See “Is Colectomy Still an Option in the Infliximab Era?” by Knafelz and Bracci on page 676.
Ulcerative colitis (UC) and Crohn disease (CD) are causes of major morbidity in children. Compared with adult-onset inflammatory bowel disease (IBD), disease course in children with IBD tends to be more severe and disease localization more extensive (1,2). In UC, acute and chronic active disease is treated with 5-aminosalicylate preparations, corticosteroids (SST), and immunomodulators (IMs) (azathioprine/mercaptopurine [AZA/6MP), calcineurine inhibitors, or leukocyte apheresis). If remission is not achieved by medical treatment, surgical treatment by colectomy can be curative and, in severe cases, lifesaving (3). Although surgery is the treatment of choice in severe UC refractory to medical therapy, it involves the placement of an ileostomy as well as the risk of surgical complications, decreased fertility, and psychosocial burdens (4).
In adults with UC, infliximab (IFX) has proven to be relatively safe and efficacious in reducing colectomy rates (5–8). Consequently, IFX has been adapted as a possible last medical option before colectomy in many pediatric centers (9). Population-based studies have shown a decreased risk of surgery in pediatric patients with IBD treated with IM and IFX (10,11). Although studies in pediatric patients with IBD are few and the numbers of patients included in most cases are small (9,12), there is a growing evidence to support the use of IFX in pediatric UC. In 2011, the Food and Drug Administration approved the use of IFX in moderate-to-severe UC in children 6 years and older, who have had an inadequate response to conventional therapy (13). This approval was in part based on a study of 60 children who demonstrated a short-term response rate at 8 weeks of 73%, and an estimated 54-week remission in 29%, with a safety profile comparable with adult patients with UC (14). Serious, but uncommon, reported adverse events during IFX therapy include infusion-related anaphylaxis, severe infections, and hepatosplenic T-cell lymphoma (15). The aim of our study was to retrospectively assess the clinical response, risk of colectomy, and safety of IFX treatment in pediatric UC.
Children with UC younger than 15 years at diagnosis were included. Patients were treated with IFX at 3 Danish pediatric IBD centers (Hvidovre University Hospital, Hans Christian Andersen Children's Hospital, and Aarhus University Hospital) during the period April 1, 2005, to May 1, 2012. The patients were identified from local databases on IFX treatment. The diagnosis of UC was based on the Porto and Copenhagen criteria (16,17). Data were collected retrospectively by reviewing the patient charts. One reviewer (S.D.N.) collected the data. In case of doubt, consensus was reached with a second reviewer (V.W./C.J.). Age at diagnosis, age at start of IFX treatment, disease localization according to the Paris classification (18), disease activity, and medication introduced before and after first infusion of IFX in the induction treatment were registered. All adverse events we registered and divided into four categories: mild, infusion-related events (including transient headache, mild flushing, erythema, or asymptomatic transient hypotension), moderate infusion–related events (anaphylactic events requiring medical treatment), mild and moderate late events (including uncomplicated bacterial infections), and severe events contraindicating further treatment.
IFX treatment (5 mg/kg) was given as an induction treatment at weeks 0, 2, and 6. The patients completing the induction treatment either continued on IFX maintenance treatment every 8 weeks, received other maintenance treatment, or were colectomized. Maintenance IFX treatment was given according to the individual clinical response. Shortening of interval or increasing dosage of IFX (10 mg/kg) was instituted in case of decrease or loss of response.
IFX-treated patients with UC were classified as having either acute disease or chronic active disease. Patients in the acute disease group had severe symptoms and failed to respond to conventional treatment (SST with or without IM) before IFX. The patients in the chronic active group were SST dependent (19) (with or without IM). Response was defined as clinical response only. Endoscopic and mucosal remissions were not evaluated, because re-endoscopy was not routinely performed, and an analysis for fecal calprotectin was not available during the first part of the study period. Symptoms were registered and treatment response was divided into the following: complete remission (≤2 stools per day, no blood, pus, mucus, abdominal pain, or weight loss), partial remission (≤4 stools per day, presence of either blood, pus, mucus or abdominal pain less than daily, and no fever or weight loss), and no remission (20). Calculation of Pediatric Ulcerative Colitis Activity Index score was not possible owing to the retrospective design of the study.
