Journal of Pediatric Gastroenterology & Nutrition:
Safety of Infliximab Treatment in Pediatric Patients with Inflammatory Bowel Disease
Friesen, Craig A.; Calabro, Cheryl; Christenson, Kathy; Carpenter, Ellen; Welchert, Eleanor; Daniel, James F.; Haslag, Sara; Roberts, Charles C.
Section of Gastroenterology, The Children’s Mercy Hospital and Clinics, Kansas City, Missouri
Address correspondence and reprint requests to: Craig A. Friesen, MD, Section of Pediatric Gastroenterology, Children’s Mercy Hospital and Clinics, 2401 Gillham Road, Kansas City, Missouri 64108 (e-mail: firstname.lastname@example.org).
Background: Infliximab appears to be efficacious in the treatment of pediatric Crohn disease (CD). There are few large-scale pediatric studies on the complications of infliximab therapy.
Methods: A retrospective review of all infliximab infusions administered to IBD patients at a tertiary children’s hospital was undertaken. Data was obtained from an infliximab infusion database maintained in the section of Pediatric Gastroenterology, pharmacy records and patient charts.
Results: 594 infusions were administered to 111 IBD patients (88 CD and 23 UC; 55 male and 56 female; ages 4 to 20 years; mean age, 13.4 years). The number of infusions ranged from 1 to 24 with a mean of 5.4/patient. Infusion reactions occurred in 8.1% of patients (seven early and two delayed) and in 1.5% of all infusions. Reactions occurred more frequently in female patients (14% versus 2%; P = 0.03). All reactions were mild and responded rapidly to treatment. Four patients had infections deemed unusual, including three cutaneous tinea infections and one case of shingles.
Conclusion: Infliximab is safe in pediatric IBD patients with a low incidence of generally mild reactions that respond rapidly to intervention. Infusion reactions are more common in female patients. Our patients had no serious infectious complications, although cutaneous tinea infection may represent a newly reported associated complication.
Infliximab is a chimeric monoclonal antibody against tumor necrosis factor-α (TNF-α). It is effective in the treatment of moderate to severe Crohn disease (CD) in adults (1–2). Repeated doses at 8-week intervals are effective as maintenance therapy for adults with CD (3). Although pediatric experience is limited, infliximab appears to be effective in the treatment of CD in children and adolescents (4–9).
Infliximab side effects in adults include acute infections and reactivation of latent tuberculosis (TB), infusion reactions, delayed hypersensitivity reactions, serum sickness and an association with malignancy (3,10). In adults, infusion reactions occur in 3% to 6% of infusions affecting 6% to 32% of patients depending on concomitant use of immunosuppressive medications (3,11,12). Stephens et al. recently reported on 432 infliximab infusions administered to 82 pediatric CD patients, the largest experience to date (7). Infusion reactions occurred in 5.3% of infusions and unusual infections in 4% of patients. In a smaller study comparing children and adults, infusion reactions were less frequent in children than adults (13).
We report our experience with 594 infusions in 111 pediatric inflammatory bowel disease (IBD) patients to further delineate the incidence of complications associated with infliximab in this patient population.
SUBJECTS AND METHODS
We reviewed all infliximab infusions administered to patients with inflammatory bowel disease (IBD) at the Children’s Mercy Hospital between July 1, 1998, and April 14, 2003. Data was obtained from an infliximab infusion database maintained by the section of Pediatric Gastroenterology, hospital pharmacy records and patient charts. Data gathered included age, gender, diagnosis, medications and number of infusions. All immediate symptoms were recorded at the time of the infusion and all immediate and delayed symptoms were recorded in the infusion database. Additionally, any infections other than common viral infections (e.g., upper respiratory infections) were recorded in the patient chart and database at the time of occurrence. The database and charts were reviewed to determine the incidence and type of infusion reactions and the incidence of unusual infections.
Infusions were given in a hospital setting either an inpatient unit or outpatient observation unit. Outpatient infusions were administered in an infusion center with continuous observation by a nurse. According to our standard practice, all patients were premedicated with prednisolone (1 mg/kg to a maximum of 50 mg IV) and diphenhydramine (1 mg/kg to a maximum of 50 mg IV). The same regimen was used in patients re-infused after a previous reaction. Any immediate reactions were treated with additional doses of diphenhydramine and slowing of the infusion rate or discontinuation of the infusion.
