The Impact of Vitamin D on Response to Anti-tumor Necrosis Factor-α Therapy in Children With Inflammatory Bowel Disease.

OBJECTIVES: Experimental studies have shown that vitamin D has an immunomodulatory effect on the innate and adaptive immune systems. Associations between vitamin D deficiency and development or progression of inflammatory bowel diseases (IBDs) are reported, but a cause-and-effect relationship between pretreatment 25 hydroxyvitamin D [25(OH)D] levels and response to anti-tumor necrosis factor-α (anti-TNF) therapy is not established. METHODS: This retrospective study evaluated pediatric IBD patients who had 25(OH)D levels drawn within 3 months of initiating infliximab and/or adalimumab treatment. Demographic features, Paris classification, baseline 25(OH)D levels, disease activity, and laboratory results before and after 3 months of anti-TNF therapy were collected. The interaction between vitamin D insufficiency at induction and lack of response to anti-TNF therapy at 3 months was determined. RESULTS: Of the 383 patients, 76 met inclusion criteria. Sixty-five patients (85.5%) had Crohn disease (CD) and 11 (14.5%) had ulcerative colitis. Seven patients had 25(OH)D levels obtained during both infliximab and adalimumab induction; hence 83 subjects were evaluated (infliximab: 70 patients, adalimumab: 13 patients). 25(OH)D <30 ng/mL was found in 55 of 83 (66.3%) subjects. There were no differences in gender, IBD type, disease activity scores between vitamin D-sufficient and vitamin D-insufficient groups. In CD, proximal gastrointestinal tract inflammation was associated with vitamin D insufficiency (P = 0.019), but other Paris classification parameters and laboratory results were similar in 2 groups. Early termination of anti-TNF therapy was significantly higher in patients who had vitamin D insufficiency (14.5% vs 0%, P = 0.034). CONCLUSIONS: Vitamin D insufficiency before anti-TNF treatment may result in poor response to induction therapy.

Additional Intestinal Mucosal Biopsy Sampling for Research Is Safe During Pediatric Endoscopic Procedures.

Advancing the understanding of inflammatory bowel disease (IBD) pathogenesis has been facilitated by mechanistic studies that require human intestinal tissue. Enrolling pediatric subjects into these studies improves our knowledge of IBD in this underserved population. Given the additional research protections granted to children, institutional review boards (IRBs) must weigh the benefit of obtaining research biopsies against perceived risks. Although obtaining clinical biopsies from children is generally considered safe, there are only limited data on the safety of obtaining research biopsies in children.1-6.

Performance of Surveillance MR Enterography (MRE) in Asymptomatic Children and Adolescents With Crohn's Disease.

BACKGROUND: MR enterography (MRE) is the primary modality for evaluating small bowel disease in pediatric Crohn's patients. Standard clinical practice includes imaging patients at diagnosis and during symptomatic recurrence. The role for MRE in surveillance of asymptomatic Crohn's patients has not yet been established. PURPOSE: To determine whether MRE imaging features are associated with clinical recurrence. STUDY TYPE: Retrospective. POPULATIONS: Pediatric Crohn's patients who underwent MRE while asymptomatic, defined by pediatric gastroenterologists using a physician global assessment; 35 MREs were identified. FIELD STRENGTH/SEQUENCE: 1.5T including T2 -weighted single-shot fast spin echo, balanced steady-state free precession, diffusion-weighted, and contrast-enhanced multiphase T1 -weighted gradient recalled echo sequences. ASSESSMENT: MREs were reviewed by three radiologists independently for mural thickening, T2 -weighted hyperintensity, diffusion restriction, hyperenhancement, vasa recta engorgement, and overall assessment of disease activity. Two pediatric gastroenterologists reviewed patient medical records for 6 months following MRE to evaluate for recurrence, defined as Crohn's-related treatment escalation, surgery, or hospitalization. STATISTICAL TESTS: Fisher's exact test, Wald chi-square test, and model selection by Akaike information criterion minimization were used to assess statistical significance of MRE imaging features. RESULTS: Of 35 MREs identified, seven cases demonstrated clinical recurrence at 6 months (20%); 28 cases remained in remission (80%). Imaging features of active disease were present in 86% of patients with recurrence compared to 29% of patients in remission (P = 0.01). Wall thickening, T2 -weighted hyperintensity, hyperenhancement, and diffusion restriction were significantly associated with recurrence. Multivariate regression analysis determined diffusion restriction to be the best predictor of recurrence within 6 months (P = 0.001, area under the curve 0.786). DATA CONCLUSION: MRE performed on young asymptomatic Crohn's patients can identify patients who have a high probability of developing clinical recurrence in a 6-month period, indicating a potential role for surveillance imaging to assess for subclinical active disease. LEVEL OF EVIDENCE: 3 Technical Efficacy Stage 5 J. Magn. Reson. Imaging 2019;50:1955-1963.

