Genetic coding variant in complement factor B (CFB) is associated with increased risk for perianal Crohn's disease and leads to impaired CFB cleavage and phagocytosis.

OBJECTIVE: Perianal Crohn's disease (pCD) occurs in up to 40% of patients with CD and is associated with poor quality of life, limited treatment responses and poorly understood aetiology. We performed a genetic association study comparing CD subjects with and without perianal disease and subsequently performed functional follow-up studies for a pCD associated SNP in Complement Factor B (CFB). DESIGN: Immunochip-based meta-analysis on 4056 pCD and 11 088 patients with CD from three independent cohorts was performed. Serological and clinical variables were analysed by regression analyses. Risk allele of rs4151651 was introduced into human CFB plasmid by site-directed mutagenesis. Binding of recombinant G252 or S252 CFB to C3b and its cleavage was determined in cell-free assays. Macrophage phagocytosis in presence of recombinant CFB or serum from CFB risk, or protective CD or healthy subjects was assessed by flow cytometry. RESULTS: Perianal complications were associated with colonic involvement, OmpC and ASCA serology, and serology quartile sum score. We identified a genetic association for pCD (rs4151651), a non-synonymous SNP (G252S) in CFB, in all three cohorts. Recombinant S252 CFB had reduced binding to C3b, its cleavage was impaired, and complement-driven phagocytosis and cytokine secretion were reduced compared with G252 CFB. Serine 252 generates a de novo glycosylation site in CFB. Serum from homozygous risk patients displayed significantly decreased macrophage phagocytosis compared with non-risk serum. CONCLUSION: pCD-associated rs4151651 in CFB is a loss-of-function mutation that impairs its cleavage, activation of alternative complement pathway, and pathogen phagocytosis thus implicating the alternative complement pathway and CFB in pCD aetiology.

Real-world impact of infliximab precision-guided dosing on management of patients with IBD.

OBJECTIVES: Evaluate the clinical utility of a precision-guided dosing test for infliximab (IFX) and its impact on treatment decision-making for inflammatory bowel disease (IBD). STUDY DESIGN: Prospective, multisite, clinical experience program. METHODS: Health care providers were given access to PredictrPK IFX, a precision-guided dosing test, for their patients with IBD on maintenance IFX therapy. Blood samples were drawn 20 to 56 days post infusion. A Bayesian data assimilation tool used clinical and serologic data to generate individual pharmacokinetic profiles and forecast trough IFX. Results were reported to providers to aid in-therapy management decisions and the decision-making process was assessed through questionnaires. Relationships between forecasted IFX concentration, disease activity, and therapy management decisions were analyzed by logistic regression. RESULTS: PredictrPK IFX was used for 275 patients with IBD by 37 providers. In 58% of cases, providers modified treatment plans based on the results, including dose modifications (41%; of these, one-third decreased dose) and discontinuation (8%) of IFX. Of the 42% where treatment was not modified, 97.5% had IFX levels of 5 µg/mL or greater. Patients with IFX concentrations less than 5 µg/mL were 3 and 7.3 times more likely to have active disease or discontinue IFX, respectively. There was unanimous agreement among providers who completed a postprogram survey that PredictrPK IFX was beneficial in guiding treatment decisions and added more value to their practice than routine therapeutic drug monitoring. CONCLUSIONS: PredictrPK IFX enables earlier and more precise dose optimization of IFX in patients with IBD, exerting a substantial impact on treatment decisions that may result in improved health outcomes and overall cost savings.

Predictors of proctocolectomy in children with ulcerative colitis.

