- Email: [email protected]
Timing Infliximab Therapy in Pediatric Crohn’s Disease
GASTROENTEROLOGY 2007;132:1167–1183
EDITORIALS Timing Infliximab Therapy in Pediatric Crohn’s Disease
See “Induction and maintenance infliximab therapy for the treatment of moderate-tosevere Crohn’s disease in children,” by Hyams JS, Crandall W, Kugathasan S, et al, on page 863.
T
he REACH study reported in this issue of GASTROby Hyams et al1 addresses clinically important questions regarding the effect of infliximab (Remicade) in pediatric patients with Crohn’s disease. It is apparent that other medical options are available for children and adolescents with moderate to severe Crohn’s disease that have documented efficacy and side effects. Several pediatric studies have documented corticosteroid-induced (CS) response and remission in children and adolescents with new-onset and relapsing Crohn’s disease.2– 4 Markowitz et al2 reported 89% remission rate for a new-onset pediatric population with Crohn’s disease whether they received prednisone equivalent to 1–2 mg/kg per day plus placebo or that dose combined with 1.5 mg/kg of 6-mercaptopurine (6MP). However, the duration of response was significantly prolonged in the combined therapy group with a relapse rate at 18 months of only 9% versus 47% for prednisone with placebo. Repeated courses of CS were needed in 57% of the prednisone plus placebo group compared with 4% for prednisone/6MP. Similar outcomes were described in a subsequent multicenter study of 109 newly diagnosed patients ⬍16 years with Crohn’s disease who received prednisone at 1–2 mg/kg per day.3 At 3 months, 60% had complete response and were off CS, 34% had a partial response, and 17% were steroid resistant. At 1 year, 61% continued to have a prolonged response with the majority maintained on 6MP, azathioprine, or methotrexate. However, 31% were corticosteroid dependent, which was defined as receiving continuous steroids for ⬎6 months or having had an initial 3-month course and subsequently requiring additional courses of CS. Interestingly, the pattern of response was not influenced by the following factors at baseline: age at diagnosis, disease activity as assessed by Physician Global Assessment or Pediatric Crohn’s Disease Activity Index (PCDAI),5,6 site of involvement, extraintestinal manifestations, family history, or laboratory tests including complete blood count, erythrocyte sedimentation rate, or albumin. The most signifENTEROLOGY
icant factor associated with the development of CS dependency and subsequent need for surgery was growth impairment or failure at baseline. A population-based study from Olmsted County, Minnesota, described the course of 26 patients who were treated with CS before 19 years of age.4 Outcome at 30 days included complete remission in 62%, partial remission in 27%, and no response in 12%. At 1 year, prolonged response was present in 42%, CS dependency again noted in 31%, and 27% had had surgery. Although immunomodulatory agents may be very effective in prolonging response and remission, adverse side effects may reduce their utilization. In our reported series of 95 children and adolescents with inflammatory bowel disease who received azathioprine or 6MP, 54% had no adverse effect, 28% experienced side effects necessitating dose reduction, and 18% required drug discontinuation because of pancreatitis, recurrent fever, nausea and/or vomiting, and recurrent infections such as sinusitis.7 Some of these children respond to methotrexate, but the availability of effective alternative therapies is greatly needed to treat patients with moderate to severe disease who are steroid dependent, intolerant, or refractory to immunomodulatory agents. Anti–tumor necrosis factor (TNF) agents can be used as an alternative to or as a complimentary therapy to steroids and other immunomodulators. However, objective data should be reported to justify the high cost and long duration of treatment required to induce and maintain response and remission with infliximab and other biologic agents. The increasing number of recently reported cases of hepatosplenic T-cell lymphoma, especially in adolescent and young adult males, in whom the majority has received Remicade, again requires that we assess its role and long-term safety.8 Findings of this Pediatric Infliximab Trial. In this clinical trial (REACH), all patients received what has become the standard approach for induction with infliximab: 5 mg/kg per day at weeks 0, 2, and 6. At 10 weeks, response and remission rates were 88.4% and 58.9%, respectively. These rates are high in comparison with other studies, but as the authors point out, all patients had received immunomodulatory agents for 8 weeks before enrollment and the mean duration of disease was only 2.0 ⫾ 1.4 years. Those who responded were then randomized to a maintenance schedule of 5 mg/kg at either 8- or 12-week intervals. This reflects the alternative faced by
