Treatment for mild to moderate ulcerative colitis (UC) consists of 5-aminosalycilic (5-ASA) preparations and corticosteroids, whereas moderate to severe disease is treated with immunomodulatory therapy, such as 6-mercaptopurine (1). Patients who are unresponsive to these therapies are frequently admitted to the hospital for treatment using intravenous corticosteroids. Options are limited for patients in whom intravenous corticosteroid therapy in unsuccessful and include cyclosporine or colectomy (2,3).
Tumor necrosis factor α (TNF-α) is an important proinflammatory cytokine involved in the pathogenesis of inflammatory bowel disease (4,5). Novel biologic therapy in the form of a chimeric human–mouse antibody (infliximab) directed against this cytokine was initially investigated as a therapy for UC in 1996 (6), and the full scientific report was published recently (7). Subsequent studies concentrated on its use in Crohn disease in which it has been shown in several trials to be an effective and safe, and a steroid-sparing therapy (8–12).
Recently, a preliminary report described a beneficial role of infliximab in an open-label study of 17 adult patients with UC unresponsive to maximal medical therapy (13). Additionally, a more humanized anti–TNF-α antibody, CDP571, has shown promising results in the treatment of UC, both in an animal model and in humans (14,15).
We report the use of infliximab in nine pediatric patients with moderate to severe UC who were unresponsive to conventional medical therapy.
We retrospectively collected data on all consecutive pediatric patients with UC who received infliximab at The Children's Hospital of Philadelphia (CHOP) until July 2001. Patients in the hospital were considered eligible if their UC symptoms were unresponsive to 2-week intravenous corticosteroid therapy. Ambulatory patients were eligible if they were dependent on or resistant to corticosteroid therapy, and were not responding or allergic to 6-mercaptopurine. Inclusion criteria for the clinical response analysis included the verification of the diagnosis of UC based on clinical, endoscopic, histologic, and radiologic criteria and stable medical therapy at the time of infusion (stable dose of 5-ASA preparations and corticosteroids for 2 weeks, and 6-mercaptopurine [6-MP] for 3 months). Exemption was made for patient 2, who first received 6-MP 4 days before infliximab infusion, which was thought not to be sufficiently long to affect the efficacy analysis.
The following data were collected: demographic information; features of diagnosis of UC, including the clinical history, endoscopy reports, histology, serology, and radiograms; time from diagnosis to first infliximab infusion; clinical severity of UC at the time of infusion; concurrent medical therapy; response to infliximab; and number of infliximab infusions and adverse reactions.
The primary measured outcome was clinical response at 2 days and 2 weeks after the first infusion measured by the Lichtiger Colitis Activity Index (LCAI) score and the Physician Global Assessment (3,16). The LCAI score ranges from 0 to 21 and includes number of stools, presence of blood in the stool, presence of nocturnal stools, presence of fecal incontinence and abdominal pain, general well-being, presence of abdominal tenderness, and the need for antidiarrheal medicines. The secondary outcome was tolerance and safety of infliximab.
The Physician Global Assessment was evaluated before and 2 weeks after the first infusion. The LCAI score was calculated for each patient before infliximab infusion and 2 days and 2 weeks after the infliximab infusion, and was compared using the Wilcoxon signed rank test for nonparametric paired data. Statistical analysis was performed using the statistical package Stata 7.0 (Stata Corporation, College Station, TX, U.S.A.).
The review of the patient's records was approved by The Children's Hospital of Philadelphia Institutional Review Board. Each patient and their families were verbally informed before infusion regarding the possible side effects, including allergy, immunosuppression, and malignancy, and the lack of published data with infliximab in UC.
Infliximab (Remicade®; Centocor Inc., Malvern, PA, U.S.A.) was administered at a dose of 5 mg/kg as a 2-hour intravenous infusion. Patients were monitored for signs of adverse reactions. Patients received a variable number of infusions depending on their response and the preference of the primary gastroenterologist.