Immediate infusion reactions were defined reactions occurring during or within 1 hour after infusion. Symptoms considered immediate reactions included a drop in blood pressure, shortness of breath, oxygen desaturation, fever or any rash, including urticaria. Any symptoms occurring during the infusion were recorded and reported. Delayed reactions were defined as arthralgias or joint stiffness and/or edema occurring more than 1 day post-infusion. Delayed symptoms were recorded and reported. All patients with suspected delayed reactions were evaluated by the physician. Corticosteroid treatment of suspected delayed reactions was initiated at the discretion of the attending physician. The incidence of reactions in males and females and in patients with CD and UC was compared by Fisher’s exact test.
This study was reviewed by the Institutional Review Board of the Children’s Mercy Hospital and granted exempt status.
A total of 111 IBD patients received 594 infusions. There were 88 patients with CD (79%) and 23 with UC (21%). There were 55 males and 56 females. Patients ranged in age from 4 to 20 years with a mean of 13.4 ± 2.9 years. Patients received from 1 to 24 infusions with a mean of 5.4 ± 4.7 infusions/patient. The infusion number distribution is shown in Figure 1. CD patients received a total of 514 infusions and UC patients received a total of 80 infusions. Concomitant immunomodulating medication used included 6-mercaptopurine (6MP) or azathioprine alone in 48%, prednisone with either 6MP or azathioprine in 34%, prednisone alone in 9%, budesonide in 4% (two of the four with 6MP), methotrexate in 2% (one of the two with prednisone) and no medication in 3%.
The mean follow-up from the initiation of infliximab therapy was 19.9 ± 12.9 months (range, 1 to 54 months). A total of nine (seven early and two delayed) infusion reactions occurred. One early reaction occurred in a patient with UC, and all other reactions occurred in patients with CD. No patient with an acute reaction had more than a single reaction despite the continuation of treatments. Neither of the patients with delayed reactions received subsequent infusions. Early reactions consisted of shortness of breath and chest pain in four patients (one with hives, one with flushing, one with oxygen desaturation and one with a decrease in blood pressure), throat tightening and facial numbness in one and a rash in two. Early reactions occurred after the second dose in one patient, the third dose in two, the fourth dose in three and the eleventh dose in one. The patient reacting during the eleventh dose had a blotchy rash only. All reactions responded rapidly to IV diphenhydramine. Delayed infusion reactions occurred in two patients after their second and fifth doses, respectively. Reactions were facial and upper extremity swelling with arthralgia in one, and extremity swelling with neuralgia in the other. Both responded within days to oral prednisone. Medication was discontinued in both after 2 weeks without recurrence of symptoms. In patients with infusion reactions, concomitant immunomodulating therapy with 6MP or azathioprine was used in six patients. Three of these six patients also received prednisone, one received budesonide, one received methotrexate with prednisone and one received no other medication.
In summary, reactions were seen in 8.1% of patients and in 1.5% of total infusions. Reactions occurred in 8% of CD patients and 9% of UC patients. The reaction rates for males versus females for all patients and for patients receiving more than one infusion are shown in Figure 2.
No severe or life-threatening infections were encountered. Three patients developed cutaneous tinea infections; two responded to topical treatment alone and the third to oral griseofulvin and topical treatment. Infliximab infusions were continued after a short course of antifungal treatment without exacerbation or recurrence of infection. Shingles occurred in one patient who was also receiving azathioprine. Infliximab infusions were continued in this patient without recurrence. No other infections were identified.
Infliximab is effective in adults with CD for the short-term treatment of moderate to severe disease and as a maintenance regimen (1,3,14). Use of infliximab for pediatric CD was first reported by Hyams et al. (4). Subsequently, infliximab has been reported to be beneficial in pediatric CD patients with moderate to severe disease as well as refractory and steroid-dependent patients (8,9). Kugathasan et al. reported a response rate of 94% in 15 refractory patients and noted a more prolonged response in those patients treated less than 2 years from diagnosis (5). Stephens et al. found infliximab to have a significant steroid-sparing effect, with 58% of patients becoming completely independent of the need for corticosteroids (7).
The effectiveness of infliximab in patients with UC has not been thoroughly evaluated. We have used it in UC patients who are steroid-dependent and with steroid-resistant acute exacerbations. Mamula et al. reported short-term clinical improvement in nine children with moderate to severe UC (15). In 27 adult UC patients, Su et al. reported a positive clinical response in 83% of steroid-responsive patients but in only 33% of steroid-refractory patients (16). Likewise, Probert et al., in a randomized controlled trial, reported infliximab to be ineffective in patients with steroid-resistant UC (17).
