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Risks of Serious Infection or Lymphoma With Anti–Tumor Necrosis Factor Therapy for Pediatric Inflammatory Bowel Disease: A Systematic Review Parambir S. Dulai,* Kimberly D. Thompson,* Heather B. Blunt,‡ Marla C. Dubinsky,§ and Corey A. Siegel* *Inflammatory Bowel Disease Center, Dartmouth Hitchcock Medical Center, Lebanon, New Hampshire; ‡Biomedical Libraries, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire; and §Pediatric Inflammatory Bowel Disease Center, Cedars-Sinai Medical Center, Los Angeles, California BACKGROUND & AIMS:

Many physicians hesitate to recommend anti–tumor necrosis factor (TNF) therapy for pediatric patients with inflammatory bowel disease (IBD) because of concerns about risk of infection and cancer. We performed a systematic review to quantify the incidence of serious infection, lymphoma, and death among pediatric patients with IBD who received anti-TNF therapy. These values were compared with those expected from other treatments, from adults with IBD, and from the general pediatric population.

METHODS:

We searched MEDLINE, EMBASE, the Cochrane Collaboration, and Web of Knowledge for studies of infliximab therapy for children with ulcerative colitis or Crohn’s disease, or adalimumab therapy for children with Crohn’s disease. Standardized incidence ratios (SIRs) were calculated, comparing rates of infection and cancer among pediatric patients exposed to anti-TNF agents vs expected rates from pediatric patients not exposed to anti-TNF therapies or adult patients exposed to anti-TNF agents. Our analysis included 5528 patients with 9516 patient-years of follow-up evaluation (PYF).

RESULTS:

The rate of serious infections among pediatric patients treated with anti-TNF agents (352/ 10,000 PYF) was similar to that of pediatric patients who received immunomodulator monotherapy (333/10,000 PYF; SIR, 1.06; 95% confidence interval [CI], 0.83–1.36), but significantly lower than the expected rate for pediatric patients treated with steroids (730/10,000 PYF; SIR, 0.48; 95% CI, 0.40–0.58) or adults treated with anti-TNF agents (654/10,000 PYF; SIR, 0.54; 95% CI, 0.43–0.67). Five treatment-related deaths occurred (4 from sepsis and 1 from arrhythmia). Two patients developed lymphoma (2.1/10,000 PYF). This value was similar to the expected rate of lymphoid neoplasia in the entire pediatric population (5.8/100,000 PYF; SIR, 3.5; 95% CI, 0.35–19.6), and lower than the population of pediatric patients receiving thiopurine monotherapy (4.5/10,000 PYF; SIR, 0.47; 95% CI, 0.03–6.44), and among adults treated with anti-TNF agents (6.1/10,000 PYF; SIR, 0.34; 95% CI, 0.04–1.51).

CONCLUSIONS:

Based on a systematic review, the risk of lymphoma was no greater among children with IBD who received anti-TNF therapy than those treated with other IBD therapies or adults treated with anti-TNF agents. The rate of serious infection was significantly lower among pediatric patients with IBD treated with anti-TNF agents than those treated with steroids, or adults with IBD who received anti-TNF therapy.

Keywords: Cancer Risk; Intestine; Clinical Study; Immune Suppression; Inflammatory Bowel Disease; Anti-TNF; Lymphoma; Infection.

lassically considered relapsing and remitting illnesses, the inflammatory bowel diseases (IBDs) Crohn’s disease and ulcerative colitis, present during childhood in approximately 25% of patients.1 There has been a steady increase in the incidence of pediatric-onset IBD and the majority of these patients experience initial symptoms during the transition from childhood to adolescence.2 Therefore, the disease, which often is treated with long-term corticosteroids or immunomodulator agents,

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may result in a significant impairment in growth, development, and health-related quality of life.3–6 Abbreviations used in this paper: ADA, adalimumab; CI, confidence interval; HSTCL, hepatosplenic T-cell lymphoma; IBD, inflammatory bowel disease; IFX, infliximab; PYF, patient-years of follow-up evaluation; SIR, standardized incidence ratio; TNF, anti–tumor necrosis factor. © 2014 by the AGA Institute 1542-3565/$36.00 http://dx.doi.org/10.1016/j.cgh.2014.01.021

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Anti–tumor necrosis factor (TNF) therapy has been shown to be an effective treatment option for inducing and maintaining remission in both pediatric Crohn’s disease and ulcerative colitis.7–10 These agents also have been shown to improve growth and development significantly when instituted at an early stage.7,11–13 This has led to the re-alignment of treatment strategies toward the early initiation of anti-TNF agents for better lifetime control, or the top down approach.14–16 This approach, however, often is met with hesitancy from patients and parents because of uncertainties regarding risks of therapy.17 The decision to initiate often may be delayed until patients are believed to be sick enough to warrant the risks of therapy.18 The adverse events of most concern include serious infections and lymphoma associated with antiTNF monotherapy or when combined with an immunomodulator.19–21 The majority of the existing data in the literature are from small pediatric studies, adult IBD cohorts, or non-IBD patients exposed to anti-TNF therapy. Thus, to better understand the overall risk in pediatric IBD, we performed a systematic review of the literature to quantify the incidence of serious infection, lymphoma, and death with anti-TNF therapy in children with Crohn’s disease and ulcerative colitis. We further aimed to understand how the incidence of these events compared with other available treatment options, adult IBD patients treated with anti-TNF therapy, and the general pediatric population.

Methods Data Sources and Search Strategy The following databases were searched between March 18 and March 22, 2013: MEDLINE (PubMed, January 1946 to March 2013); Cochrane Library (Wiley, 2013 issue 1); Web of Knowledge (Web of Science, January 1900 to March 2013); and Embase (Embase.com, January 1947 to March 2013). The search included indexed terms and text words to capture the following concepts: inflammatory bowel disease, anti–tumor necrosis factor agents, and children under the age of 18. There were no language or study design restrictions. The search strategy was adjusted for the syntax appropriate for each database. The reference lists of included articles and review articles were examined for additional relevant studies. The full search strategy is available at the international prospective register of systematic reviews (PROSPERO #CRD42013004828).

