Original Articles: Gastroenterology: Inflammatory Bowel Disease
What Is Known
- Ustekinumab is a human monoclonal antibody that blocks the activity of interleukins 12 and 23.
- The IL12/IL23 pathway is implicated in Crohn disease.
- Ustekinumab is currently approved for treatment in adult psoriasis and is in advanced adult Crohn trials.
- No clinical study to date has described the use of ustekinumab specifically in pediatric Crohn disease.
What Is New
- We describe the use of ustekinumab for 4 adolescent patients with Crohn disease at our inflammatory bowel disease center.
- Two of 4 patients showed clinical improvement and remain on ustekinumab.
- Two patients discontinued therapy because of the lack of response of ustekinumab and continued complications.
The majority of children and adolescents with Crohn disease receive nutritional therapy (1), corticosteroids, azathioprine/6-mercaptopurine, methotrexate, infliximab, and adalimumab to induce and maintain remission. Although many patients with Crohn disease are well managed with the currently available medications, a subset of children with moderate, severe, or complicated Crohn disease require alternative options and/or surgery.
Genome-wide association studies have linked interleukin 12/23 with the pathology of Crohn disease (2). Ustekinumab, a human monoclonal antibody, blocks the activity of interleukins 12 and 23 by antagonizing their common p40 receptor subunit (3). Ustekinumab is currently approved for treating psoriasis and is in advanced clinical trials for use in moderate-to-severe Crohn disease (4). No clinical study to date has described its use in children.
We describe the clinical course of 4 adolescent patients with Crohn disease who received ustekinumab at the Seattle Children's Hospital Inflammatory Bowel Disease (IBD) Center.
All patients with Crohn disease who received or currently receive ustekinumab at the Seattle Children's Hospital IBD Center were identified. Patients who initiated ustekinumab at age 18 or older were excluded. We performed a retrospective chart review for patients’ clinical data, disease phenotype (based on Paris classification (5) before starting ustekinumab), treatment history, and laboratory and growth parameters at the beginning of treatment and at the most recent dose or last follow-up before ustekinumab was discontinued. Laboratory indices included: C-reactive protein (CRP), albumin, and hematocrit. Abbreviated Pediatric Crohn Disease Activity Index (abbrPCDAI) (6) scores were calculated for patients based on each available IBD Center appointment chart summaries. The abbrPCDAI omits the growth and 3 laboratory items from the PCDAI making it more feasible for a retrospective study. The scores range from 0 (remission) to 70 (severe disease). The overall correlation with the full PCDAI is good. The suggested cut off points for disease activity are <10 remission, 10 to 15 mild, 16 to 25 moderate, and >25 severe (7). Any adverse events or complications while on ustekinumab, including hospitalization or surgery, were noted.
For induction, ustekinumab dose was 90 mg subcutaneously at weeks 0 and 4, then 90 mg every 8 weeks for maintenance. Patients’ weight range was 40.5 to 57.8 kg. Ustekinumab was administered in clinic. The study was approved by the institutional review board of Seattle Children's Hospital (study #15620).
We identified 5 patients who received ustekinumab for treatment of Crohn disease at the Seattle Children's Hospital IBD Center. One patient started therapy age 18 and was excluded, leaving 4 patients; 2 females and 2 males, ages 12 to 17 years. Patients’ disease history, phenotype, and comorbidities are summarized in Table 1. The mean disease duration before commencing ustekinumab was 4.2 years (±1.0, 3.8–5.4 years). Weight ranged from 40.5 to 57.8 kg, mean 49.5 kg. All 4 patients had nonstricturing, nonpenetrating behavior and colonic involvement, with 1 patient also having ileal disease. Two had perianal disease manifesting with fistula and abscess. The abbrPCDAI indicated mild disease in 1 patient, moderate in 1, and severe in 2. All patients showed CRP elevation (normal <0.8 mg/dL), 3 of 4 patients had hypoalbuminemia (<3.8 g/dL, normal 3.8–5.4 g/dL), and 3 of 4 had variable degrees of anemia before starting ustekinumab. One patient had pre-existing psoriasis and 1 had adalimumab–induced skin lesions.
All patients were previously exposed to corticosteroids, methotrexate, azathioprine/6-mercaptopurine, and both infliximab and adalimumab. Patient 3 had also received thalidomide, and patient 2 had received certolizumab. All patients were primary responders to the first anti-tumor necrosis factor (TNF) agent but had either loss of response (3 patients) or allergy (1 patient). For the second anti-TNF agent, 2 patients showed loss of response, 1 patient had an allergic reaction, and 1 developed severe rash. Several reasons led to recommending ustekinumab in our patients: the presence of psoriasis, anti-TNF–associated skin lesions, JC virus antibody positivity, which increases the complication risk of natalizumab, unavailability of vedolizumab at the time, and concern about adverse events of thalidomide, tacrolimus, and sirolimus as potential options (8).
The first dose of ustekinumab was administered between September 2013 and April 2014 for all patients. No immunomodulators were given concomitantly. Patients received an average of 7.5 doses (±2.4, 5–10 doses) with mean therapy duration of 11 months (±4.9, 6–15 months). Ustekinumab injections were well tolerated. Multiple hospitalizations occurred for 2 patients postinduction, both nonresponders.
