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Safety and steroid-sparing experience using infliximab for Crohn’s disease at a pediatric inflammatory bowel disease center
THE AMERICAN JOURNAL OF GASTROENTEROLOGY © 2003 by Am. Coll. of Gastroenterology Published by Elsevier Science Inc.
Vol. 98, No. 1, 2003 ISSN 0002-9270/03/$30.00 PII S0002-9270(02)05829-X
Safety and Steroid-Sparing Experience Using Infliximab for Crohn’s Disease at a Pediatric Inflammatory Bowel Disease Center Michael C. Stephens, M.D., Melissa A. Shepanski, M.S., Petar Mamula, M.D., Jonathan E. Markowitz, M.D., Kurt A. Brown, M.D., and Robert N. Baldassano, M.D. The Center for Pediatric Inflammatory Bowel Disease, Division of Gastroenterology and Nutrition at The Children’s Hospital of Philadelphia, Department of Pediatrics, The University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania
OBJECTIVES: The published experience using infliximab (Remicade, Centocor, Malvern, PA) for the treatment of pediatric Crohn’s disease is limited but suggests utility in the treatment of refractory disease. Experience using infliximab at a large pediatric center is reviewed. METHODS: A retrospective review of all infliximab infusions administered to patients with Crohn’s disease (CD) was undertaken. Data were obtained from database and pharmacy records. Chart review and interviews with physicians, patients, and families were used to obtain missing data. RESULTS: A total of 432 infusions were administered to 82 patients (34 female and 48 male) with CD. The number of infusions each patient received ranged from one to 18, with a mean of 5.3 (SD 4.6) and median of 3. Of 33 patients, 19 (57.6%) became independent and remained free of corticosteroids. There was a statistically significant difference in the steroid dose between 0 and 4 wk and 0 and 8 wk. In all, 23 infusion reactions occurred (5.3%). Three patients developed herpes zoster, and one developed Listeria monocytogenes meningitis. No patients were documented to have delayed hypersensitivity reactions or malignancies. CONCLUSIONS: Infliximab is safe and effective for treating pediatric patients with CD. A steroid-sparing effect was demonstrated. The most common adverse reaction to infliximab was infusion reaction. These reactions did not preclude further use of the agent. Serious infections were seen in a small number of patients. (Am J Gastroenterol 2003;98: 104 –111. © 2003 by Am. Coll. of Gastroenterology)
(3–7), but very little experience has been reported with pediatric patients (2, 8 –10). The very first patient with CD to receive infliximab was a 13-yr-old girl with refractory Crohn’s colitis and perianal disease (2). A multicenter, double blind, dose-ranging, single infusion trial was reported in 1998 that involved 21 children with active CD (8). The overall rate of remission was 38%. Hyams et al. reported retrospectively the use of one to three infusions of infliximab in 19 children and adolescents with CD (9). A significant reduction in the Pediatric Crohn’s Disease Activity Index was noted in all patients. Infusion reaction (dyspnea, rash) was noted in three patients and was self-limited. Kugathasan et al. conducted an open label, prospective study of 15 children with CD (10). Of these patients, 14 demonstrated improvement (94%), with 67% (10 patients) in remission by 10 wk postinfusion. No serious complications were encountered. These studies demonstrate promise for the use of infliximab for CD in pediatric patients. Very few complications or problems are reported in these pediatric series. In the adult literature, side effects or complications associated with infliximab include infection, infusion reaction, delayed hypersensitivity reaction, serum sickness or lupus-like reaction, autoantibody formation, and malignancy (3–7, 11–14). Further data and experience are needed to understand the efficacy and tolerability of infliximab. We reviewed all patients who received infliximab for CD at the Center for Pediatric Inflammatory Bowel Disease within The Children’s Hospital of Philadelphia.
MATERIALS AND METHODS INTRODUCTION Infliximab is a genetically engineered monoclonal antibody against tumor necrosis factor–␣ (TNF-␣). It is a chimeric immunoglobulin (IgG1) that is 75% human and 25% mouse, with the variable domain being of murine origin (1). Since its first use for Crohn’s disease (CD) in 1993 (2), much has been published regarding its use in the adult population
A retrospective review was undertaken of all infliximab infusions administered to patients at the Children’s Hospital of Philadelphia. An IBD patient database and computerized pharmacy records were queried to determine which patients had received infliximab between October 1, 1998, and December 1, 2001. The database is maintained within the Center for Pediatric Inflammatory Bowel Disease and has
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Table 1. Sex and Ethnicity Data for Patients Receiving Infliximab for Crohn’s Disease Sex and Ethnicity Data
N (%)
Female Male White/Caucasian Black/African American Hispanic Other
34 (41.5) 48 (58.3) 71 (86.7) 7 (8.5) 2 (2.4) 2 (2.4)
been approved by the institutional review board of The Children’s Hospital of Philadelphia. All data were obtained from this database. Additional information was obtained through review of computerized medical records, hard copy patient charts and by contacting the physician of record or the patient and family by telephone or direct contact when necessary. Patients who received infliximab for diseases other than CD were excluded. Data gathered included sex, ethnicity, age, areas of involvement, surgical history, use of other immunosuppressive drugs, date of each infusion, and dosage. Complications including infusion reaction, delayed hypersensitivity reactions, and documented infections were also recorded. Treatments administered for infusion reaction (and premedication) were recorded. As a measure of efficacy, corticosteroid use was evaluated. Corticosteroid dosage was recorded at initiation of infliximab therapy, 4 and 8 wk after first infusion, as well as time to achieve complete withdrawal of steroids. The corticosteroid dosage was expressed as the milligram equivalent of prednisone/day.