MRI predictors of treatment response for perianal fistulizing Crohn disease in children and young adults.

BACKGROUND: Magnetic resonance imaging (MRI) is considered the imaging standard for diagnosis and characterization of perianal complications associated with Crohn disease in children and adults. OBJECTIVE: To define MRI criteria that could act as potential predictors of treatment response in fistulizing Crohn disease in children, in order to guide more informed study interpretation. MATERIALS AND METHODS: We performed a retrospective database query to identify all children and young adults with Crohn disease who underwent serial MRI studies for assessment of perianal symptoms between 2003 and 2010. We examined imaging features of perianal disease including fistula number, type and length, presence and size of associated abscess, and disease response/progression on follow-up MRI. We reviewed imaging studies and electronic medical records. Statistical analysis, including logistic regression, was performed to associate MR imaging features with treatment response and disease progression. RESULTS: We included 36 patients (22 male, 14 female; age range 8-21 years). Of these, 32 had a second MRI exam and 4 had clinical evidence of complete response, obviating the need for repeat imaging. Of the parameters analyzed, presence of abscess, type of fistula according to the Parks classification, and multiplicity were not predictors of treatment outcome. Maximum length of the dominant fistula and aggregate fistula length in the case of multiple fistulae were the best predictors of treatment outcome. Maximum fistula length <2.5 cm was a predictor of treatment response, while aggregate fistula length ≥2.5 cm was a predictor of disease progression. CONCLUSION: Perianal fistula length is an important imaging feature to assess on MRI of fistulizing Crohn disease.

Prospective evaluation of MR enterography as the primary imaging modality for pediatric Crohn disease assessment.

OBJECTIVE: The objectives of this study were prospective evaluation of MR enterographic accuracy for detecting Crohn disease imaging features in pediatric patients, compared with a CT reference standard, as well as determination of MR enterographic accuracy for detecting active bowel inflammation and fibrosis using a histologic reference standard. SUBJECTS AND METHODS: The study group for this blinded prospective study included 21 pediatric subjects with known Crohn disease scheduled for clinical CT and histologic bowel sampling for symptomatic exacerbation. All subjects and their parents gave informed consent to also undergo MR enterography. CT and MR enterography examinations were independently reviewed by two radiologists and were scored for Crohn disease features. All bowel histology specimens were reviewed by a single pathologist for the presence of active mucosal inflammation and mural fibrosis, followed by correlation of imaging and histologic findings. RESULTS: All 21 subjects underwent MR enterography and histologic sampling, 18 of whom also underwent CT. MR enterography had high sensitivity for detecting Crohn disease imaging features (e.g., bowel wall thickening, mesenteric inflammation, lymphadenopathy, fistula, and abscess) compared with CT, with individual sensitivity values ranging from 85.1% to 100%. Of a total of 53 abnormal bowel segments with correlation of MRI and histologic findings, MR enterography showed 86.7% accuracy (90.0% sensitivity and 82.6% specificity) for detecting active inflammation (p < 0.001). The accuracy of MR enterography for detecting mural fibrosis overall was 64.9%, compared with histology, but increased to 83.3% (p < 0.05) for detecting fibrosis without superimposed active inflammation. CONCLUSION: MR enterography can substitute for CT as the first-line imaging modality in pediatric patients with Crohn disease, on the basis of its ability to detect intestinal pathologic abnormalities in both small and large bowel as well as extraintestinal disease manifestations. Additionally, MR enterography provides an accurate noninvasive assessment of Crohn disease activity and mural fibrosis and can aid in formulating treatment strategies for symptomatic patients and assessing therapy response.