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Table 1. Differences in Clinical Response Between 8- and 12-Week Schedules 8 week (n ⫽ 52) Response at 1 year Remission at 1 year Required cross-over (lost response) PCDAI IMPACT III Steroids discontinued 10 weeks 54 weeks Height for age HACA ANA Infectious AE Infections after 14 weeks “Notable” infections
12 week (n⫽51)
63.5% 33.3% 55.8% 23.5% 19.2% 49.5% SS improved from baseline; NS between groups SS improved from baseline; NS between groups SS improved from baseline 12/24 (50%) 3/12 (25%) 22/24 (91.7%) 8/12 (66.7%) SS from baseline; no data provided by treatment groups 2.9% positive; NS between groups 22.9%–27.9%; NS between groups 39/53 (73.6%) 19/50 (38%) 30/53 (56.6%) 18/50 (36%) 8/53 (15.1%) 2/50 (4%)
SS SS SS
NS NS
SS SS NS
NOTE: Summarizing main results presented in the text, figures, and tables. Some additional statistical analyses were done if data are provided but without P values. AE, adverse event; ANA, anti-nuclear; HACA, human anti-chimeric antibody; NS, not significant; PCDAI, Pediatric Crohn’s Disease Activity Index; SS, statistically significant at the 5% level.
physicians managing pediatric patients, although data in adult patients have suggested that 8-week intervals are superior to longer variable interval administration with regard to efficacy and reduced risk of human anti-chimeric antibody (HACA) production.9,10 During the ensuing months, until the final assessment at 54 weeks, several indicators of efficacy were measured at predetermined intervals. These included a measure of disease activity (PCDAI), loss of response and areas of particular relevance to pediatric patients—reduction and discontinuation of concomitant corticosteroid medication, healthrelated quality of life (IMPACT III),11 and, for those with subnormal height and a delay in bone age of ⬎1 SD, improvement in the z-score for height for age. z-Scores are standard methods for comparing an individual child to the mean of the normal population of same gender and age and are calculated by dividing the difference between the observed and expected height by the standard deviation for children of the same age and gender.12 Measures of adverse outcomes included the development of HACA and anti-nuclear (ANA) antibodies and rate and type of acquired infections. Table 1 summarizes the main findings. Response and remission rates at 54 weeks were 63.5% and 55.8% for the 8-week group and 33.3% and 23.5% for the 12-week group, and includes patients who were crossed over. Almost one third of enrolled patients were crossed over because of loss of response during the initial maintenance period. The cross-over or “dose intensification” was less common among patients receiving infliximab at 8-week versus 12-week intervals. Response was regained in most patients following increases in dose and/or frequency. Beneficial results included a fall in mean PCDAI and improved IMPACT III score, but no significant difference was detected between patients in the 8-week and 12-week regimens.
Corticosteroids were being used at baseline in 36 of the 103 randomized patients. By week 10, 15 of 36 (41.5%) had discontinued steroids, and by week 54, 83% were off corticosteroids. Although reduction in corticosteroid use was highly significant (P ⬍ .001) for the population of patients who responded to infliximab at 10 weeks, no statistical difference between the 2 treatment groups was reported by the authors. The effect of infliximab on normalization of height for age was assessed in a subset of patients (number not provided by the authors) with a delay in bone age of ⬎1 year. The z-score for a normal population is 0.0 ⫾ 1.0. The height z-score for the reported