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Infusions were routinely administered over 2 to 3 h starting at a slow rate and increased as follows: 10 ml/h for 15 min, 20 ml/h for 15 min, 40 ml/h for 15 min, 80 ml/h for 15 min, 150 ml/h for 15 min, then 250 ml/h until the infusion was complete. The medication was mixed in 250 cc of 0.9% saline solution. A repeated measures analysis of variance was performed for corticosteroid dosing before infliximab infusion and at 4 and 8 wk after infusion. A paired samples t test was then performed to evaluate the difference between each of the conditions (baseline, 4, and 8 wk). Biostatistical computations were performed using SPSS 10.0 for Windows, 1999 (SPSS, Chicago, IL).
RESULTS A total of 82 patients received infliximab for CD. A total of 432 infusions were administered to this group. The sex and ethnicity composition of the patients included in this study is outlined in Table 1. The mean age of our patient population was 15.3 yr (range 5–23 yr), with a median of 16 yr. The distribution of age within this population is shown in Figure 1. Of the patients, 84% had colonic involvement, 78% had small bowel or upper tract disease, and 37% had perianal involvement. Thirteen patients (16%) had a history of surgery for CD before beginning therapy with infliximab. Of the patients, 80 (98%) patients were receiving other immunosuppressive drugs when infliximab therapy was initiated, and 78 were receiving 6-mercaptopurine (6-MP) or
Figure 1. Age distribution at the beginning of infliximab therapy.
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Figure 2. Distribution of number of infusions of infliximab.
azathioprine (AZA). All but one had received 6-MP/AZA for at least 3 months before beginning infliximab therapy. This single patient began 6-MP at the same time as infliximab. Two had previously received 6-MP but were changed to methotrexate (MTX) after developing pancreatitis. Both had been receiving MTX for more than 2 months before beginning infliximab. Two patients were not taking immunosuppressive medications because of a history of adverse reactions to them. The number of infusions ranged from one to 18, with a mean of 5.3 (SD 4.6) infusions and a median of 3. Length of follow-up ranged from 0 to 160 wk, with a mean of 46.4 (SD 44.0) and median of 30.5 wk. The distribution of the number of infusions is outlined in Figure 2. Of the patients, 47% received more than three infusions, 33% received more than five infusions, and 13% received more than 10 infusions. There was significant variability in the intervals between infusions (Fig. 3). The majority of patients received a second infusion within 2 wk of the first and the median interval was 15.5 days. Thereafter, a great deal of variability is seen in the intervals between infusions, as evidenced by a wide range between the 25th and 75th quartiles (data not shown). Nearly all patients received 5 mg/kg dosing of infliximab (419 of 432 infusions). Seven patients were given 10 mg/kg doses. All seven patients had received 5 mg/kg doses previously and had perceived loss of efficacy after multiple doses. These patients had received a mean of 9.9 (SD 5.0) doses before the higher dose was used. Five were perceived to have responded to the higher dose. Of the two nonresponders, one entered a multicenter, open label trial of CDP-571 (a 95% humanized anti-TNF-␣ monoclonal antibody; Celltech, Cambridge, UK) and demonstrated good
response. This patient received CDP-571 every 8 wk over a period of 6 months. The other patient had surgery and did not receive further infusions. A total of 40 patients were receiving corticosteroids when infliximab therapy was initiated (Fig. 4). Seven did not have adequate follow-up to determine steroid use after infliximab therapy, leaving 33 patients for analysis (Fig. 4). In all, 26 patients achieved steroid independence in a mean period of 24.3 ⫾ 30.1 wk (median 12 wk). Nine of the 26 patients who were successfully tapered off corticosteroids experienced relapse and resumed corticosteroid therapy. The mean time to relapse was 49.7 wk (SD 47.2, median 40) from the first infusion and 7.6 wk (SD 4.1, median 8) from the most recent infusion. Of these nine patients, three ultimately became steroid free with continued infusions (Fig. 4). An initial response (discontinuation of steroids) was seen in 78.8% of patients treated with infliximab, and ultimately, 57.6% (19/ 33) patients had long term improvement based on steroid usage. Of the 19 patients who achieved steroid independence, 12 (57%) continued to receive infliximab infusions, seven (33%) were able to remain steroid free without further infusions, and two achieved independence within 6 wk of the end of the study period, and further infusion requirements cannot be determined. The baseline, 4-wk, and 8-wk steroid dosage could be determined in 29 of 33 patients. In two patients, the dose could be determined at baseline and 8 wk but not at 4 wk. These two patients were included in analysis where possible. The mean dosage at time 0 was 33.2 ⫾ 20.8 mg (median 30), at 4 wk was 21.7 ⫾ 16.3 mg (median 25), and at 8 wk was 15.9 ⫾ 15.5 mg (median 10). Statistically significant differences between prednisone doses were found comparing doses at 0 – 4 wk and 0 – 8 wk (p ⫽ 0.001 and p ⬍ 0.01,
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Figure 3. Plot of median number of days for each infusion interval. Bar plots superimposed in figure depict number of patients for each interval.