Psyche Meets the Gatekeepers: Creating a More Humane Culture for Women in Medicine.

In the Greek myth of Psyche and Eros, Psyche must fulfill four seemingly impossible tasks to achieve full consciousness before she can be reunited with her bridegroom, Eros. From early childhood, girls and women can encounter gender stereotyping, sexual harassment and assault, and other gender-related challenges. Although both men and women can face mistreatment in medical school, female students experience sexual harassment and sexual assault at higher rates than male students. In medical training and career advancement, women often face additional obstacles unrelated to the formal education of physicians, such as salary and promotional disparities, and lack of mentorship, sponsorship, or role models. The suicide rate for male physicians is nearly 1.5 times higher than the general population; for female physicians, it is more than twice as high. Parenthood can pose additional challenges for mothers and fathers early in their academic careers, and women are vastly underrepresented as they try to move past the "gatekeepers" into leadership roles. Using the framework of the Psyche and Eros myth to examine the trajectory of a female physician's career, this article provides insights into these challenges, as well as strategies to address some of these inequities, such as programs to support female promotion and leadership, expanded mentorship and mentor models, sponsorship opportunities, leadership accountability, implicit bias training, and others. The authors call for the participation of both men and women as essential in ventures to create a more humane environment for the training and practice of medicine.

Improving Clinical Remission Rates in Pediatric Inflammatory Bowel Disease with Previsit Planning.

Inflammatory Bowel Disease (IBD) is a chronic autoimmune inflammatory disease of the intestine which can lead to malnutrition, poor quality of life, and colon cancer.(1-4) Although there is no cure for the disease, clinical remission is the primary goal.(5) The Center for Inflammatory Bowel Disease at MassGeneral Hospital for Children (MGHfC) adopted a Previsit Planning (PVP) model to identify and discuss symptomatic patients prior to their appointments to identify specific issues that impact disease management.(6-8) The Registry from ImproveCareNow (ICN), the international Quality Improvement Collaborative for the management of Crohn's Disease and Ulcerative Colitis in pediatric and adolescent patients, was used to capture information from each ambulatory visit and hospitalization. Using the Model for Improvement framework, the team began a weekly review and made care recommendations of patients with active disease who were cared for by one physician. Interventions were modified over multiple Plan-Do-Study-Act (PDSA) improvement cycles to increase the number of providers and to include patients with mild or moderate disease activity.(9) Feedback from the providers regarding this process was elicited via a REDCap survey and the clinical remission rate was tracked using the ICN Registry. The clinical remission rate for the Center's patients increased from 77% (n=597) in September 2014 to 83% (n=585) in August 2015 and has been maintained. 78% of responding providers indicated that they found the PVP recommendations helpful "all of the time". One hundred percent who responded to the survey said that they have used at least one recommendation provided to them. PVP for management of a chronic disease in pediatrics is feasible, even in a high volume practice. This process at MGHfC has resulted in the improvement of clinical remission rate. PDSA cycles were used to document successes and failures to help guide the work. Ongoing expansion of this PVP practice to all providers continues with the anticipation of including input from patients and their families, as well.

Effectiveness of anti-TNFα for Crohn disease: research in a pediatric learning health system.

