Severe Crohn's Disease Research Articles

Ustekinumab: "Real-world" outcomes and potential predictors of nonresponse in treatment-refractory Crohn's disease.

BACKGROUNDUstekinumab was approved in Europe for the treatment of adults with moderate to severe Crohn's disease (CD) in 2016, and there is an urgent need for data on its everyday use.AIMTo obtain data on the daily use of ustekinumab.METHODSThis is a retrospective monocentric study. Patients with moderate to severe CD who began ustekinumab therapy at the inflammatory bowel diseases outpatient clinic of the Heidelberg University Hospital between December 2016 and March 2018 were selected based on electronic patient files. The primary study endpoint was combined steroid-free clinical remission or steroid-free clinical response at 24 ± 6 wk of ustekinumab therapy. Secondary study endpoints were: achievement of mucosal healing, sonographic and magnetic resonance imaging response, biochemical response, the need for intestinal surgery within 24 ± 6 wk after treatment initiation, the occurrence of adverse events, treatment discontinuation due to nonresponse or adverse events, improvement of extraintestinal manifestations, clinical response at 48 ± 6 wk of therapy, and association of response with nucleotid oligodimerisation domain 2 mutations.RESULTSFifty-seven patients with CD (5.3% anti-tumour necrosis factor α naïve, 63.2% having undergone at least one intestinal surgery) were included in the study. Twenty patients (35.1%) achieved steroid-free clinical remission, 6 (10.5%) steroid-free clinical response and 31 (54.4%) were non-responders. Treatment discontinuation due to adverse events occurred in two patients (3.5%). Male sex, the presence of extraintestinal manifestations and the use of steroids at baseline were predictors of nonresponse to ustekinumab therapy.CONCLUSIONIn a “real-world” treatment-refractory cohort of patients with CD, ustekinumab appeared efficacious and safe.

Toll-like receptor 3 (TLR3) variant and NLRP12 mutation confer susceptibility to a complex clinical presentation

Genetic aberrations in the toll-like receptor (TLR)3 pathway are associated with increased susceptibility to herpes simplex virus (HSV) infections. Leucine-rich repeat and PYD-containing protein (NLRP)12 is a component of the inflammasome apparatus, which is critical to an immediate innate inflammatory response. Aberrations in NLRP12 have been shown to mediate auto-inflammation. In this study, we present a 44-year old patient with severe HSV esophagitis and Crohn's disease. An immune and genetic investigation confirmed two coinciding genetic mutations in TLR3 and NLRP12. Our findings support conducting laboratory workup that targets TLR3 pathway in the immunocompetent host developing recurrent HSV infections.

The Little Beast That Pretended to Be a Severe Crohn's Disease

A 49-year-old woman attended our unit with progressive abdominal pain that progressively worsened over a period of several months, accompanied by chronic diarrhea with 3–4 stools per day, without rectal bleeding. She had no personal or family history of digestive disease and she had travelled to Vietnam and to India 3 and 10 years ago, respectively. Blood testing revealed moderate biological inflammatory syndrome (C-reactive protein levels ranging from 10 to 15 mg/L). Bacterologic stool examinations, Clostridium difficile testing and parasitological stool examinations were all negative for 3 days in a row.

Effects of Ustekinumab on Histologic Disease Activity in Patients With Crohn’s Disease