respectively) (Fig. 5). No difference was found between 4-wk and 8-wk postinfusion doses of prednisone (p ⫽ 0.110). Nine patients required surgery after therapy with infliximab (eight resections and one dilation). None had complications during or after surgery, including infections or problems with wound healing. Only one of these patients received further infusions after surgery. A total of 23 infusion reactions occurred in 12 patients (5.3% of 432 infusions and 14.6% of 82 patients). Eight patients received a total of 47 infusions after experiencing an infusion reaction. In 11 instances (23.4%), infusion reactions recurred. Premedication was administered in 39 of the 47 infusions. Medications used were acetaminophen (91.7%), diphenhydramine (100%), and corticosteroids (58.3%). Symptoms noted during infusion reactions were chest tightness, shortness of breath, hypoxemia, flushing, fever, headache, nausea/vomiting, itching, hypotension, tachycardia, and chills. Treatments administered for these reactions were diphenhydramine (60.9%), acetaminophen (17.4%), epinephrine (13.0%), oxygen (13.0%), corticosteroids (8.7%), and albuterol (8.7%). Reduced infusion rates were used to complete doses when reactions occurred. The rate used in these situations was one step lower (using the incremental rate increases described above) than the rate being used when the reaction occurred. In one illustrative case, infusion rate seemed to be related to infusion reaction. This patient had an anaphylactic reac-
tion during the seventh infusion with hypotension, tachycardia, hypoxemia, and shortness of breath. Epinephrine, diphenhydramine, and oxygen were administered. An eighth infusion was given 5 months later under observation in the intensive care unit. Pretreatment and a slower infusion rate (maximum 80 ml/h) were used and only mild facial flushing occurred. When a higher rate was used for the ninth dose, the patient experienced shortness of breath, chest pain, facial swelling, tachycardia, headache, and generalized flushing. Three subsequent infusions were given using the slower rate, with mild facial flushing occurring in one infusion and no complications in the other two. In all infusions after the anaphylactic reaction, the patient was pretreated with acetaminophen, methylprednisolone, and diphenhydramine. Three patients developed shingles within 14 days of an infusion of infliximab. All received acyclovir and recovered. One patient developed Listeria monocytogenes meningitis and has been reported in detail elsewhere (15). This patient received i.v. antibiotics and recovered. No malignancies have been reported in this group of patients. No delayed hypersensitivity reactions were documented.
DISCUSSION This review represents the largest cohort of pediatric patients receiving infliximab for CD. In comparison to the adult literature, there is a significant paucity of published experience using infliximab in the pediatric population.
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Figure 4. Flow chart demonstrating outcomes of patients taking corticosteroids when beginning infliximab therapy.
Nearly all patients were receiving 6-MP/AZA or MTX while on infliximab therapy. We strive to use these agents in combination with infliximab where tolerated. We believe that there is good rationale for this approach. Maini et al. (16) reported a synergy between low dose immunosuppressive drugs and infliximab, in addition to a reduced incidence of human antichimeric antibodies (HACA) in patients with rheumatoid arthritis. Data from the ACCENT I trial (17) has also shown a tendency toward improved outcome when infliximab is used with 6-MP/AZA. Others have recently reported a reduced incidence of infusion reaction with concomitant use of 6-MP/AZA (18). Many of the patients received multiple infusions. Although a formal policy has not been adapted at our institution, the majority of patients being treated for luminal disease now receive an initial two-dose regimen (an initial dose is given with a second infusion 2 wk later). Patients with fistulous disease receive induction therapy at 0, 2, and 6 wk in concert with recommendations by the United States Food and Drug Administration. Patients are monitored, and further infusions are given as evidence of worsening disease activity develops. After a pattern has been established, in-
fusions are scheduled at intervals to allow treatment just before the anticipated onset of symptoms. After periods of extended remission, attempts are made to extend the interval between infusions. The rationale for this approach for luminal disease is based on personal communication with the investigators in the ACCENT I trial. These investigators observed that a subgroup of patients with little or no response to the initial dose may respond after the second infusion. They did not see further improvements in the response rate after the third infusion. We therefore will give a second infusion at 2 wk before determining whether a patient is a nonresponder. In responders, doses are then administered as disease activity warrants. Reviewing the intervals between infusions (Fig. 3), a trend toward shorter intervals may be appreciated after multiple infusions. The overall slope of the median interval plot seems to be negative as the number of infusions increases. This decline eventually plateaus. These trends are difficult to interpret, given the variability seen and the small patient numbers at higher intervals. Larger patient numbers would be required to adequately study these trends. Such a
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Figure 5. Box plot of steroid dosage at baseline, 4 wk and 8 wk. The upper and lower boundaries of each box represents the upper and lower quartile whereas the median is represented by the horizontal line within each box. The range is represented by the upper and lower limits of the vertical lines. Statistically significant differences between prednisone doses were found comparing 0 – 4 wk and 0 – 8 wk doses (p ⫽ 0.001, p ⬍ 0.01, respectively).