Infliximab therapy has been associated with both infusion reactions and delayed hypersensitivity reactions (3). Infusion reactions have been reported in 3% to 13% of adults receiving infliximab (2,3,10). Human antichimeric antibodies develop in 14% of adults treated with infliximab and are associated with an increased incidence of reactions (3,10). Co-therapy with immunomodulating drugs is associated with a decrease in infliximab reactions (10). Hanauer et al. reported infusion reactions in 8% of patients receiving both steroids and immunosuppressives compared with 20% of patients receiving immunosuppressives alone and 32% of patients receiving neither (3).
Until recently, there has been a lack of information on infliximab reactions in pediatric CD. In the largest previous pediatric series, Stephens et al. reported the side effect that occurred in 82 patients receiving 432 infusions (7). Acute infusion reactions occurred in 5.3% of infusions, and no patient experienced delayed reactions. Crandall and Mackner reported infusion reactions in 8.5% of infusions affecting 38.6% of the patients (18). In our patients, infusion reactions occurred in only 1.5% of infusions and affected 8% of the patients. All patients at our institution are premedicated with intravenous methylprednisolone and diphenhydramine, which may have been responsible for the low reaction rate. The use of this premedication regimen was initiated empirically to decrease the frequency of reactions and has been continued because of an observed low reaction rate. Intravenous hydrocortisone has been associated with decreased human antichimeric antibody formation and a trend towards a decrease in infusion reactions from 25% to 15% (P = 0.06) (19). It is possible that some symptoms that may not be associated with physical changes (e.g., headaches or shortness of breath) were not reported by our patients who frequently sleep through much of the infusion after premedication with diphenhydramine. All early reactions at our institution were mild, responded rapidly to therapy and did not preclude continued use of infliximab. Both patients with a delayed reaction declined further infusions.
In our series, gender was a risk factor for a reaction to infliximab with reactions in 14% of females versus 2% of males. Female gender has previously been found (by stepwise logistic regression analysis) to be a risk factor for reaction to a second infusion in pediatric patients predominantly being treated for inflammatory bowel disease (18). Gender has also been identified as a risk factor in adults (20). An explanation for this association has not yet been identified.
The other major concern with infliximab, as with any immunomodulatory drug, is increased susceptibility to infection. TNF-α has a wide range of immune effects, including production of proinflammatory cytokines, promotion of macrophage differentiation and induction of adhesion molecule expression (21). TNF-deficient mice are particularly susceptible to infections such as Candida (22). Infliximab therapy produces a significant down-regulation in mucosal inflammation with a decrease in both polymorphonuclear cells and T lymphocytes (23). T-cell immunodeficiencies are characterized by opportunistic infections with viruses, Pneumocystis carinii and fungi. However, Cornillie et al. were not able to demonstrate systemic suppression of T-cell density or immunocompetence after a single infliximab infusion (24).
The most common infections associated with infliximab therapy are upper respiratory infections (3,14). Although a number of case reports describe a variety of other infections after infliximab, the most commonly reported infections are tuberculosis, histoplasmosis, Listeria monocytogenes and Herpes zoster (25–27). No serious life-threatening infections were seen in our patients, although one patient developed Herpes zoster or shingles. Upper respiratory infections are not tracked at our institution, so their incidence is not known. We noted three patients with cutaneous fungal infection. All occurred near the time that an infusion was due. Although treatment of each infection delayed the next infusion for 1 to 2 weeks, the infections did not preclude further infusions. There were no recurrences with further therapy. Overall, unusual infections were seen in 3.6% of our patients. This is comparable to the 5% rate reported by Stephens et al. and the 4% to 8% rate reported in adults (3,7,12).
In conclusion, our experience supports the use of infliximab as a safe treatment modality for pediatric IBD with a low incidence of generally mild reactions that respond rapidly to interventions. Severe non-infectious reactions such as delayed hypersensitivity reactions can still occur and may preclude further use of this medication. Reactions appear to be more common in female patients. Although associated serious infections appear to be uncommon, cutaneous fungal infections may represent a new complication amenable to therapy that did not necessitate discontinuation of treatment with infliximab.
