"Deficiency in ELF4, X-Linked": a Monogenic Disease Entity Resembling Behçet's Syndrome and Inflammatory Bowel Disease.

Defining monogenic drivers of autoinflammatory syndromes elucidates mechanisms of disease in patients with these inborn errors of immunity and can facilitate targeted therapeutic interventions. Here, we describe a cohort of patients with a Behçet's- and inflammatory bowel disease (IBD)-like disorder termed "deficiency in ELF4, X-linked" (DEX) affecting males with loss-of-function variants in the ELF4 transcription factor gene located on the X chromosome. An international cohort of fourteen DEX patients was assessed to identify unifying clinical manifestations and diagnostic criteria as well as collate findings informing therapeutic responses. DEX patients exhibit a heterogeneous clinical phenotype including weight loss, oral and gastrointestinal aphthous ulcers, fevers, skin inflammation, gastrointestinal symptoms, arthritis, arthralgia, and myalgia, with findings of increased inflammatory markers, anemia, neutrophilic leukocytosis, thrombocytosis, intermittently low natural killer and class-switched memory B cells, and increased inflammatory cytokines in the serum. Patients have been predominantly treated with anti-inflammatory agents, with the majority of DEX patients treated with biologics targeting TNFα.

No Increased Risk of Taking Additional Intestinal Mucosal Research Biopsies From the Duodenum During Pediatric Endoscopy.

Studies involving human intestinal tissue are essential for advancing the field of celiac disease (CeD), as diagnosis requires duodenal biopsies. Performing studies in children helps to better understand CeD in this important subpopulation. This study aims to determine the risk in obtaining duodenal research biopsies during pediatric endoscopy. In this retrospective chart review from 2016 to 2022 of 1180 research subjects and controls, there were 18 procedure-related adverse events within 48 hours. Most adverse events were for symptoms of pain and fever. There was no increased risk of adverse events if additional duodenal research biopsies were taken during pediatric endoscopy.

Microgranulomas at Diagnosis Are Associated With Need for Antitumor Necrosis Factor Escalation in Pediatric Crohn Disease.

INTRODUCTION: Granulomas are a pathologic hallmark of Crohn disease (CD) although they are found in only a subset of patients. Well-formed granulomas are associated with an aggressive phenotype although it is unknown if microgranulomas confer a similar phenotype. This study sought to define the incidence of microgranulomas in pediatric CD and compare the clinical course with cases with granulomas and those without granulomatous inflammation. METHODS: We performed a single-center, retrospective study of pediatric CD patients who had at least 3 years of follow-up. initial diagnostic biopsies were systematically re-examined by a gastrointestinal pathologist. A priori definitions of granuloma (10+ histiocytes) and microgranuloma (4-9 histiocytes) were used. Disease outcomes of hospitalization, development of complicated disease behavior, perianal disease, and the use of anti-tumor necrosis factor (anti-TNF) therapy were assessed by Kaplan-Meier survival plots. RESULTS: This study included 138 subjects with an average follow-up of 4.6 years. Granulomas were seen in 38 of 138 subjects (27.5%) and an additional 38 subjects (27.5%) had at least 1 microgranuloma (in the absence of granulomas). Escalation to anti-TNF therapy was higher in CD with granulomas (P  = 0.001) and microgranulomas (P  = 0.0001) compared with those without granulomatous inflammation. CONCLUSIONS: A significant subset of pediatric CD patients have microgranulomas (in the absence of well-defined granulomas). Children with CD who have microgranulomas are escalated to anti-TNF therapy more frequently than those without granulomatous inflammation (and at a similar rate to those with granulomas). Pathologists should have a low threshold to report microgranulomas as they may help to predict disease behavior.

Adolescents With Inflammatory Bowel Disease Have Decreased Rates of Health Maintenance Visits.