study could be useful in developing recommendations for the frequency of infusions. In a number of patients, a diminished response was noted after multiple infusions. This has also been reported in adult patients and the development of HACA has been suggested as a possible explanation for this phenomenon (19). Increasing the dosage to 10 mg/kg seemed to overcome this effect in five of seven patients. These infusions were given with the hypothesis that saturation of HACAs could allow increased efficacy (20). One patient who did not respond to an increased dosage did show improvement with a more humanized anti–TNF agent (CDP-571) (21). Preliminary studies have been undertaken using CDP-571 (22); however, we do not wish to imply that it should be used in all patients who have loss of response to infliximab. Further studies are needed to determine the role for CDP-571 in CD. Another more humanized anti–TNF-␣ agent (etanercept) has been studied in CD, with less impressive results (23, 24). Newer generation anti–TNF-␣ agents will require careful evaluation to determine their usefulness, as the mechanism of action may not be the same for each agent (25). Roughly one half of our patients were receiving corticosteroids when they began infliximab therapy. More than half became steroid independent with continued therapy. Time to steroid independence was quite variable (range 2–125 wk). These data use a less sensitive measure of response (steroid use) compared to most adult studies (disease activity indices) (6). There are no published data regarding steroid use
in adults receiving infliximab. In the ACCENT I trial (17), 29% of patients in treatment groups were steroid independent after 52 wk of treatment. Additionally, patients in treatment groups were able to taper steroid doses more quickly that those in the placebo group. Other noncontrolled studies have reported steroid independence rates ranging from 40% to 73% (3, 26, 27). The data on steroid dosing clearly demonstrate a steroid-sparing effect, with statistically significant reductions in corticosteroid doses at 4 and 8 wk. In this series, infusion reaction was the most frequent complication. These reactions (even when severe) did not preclude further treatment with infliximab. The frequency with which infusion reaction occurred was similar to that seen in the adult population. The use of premedication with anti-inflammatory or antihistamine agents in patients with a history of infusion reaction was widely used by the physicians at our center. Use of slower infusion rates to complete infusions after reaction or with subsequent infusions was common. We did not encounter any evidence of delayed hypersensitivity reaction in this study even among patients with drug holidays exceeding 6 months. In patients with a significant interval between infusions (2– 4 yr), delayed hypersensitivity reactions seem to be much more common (25%) (13). Many of the patients at our center received corticosteroids after long interinfusion intervals (⬎6 months). In this situation, methylprednisolone was typically given for 6 days
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p.o. (Medrol Dosepak, Pharmacia-Upjohn, Kalamazoo, MI), with the infliximab infusion administered on day 3. A similar approach was recently reported by Pannaccione et al. (28). Serological evaluations (for HACA and anti-double stranded DNA) were not routinely performed and cannot be commented upon. Several patients developed infections after infliximab infusion. Given the seriousness of the infections seen, we believe that patients who develop symptoms of infection after infusion should be carefully evaluated. Less serious infections were not documented and their incidence is not known in this cohort. Data from the recently published ACCENT I trial show no difference in infection rates between the placebo group and treatment groups (17). Recent guidelines from the manufacturer have recommended screening for latent tuberculosis in patients receiving infliximab. A policy for screening these patients has recently been adopted within our institution, including skin testing and chest radiography. Established patients undergo both skin testing and chest radiography. Patients who will be starting therapy have skin testing before receiving infliximab. The addition of chest radiography is not a part of the original guidelines and evolved through consultation with the infectious disease division at our institution. The rationale for this approach was based on the hypothetical possibility of anergy in patients already on infliximab therapy. Recent data have supported this hypothesis (29). Malignancy was not reported in any of the patients at our center. Long term follow-up is needed to understand the possible significance of infliximab with regard to the development of malignancy in pediatric patients. In this cohort, infliximab was well tolerated over multiple infusions. Infusion reaction was the most common complication, and this did not preclude further use of the agent. Serious infection was seen in a small number of patients, and warrants early and aggressive evaluations of patients who develop symptoms of infection after infliximab infusions. A steroid-sparing effect was noted, showing statistically significant reductions in steroid use 4 and 8 wk after infusion.
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17. Reprint requests and correspondence: Robert N. Baldassano, M.D., Division of Gastroenterology and Nutrition, The Children’s Hospital of Philadelphia, 34th and Civic Center Boulevard, Philadelphia, PA 19104. Received Feb. 22, 2002; accepted July 8, 2002.
REFERENCES 1. Knight DM, Trinh H, Le J, et al. Construction and initial characterization of a mouse-human chimeric anti-TNF antibody. Mol Immunol 1993;30:1443–53. 2. Derkx B, Taminiau J, Radema S, et al. Tumour-necrosis-factor antibody treatment in Crohn’s disease. Lancet 1993;342: 173–4. 3. Farrell RJ, Shah SA, Lodhavia PJ, et al. Clinical experience
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with infliximab therapy in 100 patients with Crohn’s disease. Am J Gastroenterol 2000;95:3490 –7. Hanauer S, Lichtenstein GR, Columbel J-F, et al. Maintenance infliximab is safe, effective and steroid-sparing in Crohn’s disease: Preliminary results from the Accent I trial. Gastroenterology 2001;120:A-21. 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. 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. Targan SR, Hanauer SB, van Deventer SJ, et al. A short-term study of chimeric monoclonal antibody cA2 to tumor necrosis factor alpha for Crohn’s disease. Crohn’s Disease cA2 Study Group. N Engl J Med 1997;337:1029 –35. Baldassano RN, Vasiliauskas E, Braegger CP, et al. A multicenter study of infliximab (anti-TNF alpha antibody) in the treatment of children with active Crohn’s disease. Gastroenterology 1999;116:A665. Hyams JS, Markowitz J, Wyllie R. Use of infliximab in the treatment of Crohn’s disease in children and adolescents. J Pediatr 2000;137:192–6. Kugathasan S, Werlin SL, Martinez A, et al. Prolonged duration of response to infliximab in early but not late pediatric Crohn’s disease. Am J Gastroenterol 2000;95:3189 –94. Schaible TF. Long term safety of infliximab. Can J Gastroenterol 2000;14(suppl C):29 –32C. Sandborn WJ, Hanauer SB. Antitumor necrosis factor therapy for inflammatory bowel disease: A review of agents, pharmacology, clinical results, and safety [see comments]. Inflamm Bowel Dis 1999;5:119 –33 (review). Hanauer SB, Rutgeerts P, D’Haens G, et al. Delayed hypersensitivity to infliximab re-infusion after 2– 4 year interval without treatment. Gastroenterology 1999;116:A731. Sachmechian A, Vasiliauskas E, Abreu-Martin MT, et al. Malignancy following Remicade therapy: Incidence and characteristics. Gastroenterology 2001;120:A619. Kamath BM, Mamula P, Baldassano RN, et al. Listeria meningitis after treatment with infliximab. J Pediatr Gastroenterol Nutr 2002;34(4):410 –2. Maini R, Breedveld F, Kalden J, et al. Therapeutic efficacy of multiple intravenous infusions of anti-tumor necrosis factor ␣ monoclonal antibody combined with low-dose weekly methotrexate in rheumatoid arthritis. Arthritis Rheum 1998;41: 1552–63. Hanauer SB, Feagan BG, Lichtenstein GR, et al. Maintenance infliximab for Crohn’s disease: The ACCENT I randomised trial. Lancet 2002;359:1541–9. Han PD, Cohen RD, Motamedi F, et al. Infliximab infusion reactions. The influence of sex and drugs. Gastroenterology 2002;122(suppl 1):A-612. Farrell RJ, Alsahli M, Falchuk KR, et al. Human anti-chimeric antibody levels correlate with lack of response and infusion reactions following infliximab therapy. Gastroenterology 2001;120(suppl 1):A-69. Noman M, Baert F, Vermeire S, et al. Post infusion infliximab levels determine duration of response in Crohn’s disease and are directly related to infusion reactions. Gastroenterology 2002;122(suppl 1):P-83. Joachim K. Update on D2E7: A fully human anti-tumour necrosis factor ␣ monoclonal antibody. Ann Rheum Dis 2000; 59(suppl 1):i44 –5. Sandborn WJ, Feagan BG, Hanauer SB, et al. An engineered
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human antibody to TNF (CDP571) for active Crohn’s disease: A randomized double-blind placebo-controlled trial. Gastroenterology 2001;120:1330 –8. 23. D’Haens G, Swijsen C, Noman M, et al. Etanercept in the treatment of active refractory Crohn’s disease: A single-center pilot trial. Am J Gastroenterol 2001;96:2564 –8. 24. Sandborn WJ, Hanauer SB, Katz S, et al. Etanercept for active Crohn’s disease: A randomized, double-blind, placebo-controlled trial [see comments]. Gastroenterology 2001;121: 1088 –94. 25. Van Den Brande JMH, Braat H, Van Den Brink R, et al. A possible mechanism for the difference in efficacy of infliximab and etanercept in the treatment of Crohn’s disease. Gastroenterology 2002;122(suppl 1):A-260.