patients was ⫺1.5 at baseline and improved to ⫺1.2 at week 30, and ⫺1.0 at week 54. These were highly significant in this selected population (P ⬍ .001). Other groups (but not all) have previously reported improved height in pediatric patients treated with infliximab.13–15 Serologic monitoring included detection of HACA and ANA antibodies collected at 0, 30, and 54 weeks. HACA developed in 2.9% of patients (no difference between the 8- and 12-week groups), remained negative in 20%, but was inconclusive in the majority (77%) owing to the presence of measurable infliximab. This is in contrast to HACA positivity reported in 35% of pediatric patients in a retrospective study when maintenance doses were given at variable intervals. These authors noted no difference in HACA relative to the length of the interval between doses.16 Newly positive ANA was detected in 22.9%–27.9% of patients in the 8- and 12-week groups and anti-dsDNA in 5.9%– 8.3% of these groups. Within the time of the study, no new cases of autoimmune disease were reported. Safety data are presented for all 112 patients, including the 24 who withdrew from the study before week 54, a good practice in clinical trial reporting. Although the incidence of respiratory tract infections was similar be-
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tween the 2 groups (32%–35%), “notable infections,” which included pneumonia, herpes zoster, and abscess, occurred primarily in the 8-week group. No deaths, demyelinating disorders, malignancies, optic neuritis, or seizures were observed during the 54-week study period. Infusion reactions occurred in similar proportions of patients (17% and 18%, respectively) in the 8- and 12week groups. Statistical Analysis and Comments. The study utilized a design that is different from classic randomized clinical trials. All eligible patients received 3 doses of infliximab as the induction therapy. Only patients who responded to the induction therapy were randomized to receive 3 or 5 doses of maintenance infliximab therapy. This induction period not only mimics clinical practice, but also serves as the selection of complaints and responders to make the comparison of maintenance treatment less obscure. Patients who stay in the trial are those motivated and are less like to withdraw consent after randomization. Excluding nonresponders and those with adverse events makes the remaining cohort more homogeneous, and thus increases study power. The comparison of the 2 maintenance strategies is valid with this study design. However, the estimate of therapy effect is biased upward. As a result, practicing gastroenterologists may observe lower response rate at week 54 in their unselected patient population. As discontinued study participation is one component of the nonresponse definition, the current study design is prone to bias of differential loss to follow-up. Frequent patient contact and clinic visits usually keep patients motivated and staying in the study. The current study compared every-8-week and every-12-week treatments and the 2 arms had different clinical visit schedules. So the effect of drug maintenance interval (every-8-week versus every-12-week) may be confounded by different frequency of clinic visits. The study did observe more discontinuation in the every-12-week arm. An improvement in study design would be that the 2 groups have the same clinic visit schedule, even without infusion in some visits. The study power to detect a difference between the every-8-week and every-12-week treatment regimens is unacceptably low (67% or 31%) based on the assumptions made before data collection. Fortunately for the patients and investigators, there were more responders to the induction therapy than investigators expected so more patients were randomized for the maintenance treatment. Although there is no point in discussing power for a positive study, an underpowered study does not guarantee detection of an expected effect in future and should not be encouraged. In general, the study was well documented and analyzed. The analysis stuck to the intention-to-treat principle for the primary end points of efficacy. In the evaluation of the changes in PCDAI and IMPACT III scores,