Study Selection and Extraction Studies were included for analysis if they met the following inclusion criteria: study design of randomized controlled trials, cohort studies, or case series of 5 or more consecutive patients (to avoid selection bias);

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published articles or meeting abstracts; treatment included infliximab (IFX) for Crohn’s disease, ulcerative colitis, or indeterminate colitis, and/or adalimumab (ADA) for Crohn’s disease; population of pediatric patients (18 y); clearly reported adverse outcomes and follow-up evaluation. Studies including both adult (>18 y) and pediatric patients were included if pediatric data were reported separately or if the median age at anti-TNF initiation was 18 years or younger. Review articles and case series with fewer than 5 patients were excluded. Given the lack of a clear denominator at risk, studies reporting on adverse event registry databases were excluded. Studies with insufficient data for adverse outcomes and follow-up evaluation were excluded only after attempting to contact the primary author(s). Two reviewers (P.S.D. and K.D.T.) independently evaluated each of the articles for eligibility. Inclusion decisions for each article were made independently based on the eligibility criteria, with disagreements being resolved by a third reviewer (C.A.S.) and consensus. Data were abstracted by P.S.D. using a predesigned data extraction tool and were verified by K.D.T. This electronic data collection form (Excel; Microsoft, Redmond, WA) included study design, population size and median age, median time of follow-up evaluation, sex, specific anti-TNF agent, percentage taking immunomodulators, and number of serious infections, lymphomas, and deaths. The reviewer (P.S.D.) contacted the primary author(s) as required to obtain any necessary missing data from the original publications and because no language restrictions were applied, publications were translated into English as required. The reviewers followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) standards for systematic review.

Outcomes and Analysis Pooled summary estimates. Our primary outcome of interest was the absolute rate of serious infection, lymphoma, and death with anti-TNF therapy in pediatric IBD. These rates were calculated based on the total number of events occurring during total patient-years of follow-up evaluation (PYF). Patient-years were calculated by multiplying the follow-up time (months) by the total number of subjects and subsequently converting the follow-up time to years. Infections were classified as serious if they were categorized as serious by the original investigator(s) or resulted in discontinuation of therapy, hospitalization, or death. Given the inherit risk for under-reporting serious infections with retrospective studies, a sensitivity analysis was performed with only prospective studies. We further compared the rates of serious infection within these prospective trials between the 2 anti-TNF agents IFX and ADA. Comparison with prior data and the general pediatric population. We further aimed to compare the rate of

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with the expected rate of serious infection with glucocorticoid (>10 mg/d) or immunomodulator therapy in pediatric patients, and anti-TNF therapy in adult IBD. The expected rate with glucocorticoid and immunomodulator therapy was derived from a large national Medicaid-based cohort of juvenile idiopathic arthritis patients.22 The expected rate of serious infection with anti-TNF therapy in adult IBD was derived from a pooled analysis of 10 adult IBD clinical trials.23 Our secondary outcome of interest was to compare the rate of lymphoma with anti-TNF therapy in pediatric IBD with the expected rate of lymphoma among pediatric subjects not exposed to anti-TNF agents and adult IBD patients exposed to anti-TNF agents. The expected rate of lymphoma among pediatric subjects not exposed to antiTNF agents was derived from 2 sources: the Surveillance Epidemiology and End Results cancer registry24 and a large single-center cohort of pediatric IBD patients treated with thiopurine monotherapy.25 The expected rate of lymphoma among adult IBD patients exposed to anti-TNF agents was derived from a meta-analysis of adult Crohn’s disease patients treated with anti-TNF therapy.20 By using the STATA “incidence ratio (IR)” command (version 10.0; STATA, College Station, TX), the relative rates for serious infection and lymphoma were calculated as standardized incidence ratios (SIRs) when comparisons were made with expected outcomes, and as incidence rate ratios when comparisons were made between anti-TNF agents.

Results Study Characteristics The initial search strategy yielded 2243 publications. Of those, 1917 were excluded after screening titles and abstracts. Subsequently, 326 articles were retrieved in full text, of which 65 studies met our eligibility criteria (Figure 1). These 65 studies reported on a total of 5528 patients with 9516 PYF. Five studies were randomized controlled trials,7–9,26,27 7 were case series,28–34 and 53 were cohort studies.10,35–87 The majority of studies reported on cohorts of fewer than 100 patients, and nearly 75% of included patients had a mean per-patient followup period of shorter than 2 years (Tables 1 and 2).

Serious Infections There were a total of 309 serious infections during the 9516 PYF, yielding an absolute rate of 325 per 10,000 PYF. When only including prospective studies,7–10,26,27,32,34,36,37,39–43,51–54,56,65,68,71,74,84,87 4076 patients (294 ADA, 3782 IFX) developed a total of 256 serious infections (16 ADA, 240 IFX) during 7276 patientyears of follow-up evaluation (545 ADA, 6731 IFX), yielding an absolute rate of 352 per 10,000 PYF. The rate of serious infection in prospective studies was similar

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Figure 1. Flow diagram of the studies identified in the search, and reasons for study exclusion.

between the 2 anti-TNF agents (ADA 294 per 10,000 PYF vs IFX 357 per 10,000 PYF; incidence rate ratio, 0.82; P ¼ .46; 95% confidence interval [CI], 0.46–1.37). The rate of serious infections seen with anti-TNF therapy in pediatric IBD is similar to the expected rate of serious infection with immunomodulator therapy in pediatric patients (333 per 10,000 PYF; SIR, 1.06; P ¼ .65; 95% CI, 0.83–1.36), but significantly lower than the expected rate with glucocorticoid use in pediatric patients (730 per 10,000 PYF; SIR, 0.48; P < .001; 95% CI, 0.40–0.58) and anti-TNF therapy in adult IBD (654 per 10,000 PYF; SIR, 0.54; P < .001; 95% CI, 0.43–0.67).