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26. Cohen RD, Tsang JF, Hanauer SB. Infliximab in Crohn’s disease: First anniversary clinical experience. Am J Gastroenterol 2000;95:3469 –77. 27. Ricart E, Panaccione R, Loftus EV, et al. Infliximab for Crohn’s disease in clinical practice at the Mayo Clinic: The first 100 patients. Am J Gastroenterol 2001;96:722–9. 28. Panaccione R. Overcoming. “Delayed-type hypersensitivity reactions” in patients receiving repeated doses of infliximab: A report of 5 cases. Gastroenterology 2002;122(suppl 1):A-613. 29. Mow WS, Abreu MT, Papadakis KA, et al. High incidence of anergy limits the usefulness of PPD screening for tuberculosis (TB) prior to remicade in inflammatory bowel disease (IBD). Gastroenterology 2002;122(suppl 1):P-83.
Vol. 98, No. 1, 2003 ISSN 0002-9270/03/$30.00 PII S0002-9270(02)05829-X
Safety and Steroid-Sparing Experience Using Infliximab for Crohn’s Disease at a Pediatric Inflammatory Bowel Disease Center Michael C. Stephens, M.D., Melissa A. Shepanski, M.S., Petar Mamula, M.D., Jonathan E. Markowitz, M.D., Kurt A. Brown, M.D., and Robert N. Baldassano, M.D. The Center for Pediatric Inflammatory Bowel Disease, Division of Gastroenterology and Nutrition at The Children’s Hospital of Philadelphia, Department of Pediatrics, The University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania
OBJECTIVES: The published experience using infliximab (Remicade, Centocor, Malvern, PA) for the treatment of pediatric Crohn’s disease is limited but suggests utility in the treatment of refractory disease. Experience using infliximab at a large pediatric center is reviewed. METHODS: A retrospective review of all infliximab infusions administered to patients with Crohn’s disease (CD) was undertaken. Data were obtained from database and pharmacy records. Chart review and interviews with physicians, patients, and families were used to obtain missing data. RESULTS: A total of 432 infusions were administered to 82 patients (34 female and 48 male) with CD. The number of infusions each patient received ranged from one to 18, with a mean of 5.3 (SD 4.6) and median of 3. Of 33 patients, 19 (57.6%) became independent and remained free of corticosteroids. There was a statistically significant difference in the steroid dose between 0 and 4 wk and 0 and 8 wk. In all, 23 infusion reactions occurred (5.3%). Three patients developed herpes zoster, and one developed Listeria monocytogenes meningitis. No patients were documented to have delayed hypersensitivity reactions or malignancies. CONCLUSIONS: Infliximab is safe and effective for treating pediatric patients with CD. A steroid-sparing effect was demonstrated. The most common adverse reaction to infliximab was infusion reaction. These reactions did not preclude further use of the agent. Serious infections were seen in a small number of patients. (Am J Gastroenterol 2003;98: 104 –111. © 2003 by Am. Coll. of Gastroenterology)
(3–7), but very little experience has been reported with pediatric patients (2, 8 –10). The very first patient with CD to receive infliximab was a 13-yr-old girl with refractory Crohn’s colitis and perianal disease (2). A multicenter, double blind, dose-ranging, single infusion trial was reported in 1998 that involved 21 children with active CD (8). The overall rate of remission was 38%. Hyams et al. reported retrospectively the use of one to three infusions of infliximab in 19 children and adolescents with CD (9). A significant reduction in the Pediatric Crohn’s Disease Activity Index was noted in all patients. Infusion reaction (dyspnea, rash) was noted in three patients and was self-limited. Kugathasan et al. conducted an open label, prospective study of 15 children with CD (10). Of these patients, 14 demonstrated improvement (94%), with 67% (10 patients) in remission by 10 wk postinfusion. No serious complications were encountered. These studies demonstrate promise for the use of infliximab for CD in pediatric patients. Very few complications or problems are reported in these pediatric series. In the adult literature, side effects or complications associated with infliximab include infection, infusion reaction, delayed hypersensitivity reaction, serum sickness or lupus-like reaction, autoantibody formation, and malignancy (3–7, 11–14). Further data and experience are needed to understand the efficacy and tolerability of infliximab. We reviewed all patients who received infliximab for CD at the Center for Pediatric Inflammatory Bowel Disease within The Children’s Hospital of Philadelphia.