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paired t tests were used with last observation carried forward method for missing values. This approach is less efficient and conservative (bias against the benefit) in assessing the treatment benefit. Possibly, this is one of the reasons why no significant difference was identified in quality-of-life score between the 2 maintenance arms. Likelihood-based methods, such as mixed effect models, are recommended in analyzing longitudinal studies with dropping out. The authors are to be commended for designing a study to evaluate infliximab in the clinically significant, and unfortunately common, situation of pediatric patients who still have active Crohn’s disease despite 8 weeks of immunomodulatory therapy. The response and remission rates at 1 year and reduced loss of response with 8- versus 12-week infusion intervals for maintenance support the authors’ conclusions regarding the superiority of the more frequent dosing. However, it should be emphasized that these findings apply only to the first year of therapy. Whether patients who have responded at 1 year can be changed to 12-week or longer intervals or discontinued is an important question and not addressed by this study. In a recent Danish report,15 42% of pediatric patients receiving infliximab were “infliximab dependent,” meaning that repeated infusions were required to prevent relapse. The concept of whether the use of biologic agents early in the course of therapy would change the course of disease and improve the frequency of response to immunomodulatory or other forms of therapy as well as immunotherapy as a sole form of treatment need to be addressed in a separate study. From an ethical perspective, gastroenterologists caring for children with Crohn’s disease are only too aware of the range of serious and fatal infections reported in pediatric patients receiving infliximab such as Listeria monocytogenes meningitis, histoplasmosis, pneumonia, and herpes zoster.16 This, coupled with the high cost of the agent and its administration, and recent questions regarding malignancy (especially hepatosplenal T-cell lymphoma) would mandate that a future study focus on a similar group of moderate to severely affected patients. Finally, whether infliximab is equivalent or superior to other anti-TNF biologic agents is also not evaluated in this study but is an issue of interest to patients given the ease of subcutaneous versus intravenous administration. This important prospective study of infliximab for moderately severe Crohn’s disease in pediatric patients suggests that lower rates of clinical response and remission and increased frequency of requiring dose escalation of infliximab occur in pediatric patients receiving infliximab at 12- rather than 8-week intervals. Other findings, such as corticosteroid reduction at 1 year, health-related quality of life (IMPACT III), development of HACA and ANA antibodies, and change in z-score for height, although mostly significant for a change from baseline,
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were not powered to demonstrate a significant difference between the 2 maintenance regimens. Most important, long-term efficacy (loss of response) and safety (lifethreatening and fatal infections and the risk of malignancy) of infliximab are presently undetermined for this population. It is unclear whether earlier intervention with infliximab and maintenance with immunomodulatory agents is able to prevent the “infliximab dependency” that is replacing corticosteroid dependency in our therapeutic repetoire.15
BARBARA S. KIRSCHNER Section of Pediatric Gastroenterology, Hepatology, and Nutrition The University of Chicago Comer Children’s Hospital Chicago, Illinois DEZHENG HUO Department of Health Studies The University of Chicago Chicago, Illinois
GASTROENTEROLOGY Vol. 132, No. 3