1. Targan SR, Hanauer SB, vanDeventer SJH, et al. A short-term study of chimeric monoclonal antibody cA2 to tumor necrosis factor alpha for Crohn’s disease. N Engl J Med
2. Cohen RD, Tsang JF, Hanauer SB. Infliximab in Crohn’s disease: first anniversary clinical experience. Am J Gastroenterol
3. Hanauer SB, Feagan BG, Lichtenstein GR, et al. Maintenance infliximab for Crohn’s disease: the ACCENT I randomized trial. Lancet
4. Hyams JS, Markowitz J, Wyllie R. Use of infliximab in the treatment of Crohn’s disease in children and adolescents. J Pediatr
5. Kugathasan S, Werlin SL, Martinez A, Rivera MT, Heikenen JB, Binion DG. Prolonged duration of response to infliximab in early, but not late pediatric Crohn’s disease. Am J Gastroenterol
6. Serrano MS, Schmidt-Sommerfeld E, Kilbaugh TJ, Brown RF, Udall JN, Mannick EE. Use of infliximab in pediatric patients with inflammatory bowel disease. Ann Pharmacother
7. Stephens MC, Shepanski MA, Mamula P, Markowitz JE, Brown KA, Baldassano RN. Safety and steroid-sparing experience using infliximab for Crohn’s disease at a pediatric inflammatory bowel disease center. Am J Gastroenterol
8. Baldassano R, Braegger CP, Escher JC, et al. Infliximab (Remicade) therapy in the treatment of pediatric Crohn’s disease. Am J Gastroenterol
9. Cezard J-P, Nouaili N, Talbotec C, et al. A prospective study of the efficacy and tolerance of a chimeric antibody to tumor necrosis factors (Remicade) in severe pediatric Crohn’s disease. J Pediatr Gastroenterol Nutr
10. Sandborn WJ, Hanauer SB. Antitumor necrosis factor therapy for inflammatory bowel disease: a review of agents, pharmacology, clinical results, and safety. Inflamm Bowel Dis
11. Cheifetz A, Smedley M, Martin S, et al. The incidence and management of infusion reactions to infliximab: a large center experience. Am J Gastroenterol
12. Colombel J-F, Loftus EV, Tremaine WJ, et al. The safety profile of infliximab in patients with Crohn’s disease: the Mayo clinic experience in 500 patients. Gastroenterol
13. Kugathasan S, Levy MB, Saeian K, et al. Infliximab retreatment in adults and children with Crohn’s disease: risk factors for development of delayed severe systemic reaction. Am J Gastroenterol
14. 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. Gastroenterol
15. Mamula P, Markowitz JE, Brown KA, Hurd LB, Piccoli DA, Baldassano RN. Infliximab as a novel therapy for pediatric ulcerative colitis. J Pediatr Gastroenterol Nutr
16. Su C, Salzberg BA, Lewis JD, et al. Efficacy of anti-tumor necrosis factor therapy in patients with ulcerative colitis. Am J Gastroenterol
17. Probert CS, Hearing SD, Schreiber S, et al. Infliximab in moderately severe glucocorticoid resistant ulcerative colitis: a randomized controlled trial. Gut
18. Crandall WV, Mackner LM. Infusion reactions to infliximab in children and adolescents: frequency, outcome, and a predictive model. Aliment Pharmacol Ther
19. Farrell RJ, Alsahli M, Jeen YT, Falchuk KR, Peppercorn MA, Michetti P. Intravenous hydrocortisone premedication reduces antibodies to infliximab in Crohn’s disease: a randomized control trial. Gastroenterol
20. Han PD, Cohen RD, Motamedi F, Hanauer SB. Infliximab infusion reactions: the influence of sex and drugs [abstract]. Gastroenterol
2002;122 (Supp. 4):A612.
21. Bresnihan B, Cunnane G. Infection complications associated with the use of biologic agents. Rheum Dis Clin N Am
22. Marino MW, Dunn A, Grail D, et al. Characterization of tumor necrosis factor-deficient mice. Proc Natl Acad Sci U S A
23. Baert FJ, D’haens GR, Peeters M, et al. Tumor necrosis factor α antibody (infliximab) therapy profoundly down-regulates the inflammation in Crohn’s ileocolitis. Gastroenterol
24. Cornillie F, Shealy D, D’haens G, et al. Infliximab induces potent anti-inflammatory and local immunomodulatory activity but no systemic immune suppression in patients with Crohn’s disease. Aliment Pharmacol Ther
25. Keane J, Gershon S, Wise RP, et al. Tuberculosis associated with infliximab, a tumor necrosis factor α-neutralizing agent. N Engl J Med
26. Lee JH, Slifman NR, Gershon SK, et al. Life-threatening Histoplasmosis complicating immunotherapy with tumor necrosis factor α antagonists infliximab and etanercept. Arthritis Rheum
27. Slifman NR, Gershon SK, Lee JH, Edwards ET, Braun MM. Listeria monocytogenes infection as a complication of treatment with tumor necrosis factor α-neutralizing agents. Arthritis Rheum
This article has been cited 25 time(s).