MATERIALS AND METHODS INTRODUCTION Infliximab is a genetically engineered monoclonal antibody against tumor necrosis factor–␣ (TNF-␣). It is a chimeric immunoglobulin (IgG1) that is 75% human and 25% mouse, with the variable domain being of murine origin (1). Since its first use for Crohn’s disease (CD) in 1993 (2), much has been published regarding its use in the adult population
A retrospective review was undertaken of all infliximab infusions administered to patients at the Children’s Hospital of Philadelphia. An IBD patient database and computerized pharmacy records were queried to determine which patients had received infliximab between October 1, 1998, and December 1, 2001. The database is maintained within the Center for Pediatric Inflammatory Bowel Disease and has
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Table 1. Sex and Ethnicity Data for Patients Receiving Infliximab for Crohn’s Disease Sex and Ethnicity Data
N (%)
Female Male White/Caucasian Black/African American Hispanic Other
34 (41.5) 48 (58.3) 71 (86.7) 7 (8.5) 2 (2.4) 2 (2.4)
been approved by the institutional review board of The Children’s Hospital of Philadelphia. All data were obtained from this database. Additional information was obtained through review of computerized medical records, hard copy patient charts and by contacting the physician of record or the patient and family by telephone or direct contact when necessary. Patients who received infliximab for diseases other than CD were excluded. Data gathered included sex, ethnicity, age, areas of involvement, surgical history, use of other immunosuppressive drugs, date of each infusion, and dosage. Complications including infusion reaction, delayed hypersensitivity reactions, and documented infections were also recorded. Treatments administered for infusion reaction (and premedication) were recorded. As a measure of efficacy, corticosteroid use was evaluated. Corticosteroid dosage was recorded at initiation of infliximab therapy, 4 and 8 wk after first infusion, as well as time to achieve complete withdrawal of steroids. The corticosteroid dosage was expressed as the milligram equivalent of prednisone/day.
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Infusions were routinely administered over 2 to 3 h starting at a slow rate and increased as follows: 10 ml/h for 15 min, 20 ml/h for 15 min, 40 ml/h for 15 min, 80 ml/h for 15 min, 150 ml/h for 15 min, then 250 ml/h until the infusion was complete. The medication was mixed in 250 cc of 0.9% saline solution. A repeated measures analysis of variance was performed for corticosteroid dosing before infliximab infusion and at 4 and 8 wk after infusion. A paired samples t test was then performed to evaluate the difference between each of the conditions (baseline, 4, and 8 wk). Biostatistical computations were performed using SPSS 10.0 for Windows, 1999 (SPSS, Chicago, IL).
RESULTS A total of 82 patients received infliximab for CD. A total of 432 infusions were administered to this group. The sex and ethnicity composition of the patients included in this study is outlined in Table 1. The mean age of our patient population was 15.3 yr (range 5–23 yr), with a median of 16 yr. The distribution of age within this population is shown in Figure 1. Of the patients, 84% had colonic involvement, 78% had small bowel or upper tract disease, and 37% had perianal involvement. Thirteen patients (16%) had a history of surgery for CD before beginning therapy with infliximab. Of the patients, 80 (98%) patients were receiving other immunosuppressive drugs when infliximab therapy was initiated, and 78 were receiving 6-mercaptopurine (6-MP) or
Figure 1. Age distribution at the beginning of infliximab therapy.
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Figure 2. Distribution of number of infusions of infliximab.
azathioprine (AZA). All but one had received 6-MP/AZA for at least 3 months before beginning infliximab therapy. This single patient began 6-MP at the same time as infliximab. Two had previously received 6-MP but were changed to methotrexate (MTX) after developing pancreatitis. Both had been receiving MTX for more than 2 months before beginning infliximab. Two patients were not taking immunosuppressive medications because of a history of adverse reactions to them. The number of infusions ranged from one to 18, with a mean of 5.3 (SD 4.6) infusions and a median of 3. Length of follow-up ranged from 0 to 160 wk, with a mean of 46.4 (SD 44.0) and median of 30.5 wk. The distribution of the number of infusions is outlined in Figure 2. Of the patients, 47% received more than three infusions, 33% received more than five infusions, and 13% received more than 10 infusions. There was significant variability in the intervals between infusions (Fig. 3). The majority of patients received a second infusion within 2 wk of the first and the median interval was 15.5 days. Thereafter, a great deal of variability is seen in the intervals between infusions, as evidenced by a wide range between the 25th and 75th quartiles (data not shown). Nearly all patients received 5 mg/kg dosing of infliximab (419 of 432 infusions). Seven patients were given 10 mg/kg doses. All seven patients had received 5 mg/kg doses previously and had perceived loss of efficacy after multiple doses. These patients had received a mean of 9.9 (SD 5.0) doses before the higher dose was used. Five were perceived to have responded to the higher dose. Of the two nonresponders, one entered a multicenter, open label trial of CDP-571 (a 95% humanized anti-TNF-␣ monoclonal antibody; Celltech, Cambridge, UK) and demonstrated good
response. This patient received CDP-571 every 8 wk over a period of 6 months. The other patient had surgery and did not receive further infusions. A total of 40 patients were receiving corticosteroids when infliximab therapy was initiated (Fig. 4). Seven did not have adequate follow-up to determine steroid use after infliximab therapy, leaving 33 patients for analysis (Fig. 4). In all, 26 patients achieved steroid independence in a mean period of 24.3 ⫾ 30.1 wk (median 12 wk). Nine of the 26 patients who were successfully tapered off corticosteroids experienced relapse and resumed corticosteroid therapy. The mean time to relapse was 49.7 wk (SD 47.2, median 40) from the first infusion and 7.6 wk (SD 4.1, median 8) from the most recent infusion. Of these nine patients, three ultimately became steroid free with continued infusions (Fig. 4). An initial response (discontinuation of steroids) was seen in 78.8% of patients treated with infliximab, and ultimately, 57.6% (19/ 33) patients had long term improvement based on steroid usage. Of the 19 patients who achieved steroid independence, 12 (57%) continued to receive infliximab infusions, seven (33%) were able to remain steroid free without further infusions, and two achieved independence within 6 wk of the end of the study period, and further infusion requirements cannot be determined. The baseline, 4-wk, and 8-wk steroid dosage could be determined in 29 of 33 patients. In two patients, the dose could be determined at baseline and 8 wk but not at 4 wk. These two patients were included in analysis where possible. The mean dosage at time 0 was 33.2 ⫾ 20.8 mg (median 30), at 4 wk was 21.7 ⫾ 16.3 mg (median 25), and at 8 wk was 15.9 ⫾ 15.5 mg (median 10). Statistically significant differences between prednisone doses were found comparing doses at 0 – 4 wk and 0 – 8 wk (p ⫽ 0.001 and p ⬍ 0.01,
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Figure 3. Plot of median number of days for each infusion interval. Bar plots superimposed in figure depict number of patients for each interval.