INTRODUCTION: Inflammatory bowel disease (IBD) commonly presents during adolescence and may affect health care utilization. This study aimed to assess rates of health maintenance examinations (HMEs) in adolescents with IBD with their primary care physicians (PCPs). METHODS: This is a single center, case-control study of adolescents with IBD who received their IBD care and primary care within the same healthcare system. Adolescents diagnosed with IBD between 13 and 17 years of age were matched 1:1 by age, gender, race/ethnicity, and insurance status to healthy controls. Patient demographics, IBD characteristics, and health outcomes were extracted from the medical record. HME rate was defined as having one HME with a PCP during a 12-month period. RESULTS: This study included 150 IBD-control matched pairs. HME rates were similar at baseline between cases and controls (83% vs 85%, P = 0.53) but approached significance in year 1 post-diagnosis (77% vs 85%, P = 0.056). In year 2 post-diagnosis, IBD patients had less frequent HME (62% vs 74%, P = 0.0486). Disease severity did not affect HME rates. IBD patients from under-represented minority groups had lower rates than matched controls (46.2% vs 91.7%, P = 0.03). Meningococcal and human papilloma vaccination rates were lower in cases versus controls (79% vs 94%, P = 0.0005 and 60% vs 84%, P < 0.0001). CONCLUSION: Adolescents with IBD have less frequent HME and lower rates of certain vaccinations than their peers. Those from underrepresented minority groups are at particular risk. Given the important issues addressed at HMEs, gastroenterologists should recommend that adolescents with IBD have ongoing PCP engagement to optimize health outcomes.

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.

Pig endothelial protein C receptor is functionally compatible with the human protein C pathway.

BACKGROUND: Endothelial protein C receptor (EPCR) plays an anticoagulant and anti-inflammatory role by promoting the activation of protein C by thrombin bound to thrombomodulin (TBM). Incompatibility between pig TBM and human/primate thrombin is thought to contribute to dysregulated coagulation in pig-to-primate organ xenografts, and expression of human TBM (hTBM) in pigs has shown benefit in preclinical models. However, it is not known whether there are incompatibilities-or molecular barriers-between endogenous pig EPCR (pEPCR) and transgenically expressed human TBM. AIM: To clone and express pEPCR, and determine its function in the human protein C pathway in vitro. METHODS: Pig endothelial protein C receptor cDNA was generated from pig lung RNA by RT-PCR. Primate COS-7 transfectants expressing various combinations of human and pig TBM and EPCR were incubated with human thrombin and human protein C, and tested for TBM cofactor activity. RESULTS: The predicted protein sequence of pEPCR shared 72.3% amino acid sequence identity with hEPCR, and residues critical for protein C binding were conserved. COS-7 cells transfected with hEPCR, pEPCR or vector showed minimal TBM cofactor activity (0.13 ± 0.04, 0.13 ± 0.02 and 0.14 ± 0.06 U, respectively). The cofactor activity of hTBM-transfected cells (1.18 ± 0.29 U) was 8-fold higher than vector-transfected cells (P = .004) and further increased 4-fold and 3-fold by co-transfection with hEPCR (5.01 ± 1.12 U, P = .004) or pEPCR (3.73 ± 0.65 U, P = .003), respectively. CONCLUSIONS: Our data show that pEPCR is largely compatible with the human TBM/thrombin complex, when expressed on COS-7 cells in vitro, promoting the activation of human protein C. These findings suggest that endogenous pEPCR will enhance the activity of transgenic hTBM in the xenograft setting.

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.

Isolated Internal Carotid Artery Thrombus and Cerebral Infarction in a Patient with Necrotizing Pancreatitis: Case Report.

Isolated internal carotid artery (ICA) thrombus in the absence of underlying atherosclerotic disease is a rare entity. We report a case of a patient presenting with right arm weakness, slurred speech, and altered mental status in the setting of acute on chronic pancreatitis. The patient was found to have scattered left cerebral hemisphere cortical infarctions, and catheter angiography confirmed the presence of intraluminal left ICA thrombus, with no evidence of atherosclerotic disease in the cervical or intracranial vasculature. Further workup also demonstrated the presence of anemia of chronic disease. The patient was initiated on anticoagulation, and follow-up imaging demonstrated a complete resolution of the left ICA thrombus. In the reported case, coagulopathy in the setting of acute on chronic pancreatitis was presumably the primary etiology. Anemia of chronic disease, related to a proinflammatory state, may also play a contributory role.