OBJECTIVES: Few clinical predictors are associated with definitive proctocolectomy in children with ulcerative colitis (UC). The purpose of the present study was to identify clinical predictors associated with surgery in children with UC using a disease-specific database. METHODS: Children diagnosed with UC at age <18 years were identified using the Pediatric Inflammatory Bowel Disease Consortium (PediIBDC) database. Demographic and clinical variables from January 1999 to November 2003 were extracted alongside incidence and surgical staging. RESULTS: Review of the PediIBDC database identified 406 children with UC. Approximately half were girls (51%) with an average age at diagnosis of 10.6 ±â€Š4.4 years in both boys and girls. Average follow-up was 6.8 (±4.0) years. Of the 57 (14%) who underwent surgery, median time to surgery was 3.8 (interquartile range 4.9) years after initial diagnosis. Children presenting with weight loss (hazard ratio [HR] 2.55, 99% confidence interval [CI] 1.21-5.35) or serum albumin <3.5 g/dL (HR 6.05, 99% CI 2.15-17.04) at time of diagnosis and children with a first-degree relative with UC (HR 1.81, 99% CI 1.25-2.61) required earlier surgical intervention. Furthermore, children treated with cyclosporine (HR 6.11, 99% CI 3.90-9.57) or tacrolimus (HR 3.66, 99% CI 1.60-8.39) also required earlier surgical management. Other symptoms, laboratory tests, and medical therapies were not predictive for need of surgery. CONCLUSION: Children with UC presenting with hypoalbuminemia, weight loss, a family history of UC, and those treated with calcineurin inhibitors frequently require restorative proctocolectomy for definitive treatment. Early identification and recognition of these factors should be used to shape treatment goals and initiate multidisciplinary care at the time of diagnosis.

Ewing's Sarcoma in a Patient with Crohn's Disease Treated with Ustekinumab: A Case Report.

Biologic therapies have revolutionized the treatment of immune-mediated diseases. They are generally well tolerated; however, there are reports of malignancies associated with the use of these drugs. This case is of an adolescent with refractory Crohn's disease treated with ustekinumab, who subsequently developed Ewing's sarcoma. Patients treated with ustekinumab have reportedly developed B cell lymphoma, epithelioid sarcoma, as well as cancer of the lung, esophagus, ovary, testis, kidney, and thyroid. However, this is the first documented case of a patient treated with ustekinumab to develop Ewing sarcoma.

Oral tacrolimus for steroid-dependent and steroid-resistant ulcerative colitis in children.

PURPOSE: To evaluate tacrolimus in 3 situations: for the induction of remission in children with severe steroid-resistant ulcerative colitis (UC); for steroid sparing in children with steroid-dependent UC in whom treatment with other immunosuppressants fails; and for the maintenance of remission in children with steroid-dependent and steroid-resistant UC. PATIENTS AND METHODS: We retrospectively evaluated 18 consecutive patients (13 with pancolitis) who were treated with oral tacrolimus at our institution from May 1999 to October 2005. Nine patients had steroid-resistant UC and 9 patients were steroid-dependent. We started patients initially on tacrolimus 0.2 mg/kg divided twice daily, with a goal plasma trough level of 10 to 15 ng/mL for the first 2 weeks, and then titrated doses to achieve plasma levels between 7 and 12 ng/mL after induction. RESULTS: Of the 18 patients in this study, 17 showed a positive response to tacrolimus therapy (ie, cessation of diarrhea and other symptoms) and 5 showed a prolonged response to tacrolimus. The mean time from initiation of tacrolimus therapy until response was 8.5 days. The mean duration of response was 260 days. Eleven of 18 patients required colectomy, including all of the patients with steroid-resistant UC, but only 2 of 9 who were steroid-dependent. The mean time from initiation of tacrolimus until colectomy was 392 days. CONCLUSIONS: It is possible that tacrolimus may benefit selected patients with steroid-dependent UC, including those who are intolerant of 6-mercaptopurine or azathioprine. Conversely, patients with steroid-resistant UC are unlikely to sustain a prolonged clinical response to tacrolimus and seem to require colectomy eventually. Careful considerations of risk versus benefit, as well as close monitoring for adverse effects, are essential in all patients.

Out-of-pocket Cost Burden in Pediatric Inflammatory Bowel Disease: A Cross-sectional Cohort Analysis.