Although ustekinumab is an effective therapy for moderate to severe Crohn's disease (CD), its effects on the microscopic manifestations of CD are unknown. We evaluated the effects of ustekinumab on histologic CD activity in an analysis of data from 251 participants in phase 3 induction and maintenance studies. Two endoscopic biopsy samples were collected at weeks 0, 8, and 44 from the ileum, splenic flexure, and rectum (18 biopsy samples from each patient). Histologic activity was assessed based on global histology activity scores (GHASs). At week 8, the mean GHAS was significantly reduced after ustekinumab induction treatment (from 10.4 ± 7.0 to 7.1 ± 5.9; P < .001) but not in patients who received placebo (from 9.2 ± 6.4 to 7.8 ± 6.2). At week 44 in the randomized maintenance therapy population, the mean GHAS remained reduced from week 8 in patients who received subcutaneous ustekinumab (90 mg every 8 weeks; from 7.4 ± 7.7 to 6.1 ± 4.7) but not every 12 weeks (from 5.3 ± 3.9 to 8.7 ± 4.1) or placebo (from 9.2 ± 3.8 to 10.9 ± 7.1). In the pooled (randomized and nonrandomized) maintenance therapy population, histologic improvement continued in patients given ustekinumab every 8 weeks (from 7.1 ± 6.2 to 5.2 ± 4.2; P < .0001) but not in those given ustekinumab every 12 weeks (from 6.1 ± 5.7 to 7.2 ± 5.1) or placebo (from 8.2 ± 4.2 to 8.9 ± 6.8). A significantly greater proportion of patients achieved histologic response (≥50% decrease in GHAS from baseline) at week 44 if they received ustekinumab every 8 weeks (50% in the randomized maintenance population and 54% in the pooled maintenance population) compared with every 12 weeks (17% and 39% in the randomized and pooled populations, respectively) or placebo (0% and 22% in the randomized and pooled populations, respectively) (P= .0137 for every 8 weeks vs placebo and P= .3529 for every 12 weeks vs placebo in the randomized population; P= .0168 for every 8 weeks vs placebo and P= .3069 for every 12 weeks vs placebo in the pooled population). Regional and overall mean GHASs correlated with the simple endoscopic score for CD (r= .6255, P < .0001). Multivariate analysis found an association between histologic improvement and endoscopic or histologic burden at baseline. In an analysis of data from participants in phase 3 induction and maintenance trials, we found histologic improvement in a greater proportion of patients given ustekinumab vs placebo. The largest improvements occurred in patients who received ustekinumab maintenance therapy every 8 weeks. ClinicalTrials.gov nos. NCT01369329, NCT01369342, and NCT01369355.

Endoscopic, Radiologic, and Histologic Healing With Vedolizumab in Patients With Active Crohn’s Disease

Vedolizumab is a gut-selective monoclonal antibody for the treatment of moderately to severely active Crohn's disease (CD). We performed a prospective study of endoscopic, radiologic, and histologic healing in patients with CD who received vedolizumab therapy. We performed a phase 3b, open-label, single-group study of 101 patients with at least 3 months of active CD (a CD Activity Index [CDAI] score of 220-450, a simple endoscopic score for CD [SES-CD] of 7 or more, 1 or more mucosal ulcerations [identified by endoscopy], and failure of conventional therapy) from March 2015 through December 2017. Among the patients enrolled, 54.5% had previous failure of 1 or more tumor necrosis factor (TNF) antagonists and 44.6% had severe endoscopic disease activity (SES-CD scores above 15) at baseline. Participants received vedolizumab (300 mg intravenously) at weeks 0, 2, and 6, and then every 8 weeks thereafter, for 26 weeks (primary study) or 52 weeks (substudy, 56 patients). The primary endpoint at week 26 was endoscopic remission (SES-CD score of 4 or less); other endpoints included endoscopic response (50% reduction in SES-CD), radiologic remission (magnetic resonance index of activity score below 7), and histologic response (modified global histologic disease activity score of 4 or less). At week 26, 11.9% of patients were in endoscopic remission (95% confidence interval [CI] 6.3-9.8); at week 52, 17.9% of the patients were in endoscopic remission (95% CI 8.9-30.4). Higher proportions of patients naïve to TNF antagonists achieved endoscopic remission than patients with TNF-antagonist-failure at weeks 26 and 52. Higher proportion of patients with moderate CD (SES-CD scores, 7-15) achieved endoscopic remission at weeks 26 and 52 than patients with severe CD (SES-CD scores above 15). The proportion of patients with complete mucosal healing increased over time, with greater rates of healing in the colon than in the ileum. Remission was detected by magnetic resonance enterography in 21.9% of patients at week 26 (95% CI 9.3-40.0) and in 38.1% at week 52 (95% CI 18.1-61.6). At week 26, 24.4% of patients had a histologic response in the colon (95% CI 15.3-35.4) and 28.3% of patients had a histologic response in theileum (95% CI 17.5-41.4). At week 52, 20.5% of patients had a histologic response in the colon (95% CI 9.8-35.3) and 34.3% of patients had a histologic response in the ileum (95% CI 19.1-52.2). There were no notable safety issues, including worsening of extraintestinal manifestations. In a phase 3b trial, we found that 26 and 52 weeks of treatment with vedolizumab (300 mg, at weeks 0, 2, and 6, and then every 8 weeks thereafter) induces endoscopic, radiologic, and histologic healing in patients with moderately to severely active CD. ClinicalTrials.gov no: NCT02425111.