Exome sequencing analysis reveals variants in primary immunodeficiency genes in patients with very early onset inflammatory bowel disease.

BACKGROUND & AIMS: Very early onset inflammatory bowel disease (VEO-IBD), IBD diagnosed at 5 years of age or younger, frequently presents with a different and more severe phenotype than older-onset IBD. We investigated whether patients with VEO-IBD carry rare or novel variants in genes associated with immunodeficiencies that might contribute to disease development. METHODS: Patients with VEO-IBD and parents (when available) were recruited from the Children's Hospital of Philadelphia from March 2013 through July 2014. We analyzed DNA from 125 patients with VEO-IBD (age, 3 wk to 4 y) and 19 parents, 4 of whom also had IBD. Exome capture was performed by Agilent SureSelect V4, and sequencing was performed using the Illumina HiSeq platform. Alignment to human genome GRCh37 was achieved followed by postprocessing and variant calling. After functional annotation, candidate variants were analyzed for change in protein function, minor allele frequency less than 0.1%, and scaled combined annotation-dependent depletion scores of 10 or less. We focused on genes associated with primary immunodeficiencies and related pathways. An additional 210 exome samples from patients with pediatric IBD (n = 45) or adult-onset Crohn's disease (n = 20) and healthy individuals (controls, n = 145) were obtained from the University of Kiel, Germany, and used as control groups. RESULTS: Four hundred genes and regions associated with primary immunodeficiency, covering approximately 6500 coding exons totaling more than 1 Mbp of coding sequence, were selected from the whole-exome data. Our analysis showed novel and rare variants within these genes that could contribute to the development of VEO-IBD, including rare heterozygous missense variants in IL10RA and previously unidentified variants in MSH5 and CD19. CONCLUSIONS: In an exome sequence analysis of patients with VEO-IBD and their parents, we identified variants in genes that regulate B- and T-cell functions and could contribute to pathogenesis. Our analysis could lead to the identification of previously unidentified IBD-associated variants.

MR Enterographic Findings as Biomarkers of Mucosal Healing in Young Patients With Crohn Disease.

OBJECTIVE: The purpose of this study was to investigate the MR enterographic findings that best correlate with mucosal healing assessed with ileocolonoscopy. MATERIALS AND METHODS: Patients with Crohn disease who underwent two ileocolonoscopic examinations and also underwent MR enterography close in time to the second endoscopic examination were included in a retrospective study. Two pediatric gastroenterologists blinded to the imaging findings reviewed the endoscopic examinations to assess for mucosal healing, defined as resolution of inflammation within a bowel segment at subsequent ileocolonoscopy. Two radiologists blinded to endoscopic and clinical data interpreted the MR enterographic images. Sensitivity, specificity, and accuracy for mucosal healing were calculated for several imaging features. RESULTS: A total of 30 patients (15 female patients, 15 male patients; age range, 8-24 years; mean, 17.2 ± 3.2 years) with pediatric-onset Crohn disease were examined. The average time between MR enterography and the second ileocolonoscopic examination was 12.7 ± 7.9 days. A total of 202 bowel segments from the terminal ileum to rectum were evaluated in the 60 ileocolonoscopic examinations. Forty-four bowel segments exhibited mucosal healing, and 37 segments exhibited persistent inflammation. At imaging, the MR index of activity score in mucosal healing segments was 6.6 ± 3.4, compared with 13.7 ± 9.7 in segments without mucosal healing (p = 0.0001). The average bowel wall thickness in healing segments was 2.7 ± 0.9 mm compared with 4.7 ± 3.1 mm in persistently inflamed segments (p = 0.0004). An MR index of activity score less than 8 had the highest accuracy for mucosal healing (accuracy, 74%; sensitivity, 84%; specificity, 62%; p < 0.0001). Mucosal hyperenhancement (72%, 98%, 41%), mesenteric hypervascularity (72%, 98%, 41%), bowel wall edema (72%, 93%, 46%), and bowel wall thickness less than 4 mm (72%, 84%, 57%) were also strongly associated with mucosal healing (p < 0.0003). CONCLUSION: In this study MR enterography was accurate for assessing mucosal healing, an important therapeutic endpoint in pediatric patients with Crohn disease.