Lymphoma Two patients developed a lymphoma during the follow-up evaluation, yielding an absolute rate of 2.1 per 10,000 PYF.76,88 The first was a 14-year-old girl with Table 1. Characteristics of Included Studies (n ¼ 65) Published articles Prospective Multicenter Non-US site Study size, patients (n) 100 Mean follow-up period per patient (y) 2

77% 40% 46% 69% 68% 17% 15% 45% 29% 26%

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Table 2. Characteristics of Included Patients (n ¼ 5528) 13.6  2.2 56% 9516

Mean age, y ( SD) Malea Follow-up, total patient years IBD and treatment characteristics Crohn’s disease IFX ADA Ulcerative colitis Indeterminate Concomitant ISa

84% 90% 10% 11% 5% 80%

IS, immunosuppressant (azathioprine, 6-mercaptopurine, or methotrexate). a The number of male patients was not available for 9 studies (346 patients) and the number of patients treated with concomitant IS were not available for 4 studies (2951 patients).

Crohn’s disease. Within the first 3 months of diagnosis, the patient was initiated on prednisone, mesalamine, and 6-mercaptopurine. The patient subsequently was begun on IFX in addition to 6-mercaptopurine. Three years after her diagnosis, 2.5 years after beginning IFX therapy, the patient underwent an ileocolonic resection, during which she was found to have a stage II Hodgkin lymphoma. The second patient (demographics not available) failed induction therapy with 3 doses of IFX in addition to azathioprine. This patient underwent a brief course of therapy with tacrolimus for an unspecified duration and 3 years after stopping IFX the patient was diagnosed with a non-Hodgkin lymphoma (B-cell lymphoma). When compared with the expected rate of lymphoma among the general pediatric population, there was a nonsignificant increase in the risk of lymphoma with anti-TNF therapy in pediatric IBD (5.8 per 100,000; SIR, 3.5 P ¼ .18; 95% CI, 0.35–19.6). The rate of lymphoma with anti-TNF therapy in pediatric IBD was numerically, but not statistically, lower than that seen with thiopurine monotherapy in pediatric IBD (4.5 per 10,000 PYF; SIR, 0.47; P ¼ .48; 95% CI, 0.03–6.44) and anti-TNF therapy in adult IBD (6.1 per 10,000 PYF: SIR, 0.34; P ¼ .14; 95% CI, 0.04–1.51) (Table 3).

Death Seven patient deaths occurred. Two of which were believed to be unrelated to anti-TNF therapy: 1 patient died of metastatic undifferentiated colon cancer 9 years

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after stopping IFX therapy and 1 patient died of multiorgan failure in the setting of significant dehydration from surgical complications 5 years after stopping IFX.85 The remaining 5 deaths were included in our analysis, making for an absolute rate of 5.3 per 10,000 PYF. Of the 5 patients who were included in our analysis, 2 had been treated with ADA and the remaining 3 were treated with IFX. Both patients treated with ADA died of central line–related sepsis.48 Of the 3 IFX-related deaths, 1 patient died of azathioprine-induced neutropenia with sepsis,67 1 patient died of sepsis in the setting of a bone marrow transplant,76 and the third died of a fatal arrhythmia.88 This patient also had suffered a near-fatal cardiac arrest secondary to an arrhythmia before initiating IFX therapy (Table 4).

Discussion Anti-TNF therapy is an effective treatment option for inducing and maintaining remission in pediatric IBD. Despite this shown efficacy and the realignment of treatment goals toward achieving early mucosal healing, the use of these agents still often is met with great hesitancy because of concerns surrounding their safety profile and long-term risks. The safety issues that have generated the most interest center around potential infectious and malignant complications. Our pooled analysis showed that the rate of serious infection with anti-TNF therapy in pediatric IBD is comparable with the expected rate with pediatric immunomodulator therapy and significantly lower than the expected rate with pediatric steroid use or anti-TNF therapy in adult IBD. Furthermore, the use of anti-TNF therapy in pediatric IBD does not appear to significantly increase the risk of lymphoma. Our results are consistent with previous findings regarding steroid use. Steroids have been shown to increase the risk of serious infection in IBD and nonIBD patients significantly.22,89 The Crohn’s Therapy, Resource, Evaluation, and Assessment Tool (TREAT) registry, a large observational adult Crohn’s disease registry, showed that prednisone use was an independent predictor of serious infection and IFX allowed for the tapering and discontinuation of steroids.89 The Pediatric IBD Collaborative Research Group Registry also

Table 3. Rate of Lymphoma With Anti-TNF Therapy and Comparison With Expected Rates Pediatric anti-TNF/ SEER/ Thiopurine/ Adult anti-TNF/ 10,000 PYF 100,000 PYF SIR (95% CI) 10,000 PYF SIR (95% CI) 10,000 PYF SIR (95% CI) Lymphoid neoplasias Hodgkin lymphoma NHL

2.1 1.05 1.05

5.8 1.2 4.6

3.5 (0.35–19.6) 10.5 (0.13–824) 2.1 (0.04–18.8)

4.5 2.25 2.25

0.47 (0.03–6.44) 0.47 (0.01–36.6) 0.47 (0.01–36.6)

NOTE. There were no reported cases of Hodgkin lymphoma with anti-TNF therapy in the adult IBD data used for comparison. NHL, non-Hodgkin lymphoma; SEER, Surveillance Epidemiology and End Results cancer registry.