VITALITY: impact of adalimumab on health and disability outcomes in patients with Crohn’s disease, rheumatoid arthritis, or psoriasis treated in clinical practice in New Zealand

Objective: VITALITY, a 6-month, multicenter, prospective, observational study, assessed the effects of originator adalimumab (HUMIRA) on health and disability outcomes in patients with Crohn’s disease (CD), rheumatoid arthritis (RA), or psoriasis treated in routine clinical practice in New Zealand (NZ).Methods: Biologic-naïve adults initiating adalimumab in accordance with NZ funding requirements were recruited. The primary endpoint was 6-month change from baseline in World Health Organization Disability Assessment Schedule (WHODAS) 2.0 score in all participants completing the study (full analysis set). Secondary endpoints included 6-month change in other patient-reported outcomes (PROs) of work activity and wellbeing (Work Productivity and Activity Impairment Questionnaire: General Health, Kessler Psychological Distress Scale, Flourishing Scale, and Subject Vitality Scale) and in disease-specific PRO measures.Results: In total, 164 participants with severe disease initiating adalimumab completed the WHODAS 2.0 at baseline, of whom 114 (69.5%) completed the study at 6 months. Mean WHODAS 2.0 score halved from 15.2 points (SD = ±9.1) at baseline to 7.3 points (SD = ±7.2) after 6 months’ adalimumab treatment (mean difference = 7.9 points; 95% CI = 6.4–9.4; p < .001), with statistically significant improvements seen as early as 2 months after adalimumab initiation (p < .001). The proportion of participants with a WHODAS 2.0 score ≥ 10 more than halved, from 68.3% to 28.9%, between baseline and 6 months. Other PROs also improved significantly at 6 months, as did disease-specific measures. No new adalimumab safety signals were observed.Conclusions: Health and disability outcomes improved significantly after 6 months of adalimumab use in NZ patients with severe CD, RA, or psoriasis.Clinicaltrials.gov: NCT02451839.

P027 Vedolizumab induced extensive purpuric dermatitis in patient with severe Crohn's disease: A case report

INTRODUCTION: Crohn's disease is an idiopathic and inflammatory disease of the intestinal tract associated with significant morbidity and mortality. Currently available treatment options for Crohn's disease includes anti-inflammatory drugs, immunosuppressant, biologic agents, antibiotics, and drugs for symptomatic relief. However, variety of dermatological side effects has been reported in literature associated with these modalities. Vedolizumab is approved to induce and maintain remission in moderate to severe Crohn's disease with relatively low side effect profile. Here we present the first reported case of extensive purpuric dermatitis associated with Vedolizumab. CASE: A 56-year-old African American male with history of severe Crohn's disease presented with the complains of extensive bilateral lower extremity rash. Crohn's disease was diagnosed in 2012 involving duodenum and terminal ileum. He was previously treated but failed to respond to 6 mercaptopurine (6-MP), mesalamine, steroids and infliximab infusions. Vedolizumab was started after he failed infliximab. According to patient he noticed rash first time 5 days after first dose of Vedolizumab. He received total of 4 biweekly doses of Vedolizumab before presentation to clinic with rash. Rash was pruritic in nature and started on ankle and progressively got worsened involving legs and thighs. Patient denied history of fever and chills. Review of system was negative. On physical examination well-demarcated, brownish pigmentation over the lower extremities were noticed. He denied use of any other newly prescribed or over the counter medications. Patient underwent a formal dermatologic evaluation. Shave biopsy was done that showed irritated hyper and parakeratotic skin with spongiosis, extravasated red blood cells and inflammatory infiltrate comprising of lymphocytes, histiocytes, neutrophils and eosinophils findings consistent with drug induced purpuric dermatitis. Patient was started on topical triamcinolone. He reported slight improvement in his rash one month after Vedolizumab infusion was discontinue. DISCUSSION: Vedolizumab is a humanized monoclonal antibody that selectively inhibits the binding of α4β7 integrin to intestinal mucosal cell adhesion molecule (MAdCAM-1) and has no effect on α4β1 integrin adhesion on the vascular cell adhesion molecule 1 (VCAM-1). As a result, cutaneous migration of lymphocytes including by VCAM-1 is unaffected. Cutaneous complications of Vedolizumab including rash and hypersensitivity reaction are reported in &lt;1% of patient. Till date only one report of Vedolizumab associated paradoxical psoriasis has been reported. This is the first reported case of extensive purpuric dermatitis (PD) associated with Vedolizumab. Exact etiology of PD is unknown but cell-mediated immunity might play a role. This inflammatory infiltrate leads to vascular fragility and subsequent leakage of erythrocytes. Management of drug induced PD involves discontinuation of offending medication. Topical corticosteroid therapy may be of some help, especially for pruritus, but prolonged use should be avoided. CONCLUSION: Though dermatological complications associated with Vedolizumab are rare but can be potentially debilitating for our patients. Prompt identification and discontinuation of Vedolizumab is critical in preventing morbidity associated with these side effects.