Utility of Screening for Cerebral Vasospasm Using Digital Subtraction Angiography.

BACKGROUND AND PURPOSE: Cerebral arterial vasospasm (CVS) is a common complication of aneurysmal subarachnoid hemorrhage strongly associated with neurological deterioration and delayed cerebral ischemia (DCI). The utility of screening for CVS as a surrogate for early detection of DCI, especially in patients without clinical signs of DCI, remains uncertain. METHODS: We performed a retrospective analysis of 116 aneurysmal subarachnoid hemorrhage patients who underwent screening digital subtraction angiography to determine the association of significant CVS and subsequent development of DCI. Patients were stratified into 3 groups: (1) no symptoms of DCI before screening, (2) ≥1 episodes of suspected DCI symptoms before screening, and (3) unable to detect symptoms because of poor examination. RESULTS: Patients asymptomatic before screening had significantly lower rates of CVS (18%) compared with those with transient symptoms of DCI (60%; P<0.0001). None of the 79 asymptomatic patients developed DCI after screening, regardless of digital subtraction angiography findings, compared with 56% of those with symptoms (P<0.0001). Presence of CVS was significantly associated with DCI in those with transient symptoms and in those whose examinations did not permit clear assessment (odds ratio 16.0, 95% confidence interval 2.2-118.3, P=0.003). CONCLUSIONS: Patients asymptomatic before screening have low rates of CVS and seem to be at negligible risk of developing DCI. Routine screening of asymptomatic patients seems to have little utility. Screening may still be considered in patients with possible symptoms of DCI or those with examinations too poor to clinically detect symptoms because finding CVS may be useful for risk stratification and guiding management.

Amyloid-ß efflux from the central nervous system into the plasma.

OBJECTIVE: The aim of this study was to measure the flux of amyloid-ß (Aß) across the human cerebral capillary bed to determine whether transport into the blood is a significant mechanism of clearance for Aß produced in the central nervous system (CNS). METHODS: Time-matched blood samples were simultaneously collected from a cerebral vein (including the sigmoid sinus, inferior petrosal sinus, and the internal jugular vein), femoral vein, and radial artery of patients undergoing inferior petrosal sinus sampling. For each plasma sample, Aß concentration was assessed by 3 assays, and the venous to arterial Aß concentration ratios were determined. RESULTS: Aß concentration was increased by ∼7.5% in venous blood leaving the CNS capillary bed compared to arterial blood, indicating efflux from the CNS into the peripheral blood (p < 0.0001). There was no difference in peripheral venous Aß concentration compared to arterial blood concentration. INTERPRETATION: Our results are consistent with clearance of CNS-derived Aß into the venous blood supply with no increase from a peripheral capillary bed. Modeling these results suggests that direct transport of Aß across the blood-brain barrier accounts for ∼25% of Aß clearance, and reabsorption of cerebrospinal fluid Aß accounts for ∼25% of the total CNS Aß clearance in humans. Ann Neurol 2014;76:837-844.

Occult Blood and Perianal Examination: Value Added in Pediatric Inflammatory Bowel Disease Screening.