6.1 6.1

0.34 (0.04–1.51) 0.17 (0.01–1.14)

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Table 4. Anti-TNF Therapy–Related Deaths Patient ADA 15-year-old boy with panenteric CD

13-year-old boy with ileocolonic and perianal CD complicated by peristomal pyoderma gangrenosum, growth delay, and stricturing

IFX Crohn’s disease (demographics n/a)

Treatment history

Course

Thiopurine and MTX intolerance, loss of response to IFX despite adjustments

Hospitalized for an acute flare for which he received enteral nutrition via a gastrotomy tube, MTX (24 mg/m2), and ADA. A central venous catheter was inserted, and he was sent home on total parenteral nutrition. Seven months later, after 20 doses of ADA in combination with MTX, the patient developed staphylococcus bacteremia along with invasive pulmonary aspergillosis. This progressed to septic shock, multiorgan failure, and death. Begun on ADA (40 mg/40 mg induction) in combination with AZA and filgrastim. Started on home parenteral nutrition via a central venous catheter. Approximately 7 months later, after 19 doses of ADA, the patient developed Escherichia coli and Candida sepsis with ensuring septic shock, multiorgan failure, and death.

High dose steroids, AZA, IFX, filgrastim, colostomy

AZA, surgery

IBD (demographics n/a)

Not specified

11-year-old boy with gastroduodenal and colonic CD

Prednisone, AZA, enteral nutrition

Malnourished patient who had undergone multiple surgical procedures. Treatment course was complicated by AZA-induced leukopenia. The patient was initiated on IFX therapy and died of uncontrollable bacterial sepsis 5 months later. Underwent treatment with IFX and AZA. Failed induction (3 doses) and began tacrolimus for an unspecified duration. Three years after stopping IFX, the patient was diagnosed with a B-cell lymphoma. Subsequently underwent a bone marrow transplant and 1 year later, 6 years after stopping IFX, the patient died of sepsis. Between 1 and 1.5 years after diagnosis the patient received 4 doses of IFX. Two years after being diagnosed with CD, he suffered a cardiac arrest secondary to a cardiac arrhythmia with a long QT interval. He previously had suffered a nearsudden cardiac death from arrhythmia before being diagnosed with CD.

AZA, azathioprine; CD, Crohn’s disease; MTX, methotrexate; n/a, not available.

recently showed that the rate of prolonged exposure to prednisone has decreased significantly over the past decade and this decrease is in parallel to an increase in the use of anti-TNF therapy.90 Although infectious complications of anti-TNF therapy may be life-threatening and are considerably more common than malignancy, the fear of developing cancer may be the most significant barrier for parents and patients to overcome before initiating anti-TNF therapy. These concerns arise from the available adult IBD or non-IBD literature,20,21 and case reports of hepatosplenic T-cell lymphoma (HSTCL). In our systematic review, 2 patients developed lymphoma (1 Hodgkin and 1 nonHodgkin) during the 9516 PYF, which was equal to an incidence of 2.1 per 10,000 PYF. This incidence was numerically, but not statistically, different than when compared with the expected rate of lymphoma among the general US pediatric population. The incidence of

lymphoma with anti-TNF therapy in pediatric IBD was lower than the reported incidence of lymphoma with thiopurine monotherapy in pediatric IBD or anti-TNF therapy in adult IBD. Older age, sex, and duration of IBD have been associated with an increased risk of lymphoproliferative disorders and may help to explain the observed differences in lymphoma rates between pediatric and adult IBD patients exposed to anti-TNF therapy.91,92 Although the differences in lymphoma rates between pediatric anti-TNF therapy and thiopurine monotherapy were not statistically significant, previous studies have shown an increased risk for lymphoma with thiopurines relative to anti-TNF agents.91,92 With approximately 80% of our cohort undergoing concomitant therapy with an immunomodulatory agent, including both patients developing lymphoma, it is unclear if the risk of lymphoma still exists when pediatric patients are taking anti-TNF

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monotherapy, or methotrexate instead of a thiopurine. Although there were no patients in our analysis who developed lymphoma who were taking methotrexate, because of the relatively low methotrexate exposure in this population we do not feel confident in concluding that methotrexate does not have an associated risk of malignancy. Adult rheumatoid arthritis data have shown that combination therapy with methotrexate adds no additional risk for lymphoma with anti-TNF agents.93,94 Adult IBD data have suggested that IFX monotherapy carries no additional lymphoma risk beyond that seen with placebo. However, further studies still are needed to understand the risk of lymphoma associated with antiTNF monotherapy or methotrexate combination therapy in pediatric and adult IBD. An important limitation of our analysis was the inability to comment on the risk of HSTCL in children with IBD. This was because cases of HSTCL were not reported in the articles included based on our methods, and cases of HSTCL have not been collected systematically with a known denominator. Therefore, it was not possible to calculate an incidence of occurrence of HSTCL and compare this with children with IBD without anti-TNF exposure. At this time, a reasonable conclusion about HSTCL is that it appears to be driven mostly by thiopurines, and a longer duration of thiopurine therapy (with or without anti-TNF) is associated with a higher risk.95,96 Another limitation was the relatively short duration of per-patient follow-up evaluation. The majority of patients had a mean follow-up period of shorter than 2 years and both pediatric lymphomas developed 3 years after exposure to IFX, leaving this study underpowered to assess the risk of lymphoma adequately. Therefore, although these data are promising, they are not definitive in answering the question of whether anti-TNF therapy is associated with an increased risk of lymphoma, particularly with long-term use. This raises an important question as to whether the lymphoma risk with anti-TNF therapy is exposure-dependent or a cumulative risk that is dependent on the duration of therapy. The 5-year follow-up evaluation of the TREAT registry yielded a lymphoma rate (5 per 10,000 PYF) similar to that reported initially in adult IBD patients exposed to anti-TNF therapy.20,97 This would suggest that the lymphoma risk with anti-TNF therapy is exposure dependent and patients carry no additional risk with continued use, but long-term follow-up studies are needed in pediatric patients. We did not have an ideal comparison group for the rate of serious infection with nonbiologic therapy. We have extrapolated data from a pediatric cohort suffering from a similar chronic inflammatory process: juvenile idiopathic arthritis. It would be expected that IBD patients would be at higher risk for serious infections as a result of the surgical complications, abscess formation, and nutritional deficiencies seen in these patients, but the rate of serious infection with anti-TNF therapy in our pooled analysis was similar to the reported rate of