OBJECTIVES: ImproveCareNow (ICN) is the largest pediatric learning health system in the nation and started as a quality improvement collaborative. To test the feasibility and validity of using ICN data for clinical research, we evaluated the effectiveness of anti-tumor necrosis factor-α (anti-TNFα) agents in the management of pediatric Crohn disease (CD). METHODS: Data were collected in 35 pediatric gastroenterology practices (April 2007 to March 2012) and analyzed as a sequence of nonrandomized trials. Patients who had moderate to severe CD were classified as initiators or non-initiators of anti-TNFα therapy. Among 4130 patients who had pediatric CD, 603 were new users and 1211 were receiving anti-TNFα therapy on entry into ICN. RESULTS: During a 26-week follow-up period, rate ratios obtained from Cox proportional hazards models, adjusting for patient and disease characteristics and concurrent medications, were 1.53 (95% confidence interval [CI], 1.20-1.96) for clinical remission and 1.74 (95% CI, 1.33-2.29) for corticosteroid-free remission. The rate ratio for corticosteroid-free remission was comparable to the estimate produced by the adult SONIC study, which was a randomized controlled trial on the efficacy of anti-TNFα therapy. The number needed to treat was 5.2 (95% CI, 3.4-11.1) for clinical remission and 5.0 (95% CI, 3.4-10.0) for corticosteroid-free remission. CONCLUSIONS: In routine pediatric gastroenterology practice settings, anti-TNFα therapy was effective at achieving clinical and corticosteroid-free remission for patients who had Crohn disease. Using data from the ICN learning health system for the purpose of observational research is feasible and produces valuable new knowledge.

Shortcomings of the inflammatory bowel disease Serology 7 panel.

OBJECTIVE: The goal was to compare the predictive values of the Prometheus Inflammatory Bowel Disease (IBD) Serology 7 (IBD7) panel (Prometheus Laboratories, San Diego, CA) with the predictive values of routine blood tests in a population of children referred for initial evaluation of suspected IBD. METHODS: Medical records of pediatric patients referred for evaluation of IBD for whom IBD7 testing was performed at Prometheus Laboratories between January 2006 and November 2008 were reviewed. Patients underwent diagnosis by pediatric gastroenterologists on the basis of clinical, radiologic, endoscopic, and pathologic evaluations. RESULTS: A total of 394 records were identified. We excluded 90 records on the basis of age of >21 years, previous diagnosis of IBD, or unclear diagnosis. The prevalence of IBD in this cohort was 38%. The sensitivity, specificity, positive predictive value, negative predictive value, and kappa value for the serological panel were 67%, 76%, 63%, 79%, and 42%, respectively, compared with values for a combination of 3 abnormal routine laboratory test results of 72%, 94%, 85%, 79%, and 47%. The antiflagellin antibody assay, the newest assay added to the panel, had sensitivity of 50% and specificity of 53%. Repeat serological testing failed to produce consistent results for 4 of 10 patients. CONCLUSION: Despite its recent inclusion of the antiflagellin assay, the IBD7 panel has lower predictive values than routine laboratory tests in pediatric screening for IBD.

Low-dose CT colonography in children: initial experience, technical feasibility, and utility.

BACKGROUND: CT colonography (CTC) is utilized as a diagnostic tool in the detection of colon polyps and early colorectal cancer in adults. Large studies in the literature, although focused on adult populations, have shown CTC to be a safe, accurate, non-invasive technique. OBJECTIVE: We evaluated the technical feasibility of CTC in children using a low-dose technique. MATERIALS AND METHODS: From November 2001 to April 2004 we evaluated eight patients (3-17 years) with non-contrast CTC. Seven of the patients had CTC, followed by standard colonoscopy (SC) the same day; in one patient, CTC followed a failed SC. CTC results were compared to results of SC. The estimated effective dose from each CTC was calculated and compared to that of standard barium enema. RESULTS: CTC results were consistent with those of SC. Sensitivity for polyps 5-10 mm was 100%, and sensitivity for polyps 10 mm and larger was 66.7%. The estimated mean effective dose was 2.17 mSv for CTC, compared to the 5-6 mSv for a standard air-contrast barium enema in a small child. CONCLUSION: Our initial experience shows CTC in children is well-tolerated, safe, and useful. The procedure can be performed successfully with a low radiation dose, and preliminary results compare well with SC.