OBJECTIVES: Pediatric inflammatory bowel disease (IBD) often presents insidiously and standard blood tests are normal in 20% of patients. We hypothesize that fecal occult blood testing (FOBT) and the perianal examination in addition to blood tests provide important information during the screening process for IBD. The aim of the present study was to measure the diagnostic value of adding FOBT and perianal examination to standard screening laboratories in evaluating children and adolescents for IBD. METHODS: The medical records of consecutive patients undergoing ileocolonoscopy for IBD were reviewed. Laboratory test results, FOBT, and perianal examination before the decision to perform the ileocolonoscopy were recorded. Standard limits of laboratory tests were used. Multivariate logistic regression was performed on a discovery cohort and applied to an independent validation cohort. RESULTS: The discovery cohort included 335 patients (85 IBD and 250 non-IBD). A total of 61.2% had FOBT and perianal examination performed before the decision to perform the ileocolonoscopy. A total of 119 patients had complete blood testing, FOBT, and perianal examination available for full analysis. The sensitivity of the laboratory testing was 80.5% for IBD, and the sensitivity of FOBT with perianal examination was 66.9%. The combined sensitivity of laboratory testing and FOBT with perianal examination was, however, 97.6%. The most predictive model included C-reactive protein, platelet counts, and FOBT with perianal examination and was superior to the laboratory value-only model (P < 0.001) that was validated in a separate cohort. CONCLUSIONS: Perianal examination and FOBT improve sensitivity in screening children for IBD.

Surgical Revascularization in North American Adults with Moyamoya Phenomenon: Long-Term Angiographic Follow-up.

BACKGROUND: North American and Asian forms of moyamoya have distinct clinical characteristics. Asian adults with moyamoya are known to respond better to direct versus indirect revascularization. It is unclear whether North American adults with moyamoya have a similar long-term angiographic response to direct versus indirect bypass. METHODS: A retrospective review of surgical revascularization for adult moyamoya phenomenon was performed. Preoperative and postoperative cerebral angiograms underwent consensus review, with degree of revascularization quantified as extent of new middle cerebral artery (MCA) territory filling. RESULTS: Late angiographic follow-up was available in 15 symptomatic patients who underwent 20 surgical revascularization procedures. In 10 hemispheres treated solely with indirect arterial bypass, 3 had 2/3 revascularization, 4 had 1/3 revascularization, and 3 had no revascularization of the MCA territory. In the 10 hemispheres treated with direct arterial bypass (8 as a stand-alone procedure and 2 in combination with an indirect procedure), 2 had complete revascularization, 7 had 2/3 revascularization, and 1 had 1/3 revascularization. Direct bypass provided a higher rate of "good" angiographic outcome (complete or 2/3 revascularization) when compared with indirect techniques (P = .0198). CONCLUSIONS: Direct bypass provides a statistically significant, more consistent, and complete cerebral revascularization than indirect techniques in this patient population. This is similar to that reported in the Asian literature, which suggests that the manner of presentation (ischemia in North American adults versus hemorrhage in Asian adults) is likely not a contributor to the extent of revascularization achieved after surgical intervention.

Wiskott-Aldrich syndrome protein (WASP) and N-WASP are critical for peripheral B-cell development and function.

The Wiskott-Aldrich syndrome protein (WASP) is a key cytoskeletal regulator of hematopoietic cells. Although WASP-knockout (WKO) mice have aberrant B-cell cytoskeletal responses, B-cell development is relatively normal. We hypothesized that N-WASP, a ubiquitously expressed homolog of WASP, may serve some redundant functions with WASP in B cells. In the present study, we generated mice lacking WASP and N-WASP in B cells (conditional double knockout [cDKO] B cells) and show that cDKO mice had decreased numbers of follicular and marginal zone B cells in the spleen. Receptor-induced activation of cDKO B cells led to normal proliferation but a marked reduction of spreading compared with wild-type and WKO B cells. Whereas WKO B cells showed decreased migration in vitro and homing in vivo compared with wild-type cells, cDKO B cells showed an even more pronounced decrease in the migratory response in vivo. After injection of 2,4,6-trinitrophenol (TNP)-Ficoll, cDKO B cells had reduced antigen uptake in the splenic marginal zone. Despite high basal serum IgM, cDKO mice mounted a reduced immune response to the T cell-independent antigen TNP-Ficoll and to the T cell-dependent antigen TNP-keyhole limpet hemocyanin. Our results reveal that the combined activity of WASP and N-WASP is required for peripheral B-cell development and function.