Two patients demonstrated sustained clinical response and currently remain on ustekinumab (patients 2 and 4). AbbrPCDAI decreased within 4 to 8 weeks after ustekinumab initiation (Fig. 1A and B). Both patients were receiving prednisone immediately before commencing ustekinumab, and both were successfully weaned off and did not receive any further steroids. Patient 2 had resolution of the bloody diarrhea, nausea, fatigue, and rectal pain. Albumin levels (Fig. 2C) markedly improved from 2.9 to 4.7 g/dL, hematocrit normalized, and body mass index (BMI) improved from 20.0 to 21.8 kg/m2 (Fig. 2A). After 14 months of therapy, patient 2 showed loss of response with symptoms surfacing 2 to 3 weeks before the next ustekinumab injection. She is receiving the dose at 7 instead of 8 weeks and reports no active symptoms as of the last follow-up reflecting and abbrPCDAI of zero with normal blood counts and CRP. Patient 4 had pain and nonbloody diarrhea before ustekinumab initiation. Both symptoms and pre-existing psoriasis improved subsequently. Albumin normalized (3.5–3.8 g/dL). Similarly hematocrit (Fig. 2D) normalized. CRP, however, remained elevated (latest level 2.2 mg/dL) and BMI did not improve. The abbrPCDAI score remains at 5 because of mild diarrhea, with no other active symptoms.
Patients 1 and 3 eventually discontinued ustekinumab because of clinical worsening, complications, or no improvement. The duration of ustekinumab therapy for the unresponsive patients was 6 and 7 months. CRP remained elevated, and anemia and hypoalbuminemia persisted (Fig. 2).
Patient 1 was hospitalized 4 times within 1 to 5 months of induction due to Crohn flare, Clostridium difficile infection, and 2 recurrences of perianal abscess. The perianal abscess was surgically managed and ustekinumab was subsequently discontinued. The child was started on thalidomide and underwent an ileocecal resection for a symptomatic stricture with last follow-up 11 months post ustekinumab.
Patient 3 was hospitalized 5 times within 1 to 5 months of starting ustekinumab. The first hospitalization was to initiate total parenteral nutrition via central line due to ongoing weight loss. Three admissions were due to fever attributed to upper respiratory tract infection, urinary tract infection, and culture positive central line infection. Last admission was due to a Crohn flare after which she received steroids, discontinued ustekinumab, and started vedolizumab with last follow-up 8 months post ustekinumab.
The incidence of IBD, affecting mostly children and young adults, has increased over the past several decades (9). Although the majority of children present with inflammatory Crohn phenotype (Paris Classification B1 (5)), disease phenotype often changes to stricturing (B2) and internally penetrating (B3) behavior over time (10). Similarly, the presence of perianal fistulizing disease also increases with time. The surgery incidence at 5 years from diagnosis in Crohn disease is 18% and 21% in pediatric and adult patients, respectively (11). The overwhelming majority of children with Crohn disease receive the standard therapies which are also used in adult patients.
The goals of treating IBD in children are to control symptoms (achieve clinical remission), restore growth and puberty progression, preserve the bone density, and support the psychosocial well-being of the child. Minimizing corticosteroid exposure is of importance, especially in children, due to the effect on growth and development. There is current interest in achieving mucosal healing as a worthy target for therapies. Mucosal healing predicts sustained clinical remission in patients with early-stage Crohn disease (12). Many children with Crohn disease end up receiving anti-TNF-alpha agents due to intolerance or inadequacy of 6-mercaptopurine/azathioprine and methotrexate, or due to steroid dependence. Although the anti-TNF agents infliximab and adalimumab are effective for many, allergy, adverse events, and loss of response can complicate the treatment course (13). This necessitates alternative treatment options with the ideal goal of avoiding corticosteroids. For children with disease not amenable to surgery (eg, absence of isolated ileocecal Crohn, symptomatic stricture, internal fistula), there are several other medical therapies showing some efficacy in pediatric Crohn including natalizumab, thalidomide, sirolimus, and more recently vedolizumab (14–17).
Ustekinumab is approved for use in adult psoriasis (18). It is a monoclonal antibody that targets the p40 subunit of cytokines interleukin-12 and interleukin-23 (IL-12/23p40), which is implicated in Crohn disease pathology. Previous studies have suggested its general safety and efficacy to induce clinical improvement in patients with moderate to severe Crohn disease (19,20). Ustekinumab use was described for Crohn disease with concomitant anti-TNF–associated skin lesions (21). Two recent publications report successful and unsuccessful use of ustekinumab for 2 children with severe Crohn disease (22,23).
Two of our 4 patients showed clinical improvement: 1 patient remained with elevated CRP and unchanged BMI, whereas the second showed loss of response, a phenomenon seen with other biological therapies. Two patients stopped treatment due to lack of response and continued with a complicated disease course with multiple hospitalizations pre- and post-ustekinumab. However, ustekinumab cannot be ruled out as a contributing factor for the described complications.