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References 1. Hyams JS, Crandall W, Kugathasan S, Griffiths A, Olson A, Johanns J, Liu G, Traverse S, Heuschkel R, Markowitz J, Cohen S, Winter H, Veereman-Wauters G, Ferry G, Baldassano R. Induction and maintenance infliximab therapy for the treatment of moderate-to-severe Crohn’s disease in children. Gastroenterology 2007;132:863– 873. 2. Markowitz J, Grancher K, Kohn N, Daum F. A multicenter trial of 6-mercaptopurine and prednisone in children with newly diagnosed Crohn’s disease. Gastroenterology 2000;119:895–902. 3. Markowitz J, Hyams J, Mack D, Leleiko N, Evans J, Kugathasan S, Pfefferkorn M, Mezoff A, Rosh J, Volia V, Otley A, Griffiths A, Moyer MS, Oliva-Hemker M, Wyllie R, Rothbaum R, Bousvaros A, Delrosario JF, Hale S, Lerer T. Corticosteroid therapy in the age of infliximab: Acute and 1-year outcomes in newly diagnosed children with Crohn’s disease. Clin Gastroenterol Nutr 2006; 4:1124 –1129. 4. Tung J, Loftus EV, Freese DK, El-Youssef M, Zinsmeister AR, Melton II J, Harmsen WS, Sandborn WJ, Faubion Jr WA. A population-based study of the frequency of corticosteroid resistance and dependence in pediatric patients with Crohn’s disease and ulcerative colitis. Inflamm Bowel Dis 2006;12:1093–1100. 5. Hyams JS, Ferry GD, Mandel FS, Gryboski JD, Kibort PM, Kirschner BS, Griffiths AM, Katz AJ, Grand RJ, Boyle JT, Michener WM, Levy JS, Lesser ML. Development and validation of a pediatric Crohn’s disease activity index. J Pediatr Gastroenterol Nutr 1991;12:439 – 447. 6. Hyams J, Markowitz J, Otley A, Rosh J, Mack D, Bousvaros A, Kugathasan S, Pfefferkorn M, Volia V, Evans J, Treem W, Wyllie R,
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Rothbaum R, Delrosario JF, Katz A, Mezoff A, Oliva-Hemker M, Lerer T, Griffiths A. Evaluation of the pediatric Crohn’s disease index: a prospective multicenter experience. J Pediatr Gastroenterol Nutr 2005;41:416 – 421. Kirschner BS. Safety of azathioprine and 6-mercaptopurine in children and adolescents with inflammatory bowel disease. Gastroenterology 1998;115:813– 821. Thayu M, Markowitz JE, Mamula P, Russo PA, Muinos WI, Baldassano RN. Hepatosplenic T-cell lymphoma in an adolescent after immunomodulatory and biologic therapy for Crohn’s disease. J Pediatr Gastroenterol Nutr 2005;40:220 –222. Hanauer SB, Feagan BG, Lichtenstein GR, Mayer LF, Schreiber S, Colombel JF, Rachmilewitz D, Wolf DC, Olson A, Bao W, Rutgeerts P; Accent 1 Study Group. Maintenance infliximab for Crohn’s disease: the ACCENT 1 randomised clinical trial. Lancet 2002; 359:1541–1549. Rutgeerts P, Diamond RH, Bala M, Olson A, Lichtenstein GR, Bao W, Patel K, Wolf DC, Safdi M, Colombel JF, Lashner B, Hanauer SB. Scheduled maintenance treatment with infliximab is superior to episodic treatment for the healing of mucosal ulceration associated with Crohn’s disease. Gastrointest Endosc 2006;63: 433– 442. Otley A, Smith C, Nicholas D, Munk M, Avolio J, Sherman PM, Griffiths AM. The IMPACT questionnaire: a valid measure of health-related quality of life in pediatric inflammatory bowel disease. J Pediatr Gastroenterol Nutr 2002;35:557–563. Waterlow JC, Buzina R, Keller W, Lane JM, Nichaman MZ, Tanner JM. The presentation and use of height and weight data for comparing nutritional status of groups of children under the age of 10 years. Bull WHO 1977;55:489 – 498. Cezard JP, Nouaili N, Talbotec C, Hugot JP, Gobert DG, Schmitz J, Mougenot JF, Alberti C, Goulet O. A prospective study of the efficacy and tolerance of a chimeric antibody to tumour necrosis factors (Remicade) in severe pediatric Crohn’s. J Pediatr Gastroenterol Nutr 2003;36:632– 636. Borrelli O, Bascietto C, Viola F, Bueno de Mesquita M, Barbato M, Mancini V, Bosco S, Cucchiara S. Infliximab heals intestinal inflammatory lesions and restores growth in children with Crohn’s disease. Dig Liver Dis 2004;36:342–347. Wewer V, Riis L, Vind I, Husby S, Munkholm P, Paerregaard A. Infliximab dependency in a national cohort of children with Crohn’s disease. J Pediatr Gastroenterol Nutr 2006;42:40 – 45. Miele E, Markowitz JE, Mamula P, Baldassano RN. Human antichimeric antibody in children and young adults with inflammatory bowel disease receiving infliximab. J Pediatr Gastroenterol Nutr 2004;38:502–508.
Address requests for reprints to: Barbara S. Kirschner, MD, Section of Pediatric Gastroenterology, Hepatology and Nutrition, The University of Chicago Comer Children’s Hospital, 5839 S. Maryland Avenue, MC-4065, Chicago, Illinois 60637. e-mail: [email protected]; fax: (773) 702-0666. © 2007 by the AGA Institute 0016-5085/07/$32.00 doi:10.1053/j.gastro.2007.01.063
EDITORIALS Timing Infliximab Therapy in Pediatric Crohn’s Disease
See “Induction and maintenance infliximab therapy for the treatment of moderate-tosevere Crohn’s disease in children,” by Hyams JS, Crandall W, Kugathasan S, et al, on page 863.