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serious infection with anti-TNF therapy in this cohort of juvenile idiopathic arthritis patients (350 per 10,000 PYF). Therefore, these 2 cohorts likely are similar in their baseline risk for infection and the rates of serious infection reported with nonbiologic therapies likely are similar to what can be expected in pediatric IBD. Currently, no data are available to quantify the rate of serious infection with nonbiologic therapies in pediatric IBD and large prospective observational studies still are needed to accurately compare the long-term risk of serious infection and lymphoma with anti-TNF therapy with other nonbiologic therapies. In summary, our pooled analysis showed that antiTNF therapy in pediatric IBD appears to be safe and well tolerated. Overall, the risk of serious infection, lymphoma, and death with anti-TNF therapy in pediatric IBD is very low. The rate of serious infection with antiTNF therapy in pediatric IBD is significantly lower than that seen with pediatric steroid use or anti-TNF therapy in adult IBD. Anti-TNF therapy does not appear to increase the rate of lymphoma significantly when compared with the pediatric patients not exposed to anti-TNF therapy or adult IBD patients exposed to antiTNF therapy.

References 1. Griffiths AM. Specificities of inflammatory bowel disease in childhood. Best Pract Res Clin Gastroenterol 2004;18:509–523. 2. Benchimol EI, Fortinsky KJ, Gozdyra P, et al. Epidemiology of pediatric inflammatory bowel disease: a systematic review of international trends. Inflamm Bowel Dis 2011;17:423–439. 3. Karwowski CA, Keljo D, Szigethy E. Strategies to improve quality of life in adolescents with inflammatory bowel disease. Inflamm Bowel Dis 2009;15:1755–1764. 4. Levine A, Griffiths A, Markowitz J, et al. Pediatric modification of the Montreal classification for inflammatory bowel disease: the Paris classification. Inflamm Bowel Dis 2011;17:1314–1321. 5. Kanof ME, Lake AM, Bayless TM. Decreased height velocity in children and adolescents before the diagnosis of Crohn’s disease. Gastroenterology 1988;95:1523–1527. 6. Hildebrand H, Karlberg J, Kristiansson B. Longitudinal growth in children and adolescents with inflammatory bowel disease. J Pediatr Gastroenterol Nutr 1994;18:165–173. 7. Hyams J, Crandall W, Kugathasan S, et al. Induction and maintenance infliximab therapy for the treatment of moderateto-severe Crohn’s disease in children. Gastroenterology 2007; 132:863–873, quiz 1165–1166. 8. Hyams JS, Griffiths A, Markowitz J, et al. Safety and efficacy of adalimumab for moderate to severe Crohn’s disease in children. Gastroenterology 2012;143:365–374.e2. 9. Hyams J, Damaraju L, Blank M, et al. Induction and maintenance therapy with infliximab for children with moderate to severe ulcerative colitis. Clin Gastroenterol Hepatol 2012;10:391–399.e1. 10. Turner D, Mack D, Leleiko N, et al. Severe pediatric ulcerative colitis: a prospective multicenter study of outcomes and predictors of response. Gastroenterology 2010;138:2282–2291. 11. Walters TD, Gilman AR, Griffiths AM. Linear growth improves during infliximab therapy in children with chronically active severe Crohn’s disease. Inflamm Bowel Dis 2007;13:424–430.

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12. Malik S, Wong SC, Bishop J, et al. Improvement in growth of children with Crohn disease following anti-TNF-alpha therapy can be independent of pubertal progress and glucocorticoid reduction. J Pediatr Gastroenterol Nutr 2011;52:31–37. 13. Thayu M, Leonard MB, Hyams JS, et al. Improvement in biomarkers of bone formation during infliximab therapy in pediatric Crohn’s disease: results of the REACH study. Clin Gastroenterol Hepatol 2008;6:1378–1384. 14. Neurath MF, Travis SP. Mucosal healing in inflammatory bowel diseases: a systematic review. Gut 2012;61:1619–1635. 15. Colombel JF, Sandborn WJ, Reinisch W, et al. Infliximab, azathioprine, or combination therapy for Crohn’s disease. N Engl J Med 2010;362:1383–1395. 16. Abraham C, Cho JH. Inflammatory bowel disease. N Engl J Med 2009;361:2066–2078. 17. Siegel CA, Levy LC, Mackenzie TA, et al. Patient perceptions of the risks and benefits of infliximab for the treatment of inflammatory bowel disease. Inflamm Bowel Dis 2008;14:1–6.

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31. Mamula P, Markowitz JE, Cohen LJ, et al. Infliximab in pediatric ulcerative colitis: two-year follow-up. J Pediatr Gastroenterol Nutr 2004;38:298–301. 32. Romano C, Randazzo A, Famiani A, et al. Single-dose of infliximab and short term response in resistant ulcerative colitis (CU). J Pediatr Gastroenterol Nutr 2010;50:E112–E113. 33. Rosenbach Y, Hartman C, Shapiro R, et al. Adalimumab treatment in children with refractory Crohn’s disease. Dig Dis Sci 2010;55:747–753. 34. Czaja-Bulsa G, Gebala A, Korlatowicz-Bilar A. Infliximab treatment time and the mucosal healing effect in pediatric patients with severe Crohn’s disease–own experience. Przeglad Gastroenterologiczny 2012;7:87–93. 35. Szychta M, Dadalski M, Landowski P, et al. Induction therapy with infliximab in children with moderate to severe ulcerative colitis. J Crohns Colitis 2013;7:S200.