respectively) (Fig. 5). No difference was found between 4-wk and 8-wk postinfusion doses of prednisone (p ⫽ 0.110). Nine patients required surgery after therapy with infliximab (eight resections and one dilation). None had complications during or after surgery, including infections or problems with wound healing. Only one of these patients received further infusions after surgery. A total of 23 infusion reactions occurred in 12 patients (5.3% of 432 infusions and 14.6% of 82 patients). Eight patients received a total of 47 infusions after experiencing an infusion reaction. In 11 instances (23.4%), infusion reactions recurred. Premedication was administered in 39 of the 47 infusions. Medications used were acetaminophen (91.7%), diphenhydramine (100%), and corticosteroids (58.3%). Symptoms noted during infusion reactions were chest tightness, shortness of breath, hypoxemia, flushing, fever, headache, nausea/vomiting, itching, hypotension, tachycardia, and chills. Treatments administered for these reactions were diphenhydramine (60.9%), acetaminophen (17.4%), epinephrine (13.0%), oxygen (13.0%), corticosteroids (8.7%), and albuterol (8.7%). Reduced infusion rates were used to complete doses when reactions occurred. The rate used in these situations was one step lower (using the incremental rate increases described above) than the rate being used when the reaction occurred. In one illustrative case, infusion rate seemed to be related to infusion reaction. This patient had an anaphylactic reac-
tion during the seventh infusion with hypotension, tachycardia, hypoxemia, and shortness of breath. Epinephrine, diphenhydramine, and oxygen were administered. An eighth infusion was given 5 months later under observation in the intensive care unit. Pretreatment and a slower infusion rate (maximum 80 ml/h) were used and only mild facial flushing occurred. When a higher rate was used for the ninth dose, the patient experienced shortness of breath, chest pain, facial swelling, tachycardia, headache, and generalized flushing. Three subsequent infusions were given using the slower rate, with mild facial flushing occurring in one infusion and no complications in the other two. In all infusions after the anaphylactic reaction, the patient was pretreated with acetaminophen, methylprednisolone, and diphenhydramine. Three patients developed shingles within 14 days of an infusion of infliximab. All received acyclovir and recovered. One patient developed Listeria monocytogenes meningitis and has been reported in detail elsewhere (15). This patient received i.v. antibiotics and recovered. No malignancies have been reported in this group of patients. No delayed hypersensitivity reactions were documented.
DISCUSSION This review represents the largest cohort of pediatric patients receiving infliximab for CD. In comparison to the adult literature, there is a significant paucity of published experience using infliximab in the pediatric population.
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Figure 4. Flow chart demonstrating outcomes of patients taking corticosteroids when beginning infliximab therapy.
Nearly all patients were receiving 6-MP/AZA or MTX while on infliximab therapy. We strive to use these agents in combination with infliximab where tolerated. We believe that there is good rationale for this approach. Maini et al. (16) reported a synergy between low dose immunosuppressive drugs and infliximab, in addition to a reduced incidence of human antichimeric antibodies (HACA) in patients with rheumatoid arthritis. Data from the ACCENT I trial (17) has also shown a tendency toward improved outcome when infliximab is used with 6-MP/AZA. Others have recently reported a reduced incidence of infusion reaction with concomitant use of 6-MP/AZA (18). Many of the patients received multiple infusions. Although a formal policy has not been adapted at our institution, the majority of patients being treated for luminal disease now receive an initial two-dose regimen (an initial dose is given with a second infusion 2 wk later). Patients with fistulous disease receive induction therapy at 0, 2, and 6 wk in concert with recommendations by the United States Food and Drug Administration. Patients are monitored, and further infusions are given as evidence of worsening disease activity develops. After a pattern has been established, in-
fusions are scheduled at intervals to allow treatment just before the anticipated onset of symptoms. After periods of extended remission, attempts are made to extend the interval between infusions. The rationale for this approach for luminal disease is based on personal communication with the investigators in the ACCENT I trial. These investigators observed that a subgroup of patients with little or no response to the initial dose may respond after the second infusion. They did not see further improvements in the response rate after the third infusion. We therefore will give a second infusion at 2 wk before determining whether a patient is a nonresponder. In responders, doses are then administered as disease activity warrants. Reviewing the intervals between infusions (Fig. 3), a trend toward shorter intervals may be appreciated after multiple infusions. The overall slope of the median interval plot seems to be negative as the number of infusions increases. This decline eventually plateaus. These trends are difficult to interpret, given the variability seen and the small patient numbers at higher intervals. Larger patient numbers would be required to adequately study these trends. Such a
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Figure 5. Box plot of steroid dosage at baseline, 4 wk and 8 wk. The upper and lower boundaries of each box represents the upper and lower quartile whereas the median is represented by the horizontal line within each box. The range is represented by the upper and lower limits of the vertical lines. Statistically significant differences between prednisone doses were found comparing 0 – 4 wk and 0 – 8 wk doses (p ⫽ 0.001, p ⬍ 0.01, respectively).