P022 Autologous hematopoietic stem cell transplantation in refractory Crohn's disease: series case report in a Brazilian tertiary center

BACKGROUND: Crohn's disease (CD) is a chronic inflammatory and relapsing disease that can affect any segment of the gastrointestinal tract causing intestinal and extra-intestinal manifestations. A significant percentage of these patients suffer an aggressive disease course, refractory to pharmacological therapy and most of them are not favorable to surgical treatment, besides not being a curative procedure. Recent analysis of autologous haematopoietic stem cell transplantation (HSCT) showed a high rate of clinical and endoscopic remission after 1 year in these patients. METHODS: In 2015 our hospital developed a partnership protocol with ministry of health to submit adult patients from many cities of Brazil, with refractory CD to perform HSCT as an optional treatment. The follow up period of this protocol was only 6 months. We analyzed the 6 patients from this protocol to assess the efficacy and safety of autologous HSCT for refractory CD. RESULTS: Five men and 1 woman, between 43y and 19y (median age 38y), corporal index mass 20 Kg/m2 (18–25), with refractory CD, median course of illness 14y (5–23 years), all negative for X-linked inhibitor apoptosis protein (XIAP). Two patients were non-structuring non-penetrating, but only one hadn't had previous surgery. Five patients had 2–3 previous intestinal surgeries, and one had ileostomy, 2 had tuberculosis, one had multiple sclerosis, one had epilepsy and depression and one had pancreatitis as comorbities before HSCT. One patient had reactivation of tuberculosis and was treated during 6 months before the HSCT. All patients used thiopurines, metotrexate and more than one immunobiological therapies (IFX, ADA, VEDO), steroids, antibiotics, and aminosalicylates. All the 6 patients completed the mobilization, conditioning and transplantation phases, during a median time of hospitalization of 35 days (21–58d). We had no transplant related mortality. All patients had infectious complications during mobilization which included febrile neutropenia, anemia and life-threatening complications as KPC, Staphylococcus aureus infecction, and sepsis caused by E. coli. Among non-infectious complications all had mucositis, and red cell transfusion was required in all patient. The 6 months follow up of protocol all patients reached clinical and endoscopic remission and were steroid and immunosuppressive free remission. Most of them related viral infections. Only the youngest patient answered the SF36, IBDQ and PedsQL4.0 questionnaire pre and post HSCT, with improvement of health-related quality of life in all domains. Although the project last 6m, actually all patients are alive and the longest post HSCT time is 2y 9m. Only one patient restarted ADA as monotherapy (1y11m post HSCT). CONCLUSION: Due to its high complexity, risk of infections and death we consider that autologous HSCT should be an option of treatment only for patients with severe refractory CD.

Ustekinumab is effective in biological refractory Crohn's disease patients-regardless of approval study selection criteria.