18. Siegel CA. Shared decision making in inflammatory bowel disease: helping patients understand the tradeoffs between treatment options. Gut 2012;61:459–465.

36. Colletti R, Cucchiara S, Dubinsky M, et al. Malignancies in children receiving infliximab and other inflammatory bowel disease therapies: an inflammatory bowel disease multicenter, prospective, long-term registry of pediatric patients (DEVELOP) registry data. J Crohns Colitis 2013;7:S184–S185.

19. Veereman-Wauters G, de Ridder L, Veres G, et al. Risk of infection and prevention in pediatric patients with IBD: ESPGHAN IBD Porto Group commentary. J Pediatr Gastroenterol Nutr 2012;54:830–837.

37. Baldassano R, Colletti R, Cucchiara S, et al. Serious infections and associated risk factors in patients receiving infliximab and immunotherapies for children with inflammatory bowel disease: DEVELOP registry data. J Crohns Colitis 2013;7:S7–S8.

20. Siegel CA, Marden SM, Persing SM, et al. Risk of lymphoma associated with combination anti-tumor necrosis factor and immunomodulator therapy for the treatment of Crohn’s disease: a meta-analysis. Clin Gastroenterol Hepatol 2009;7:874–881.

38. Alvisi P, Barabino A, Cucchiara S, et al. Efficacy and safety of adalimumab (ADA) therapy in pediatric Crohn’s disease (CD) patients who failed infliximab (IFX): a multicenter experience of the Italian Society of Pediatric Gastroenterology Hepatology and Nutrition (SIGENP). J Crohns Colitis 2013;7:S219–S220.

21. Mariette X, Tubach F, Bagheri H, et al. Lymphoma in patients treated with anti-TNF: results of the 3-year prospective French RATIO registry. Ann Rheum Dis 2010;69:400–408. 22. Beukelman T, Xie F, Chen L, et al. Rates of hospitalized bacterial infection associated with juvenile idiopathic arthritis and its treatment. Arthritis Rheum 2012;64:2773–2780. 23. Lichtenstein GR, Rutgeerts P, Sandborn WJ, et al. A pooled analysis of infections, malignancy, and mortality in infliximaband immunomodulator-treated adult patients with inflammatory bowel disease. Am J Gastroenterol 2012;107:1051–1063. 24. SEER. Surveillance, Epidemiology, and End Results Database. Available at: http://seer.cancer.gov/. Accessed March 22, 2013. 25. Ashworth LA, Billett A, Mitchell P, et al. Lymphoma risk in children and young adults with inflammatory bowel disease: analysis of a large single-center cohort. Inflamm Bowel Dis 2012;18:838–843. 26. Ruemmele FM, Lachaux A, Cezard JP, et al. Efficacy of infliximab in pediatric Crohn’s disease: a randomized multicenter open-label trial comparing scheduled to on demand maintenance therapy. Inflamm Bowel Dis 2009;15:388–394. 27. Baldassano R, Braegger CP, Escher JC, et al. Infliximab (REMICADE) therapy in the treatment of pediatric Crohn’s disease. Am J Gastroenterol 2003;98:833–838.

39. Yokoyama Y, Fukunaga K, Miwa H, et al. Efficacy of infliximab for Japanese paediatric Crohn’s disease patients. Gastroenterology 2012;142:S376. 40. Rosh JR, Lerer T, Stephens MC, et al. Long-term outcomes after institution of adalimumab therapy in pediatric Crohn disease. Gastroenterology 2012;142:S36. 41. Pfefferkorn MD, Lerer T, Mack DR, et al. Assessment of durability of infliximab maintenance therapy in children with Crohn’s disease. Gastroenterology 2012;142:S37. 42. Kierkus J, Dadalski M, Szymanska S, et al. Maintenance therapy with infliximab for paediatric Crohn’s disease: impact on clinical remission and mucosal healing in Polish paediatric patients with severe Crohn’s disease. Przeglad Gastroenterologiczny 2012; 7:26–30. 43. Kierkus J, Dadalski M, Szymanska E, et al. The impact of infliximab induction therapy on mucosal healing and clinical remission in Polish pediatric patients with moderate-to-severe Crohn’s disease. Eur J Gastroenterol Hepatol 2012;24: 495–500. 44. Christenson K, Bass J, San Pablo W, et al. Retrospective review of infliximab use in patients less than six years of age. Inflamm Bowel Dis 2012;18:S79.

28. Gasparetto M, Corradin S, Vallortigara F, et al. Infliximab and pediatric stricturing Crohn’s disease: a possible alternative to surgery? Experience of seven cases. Acta Gastroenterol Belg 2012;75:58–60.

45. Assa A, Hartman C, Weiss B, et al. Long-term outcome of tumor necrosis factor alpha antagonist’s treatment in pediatric Crohn’s disease. J Crohns Colitis 2013;7:369–376.

29. Noe JD, Pfefferkorn M. Short-term response to adalimumab in childhood inflammatory bowel disease. Inflamm Bowel Dis 2008;14:1683–1687.

46. Absah I, Faubion WA Jr. Concomitant therapy with methotrexate and anti-TNF-alpha in pediatric patients with refractory Crohn’s colitis: a case series. Inflamm Bowel Dis 2012;18:1488–1492.

30. Mamula P, Markowitz JE, Brown KA, et al. Infliximab as a novel therapy for pediatric ulcerative colitis. J Pediatr Gastroenterol Nutr 2002;34:307–311.

47. Wanty C, Stephenne X, Sokal E, et al. [Long-term outcome of infliximab therapy in pediatric Crohn disease]. Arch Pediatr 2011;18:863–869.