study could be useful in developing recommendations for the frequency of infusions. In a number of patients, a diminished response was noted after multiple infusions. This has also been reported in adult patients and the development of HACA has been suggested as a possible explanation for this phenomenon (19). Increasing the dosage to 10 mg/kg seemed to overcome this effect in five of seven patients. These infusions were given with the hypothesis that saturation of HACAs could allow increased efficacy (20). One patient who did not respond to an increased dosage did show improvement with a more humanized anti–TNF agent (CDP-571) (21). Preliminary studies have been undertaken using CDP-571 (22); however, we do not wish to imply that it should be used in all patients who have loss of response to infliximab. Further studies are needed to determine the role for CDP-571 in CD. Another more humanized anti–TNF-␣ agent (etanercept) has been studied in CD, with less impressive results (23, 24). Newer generation anti–TNF-␣ agents will require careful evaluation to determine their usefulness, as the mechanism of action may not be the same for each agent (25). Roughly one half of our patients were receiving corticosteroids when they began infliximab therapy. More than half became steroid independent with continued therapy. Time to steroid independence was quite variable (range 2–125 wk). These data use a less sensitive measure of response (steroid use) compared to most adult studies (disease activity indices) (6). There are no published data regarding steroid use
in adults receiving infliximab. In the ACCENT I trial (17), 29% of patients in treatment groups were steroid independent after 52 wk of treatment. Additionally, patients in treatment groups were able to taper steroid doses more quickly that those in the placebo group. Other noncontrolled studies have reported steroid independence rates ranging from 40% to 73% (3, 26, 27). The data on steroid dosing clearly demonstrate a steroid-sparing effect, with statistically significant reductions in corticosteroid doses at 4 and 8 wk. In this series, infusion reaction was the most frequent complication. These reactions (even when severe) did not preclude further treatment with infliximab. The frequency with which infusion reaction occurred was similar to that seen in the adult population. The use of premedication with anti-inflammatory or antihistamine agents in patients with a history of infusion reaction was widely used by the physicians at our center. Use of slower infusion rates to complete infusions after reaction or with subsequent infusions was common. We did not encounter any evidence of delayed hypersensitivity reaction in this study even among patients with drug holidays exceeding 6 months. In patients with a significant interval between infusions (2– 4 yr), delayed hypersensitivity reactions seem to be much more common (25%) (13). Many of the patients at our center received corticosteroids after long interinfusion intervals (⬎6 months). In this situation, methylprednisolone was typically given for 6 days
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p.o. (Medrol Dosepak, Pharmacia-Upjohn, Kalamazoo, MI), with the infliximab infusion administered on day 3. A similar approach was recently reported by Pannaccione et al. (28). Serological evaluations (for HACA and anti-double stranded DNA) were not routinely performed and cannot be commented upon. Several patients developed infections after infliximab infusion. Given the seriousness of the infections seen, we believe that patients who develop symptoms of infection after infusion should be carefully evaluated. Less serious infections were not documented and their incidence is not known in this cohort. Data from the recently published ACCENT I trial show no difference in infection rates between the placebo group and treatment groups (17). Recent guidelines from the manufacturer have recommended screening for latent tuberculosis in patients receiving infliximab. A policy for screening these patients has recently been adopted within our institution, including skin testing and chest radiography. Established patients undergo both skin testing and chest radiography. Patients who will be starting therapy have skin testing before receiving infliximab. The addition of chest radiography is not a part of the original guidelines and evolved through consultation with the infectious disease division at our institution. The rationale for this approach was based on the hypothetical possibility of anergy in patients already on infliximab therapy. Recent data have supported this hypothesis (29). Malignancy was not reported in any of the patients at our center. Long term follow-up is needed to understand the possible significance of infliximab with regard to the development of malignancy in pediatric patients. In this cohort, infliximab was well tolerated over multiple infusions. Infusion reaction was the most common complication, and this did not preclude further use of the agent. Serious infection was seen in a small number of patients, and warrants early and aggressive evaluations of patients who develop symptoms of infection after infliximab infusions. A steroid-sparing effect was noted, showing statistically significant reductions in steroid use 4 and 8 wk after infusion.
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17. Reprint requests and correspondence: Robert N. Baldassano, M.D., Division of Gastroenterology and Nutrition, The Children’s Hospital of Philadelphia, 34th and Civic Center Boulevard, Philadelphia, PA 19104. Received Feb. 22, 2002; accepted July 8, 2002.
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26. Cohen RD, Tsang JF, Hanauer SB. Infliximab in Crohn’s disease: First anniversary clinical experience. Am J Gastroenterol 2000;95:3469 –77. 27. Ricart E, Panaccione R, Loftus EV, et al. Infliximab for Crohn’s disease in clinical practice at the Mayo Clinic: The first 100 patients. Am J Gastroenterol 2001;96:722–9. 28. Panaccione R. Overcoming. “Delayed-type hypersensitivity reactions” in patients receiving repeated doses of infliximab: A report of 5 cases. Gastroenterology 2002;122(suppl 1):A-613. 29. Mow WS, Abreu MT, Papadakis KA, et al. High incidence of anergy limits the usefulness of PPD screening for tuberculosis (TB) prior to remicade in inflammatory bowel disease (IBD). Gastroenterology 2002;122(suppl 1):P-83.