Primary endpoints were clinical response to IFX treatment, risk of new course of SST treatment, risk of surgery, and occurrence of adverse events. Patients, who underwent early colectomy during the induction period of IFX treatment, were excluded from the analysis of subsequent SST treatment because they had not been at risk for receiving additional SST. One center (n = 12) used adalimumab, and not SST therapy when patients had relapse during IFX, and these patients were excluded from the analysis regarding the risk of subsequent SST treatment. The study was approved by the regional ethical committee (protocol no. H-2-2009-130).
Demographics and data on adverse events are presented as total, percentage, median, and interquartile range (IQR). Time to colectomy and time to first treatment with SST are presented in Kaplan-Meier plots. Comparison was done using log-rank test. The χ2 or 2-sided Fisher exact tests were used to compare proportions, and the Mann-Whitney U test was used to compare nonparametric data. Data were analyzed using SPSS 19.0 (IBM SPSS Statistics, Armonk, NY).
A total of 46 patients with UC patients were identified among 182 IFX-treated patients with IBD. One patient was excluded because the indication for treatment was primary sclerosing cholangitis before colectomy. The study group comprised 45 patients. The median follow-up time from initiation of IFX was 15 months (IQR 4.5–29). Patient demographics are shown in Table 1. The majority of patients were treated with systemic 5-aminosalicylates (91%), and all of the patients (100%) were treated with SST before first IFX infusion of the induction treatment. Tapering of SST was attempted in all of the patients after induction of IFX. Before first IFX infusion, 29 of 45 (64%) patients were introduced to (AZA/6MP). Only 1 center (Hvidovre University Hospital) used leukocyte apheresis (n = 7) or cyclosporine (n = 2) at any time during the disease course.
Response to IFX
The initial response 6 weeks (median 42 days, IQR 41–47) after initiation of induction treatment was evaluated. A total of 8 of 45 (18%) patients did not complete the induction treatment. In 6 of 8 cases owing to lack of response: 5 of those were colectomized, and 1 was bridged to AZA/6MP by leukocyte apheresis. In 2 of 8 cases treatment was stopped because of adverse events during the induction phase: 1 achieved partial remission that was sufficient as a bridge to AZA/6MP and 1 was given adalimumab instead of IFX. We have included all of the 45 patients in the evaluation of treatment response. The response rates were complete remission, 22 of 45 (49%); partial remission, 9 of 45 (20%); and no remission, 14 of 45 (31%). After the first IFX infusion in the induction treatment, 15 of 45 (33%) patients initiated AZA/6MP. Only 1 patient, who had concurrent cystinosis, did not receive AZA/6MP at any time.
After induction treatment 27 of 45 (60%) patients continued on IFX maintenance treatment. The remaining patients either received other maintenance treatment (13/45) or were colectomized (5/45). The reasons not to choose IFX maintenance therapy were heterogeneous. In 3 of 13 patients adalimumab was used instead of IFX and in 1 of 13 tumor necrosis factor-α inhibition was discontinued as a result of an adverse event. The remaining 9 of 13 stopped IFX because of either full remission (patients with severe acute disease given treatment at the time of diagnosis 3/13) or poor response (no or partial remission in 6/13). Neither disease type (acute vs chronic active, P = 0.59), colonic disease localization (P = 0.87), or AZA/6MP initiated before versus after initiation of IFX treatment (P = 0.49) was associated with clinical remission. Biochemical markers before and after (median 42 days after first infusion, IQR 36–46) IFX induction therapy were analyzed. There were no significant differences in C-reactive protein (P = 0.83), albumin (P = 0.53), or erythrocyte sedimentation rate (P = 0.73) at initiation of IFX treatment, when stratified by subsequent responders to IFX (full + partial remission combined) versus nonresponders (no remission). After the induction treatment, C-reactive protein tended to be lower in responders (P = 0.06) than in nonresponders. The albumin level was significantly higher (P = 0.001) and erythrocyte sedimentation rate was significantly lower (P = 0.006) in responders.
Risk of SST Treatment
Thirty of 45 patients were included in the analysis. All 12 patients from 1 center were excluded owing to choice of adalimumab instead of SST in case of relapse, and 3 patients from other centers were excluded because of early colectomy, as explained in Methods. Fifteen of 30 (50%) patients were given a new course of SST, or an increased SST dosage during tapering, in spite of receiving IFX induction treatment. Three of those (20%) subsequently underwent colectomy. The cumulative risk of initiating or increasing existing SST treatment after IFX treatment is shown in Figure 1. The 1- and 2-year risks were 32% and 48%, respectively.