Twelve patients were identified for inclusion in the study. Nine patients (six females) aged 10–19 years (median, 14 years) qualified for clinical response analysis. Three patients were excluded: one received infliximab for pouchitis after colectomy, and two were not undergoing stable medical therapy for UC at the time of infusion. All excluded patients had a good clinical response to infliximab therapy. Duration of disease before the first infusion ranged from 0.2 to 13 years (median, 3.5 years). Two patients (patients 2 and 8) received infusion for new-onset fulminant colitis after no clinical response to 2-week therapy with intravenous corticosteroids. Duration of follow-up after the initiation of therapy ranged from 4 to 52 weeks (median, 20 weeks). Demographic data, disease characteristics, and concurrent therapy are shown in Table 1.
All patients underwent colonoscopy, and eight of nine patients underwent upper gastrointestinal series, with small bowel follow-through or abdominal computed tomography performed during the course of their disease. In none of the patients was evidence of small bowel disease seen during endoscopy or radiologic studies.
All patients underwent Clostridium difficile testing for toxins A and B. In seven patients, the results of the C. difficile toxin assays before the infusion were negative. In one patient, results of four consecutive assays were negative, followed by one positive result for toxin A. The patient was treated with metronidazole and there was no change in symptoms before the infusion. Another patient had a history of chronic C. difficile infection that had not responded to 3-month treatment with metronidazole, vancomycin, and rifampin. After treatment with infliximab, C. difficile toxin assay results were negative.
The Physician Global Assessment was performed by the primary gastroenterologist and one of the investigators immediately before and 2 weeks after the first infusion.
Seven (77%) patients showed improvement in the activity of their disease, whereas one patient underwent colectomy and corticosteroid therapy was restarted for another. Six patients (66%) had inactive disease 2 weeks after infusion (LCAI score, < 2). The median LCAI score was 11 before the patient's first infliximab infusion, was 1 two days after the first infusion, and was 1 two weeks after the first infusion. This was highly statistically significant (P = 0.0121 and 0.0123) for both postinfusion points when they were each compared to preinfusion scores. The stool frequency decreased from 5 or 6 stools per day before the first infusion to 0 to 2 stools at 2 days after the infusion evaluation point. Six of eight (75%) patients who experienced pain before the first infusion were free of pain 2 days after the infusion. Hematochezia resolved in seven of nine (77%) patients 2 days after infusion. The Physician Global Assessment, LCAI scores, and adverse events are shown in Table 2.
Eight patients were undergoing corticosteroid therapy before infusion. The ninth patient did not respond to infliximab and corticosteroid therapy was restarted after two infusions. In six of eight (75%) patients undergoing corticosteroid therapy, corticosteroid use was discontinued after the infusion (Fig. 1). One patient underwent colectomy, and one was prescribed a tapering dose at the time of the last evaluation.
Nine patients received a total of 31 infusions. Seven patients received a second infusion 2 weeks after the first infusion, regardless of response to the first infusion, and four patients required subsequent infusions because of worsening of their symptoms at 4- to 12-week intervals (Fig. 2).
Two patients each experienced one infusion reaction (6.5% of the total number of infusions). Generalized pruritus was noted in one and facial flushing in another patient during the first infusion. Both symptoms resolved spontaneously. One patient was premedicated with acetaminophen and diphenhydramine before subsequent infusions. No adverse events occurred with the subsequent infusions. An elevated ANA titer of 1:1280 developed in one patient after the third dose of infliximab.
