Microscopic/"Backwash" Ileitis and Its Association With Colonic Disease in New Onset Pediatric Ulcerative Colitis.

BACKGROUND: Microscopic ileitis and its association with pancolitis in adults with ulcerative colitis (UC) have been described. The incidence of ileitis and associations with colonic disease in pediatric UC have, however, not been thoroughly investigated. This study was undertaken to examine the prevalence of microscopic ileal inflammation at the time of initial diagnosis in a cohort of children with UC. METHODS: We reviewed colonoscopy and biopsy data at time of diagnosis from 105 children and young adults with treatment naïve UC; ileal and colonic mucosal biopsies were available on all patients. Ileal mucosal biopsies were examined for the presence and severity of ileal inflammation, and other histologic features. Concurrently obtained colonic mucosal biopsies were assessed to define the severity, distribution, and extent of disease; endoscopic and clinical follow-up data were reviewed. RESULTS: A total of 107 ileal mucosal biopsies and 693 corresponding colonic mucosal biopsies were examined. Seventeen of 105 patients (16%) were found to have ileal inflammation (mean age = 10.4 years, 59% girls), 14 (82%) of whom had histologic pancolitis. The presence of ileal inflammation was significantly associated with endoscopic pancolitis (P = 0.02). The association between histologic pancolitis, severity of active inflammation in the cecum, and ascending colon suggested a possible association with ileal inflammation (P = 0.06, 0.07, and 0.08 respectively), but did not reach statistical significance. CONCLUSION: Patients with new onset UC may have microscopic ileal inflammation at time of diagnosis, even if the terminal ileum appears macroscopically normal. The presence of endoscopic pancolitis is associated with the presence of histologic ileitis. In contrast to existing studies in adults, an association between the presence of ileitis and the histologic severity or the histologic extent of colitis was not observed. Children with microscopic ileitis in the context of UC do not need to be reclassified as "indeterminate colitis" or Crohn disease.

Antibodies to infliximab are associated with lower infliximab levels and increased likelihood of surgery in pediatric IBD.

BACKGROUND: Adult studies suggest antibodies to infliximab (ATI) correlate with loss of response in inflammatory bowel disease but pediatric data are limited. METHODS: We conducted a cross-sectional study of trough infliximab levels and ATI in 134 pediatric and young adult patients receiving infliximab. At the time serum was obtained demographics, disease phenotype, duration of infliximab therapy, use of combination therapy (methotrexate or 6-mercaptopurine with infliximab), and surgery were recorded. RESULTS: Assays were performed on 134 subjects currently receiving infliximab (85 male; mean age, 17.3 ± 4.3 years; 114 Crohn's disease and 20 ulcerative colitis). Infliximab use ranged from 12 days to 12 years: median 2.0 (interquartile range [1.1-4.3]) years. Twenty-seven of 134 (20%) patients had ATI ≥5 U/mL. Of patients with ATI ≥5 U/mL, 59% had infliximab levels <5 µg/mL, compared with 14% of patients with ATI <5 U/mL (P < 0.001). Ten (7%) patients (9 Crohn's disease, 1 ulcerative colitis) underwent bowel resections after beginning infliximab infusions. Sixty percent who underwent surgery had ATI ≥12 U/mL; in contrast, only 8% of patients who did not undergo surgery had ATI ≥12 U/mL (P = 0.01). At the time of serum sampling, 50 (37%) patients were receiving combination therapy, compared with 84 (63%) on infliximab alone. Combination therapy at the time of serum sampling did not correlate with either increase infliximab levels or lower ATI compared with infliximab monotherapy. However, prior immunomodulator use was associated with lower antibody levels (P = 0.007). CONCLUSIONS: ATI correlates with reduction in infliximab level and a higher risk of surgery in patients with inflammatory bowel disease.

Immunogenicity and tolerability to human papillomavirus-like particle vaccine in girls and young women with inflammatory bowel disease.

BACKGROUND: Female patients receiving immunosuppressive therapy may be at increased risk for human papillomavirus (HPV) infection and cervical neoplasia. METHODS: We administered the 3-dose HPV vaccine Gardasil to 37 females aged 9 to 26 years with inflammatory bowel disease (IBD) prescribed immunosuppressive therapy (prospective cohort). Geometric mean titers (GMT) in milli-Merck (mMu/mL) units were determined before dose 1 and 1 month after dose 3 by competitive Luminex immunoassay (cLIA) and qualitatively compared with healthy females of similar age from Merck's database. Side effects and adverse events were evaluated. Concurrently, in 15 similar patients with inflammatory bowel disease previously vaccinated by their primary care provider, we assessed antibody titers by competitive Luminex immunoassay and total immunoglobulin G LIA after dose 3 of vaccine (range, 0.5-27 months). RESULTS: Mean age of prospective patients was 15 years with 51% on anti-tumor necrosis factor therapy and 49% on immunomodulators: 33 of 37 completed all 3 doses. Seropositivity after dose 3 was 100% for types 6, 11 and 16 and 96% for type 18. Geometric mean titers for HPV-6, HPV-11, HPV-16 and HPV-18 was 1080, 1682, 3975 and 858, respectively and did not qualitatively differ from healthy females. No serious adverse events were attributable to the vaccine. In the previously vaccinated cohort, seropositivity was 100% for types 6, 11, and 16, and 40% for type 18 by competitive Luminex immunoassay (93% for HPV-18 by immunoglobulin G LIA). Titers decreased with time since dose 3. CONCLUSIONS: In this small study of patients with inflammatory bowel disease prescribed immunosuppressive therapy, Gardasil was immunogenic and there were no clinically significant vaccine-associated adverse events.