T
he REACH study reported in this issue of GASTROby Hyams et al1 addresses clinically important questions regarding the effect of infliximab (Remicade) in pediatric patients with Crohn’s disease. It is apparent that other medical options are available for children and adolescents with moderate to severe Crohn’s disease that have documented efficacy and side effects. Several pediatric studies have documented corticosteroid-induced (CS) response and remission in children and adolescents with new-onset and relapsing Crohn’s disease.2– 4 Markowitz et al2 reported 89% remission rate for a new-onset pediatric population with Crohn’s disease whether they received prednisone equivalent to 1–2 mg/kg per day plus placebo or that dose combined with 1.5 mg/kg of 6-mercaptopurine (6MP). However, the duration of response was significantly prolonged in the combined therapy group with a relapse rate at 18 months of only 9% versus 47% for prednisone with placebo. Repeated courses of CS were needed in 57% of the prednisone plus placebo group compared with 4% for prednisone/6MP. Similar outcomes were described in a subsequent multicenter study of 109 newly diagnosed patients ⬍16 years with Crohn’s disease who received prednisone at 1–2 mg/kg per day.3 At 3 months, 60% had complete response and were off CS, 34% had a partial response, and 17% were steroid resistant. At 1 year, 61% continued to have a prolonged response with the majority maintained on 6MP, azathioprine, or methotrexate. However, 31% were corticosteroid dependent, which was defined as receiving continuous steroids for ⬎6 months or having had an initial 3-month course and subsequently requiring additional courses of CS. Interestingly, the pattern of response was not influenced by the following factors at baseline: age at diagnosis, disease activity as assessed by Physician Global Assessment or Pediatric Crohn’s Disease Activity Index (PCDAI),5,6 site of involvement, extraintestinal manifestations, family history, or laboratory tests including complete blood count, erythrocyte sedimentation rate, or albumin. The most signifENTEROLOGY
icant factor associated with the development of CS dependency and subsequent need for surgery was growth impairment or failure at baseline. A population-based study from Olmsted County, Minnesota, described the course of 26 patients who were treated with CS before 19 years of age.4 Outcome at 30 days included complete remission in 62%, partial remission in 27%, and no response in 12%. At 1 year, prolonged response was present in 42%, CS dependency again noted in 31%, and 27% had had surgery. Although immunomodulatory agents may be very effective in prolonging response and remission, adverse side effects may reduce their utilization. In our reported series of 95 children and adolescents with inflammatory bowel disease who received azathioprine or 6MP, 54% had no adverse effect, 28% experienced side effects necessitating dose reduction, and 18% required drug discontinuation because of pancreatitis, recurrent fever, nausea and/or vomiting, and recurrent infections such as sinusitis.7 Some of these children respond to methotrexate, but the availability of effective alternative therapies is greatly needed to treat patients with moderate to severe disease who are steroid dependent, intolerant, or refractory to immunomodulatory agents. Anti–tumor necrosis factor (TNF) agents can be used as an alternative to or as a complimentary therapy to steroids and other immunomodulators. However, objective data should be reported to justify the high cost and long duration of treatment required to induce and maintain response and remission with infliximab and other biologic agents. The increasing number of recently reported cases of hepatosplenic T-cell lymphoma, especially in adolescent and young adult males, in whom the majority has received Remicade, again requires that we assess its role and long-term safety.8 Findings of this Pediatric Infliximab Trial. In this clinical trial (REACH), all patients received what has become the standard approach for induction with infliximab: 5 mg/kg per day at weeks 0, 2, and 6. At 10 weeks, response and remission rates were 88.4% and 58.9%, respectively. These rates are high in comparison with other studies, but as the authors point out, all patients had received immunomodulatory agents for 8 weeks before enrollment and the mean duration of disease was only 2.0 ⫾ 1.4 years. Those who responded were then randomized to a maintenance schedule of 5 mg/kg at either 8- or 12-week intervals. This reflects the alternative faced by
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Table 1. Differences in Clinical Response Between 8- and 12-Week Schedules 8 week (n ⫽ 52) Response at 1 year Remission at 1 year Required cross-over (lost response) PCDAI IMPACT III Steroids discontinued 10 weeks 54 weeks Height for age HACA ANA Infectious AE Infections after 14 weeks “Notable” infections
12 week (n⫽51)
63.5% 33.3% 55.8% 23.5% 19.2% 49.5% SS improved from baseline; NS between groups SS improved from baseline; NS between groups SS improved from baseline 12/24 (50%) 3/12 (25%) 22/24 (91.7%) 8/12 (66.7%) SS from baseline; no data provided by treatment groups 2.9% positive; NS between groups 22.9%–27.9%; NS between groups 39/53 (73.6%) 19/50 (38%) 30/53 (56.6%) 18/50 (36%) 8/53 (15.1%) 2/50 (4%)
SS SS SS
NS NS
SS SS NS
NOTE: Summarizing main results presented in the text, figures, and tables. Some additional statistical analyses were done if data are provided but without P values. AE, adverse event; ANA, anti-nuclear; HACA, human anti-chimeric antibody; NS, not significant; PCDAI, Pediatric Crohn’s Disease Activity Index; SS, statistically significant at the 5% level.