BACKGROUND: Pediatric inflammatory bowel disease (IBD), consisting of Crohn's disease (CD) and ulcerative colitis (UC), can result in significant morbidity requiring frequent health care utilization. Although it is known that the overall financial impact of pediatric IBD is significant, the direct out-of-pocket (OOP) cost burden on the parents of children with IBD has not been explored. We hypothesized that affected children with a more relapsing disease course and families in lower income strata, ineligible for need-based assistance programs, disparately absorb ongoing financial stress. METHODS: We completed a cross-sectional analysis among parents of children with IBD residing in California using an online HIPAA-secure Qualtrics survey. Multicenter recruitment occurred between December 4, 2013 and September 18, 2014 at the point-of-care from site investigators, informational flyers distributed at regional CCFA conferences, and social media campaigns equally targeting Northern, Central, and Southern California. IBD-, patient-, and family-specific information were collected from the parents of pediatric patients with IBD patients younger than 18 years of age at time of study, carry a confirmed diagnosis of CD or UC, reside in and receive pediatric gastroenterology care in California, and do not have other chronic diseases requiring ongoing medical care. RESULTS: We collected 150 unique surveys from parents of children with IBD (67 CD; 83 UC). The median patient age was 14 years for both CD and UC, with an overall 3.7 years (SD 2.8 yr) difference between survey completion and time of IBD diagnosis. Annually, 63.6%, 28.6%, and 5.3% of families had an OOP cost burden >$500, >$1000, and >5000, respectively. Approximately one-third (36.0%) of patients had emergency department (ED) visits over the past year, with 59.2% of these patients spending >$500 on emergency department copays, including 11.1% who spent >$5000. Although 43.3% contributed <$500 on procedure and test costs, 20.0% spent >$2000 in the past year. Families with household income between $50,000 and $100,000 had a statistically significant probability (80.6%) of higher annual OOP costs than families with lower income <$50,000 (20.0%; P < 0.0001) or higher income >$100,000 (64.6%; P < 0.05). Multivariate analysis revealed that clinical variables associated with uncontrolled IBD states correlated to higher OOP cost burden. Annual OOP costs were more likely to be >$500 among patients who had increased spending on procedures and tests (odds ratio [OR], 5.63; 95% confidence interval [CI], 2.73-11.63), prednisone course required over the past year (OR, 3.19; 95% CI, 1.02-9.92), at least 1 emergency department visit for IBD symptoms (OR, 2.84; 95% CI, 1.33-6.06), at least 4 or more outpatient primary medical doctor visits for IBD symptoms (OR, 2.82; 95% CI, 1.40-5.68), and history of 4 or more lifetime hospitalizations for acute IBD care (OR, 2.60; 95% CI, 1.13-5.96). CONCLUSIONS: Previously undocumented, a high proportion of pediatric IBD families incur substantial OOP cost burden. Patients who are frequently in relapsing and uncontrolled IBD states require more acute care services and sustain higher OOP cost burden. Lower middle income parents of children with IBD ineligible for need-based assistance may be particularly at risk for financial stress from OOP costs related to ongoing medical care.

Postoperative complications and health care use in children undergoing surgery for ulcerative colitis.

OBJECTIVES: Medical and surgical approaches toward children with ulcerative colitis (UC) vary and have differing implications for health care use. The goal of this study was to define hospital use and complications for children with UC before and after staged restorative proctocolectomy. PATIENTS AND METHODS: A retrospective study of the California Patient Discharge Dataset from 1999 to 2007 of children aged 2 to 18 years with UC who underwent colectomy was performed (N = 218). Surgical staging was determined alongside hospital type (children's vs non-children's) and surgical case volume. Postoperative complications and hospital length of stay were analyzed using multivariate regression. RESULTS: The cohort was mostly male (56%) and white (80%), had private insurance (78%), and underwent colectomy at a children's hospital (62%). Overall, 65% required a separate hospital admission before admission for colectomy. Single-, 2-, and 3-stage procedures were performed in 19 (9%), 144 (66%), and 38 (17%) children. The mean admissions per patient were 1.8 ± 2.4 before colectomy and 0.7 ± 1.6 after surgical completion. Surgical complications occurred in 100 (49%) children, with 39% being attributed to postoperative infection. Children with public insurance (odds ratio, 2.18; 95% confidence interval, 1.0-4.85) and those who underwent colectomy at a non-children's hospital (odds ratio, 2.53; 95% confidence interval, 1.0-6.37) had increased likelihood of surgical complications. Finally, nonwhite race, surgical staging, and undergoing colectomy at a low- or medium-volume hospital resulted in prolonged hospitalization (P < .05). CONCLUSIONS: Children with UC who undergo colectomy use a large number of hospital resources before surgery and exhibit decreased hospital use after surgical completion. Children undergoing colectomy at children's and high-volume hospitals experience fewer surgical complications and shorter hospitalization.