Background/AimsUstekinumab is effective in active Crohn’s disease. In a retrospective study, we assessed the clinical outcome in nonresponders to anti-tumor necrosis factor therapy, and/or conventional therapy and/or the α4β7-integrin inhibitor vedolizumab. As approval study populations do not always reflect the average “real world” patient cohort, we assessed weather patients who would not have qualified for approval studies show similar outcomes. MethodsForty-one patients with mild to severe active Crohn’s disease were treated with ustekinumab (intravenous 6 mg per kg/body weight) followed by subcutaneous ustekinumab (90 mg) at week 8. Depending on the clinical response maintenance therapy was chosen every 8 or 12 weeks. Clinical response was defined by Crohn’s Disease Activity Index (CDAI) decline, decline of stool frequency or clinical improvement. Inclusion criteria for approval studies were assessed. ResultsThe 58.5% (24/41) showed clinical response to ustekinumab. The 58.3% of this group (14/24) achieved clinical remission. Clinical response correlated significantly with drop of stool frequency and improvement of CDAI score. The 39 out of 41 patients had no side effects and we observed no serious infections. About a third of our patients would not have met ustekinumab approval study criteria. However, patients who did not meet study criteria showed clinical improvement numerically in the same range compared to patients who would have qualified for approval studies. ConclusionsUstekinumab is effective, safe and well tolerated in a highly therapy refractory patient cohort. Even though a reasonable number of patients did not meet ustekinumab approval study criteria, approval study results seem to be representative to the overall patient cohort.

Development and Validation of Machine Learning Models in Prediction of Remission in Patients With Moderate to Severe Crohn Disease

Biological therapies have revolutionized inflammatory bowel disease management, but many patients do not respond to biological monotherapy. Identification of likely responders could reduce costs and delays in remission. To identify patients with Crohn disease likely to be durable responders to ustekinumab before committing to long-term treatment. This cohort study analyzed data from 3 phase 3 randomized clinical trials (UNITI-1, UNITI-2, and IM-UNITI) conducted from 2011 to 2015. Participants (n = 401) were individuals with active (C-reactive protein [CRP] measurement of ≥5 mg/L at enrollment) Crohn disease who received ustekinumab therapy. Data analysis was performed from November 1, 2017, to June 1, 2018. All included patients were exposed to 1 or more dose of ustekinumab for 8 weeks or more. Random forest methods were used in building 2 models for predicting Crohn disease remission, with a CRP level lower than 5 mg/dL as a proxy for biological remission, beyond week 42 of ustekinumab treatment. The first model used only baseline data, and the second used data through week 8. In total, 401 participants, with a mean (SD) age of 36.3 (12.6) years and 170 male (42.4%), were included. The week-8 model had a mean area under the receiver operating characteristic curve (AUROC) of 0.78 (95% CI, 0.69-0.87). In the testing data set, 27 of 55 participants (49.1%) classified as likely to have treatment success achieved success with a CRP level lower than 5 mg/L after week 42, and 7 of 65 participants (10.8%) classified as likely to have treatment failure achieved this outcome. In the full cohort, 87 patients (21.7%) attained remission after week 42. A prediction model using the week-6 albumin to CRP ratio had an AUROC of 0.76 (95% CI, 0.71-0.82). Baseline ustekinumab serum levels did not improve the model's prediction performance. In patients with active Crohn disease, demographic and laboratory data before week 8 of treatment appeared to allow the prompt identification of likely nonresponders to ustekinumab without the need for costly drug-level monitoring.

538 – A Blood Based Pre-Surgical Transcriptomic Signature Identifies a Severe Crohn's Disease Subtype and is Predictive of a Post Surgery Decrease in Pro-Inflammatory Pathway Activation

538 – A Blood Based Pre-Surgical Transcriptomic Signature Identifies a Severe Crohn's Disease Subtype and is Predictive of a Post Surgery Decrease in Pro-Inflammatory Pathway Activation

Tu1746 – A Phase 3 Study of Vedolizumab for Induction and Maintenance Therapy in Japanese Patients with Moderate to Severe Crohn's Disease

Tu1746 – A Phase 3 Study of Vedolizumab for Induction and Maintenance Therapy in Japanese Patients with Moderate to Severe Crohn's Disease

260 – Identification of Pathogenic Bacteria in Severe Crohn's Disease

260 – Identification of Pathogenic Bacteria in Severe Crohn's Disease

Safety Evaluation of ABX464 in Patients With Moderate to Severe Active Crohn's Disease

Safety Evaluation of ABX464 in Patients With Moderate to Severe Active Crohn's Disease

Diverting Ostomy: For Whom, When, What, Where, and Why.