physicians managing pediatric patients, although data in adult patients have suggested that 8-week intervals are superior to longer variable interval administration with regard to efficacy and reduced risk of human anti-chimeric antibody (HACA) production.9,10 During the ensuing months, until the final assessment at 54 weeks, several indicators of efficacy were measured at predetermined intervals. These included a measure of disease activity (PCDAI), loss of response and areas of particular relevance to pediatric patients—reduction and discontinuation of concomitant corticosteroid medication, healthrelated quality of life (IMPACT III),11 and, for those with subnormal height and a delay in bone age of ⬎1 SD, improvement in the z-score for height for age. z-Scores are standard methods for comparing an individual child to the mean of the normal population of same gender and age and are calculated by dividing the difference between the observed and expected height by the standard deviation for children of the same age and gender.12 Measures of adverse outcomes included the development of HACA and anti-nuclear (ANA) antibodies and rate and type of acquired infections. Table 1 summarizes the main findings. Response and remission rates at 54 weeks were 63.5% and 55.8% for the 8-week group and 33.3% and 23.5% for the 12-week group, and includes patients who were crossed over. Almost one third of enrolled patients were crossed over because of loss of response during the initial maintenance period. The cross-over or “dose intensification” was less common among patients receiving infliximab at 8-week versus 12-week intervals. Response was regained in most patients following increases in dose and/or frequency. Beneficial results included a fall in mean PCDAI and improved IMPACT III score, but no significant difference was detected between patients in the 8-week and 12-week regimens.
Corticosteroids were being used at baseline in 36 of the 103 randomized patients. By week 10, 15 of 36 (41.5%) had discontinued steroids, and by week 54, 83% were off corticosteroids. Although reduction in corticosteroid use was highly significant (P ⬍ .001) for the population of patients who responded to infliximab at 10 weeks, no statistical difference between the 2 treatment groups was reported by the authors. The effect of infliximab on normalization of height for age was assessed in a subset of patients (number not provided by the authors) with a delay in bone age of ⬎1 year. The z-score for a normal population is 0.0 ⫾ 1.0. The height z-score for the reported patients was ⫺1.5 at baseline and improved to ⫺1.2 at week 30, and ⫺1.0 at week 54. These were highly significant in this selected population (P ⬍ .001). Other groups (but not all) have previously reported improved height in pediatric patients treated with infliximab.13–15 Serologic monitoring included detection of HACA and ANA antibodies collected at 0, 30, and 54 weeks. HACA developed in 2.9% of patients (no difference between the 8- and 12-week groups), remained negative in 20%, but was inconclusive in the majority (77%) owing to the presence of measurable infliximab. This is in contrast to HACA positivity reported in 35% of pediatric patients in a retrospective study when maintenance doses were given at variable intervals. These authors noted no difference in HACA relative to the length of the interval between doses.16 Newly positive ANA was detected in 22.9%–27.9% of patients in the 8- and 12-week groups and anti-dsDNA in 5.9%– 8.3% of these groups. Within the time of the study, no new cases of autoimmune disease were reported. Safety data are presented for all 112 patients, including the 24 who withdrew from the study before week 54, a good practice in clinical trial reporting. Although the incidence of respiratory tract infections was similar be-
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tween the 2 groups (32%–35%), “notable infections,” which included pneumonia, herpes zoster, and abscess, occurred primarily in the 8-week group. No deaths, demyelinating disorders, malignancies, optic neuritis, or seizures were observed during the 54-week study period. Infusion reactions occurred in similar proportions of patients (17% and 18%, respectively) in the 8- and 12week groups. Statistical Analysis and Comments. The study utilized a design that is different from classic randomized clinical trials. All eligible patients received 3 doses of infliximab as the induction therapy. Only patients who responded to the induction therapy were randomized to receive 3 or 5 doses of maintenance infliximab therapy. This induction period not only mimics clinical practice, but also serves as the selection of complaints and responders to make the comparison of maintenance treatment less obscure. Patients who stay in the trial are those motivated and are less like to withdraw consent after randomization. Excluding nonresponders and those with adverse events makes the remaining cohort more homogeneous, and thus increases study power. The comparison of the 2 maintenance strategies is valid with this study design. However, the estimate of therapy effect is biased upward. As a result, practicing gastroenterologists may observe lower response rate at week 54 in their unselected patient population. As discontinued study participation is one component of the nonresponse definition, the current study design is prone to bias of differential loss to follow-up. Frequent patient contact and clinic visits usually keep patients motivated