedimentation rate) had normalized: C-reactive protein from 8.04 to 0.07 mg/dL and erythrocyte sedimentation rate from 67 to 13 mm at the end of 1 hour. Albumin increased from 3.2 to 4.5 g/dL, and hemoglobin from 10.2 to 13.8 g/dL. Remission was maintained with azathioprine. At present, 1 year following induction, clinical and laboratory remission still persist. DISCUSSION TNF-α inhibitors are the only biological agents approved for pediatric CD treatment. A substantial proportion of patients, however, either are primary nonresponders or lose response over time (3). Here, we describe the first reported case of successful ustekinumab remission induction in a child with refractory CD following failure of 2 anti-TNF agents. The child achieved complete clinical and biochemical remission and was able to maintain sustained remission for 12 months following induction. Effectiveness and safety of treatment with ustekinumab were demonstrated in adult patients with CD (5). Effectiveness of ustekinumab treatment in both psoriasis and psoriatic arthritis has also been demonstrated (8); however, there is a paucity of data regarding the use of ustekinumab in pediatric patients (7). In our case, the child experienced prolonged active CD symptoms manifested by chronic arthritis and recurrent episodes of bloody diarrhea. In such a young patient who failed all of the approved therapeutic options, it is of crucial importance to achieve at least corticosteroid-free sustained response to enable growth, avoid the devastating effects of long-term corticosteroid therapy, and prevent complications such as stricturing or penetrating disease. Thus, despite limited data in the pediatric literature, we initiated induction treatment with ustekinumab. The route of administration (subcutaneous and not intravenous) and the low dose of approximately 1 mg/kg per day were chosen because of the scarce data in the pediatric literature regarding that treatment. Our experience should encourage pediatric trials aimed at considering ustekinumab as a rescue therapy in anti-TNF refractory pediatric patients with CD. In summary, we describe a dramatic resolution of symptoms in a 7-year-old boy with refractory active CD treated with ustekinumab. In addition, we provide anecdotal data on dosage and scheduling of ustekinumab in pediatric CD. The effectiveness and safety of this drug in children should be studied prospectively.