Fecal diversion is an important tool in the surgical armamentarium. There is much controversy regarding which clinical scenarios warrant diversion. Throughout this article, we have analyzed the most recent literature and discussed the most common applications for the use of a diverting stoma. These include construction of diverting ileostomy or colostomy, ostomy for low colorectal/coloanal anastomosis, inflammatory bowel disease, diverticular disease, and obstructing colorectal cancer. We conclude the following: diverting loop ileostomy is preferred to loop colostomy, an ostomy should be used for a pelvic anastomosis < 5 to 6 cm including coloanal anastomosis and ileo-anal-pouch anastomosis, severe perianal Crohn's disease frequently requires diversion, a primary anastomosis with diverting ileostomy in the setting of diverticular perforation is safe, and a diverting stoma can be used as a bridge to primary resection in the setting of an obstructing malignancy.

IL-7 receptor influences anti-TNF responsiveness and T cell gut homing in inflammatory bowel disease.

It remains unknown what causes inflammatory bowel disease (IBD), including signaling networks perpetuating chronic gastrointestinal inflammation in Crohn's disease (CD) and ulcerative colitis (UC), in humans. According to an analysis of up to 500 patients with IBD and 100 controls, we report that key transcripts of the IL-7 receptor (IL-7R) pathway are accumulated in inflamed colon tissues of severe CD and UC patients not responding to either immunosuppressive/corticosteroid, anti-TNF, or anti-α4β7 therapies. High expression of both IL7R and IL-7R signaling signature in the colon before treatment is strongly associated with nonresponsiveness to anti-TNF therapy. While in mice IL-7 is known to play a role in systemic inflammation, we found that in humans IL-7 also controlled α4β7 integrin expression and imprinted gut-homing specificity on T cells. IL-7R blockade reduced human T cell homing to the gut and colonic inflammation in vivo in humanized mouse models, and altered effector T cells in colon explants from UC patients grown ex vivo. Our findings show that failure of current treatments for CD and UC is strongly associated with an overexpressed IL-7R signaling pathway and point to IL-7R as a relevant therapeutic target and potential biomarker to fill an unmet need in clinical IBD detection and treatment.

TNF Activates FK506 Binding Protein 8 (FKBP8) Interactions That Direct Myosin Light Chain Kinase 1 (MLCK1) Recruitment to the Perijunctional Actomyosin Ring and Drive Epithelial Barrier Loss

BackgroundIntestinal barrier dysfunction is thought to contribute to progression of inflammatory bowel disease and systemic disorders. We recently reported that a specific myosin light chain kinase splice variant, MLCK1, is recruited to the apical perijunctional actomyosin ring of intestinal epithelial in both acute and chronic diarrheal disease. Disruption of MLCK1 recruitment restores tight junction barrier function and blocks progression of immune‐mediated colitis without toxicities associated with enzymatic inhibition, e.g., defective wound repair or smooth muscle function. We sought to further define the mechanisms responsible for MLCK1 recruitment to the perijunctional actomyosin ring.ObjectiveTo define MLCK1‐binding partners and the means by which they regulate intracellular targeting of MLCK1.MethodsYeast‐2‐hybrid (Y2H) screening and microscale thermophoresis (MST) were used to discover and define MLCK1‐interacting proteins. Caco‐2BBe cells, some stably expressing MLCK1‐EGFP, were cultured on Transwells. Immunofluorescence microscopy and proximity ligation assay (PLA) were used to detect intracellular protein distributions and interactions. Tight junction barrier function was measured as transepithelial electrical resistance (TER).ResultsY2H using MLCK1‐specific sequences captured the FK506‐binding/peptidylprolyl isomerase domain of FK506‐binding protein 8 (FKBP8, aka FKBP38). MST analysis showed that the recombinant MLCK1 N‐terminus bound directly to full‐length FKBP8 (Kd=~5μM). This interaction was mediated by the FK506‐binding/peptidylprolyl isomerase domain and could be blocked by FK506 (tacrolimus). Consistent with a role in barrier regulation, FK506 induced dose‐dependent TER increases in cultured epithelial monolayers. Immunofluorescent microscopy demonstrated overlapping distributions of MLCK1‐EGFP and FKBP8 at the perijunctional actomyosin ring, lateral membranes, and within the cytoplasm of intestinal epithelial cells, but PLA detected only limited direct interactions between MLCK1 and FKBP8. Tumor necrosis factor (TNF) triggered MLCK1 recruitment to the perijunctional actomyosin ring, markedly increased MLCK1‐FKBP8 interactions, as assessed by PLA, and induced barrier loss. FK506 addition to TNF‐treated monolayers displaced MLCK1 from the perijunctional ring and restored barrier function.ConclusionsTNF activates FKBP8 binding to MLCK1. This interaction is critical for TNF‐induced MLCK1 recruitment to the perijunctional actomyosin ring and subsequent barrier loss. Disruption of the MLCK1‐FKBP8 interaction could, in part, explain the efficacy of FK506 in severe Crohn's disease. We speculate that specific targeting of the MLCK1‐FKBP8 interaction may have therapeutic benefit in many diseases associated with intestinal barrier dysfunction.Support or Funding InformationSupported by the NIH (DK R01 DK068271) and the NNSF of China (81800464).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