and staying in the study. The current study compared every-8-week and every-12-week treatments and the 2 arms had different clinical visit schedules. So the effect of drug maintenance interval (every-8-week versus every-12-week) may be confounded by different frequency of clinic visits. The study did observe more discontinuation in the every-12-week arm. An improvement in study design would be that the 2 groups have the same clinic visit schedule, even without infusion in some visits. The study power to detect a difference between the every-8-week and every-12-week treatment regimens is unacceptably low (67% or 31%) based on the assumptions made before data collection. Fortunately for the patients and investigators, there were more responders to the induction therapy than investigators expected so more patients were randomized for the maintenance treatment. Although there is no point in discussing power for a positive study, an underpowered study does not guarantee detection of an expected effect in future and should not be encouraged. In general, the study was well documented and analyzed. The analysis stuck to the intention-to-treat principle for the primary end points of efficacy. In the evaluation of the changes in PCDAI and IMPACT III scores,
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paired t tests were used with last observation carried forward method for missing values. This approach is less efficient and conservative (bias against the benefit) in assessing the treatment benefit. Possibly, this is one of the reasons why no significant difference was identified in quality-of-life score between the 2 maintenance arms. Likelihood-based methods, such as mixed effect models, are recommended in analyzing longitudinal studies with dropping out. The authors are to be commended for designing a study to evaluate infliximab in the clinically significant, and unfortunately common, situation of pediatric patients who still have active Crohn’s disease despite 8 weeks of immunomodulatory therapy. The response and remission rates at 1 year and reduced loss of response with 8- versus 12-week infusion intervals for maintenance support the authors’ conclusions regarding the superiority of the more frequent dosing. However, it should be emphasized that these findings apply only to the first year of therapy. Whether patients who have responded at 1 year can be changed to 12-week or longer intervals or discontinued is an important question and not addressed by this study. In a recent Danish report,15 42% of pediatric patients receiving infliximab were “infliximab dependent,” meaning that repeated infusions were required to prevent relapse. The concept of whether the use of biologic agents early in the course of therapy would change the course of disease and improve the frequency of response to immunomodulatory or other forms of therapy as well as immunotherapy as a sole form of treatment need to be addressed in a separate study. From an ethical perspective, gastroenterologists caring for children with Crohn’s disease are only too aware of the range of serious and fatal infections reported in pediatric patients receiving infliximab such as Listeria monocytogenes meningitis, histoplasmosis, pneumonia, and herpes zoster.16 This, coupled with the high cost of the agent and its administration, and recent questions regarding malignancy (especially hepatosplenal T-cell lymphoma) would mandate that a future study focus on a similar group of moderate to severely affected patients. Finally, whether infliximab is equivalent or superior to other anti-TNF biologic agents is also not evaluated in this study but is an issue of interest to patients given the ease of subcutaneous versus intravenous administration. This important prospective study of infliximab for moderately severe Crohn’s disease in pediatric patients suggests that lower rates of clinical response and remission and increased frequency of requiring dose escalation of infliximab occur in pediatric patients receiving infliximab at 12- rather than 8-week intervals. Other findings, such as corticosteroid reduction at 1 year, health-related quality of life (IMPACT III), development of HACA and ANA antibodies, and change in z-score for height, although mostly significant for a change from baseline,
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were not powered to demonstrate a significant difference between the 2 maintenance regimens. Most important, long-term efficacy (loss of response) and safety (lifethreatening and fatal infections and the risk of malignancy) of infliximab are presently undetermined for this population. It is unclear whether earlier intervention with infliximab and maintenance with immunomodulatory agents is able to prevent the “infliximab dependency” that is replacing corticosteroid dependency in our therapeutic repetoire.15
BARBARA S. KIRSCHNER Section of Pediatric Gastroenterology, Hepatology, and Nutrition The University of Chicago Comer Children’s Hospital Chicago, Illinois DEZHENG HUO Department of Health Studies The University of Chicago Chicago, Illinois
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Address requests for reprints to: Barbara S. Kirschner, MD, Section of Pediatric Gastroenterology, Hepatology and Nutrition, The University of Chicago Comer Children’s Hospital, 5839 S. Maryland Avenue, MC-4065, Chicago, Illinois 60637. e-mail: [email protected]; fax: (773) 702-0666. © 2007 by the AGA Institute 0016-5085/07/$32.00 doi:10.1053/j.gastro.2007.01.063