Our study is limited because of its retrospective nature and small size. We did not document endoscopic changes while on therapy or use surrogates of endoscopic healing such as fecal calprotectin and bowel imaging. Our case review represents a “real life” experience with challenging Crohn disease unresponsive to the present standard medical therapies. More data are needed to define the role of ustekinumab in pediatric Crohn disease, its safety, and the optimal time to use as monotherapy or in combination with other agents. In addition, predictors to identify patients likely to respond would prove helpful in the future.
Ustekinumab was used in 4 patients with pediatric Crohn disease with 2 of 4 patients showing clinical response (1 with persistently elevated CRP). A prospective study is needed to define its efficacy, safety, and placement in managing pediatric Crohn disease in the future.
1. Ruemmele FM, Veres G, Kolho KL, et al ECCO/ESPGHAN. Consensus guidelines of ECCO/ESPGHAN on the medical management of pediatric
Crohn's disease. J Crohns Colitis
2. Wang K, Zhang H, Kugathasan S, et al Diverse genome-wide association studies associate the IL12/IL23 pathway with Crohn disease
. Am J Hum Genet
3. Benson JM, Peritt D, Scallon BJ, et al Discovery and mechanism of ustekinumab
: a human monoclonal antibody targeting interleukin-12 and interleukin-23 for treatment of immune-mediated disorders. MAbs
4. Chandar AK, Singh S, Murad MH, et al Efficacy and safety of natalizumab and vedolizumab for the management of Crohn's disease: a systematic review and meta-analysis. Inflamm Bowel Dis
5. Levine A, Griffiths A, Markowitz J, et al Pediatric
modification of the Montreal classification for inflammatory bowel disease: The Paris classification. Inflamm Bowel Dis
6. Shepanski MA, Markowitz JE, Mamula P, et al Is an abbreviated Pediatric
Crohn's Disease Activity Index better than the original? J Pediatr Gastroenterol Nutr
7. Turner D, Griffiths AM, Walters TD, et al Mathematical weighting of the pediatric
Crohn's disease activity index (PCDAI) and comparison with its other short versions. Inflamm Bowel Dis
8. Lanzillo R, Liuzzi R, Vallefuoco L, et al JC virus antibody index in natalizumab-treated patients: correlations with John Cunningham virus DNA and C-reactive protein level. Ther Clin Risk Manag
9. Burisch J, Munkholm P. Inflammatory bowel disease epidemiology. Current Opin Gastroenterol
10. Vernier-Massouille G, Balde M, Salleron J, et al Natural history of pediatric
Crohn's disease: a population-based cohort study. Gastroenterology
11. Jakobsen C, Bartek J Jr, Wewer V, et al Differences in phenotype and disease course in adult and paediatric inflammatory bowel disease—a population-based study. Aliment Pharmacol Ther
12. Baert F, Moortgat L, Van Assche G, et al Belgian Inflammatory Bowel Disease Research G, North-Holland Gut C. Mucosal healing predicts sustained clinical remission in patients with early-stage Crohn's disease. Gastroenterology
13. Hyams JS, Lerer T, Griffiths A, et al Pediatric
Inflammatory Bowel Disease Collaborative Research G. Long-term outcome of maintenance infliximab therapy in children with Crohn's disease. Inflamm Bowel Dis
14. Lazzerini M, Martelossi S, Magazzu G, et al Effect of thalidomide on clinical remission in children and adolescents with refractory Crohn disease
: a randomized clinical trial. JAMA
15. Mutalib M, Borrelli O, Blackstock S, et al The use of sirolimus (rapamycin) in the management of refractory inflammatory bowel disease in children. J Crohns Colitis
16. Namita Singh MP, Shervin Rabizadeh, Marla Dubinsky. Vedolizumab use in pediatric
patients with inflammatory bowel disease. Gastroenterology
17. Hyams JS, Wilson DC, Thomas A, et al International Natalizumab CDTG. Natalizumab therapy for moderate to severe Crohn disease
in adolescents. J Pediatr Gastroenterol Nutr
18. Zaghi D, Krueger GG, Callis Duffin K. Ustekinumab
: a review in the treatment of plaque psoriasis and psoriatic arthritis. J Drugs Dermatol
19. Khanna R, Preiss JC, MacDonald JK, et al Anti-IL-12/23p40 antibodies for induction of remission in Crohn's disease. Cochrane Database Syst Rev
20. Sandborn WJ, Gasink C, Gao LL, et al Ustekinumab
induction and maintenance therapy in refractory Crohn's disease. New Engl J Med
21. Andrisani G, Marzo M, Celleno L, et al Development of psoriasis scalp with alopecia during treatment of Crohn's disease with infliximab and rapid response to both diseases to ustekinumab
. Eur Rev Med Pharmacol Sci
22. Rinawi F, Rosenbach Y, Assa A, et al Ustekinumab
for resistant pediatric Crohn disease
. J Pediatr Gastroenterol Nutr
23. Cameron FLGV, Russell RK. Ustekinumab
in treatment refractory paediatric Crohn disease
. J Pediatr Gastroenterol Nutr
Keywords:© 2016 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology,
Crohn disease; IL12/23; pediatric; ustekinumab