PEDIATRIC CROHN DISEASE: A CASE SERIES FROM A TERTIARY CARE CENTER

Crohn disease (CD) is an inflammatory bowel disease that causes transmural inflammation of the gastrointestinal tract. Growth failure is a major complication and can occur before gastrointestinal manifestations in children with CD. We present here four such cases where short stature and undernutrition constituted major symptomatology, along with enteric features. Median age of presentation was 13 years. Intermittent abdominal pain and growth failure were the predominant clinical manifestations. Features of imaging and colonoscopy were suggestive of CD. A poor response was noted to corticosteroids and azathioprine in three children. Clinical remission was not achieved as per abbreviated pediatric CD activity index score. One child succumbed to illness secondary to dilated cardiomyopathy. A good therapeutic response with significant weight gain was observed in two children after starting biologicals. Only one child responded to oral corticosteroids and mesalamine. Considering biologicals early in chronically active moderate to severe CD can help in altering the prognosis.

Disutility Study for Adult Patients with Moderate to Severe Crohn's Disease.

BackgroundCrohn’s disease (CD) treatments and associated adverse events (AEs) can be burdensome for patients. However, specific values which quantify the impact on health-related quality of life (HRQL) for economic evaluation are lacking.ObjectivesThis study aimed to elicit health utility values for AEs related to biologic treatment and surgical complications for CD in the UK.MethodsHealth states were developed by literature review and interviews with CD patients (n=6) and gastroenterologists (n=3). Draft health states were validated in cognitive debrief interviews with patients (n=4) and gastroenterologists (n=2). Treatment AEs were described with moderate-severe CD (reference state) and included hypersensitivity, injection site reactions, serious infection, lymphoma, and tuberculosis. Surgical complications were described following bowel surgery (reference state) and included anastomotic leak, wound infection, prolonged ileus/bowel obstruction, and intra-abdominal abscess. Health states were valued by 100 members of the general public who completed background questions, EQ-5D-3L, visual analogue scale rating task and time trade-off (TTO) interviews.ResultsThe mean TTO value for reference states ‘moderate to severe CD’ and ‘bowel surgery’ were 0.70 (SD=0.28) and 0.69 (SD=0.28). Participants rated lymphoma as the worst AE/surgical complication state (0.44, SD=0.37), followed by tuberculosis (0.47, SD=0.85) and anastomotic leak (0.48, SD=0.38). Values of other AE/surgical complication states ranged from 0.76 (hypersensitivity) to 0.56 (intra-abdominal abscess).ConclusionsThis study provides utility estimates for AE and surgical complication health states not previously assessed in the context of CD. As new treatments are emerging, it is important to include these influences on quality of life in any economic evaluation of treatments.

Efficacy and Safety of Oral BT-11 in Moderate to Severe Crohn's Disease

Efficacy and Safety of Oral BT-11 in Moderate to Severe Crohn's Disease