Lymphoma risk in children and young adults with inflammatory bowel disease: analysis of a large single-center cohort.

BACKGROUND: Prior studies suggest an increased risk of lymphoma in adults with inflammatory bowel disease (IBD). Cases of lymphoma have also been reported in children with IBD. However, the precise risk of lymphoma in relation to drug exposure has not been ascertained in children. METHODS: We conducted a single-center, retrospective study of 1560 children and young adults with IBD evaluated at Children's Hospital Boston between 1979 and 2008. Of this group, 186 patients were excluded due to incorrect diagnosis, one-time second-opinion visits, or missing hospital records. The remaining 1374 patients had charts reviewed to determine whether lymphoma developed while they were receiving their clinical care at our institution and the duration of exposure to various IBD medications. The rate of lymphoma was calculated in patient-years of exposure for each class of medications utilized in IBD. RESULTS: Of 1374 patients (741 male; age at diagnosis 12.1 ± 4.0 years; 791 Crohn's disease [CD], 535 ulcerative colitis [UC], 48 IBD unclassified), we identified two patients who developed lymphoma (one Hodgkin, one anaplastic large cell), in 6624 patient-years of follow-up (mean duration follow-up 4.8 years per patient). Both patients were males (ages 12 and 18 years at time of lymphoma onset) and were receiving thiopurines but had not yet received biologics at the time of their cancer diagnosis. They were both treated with chemotherapy and are alive without cancer 32+ and 76+ months since diagnosis. The absolute incidence rate of lymphoma for patients having received thiopurines was 4.5 per 10,000 patient-years compared to the expected rate of 0.58 per 10,000 patient-years, with a standardized incidence ratio (SIR) of 7.51 (95% confidence interval [CI] 0.74-41.98). CONCLUSIONS: The overall risk of lymphoma in children with IBD is low, with only two cases seen in our hospital over a 30-year period. The lymphoma risk (as estimated by SIR) in children receiving thiopurines is comparable to that reported in studies of adults. While there may be an increased risk of lymphoma in children treated with thiopurines, the risk did not reach statistical significance in this large cohort.

Immune response to influenza vaccine in children with inflammatory bowel disease.

OBJECTIVES: Patients with inflammatory bowel disease (IBD) frequently receive immunosuppressive therapy. The immune response in these patients to vaccines has not been well studied. We conducted a prospective, open label study to evaluate the serologic response to influenza vaccine in children with IBD. METHODS: Serum was obtained from 146 children and young adults with IBD (96 Crohn's disease, 47 ulcerative colitis, and 3 indeterminate colitis) for baseline influenza titer, immediately followed by immunization with trivalent (A/Solomon Islands/3/2006 (H1N1), A/Wisconsin/67/2005 (H3N2), and B/Malaysia/2506/2004 (B)) inactivated influenza vaccine. Patients returned for repeat titers 3-9 weeks later. Seroprotection against each influenza strain was defined as hemagglutination inhibition titer > or = 40. Patients were categorized as nonimmunosuppressed (NIS; aminosalicylates only, antibiotics only, or no therapy) or immunosuppressed (IS; any immunosuppressive agent). IS patients were further subcategorized as: (i) tacrolimus, (ii) tumor necrosis factor-alpha (TNF-alpha) inhibitor, (3) immunomodulator, and (4) corticosteroids only. RESULTS: More patients were seroprotected against strains A/H1N1 and A/H3N2 than B strain (P<0.02), regardless of immunosuppression status. The proportion of seroprotected patients and geometric mean titers at post-vaccination were similar between NIS and IS groups for all three strains. Subanalysis of patients not seroprotected at baseline showed that those receiving anti-TNF therapy were less likely to be seroprotected against strain B (14%) compared to patients in the NIS group (39%, P=0.025). There were no serious vaccine-associated adverse events. CONCLUSIONS: Influenza vaccination produces a high prevalence of seroprotection in IBD patients, particularly against A strains. The vaccine is well tolerated. Routine influenza vaccination in IBD patients is recommended, irrespective of whether patients receive immunosuppressive medications.