8

Dulai et al

Clinical Gastroenterology and Hepatology Vol.

-,

No.

-

response or were intolerant to infliximab. Gastroenterology 2006;130:A656.

48. Russell RK, Wilson ML, Loganathan S, et al. A British Society of Paediatric Gastroenterology, Hepatology and Nutrition survey of the effectiveness and safety of adalimumab in children with inflammatory bowel disease. Aliment Pharmacol Ther 2011; 33:946–953. 49. Kim MJ, Lee JS, Lee JH, et al. Infliximab therapy in children with Crohn’s disease: a one-year evaluation of efficacy comparing ‘top-down’ and ‘step-up’ strategies. Acta Paediatr 2011; 100:451–455.

67. de Ridder L, Escher JC, Bouquet J, et al. Infliximab therapy in 30 patients with refractory pediatric Crohn disease with and without fistulas in The Netherlands. J Pediatr Gastroenterol Nutr 2004; 39:46–52.

50. Kelsen J, Gupta K, Grossman A, et al. Infliximab therapy in pediatric patients 7 years of age and younger. Inflamm Bowel Dis 2011;17:S5.

68. Borrelli O, Bascietto C, Viola F, et al. Infliximab heals intestinal inflammatory lesions and restores growth in children with Crohn’s disease. Dig Liver Dis 2004;36:342–347.

51. Hyams J, Walters TD, Crandall W, et al. Safety and efficacy of maintenance infliximab therapy for moderate-to-severe Crohn’s disease in children: REACH open-label extension. Curr Med Res Opin 2011;27:651–662.

69. Stephens MC, Shepanski MA, Mamula P, et al. Safety and steroid-sparing experience using infliximab for Crohn’s disease at a pediatric inflammatory bowel disease center. Am J Gastroenterol 2003;98:104–111.

52. De Bie CI, Hummel TZ, Kindermann A, et al. The duration of effect of infliximab maintenance treatment in paediatric Crohn’s disease is limited. Aliment Pharmacol Ther 2011;33:243–250.

70. Lionetti P, Bronzini F, Salvestrini C, et al. Response to infliximab is related to disease duration in paediatric Crohn’s disease. Aliment Pharmacol Ther 2003;18:425–431.

53. Tiemi J, Komati S, Sdepanian VL. Effectiveness of infliximab in Brazilian children and adolescents with Crohn disease and ulcerative colitis according to clinical manifestations, activity indices of inflammatory bowel disease, and corticosteroid use. J Pediatr Gastroenterol Nutr 2010;50:628–633.

71. Cezard JP, 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 disease. J Pediatr Gastroenterol Nutr 2003;36:632–636.

54. De Greef E, Hoffman I, D’Haens G, et al. Safety and cost of infliximab for the treatment of Belgian pediatric patients with Crohn’s disease. Acta Gastroenterol Belg 2012;75:425–431. 55. Lee JS, Lee JH, Lee JH, et al. Efficacy of early treatment with infliximab in pediatric Crohn’s disease. World J Gastroenterol 2010;16:1776–1781. 56. Hyams JS, Lerer T, Griffiths A, et al. Outcome following infliximab therapy in children with ulcerative colitis. Am J Gastroenterol 2010;105:1430–1436. 57. Roche S, Ecochard E, Martinez-Vinson C, et al. Clinical serious adverse events of infliximab in pediatric inflammatory bowel disease: a long-term retrospective study. J Pediatr Gastroenterol Nutr 2009;48:E36–E37. 58. Duricova D, Pedersen N, Lenicek M, et al. Infliximab dependency in children with Crohn’s disease. Aliment Pharmacol Ther 2009;29:792–799. 59. Wynands J, Belbouab R, Candon S, et al. 12-month follow-up after successful infliximab therapy in pediatric Crohn disease. J Pediatr Gastroenterol Nutr 2008;46:293–298. 60. de Ridder L, Rings EH, Damen GM, et al. Infliximab dependency in pediatric Crohn’s disease: long-term follow-up of an unselected cohort. Inflamm Bowel Dis 2008;14:353–358. 61. Kolho KL, Ruuska T, Savilahti E. Severe adverse reactions to infliximab therapy are common in young children with inflammatory bowel disease. Acta Paediatr 2007;96:128–130. 62. Feldman TL, Youssef NN, Ruth I, et al. Infliximab as an induction agent versus ongoing maintenance therapy in mild-moderate pediatric Crohn’s disease. Gastroenterology 2007;132:A444. 63. Fanjiang G, Russell GH, Katz AJ. Short- and long-term response to and weaning from infliximab therapy in pediatric ulcerative colitis. J Pediatr Gastroenterol Nutr 2007;44: 312–317. 64. Afzal NA, Ozzard A, Keady S, et al. Infliximab delays but does not avoid the need for surgery in treatment-resistant pediatric Crohn’ disease. Dig Dis Sci 2007;52:3329–3333. 65. Deslandres C, Faure C, Dirks MH, et al. Open label experience with adalimumab in pediatric Crohn’s disease patients who lost

66. Lamireau T, Cezard JP, Dabadie A, et al. Efficacy and tolerance of infliximab in children and adolescents with Crohn’s disease. Inflamm Bowel Dis 2004;10:745–750.