Risk of Colectomy
Ten of 45 patients underwent colectomy after a median of 77 days (IQR 26–163) after first IFX dose (Fig. 2). The cumulative 1- and 2-year risks of colectomy were 21% and 26%, respectively. Eight of 10 underwent colectomy before 128 days, and in 5 cases, the decision was made during induction of IFX. Only 1 of 22 and 0 of 9 patients with initial complete or partial remission after induction therapy underwent colectomy, corresponding to a cumulative risk of 5% and 0%, respectively. Nine of 14 patients with no remission after induction therapy were colectomized corresponding to a cumulative risk of 72%. The risk of colectomy was significantly lower for the patients with complete or partial remission, compared with those with no remission (P < 0.0005 and P = 0.004, respectively). There was no significant difference in the risk of colectomy between the patients with complete and partial remission (P = 0.51). There was no significant difference in the risk of colectomy when stratified by maintenance IFX after induction versus other treatment (P = 0.27) or acute disease versus chronic active disease (P = 0.79). All of the 6 patients with disease localization distal to splenic flexure at the time of IFX induction avoided colectomy, but there was no significant difference when compared with patients with more extensive disease (P = 0.16).
In the follow-up period a total of 21 of 45 (46%) patients experienced 28 adverse events. Ten of 45 (22%) experienced mild infusion–related adverse events, 3 of 45 (7%) had moderate infusion–related adverse events, and 5 of 45 (11%) had mild or moderate late events, and 3 of these were uncomplicated bacterial infections. Three patients (7%) had IFX discontinued owing to serious adverse events: anaphylactic shock, aseptic meningitis, and severe oral and facial angioedema.
In our retrospective study of IFX treatment in pediatric patients with UC, we found a high number of patients with complete or partial remission in response to IFX, and a low 1- and 2-year risk of colectomy; however, a substantial number of patients needed further courses of SST. IFX treatment was generally safe, but serious adverse events occurred.
The major strength of our study is the relatively large and well-characterized cohort of children with UC treated with IFX. Limitations are the retrospective design and the difference in treatment strategy after IFX induction between the 3 centers.
A high rate of clinical response to IFX has been shown in other studies. Cucchiara et al (12) reviewed 22 (4 acute, 18 chronic active) patients with UC retrospectively, and found results comparable with ours (response rate 82%). A randomized controlled study by Hyams et al (14) demonstrated a short-term response rate of 73% (week 8, n = 60). Similarly, in a prospective study Turner et al (21) found a short-term response in 76% of steroid-refractory children with acute severe disease (n = 33). A systematic review by Turner and Griffiths (22) of 6 studies of acute severe UC (including (21)) reported “response-by-discharge” rate at 75% (95% CI 67–83). In our study the total response rate (full or partial remission) was 31 of 45 (69%).
The 1- and 2-year risks of subsequently being treated with SST (32% and 48%) in our study were lower than previously reported in another descriptive study by Hyams et al (23). Their study included 52 patients with UC with a median follow-up of 30 months, and reported a 1- and 2-year SST-free rate of 38% (15/38) and 32% (9/28), corresponding to a risk of 62% and 68%, respectively. The numbers are not directly comparable because study designs are different, and the follow-up time in our study is shorter (median 15 vs 30 months).
The 1- and 2-year cumulative risks of colectomy after start of IFX treatment in our study (21% and 26%, respectively) were lower than previously reported. Hyams et al (23) found 1- and 2-year colectomy rates of 28% and 39%, respectively. The aforementioned systematic review of acute severe UC (including (21,23)) reported a “long-term colectomy-free” rate of 64% (95% CI 56–72) (22). The description “long-term” ranged from 6 to 27 months in the different studies. Cucchiara et al (12) found, during a 54-week retrospective follow-up, that 7 of 22 (32%) underwent colectomy. The use of IFX in UC has become more common, and the lower risk of colectomy in recent studies could reflect that treatment with IFX was reserved for the most critically ill patients in the earlier studies. When the group of patients eligible for IFX treatment is expanded to include the less critically ill, it is conceivable that the colectomy rate would fall owing to a reduced a priori risk of colectomy in the treatment group.
Our reported frequency of mild and moderate infusion reactions are comparable with other studies of IFX-treated children with UC (12,14,24) and CD (24). Records regarding adverse events were unavailable in 5 cases (11%). This could have led to a slight underestimate of mild adverse reactions, which was not noted in the physicians’ records. In addition to the 3 severe events, there was 1 case in which a moderate infusion–related reaction was cited as the major reason for discontinuation of the treatment. There were fewer infections than previously reported (14), which could be because of the retrospective nature of the study and the relatively small number of patients. More infections may have occurred, and may have been treated outside the hospital setting. The case of anaphylaxis occurred during adult follow-up.