This is the first report on the use of infliximab in pediatric patients with UC. Increasing understanding of inflammatory bowel disease pathogenesis has led to development of new biologic therapies. Intestinal inflammation is a result of a cascade of events, which starts with immune response to an antigen. Interaction between antigens and antigen-presenting cells leads to the activation of T cells and cytokine production. There is strong scientific evidence that TNF-α as a significant proinflammatory cytokine mediates immune response in Crohn disease (4,5). However, TNF-α is also present in increased amounts in animal models of UC, and in adults and children with UC (17–20). Preliminary data indicate that infliximab may be beneficial in a subset of patients with UC. Infliximab was investigated in UC in a double-blind, placebo-controlled study (7). Eleven patients with severe, steroid-resistant UC were enrolled and randomized to four groups: placebo, 5 mg/kg, 10 mg/kg, and 20 mg/kg. Four of eight (50%) treated patients responded, whereas none of three patients receiving placebo responded. The infusions were well tolerated. In two patients in the infliximab group, serious adverse events developed (nephrolithiasis and abdominal cellulitis). Remission was achieved in one patient who received 20 mg/kg infliximab. Another report described significant clinical, endoscopic, and histologic improvement in 16 of 17 (95%) adult patients with UC (13). The improvement occurred within 6 days in the majority of patients and lasted between 2 and 10 months. In all eight corticosteroid-dependent patients who were observed for 5 months corticosteroids were discontinued. No significant side effects were noted.
New therapies for UC have been eagerly awaited. In pediatrics, this becomes even more important for several reasons. First, the duration of UC in children may not be sufficiently long to establish the correct diagnosis and to differentiate between Crohn disease and UC. Colectomy performed in patients who are subsequently found to have Crohn disease can lead to significant postoperative complications, as was seen in 4% of patients in a series from Toronto (21). Second, up to 57% of children have moderate to severe disease at the time of examination (2,22). The results of surgical therapy for children with UC have been satisfactory, providing the cure, ensuring the appropriate growth, and improving quality of life. However, improved medical therapy may ensure that the precipitous surgery can be avoided and performed at an optimal time, thus minimizing the risk of complications and allowing additional time for patients and their families to adjust to the new diagnosis before colectomy is undertaken (23). Third, patients with known allergies to other types of immunomodulatory therapy, or a predisposition to potentially severe side effects, may also benefit from this therapy. Fourth, issues of special importance in the pediatric population of patients with inflammatory bowel disease include growth and bone density statuses. Both are adversely affected by long-term corticosteroid treatment (24,25). Also, weight gain, mood changes, cataract formation, and cosmetic side effects should not be overlooked. Use of infliximab may have a corticosteroid-sparing effect, as is the case in patients with Crohn disease and the patients who responded to infliximab therapy in this study (8,9).
In our study, patients with recent-onset disease and fulminant colitis responded to therapy, and five of seven patients with a longer disease duration responded to the same treatment. This study is too small to draw conclusions about the factors predicting response and its duration. Further studies will hopefully allow us to predict which patients with UC will benefit from this therapy.
In conclusion, this report suggests that infliximab is a well-tolerated and beneficial short-term therapy for children and adolescents with moderate to severe UC. This population would benefit from prospective, placebo-controlled trials to further evaluate the efficacy of infliximab for UC.
The authors thank student Louis Cohen (University of Pennsylvania) for his help in preparation of this manuscript.
1. Robinson M. Medical therapy of inflammatory bowel disease for the 21st century. Eur J Surg Suppl
2. Treem WR, Cohen J, Davis PM, et al. Cyclosporine for the treatment of fulminant ulcerative colitis
in children. Immediate response, long-term results, and impact on surgery. Dis Colon Rectum 1995; 38:474–9.
3. Lichtiger S, Present DH, Kornbluth A, et al. Cyclosporine in severe ulcerative colitis
refractory to steroid therapy. N Engl J Med 1994; 330:1841–5.
4. Lichtenstein GR. Is infliximab
effective for induction of remission in patients with ulcerative colitis
? Inflamm Bowel Dis 2001; 7:89–93.
5. Fiocchi C. Inflammatory bowel disease: etiology and pathogenesis. Gastroenterology 1998; 115:182–205.
6. Sands BE, Podolsky DK, Tremaine WJ, et al. Chimeric monoclonal anti-tumor necrosis factor antibody (cA2) in the treatment of severe, steroid-refractory ulcerative colitis
(UC). Gastroenterology 1996; 110:A1008.