72. Cucchiara S, Romeo E, Viola F, et al. Infliximab for pediatric ulcerative colitis: a retrospective Italian multicenter study. Dig Liver Dis 2008;40(Suppl 2):S260–S264. 73. Sant’Anna A, Gervais F, Deslandres C, et al. Outcome of infliximab therapy in pediatric Crohn’s disease: the first three years experience. Gastroenterology 2004;126:A458–A459. 74. 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;95:3189–3194. 75. Hyams JS, Markowitz J, Wyllie R. Use of infliximab in the treatment of Crohn’s disease in children and adolescents. J Pediatr 2000;137:192–196. 76. Chouliaras G, Panayiotou J, Dimakou C, et al. Biological agents in paediatric inflammatory bowel disease: a clinical observation study from Greece. Acta Gastroenterol Belg 2010;73:342–348. 77. McGinnis JK, Murray KF. Infliximab for ulcerative colitis in children and adolescents. J Clin Gastroenterol 2008;42:875–879. 78. Lee K, Binion DG, Kugathasan S. Immediate and long-term safety of infliximab in children with IBD. Gastroenterology 2005;128:A580. 79. Eidelwein AP, Cuffari C, Abadom V, et al. Infliximab efficacy in pediatric ulcerative colitis. Inflamm Bowel Dis 2005;11:213–218. 80. Russell GH, Katz AJ. Infliximab is effective in acute but not chronic childhood ulcerative colitis. J Pediatr Gastroenterol Nutr 2004;39:166–170. 81. Friesen CA, Calabro C, Christenson K, et al. Safety of infliximab treatment in pediatric patients with inflammatory bowel disease. J Pediatr Gastroenterol Nutr 2004;39:265–269. 82. Serrano MS, Schmidt-Sommerfeld E, Kilbaugh TJ, et al. Use of infliximab in pediatric patients with inflammatory bowel disease. Ann Pharmacother 2001;35:823–828. 83. Wyneski MJ, Green A, Kay M, et al. Safety and efficacy of adalimumab in pediatric patients with Crohn disease. J Pediatr Gastroenterol Nutr 2008;47:19–25. 84. Viola F, Civitelli F, Di Nardo G, et al. Efficacy of adalimumab in moderate-to-severe pediatric Crohn’s disease. Am J Gastroenterol 2009;104:2566–2571.

-

2014

85. Crombe V, Salleron J, Savoye G, et al. Long-term outcome of treatment with infliximab in pediatric-onset Crohn’s disease: a population-based study. Inflamm Bowel Dis 2011;17: 2144–2152. 86. Segarra Canton O, Infante Pina D, Tormo Carnice R. [Infliximab therapy for inflammatory bowel disease: seven years on]. An Pediatr (Barc) 2007;67:344–351. 87. Olbjorn C, Lyckander LG, Vain MH, et al. Early use of infliximab in treatment-naive pediatric Crohns disease. Gastroenterology 2011;140:S510. 88. Hyams JS, Lerer T, Griffiths A, et al. Long-term outcome of maintenance infliximab therapy in children with Crohn’s disease. Inflamm Bowel Dis 2009;15:816–822. 89. Lichtenstein GR, Feagan BG, Cohen RD, et al. Serious infections and mortality in association with therapies for Crohn’s disease: TREAT registry. Clin Gastroenterol Hepatol 2006;4:621–630. 90. Sorbara J, Mack DR, Lerer T, et al. 953 prolonged exposure to prednisone is decreasing in children with inflammatory bowel disease (IBD) during the last decade. Gastroenterology 2013; 144:S–173. 91. Beaugerie L, Brousse N, Bouvier AM, et al. Lymphoproliferative disorders in patients receiving thiopurines for inflammatory bowel disease: a prospective observational cohort study. Lancet 2009;374:1617–1625. 92. Afif W, Sandborn WJ, Faubion WA, et al. Risk factors for lymphoma in patients with inflammatory bowel disease: a casecontrol study. Inflamm Bowel Dis 2013;19:1384–1389. 93. Wolfe F, Michaud K. The effect of methotrexate and anti-tumor necrosis factor therapy on the risk of lymphoma in rheumatoid arthritis in 19,562 patients during 89,710 person-years of observation. Arthritis Rheum 2007;56:1433–1439.

Risks With Anti–TNF Therapy for Pediatric IBD

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94. Wolfe F, Michaud K. Lymphoma in rheumatoid arthritis: the effect of methotrexate and anti-tumor necrosis factor therapy in 18,572 patients. Arthritis Rheum 2004;50:1740–1751. 95. Kotlyar DS, Osterman MT, Diamond RH, et al. A systematic review of factors that contribute to hepatosplenic T-cell lymphoma in patients with inflammatory bowel disease. Clin Gastroenterol Hepatol 2011;9:36–41.e1. 96. Kotlyar DS, Blonski W, Diamond RH, et al. Hepatosplenic T-cell lymphoma in inflammatory bowel disease: a possible thiopurineinduced chromosomal abnormality. Am J Gastroenterol 2010; 105:2299–2301. 97. Lichtenstein GR, Feagan BG, Cohen RD, et al. Serious infection and mortality in patients with Crohn’s disease: more than 5 years of follow-up in the TREAT registry. Am J Gastroenterol 2012;107:1409–1422.

Reprint requests Address requests for reprints to: Corey A. Siegel, MD, MS, Inflammatory Bowel Disease Center, Dartmouth Hitchcock Medical Center, One Medical Center Drive, Lebanon, New Hampshire 03756. e-mail: [email protected]; fax: (603) 650-5225. Acknowledgments Marla Dubinsky and Corey Siegel contributed equally as senior authors. Conflicts of interest These authors disclose the following: Corey Siegel serves on the advisory board, as a consultant, and has received grant support from Abbvie, Janssen, and UCB, and is supported by grant 1R01HS021747-01 from the Agency for Healthcare Research and Quality; and Marla Dubinsky serves as a consultant to Abbvie, Janssen, UCB, and Takeda. The remaining authors disclose no conflicts.

Risks of serious infection or lymphoma with anti-tumor necrosis factor therapy for pediatric inflammatory bowel disease: a systematic review.

Many physicians hesitate to recommend anti-tumor necrosis factor (TNF) therapy for pediatric patients with inflammatory bowel disease (IBD) because of...
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