Clinical Gastroenterology and HepatologyMedical therapy for refractory pediatric Crohn's diseaseClinical Gastroenterology and Hepatology
Journal of Gastroenterology and HepatologyInfliximab improves inflammation and anthropometric measures in pediatric Crohn's diseaseJournal of Gastroenterology and Hepatology
Inflammatory Bowel DiseasesNew drugs: Kids come first; Con: First adults, then childrenInflammatory Bowel Diseases
Expert Opinion on Biological TherapyInfliximab therapy for pediatric Crohn's diseaseExpert Opinion on Biological Therapy
Crohn's disease - A review of current treatment with a focus on biologics
GastroenterologyNatural history of pediatric Crohn's disease: A population-based cohort studyGastroenterology
Drugs of TodayInfliximab for Pediatric Crohn's DiseaseDrugs of Today
Inflammatory Bowel Diseases"New drugs: Kids come first": Children should be included in trials of new biological treatmentsInflammatory Bowel Diseases
Infliximab therapy in children and adolescents with inflammatory bowel disease
Inflammatory Bowel DiseasesInfliximab dependency in pediatric Crohn's disease: Long-term follow-up of an unselected cohortInflammatory Bowel Diseases
Expert Opinion on Biological TherapyInfliximab and ulcerative colitisExpert Opinion on Biological Therapy
Acta PaediatricaSevere adverse reactions to Infliximab therapy are common in young children with inflammatory bowel diseaseActa Paediatrica
Canadian Journal of Gastroenterology
Review and clinical perspectives for the use of infliximab in ulcerative colitis
Canadian Journal of Gastroenterology, 22(3):
Expert Opinion on PharmacotherapyUpdate in the treatment of paediatric ulcerative colitisExpert Opinion on Pharmacotherapy
Clinical ImmunologyClinical and biological consequences of immunization to infliximab in pediatric Crohn's diseaseClinical Immunology
Alimentary Pharmacology & TherapeuticsInfliximab dependency in children with Crohn's diseaseAlimentary Pharmacology & Therapeutics
Current Opinion in PharmacologyPediatric gastrointestinal diseases: are drugs the answer?Current Opinion in Pharmacology
Infantile Crohn disease presenting with diarrhea and pyoderma gangrenosum
Pediatric Dermatology, 23(1):
Current Opinion in GastroenterologyChallenges and progress in pediatric inflammatory bowel diseaseCurrent Opinion in Gastroenterology
Journal of Pediatric Gastroenterology and NutritionA Home Infliximab Infusion ProgramJournal of Pediatric Gastroenterology and Nutrition
Journal of Pediatric Gastroenterology and NutritionInfliximab Dependency in a National Cohort of Children with Crohn's DiseaseJournal of Pediatric Gastroenterology and Nutrition
Journal of Pediatric Gastroenterology and NutritionShort- and Long-term Response to and Weaning from Infliximab Therapy in Pediatric Ulcerative ColitisJournal of Pediatric Gastroenterology and Nutrition
Journal of Pediatric Gastroenterology and Nutrition12-Month Follow-up After Successful Infliximab Therapy in Pediatric Crohn DiseaseJournal of Pediatric Gastroenterology and Nutrition
Journal of Pediatric Gastroenterology and NutritionInfliximab Use in Children and Adolescents With Inflammatory Bowel DiseaseJournal of Pediatric Gastroenterology and Nutrition
Journal of Pediatric Gastroenterology and NutritionSafety and Efficacy of Adalimumab in Pediatric Patients With Crohn DiseaseJournal of Pediatric Gastroenterology and Nutrition
Infliximab; Inflammatory bowel disease.
© 2004 Lippincott Williams & Wilkins, Inc.
Highlight selected keywords in the article text.