This retrospective study in 45 patients supports the use of IFX in children with UC refractory to conventional treatment. Patients with full or partial remission at 6 weeks have a low risk of colectomy and the treatment is generally well tolerated. Furthermore, the risk of starting a new course of SST after 2 years was lower than previously reported; however, a substantial number of patients received a subsequent course of SST during the follow-up period.
1. Kelsen J, Baldassano RN. Inflammatory bowel disease: the difference between children and adults. Inflamm Bowel Dis
2008; 14 (suppl 2):S9–S11.
2. 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
3. Truelove SC, Willoughby CP, Lee EG, et al. Further experience in the treatment of severe attacks of ulcerative colitis. Lancet
4. Dayan B, Turner D. Role of surgery in severe ulcerative colitis in the era of medical rescue therapy. World J Gastroenterol
5. Lawson MM, Thomas AG, Akobeng AK. Tumour necrosis factor alpha blocking agents for induction of remission in ulcerative colitis. Cochrane Database Syst Rev
2006; 3: CD005112.
6. Mortensen C, Caspersen S, Christensen NL, et al. Treatment of acute ulcerative colitis with infliximab, a retrospective study from three Danish hospitals. J Crohns Colitis
7. Rutgeerts P, Sandborn WJ, Feagan BG, et al. Infliximab for induction and maintenance therapy for ulcerative colitis. N Engl J Med
8. Jarnerot G, Hertervig E, Friis-Liby I, et al. Infliximab as rescue therapy in severe to moderately severe ulcerative colitis: a randomized, placebo-controlled study. Gastroenterology
9. Nattiv R, Wojcicki JM, Garnett EA, et al. High-dose infliximab for treatment of pediatric ulcerative colitis: a survey of clinical practice. World J Gastroenterol
10. Jakobsen C, Paerregaard A, Munkholm P, et al. Pediatric inflammatory bowel disease: increasing incidence, decreasing surgery rate, and compromised nutritional status: a prospective population-based cohort study 2007–2009. Inflamm Bowel Dis
11. Gower-Rousseau C, Dauchet L, Vernier-Massouille G, et al. The natural history of pediatric ulcerative colitis: a population-based cohort study. Am J Gastroenterol
12. Cucchiara S, Romeo E, Viola F, et al. Infliximab for pediatric ulcerative colitis: a retrospective Italian multicenter study. Dig Liver Dis
2008; 40 (suppl 2):S260–S264.
14. Hyams J, Damaraju L, Blank M, et al. Induction and maintenance therapy with infliximab for children with moderate to severe ulcerative colitis. Clin Gastroenterol Hepatol
15. Hoentjen F, van Bodegraven AA. Safety of anti-tumor necrosis factor therapy in inflammatory bowel disease. World J Gastroenterol
16. IBD Working Group of the European Society for Paediatric Gastroenterology, Hepatology and NutritionInflammatory bowel disease in children and adolescents: recommendations for diagnosis—the Porto criteria. J Pediatr Gastroenterol Nutr
17. Winther KV, Fogh P, Thomsen OO, et al. Inflammatory bowel disease (ulcerative colitis and Crohn's disease): diagnostic criteria and differential diagnosis. Drugs Today (Barc)
18. Levine A, Griffiths A, Markowitz J, et al. Pediatric modification of the Montreal classification for inflammatory bowel disease: the Paris classification. Inflamm Bowel Dis
19. Jakobsen C, Munkholm P, Paerregaard A, et al. Steroid dependency and pediatric inflammatory bowel disease in the era of immunomodulators—a population-based study. Inflamm Bowel Dis
20. Wewer V, Riis L, Vind I, et al. Infliximab dependency in a national cohort of children with Crohn's disease. J Pediatr Gastroenterol Nutr
21. Turner D, Mack D, Leleiko N, et al. Severe pediatric ulcerative colitis: a prospective multicenter study of outcomes and predictors of response. Gastroenterology
22. Turner D, Griffiths AM. Acute severe ulcerative colitis in children: a systematic review. Inflamm Bowel Dis
23. Hyams JS, Lerer T, Griffiths A, et al. Outcome following infliximab therapy in children with ulcerative colitis. Am J Gastroenterol
24. Hyams J, Walters TD, Crandall W, et al. Safety and efficacy of maintenance infliximab therapy for moderate-to-severe Crohn's disease in children: REACH open-label extension. Curr Med Res Opin