7. Sands BE, Tremaine WJ, Sandborn WJ, et al. Infliximab
in the treatment of severe, steroid-refractory ulcerative colitis
: A pilot study. Inflamm Bowel Dis 2001; 7:83–8.
8. Farrell RJ, Shah SA, Lodhavia PJ, et al. Clinical experience with infliximab
therapy in 100 patients with Crohn's disease. Am J Gastroenterol 2000; 95:3490–7.
9. Cohen RD, Tsang JF, Hanauer SB. Infliximab
in Crohn's disease: first anniversary clinical experience. Am J Gastroenterol 2000; 95:3469–77.
10. Present DH, Rutgeerts P, Targan S, et al. Infliximab
for the treatment of fistulas in patients with Crohn's disease. N Engl J Med 1999; 340:1398–405.
11. Rutgeerts P, D'Haens G, Targan S, et al. Efficacy and safety of retreatment with anti-tumor necrosis factor antibody (infliximab
) to maintain remission in Crohn's disease. Gastroenterology 1999; 117:761–9.
12. Sandborn WJ. A controlled trial of anti-tumor necrosis factor alpha antibody for Crohn's disease. Gastroenterology 1997; 113:1042–3.
13. Chey W, Hussain A, Ryan C, et al. Infliximab
is an effective therapeutic agent for ulcerative colitis
. Gastroenterology 2000; 95:A2530.
14. Evans RC, Clarke L, Heath P, et al. Treatment of ulcerative colitis
with an engineered human anti-TNFalpha antibody CDP571. Aliment Pharmacol Ther 1997; 11:1031–5.
15. Watkins PE, Warren BF, Stephens S, et al. Treatment of ulcerative colitis
in the cottontop tamarin using antibody to tumour necrosis factor alpha. Gut 1997; 40:628–33.
16. Hyams JS, Ferry GD, Mandel FS, et al. Development and validation of pediatric Crohn's Disease Activity Index. J Pediatr Gastroenterol Nutr 1991; 12:439–447.
17. Breese EJ, Michie CA, Nicholls SW, et al. Tumor necrosis factor alpha-producing cells in the intestinal mucosa of children with inflammatory bowel disease. Gastroenterology 1994; 106:1455–66.
18. Murch SH, Braegger CP, Walker-Smith JA, et al. Location of tumour necrosis factor alpha by immunohistochemistry in chronic inflammatory bowel disease. Gut 1993; 34:1705–9.
19. Murch SH, Lamkin VA, Savage MO, et al. Serum concentrations of tumour necrosis factor alpha in childhood chronic inflammatory bowel disease. Gut 1991; 32:913–7.
20. Olson AD, Ayass M, Chensue S. Tumor necrosis factor and IL-1 beta expression in pediatric patients with inflammatory bowel disease. J Pediatr Gastroenterol Nutr 1993; 16:241–6.
21. Durno C, Sherman P, Harris K, et al. Outcome after ileoanal anastomosis in pediatric patients with ulcerative colitis
. J Pediatr Gastroenterol Nutr 1998; 27:501–7.
22. Hyams JS, Davis P, Grancher K, et al. Clinical outcome of ulcerative colitis
in children. J Pediatr 1996; 129:81–8.
23. Martin LW. Current surgical management of patients with chronic ulcerative colitis
. J Pediatr Gastroenterol Nutr 1993; 17:121–31.
24. Semeao EJ, Jawad AF, Stouffer NO, et al. Risk factors for low bone mineral density in children and young adults with Crohn's disease. J Pediatr 1999; 135:593–600.
25. Griffiths AM, Nguyen P, Smith C, et al. Growth and clinical course of children with Crohn's disease. Gut 1993; 34:939–43.