Update on Emerging Pharmacologic Therapies for Patients With Eosinophilic Esophagitis.

Eosinophilic esophagitis (EoE) is a chronic immune-mediated condition identified by eosinophilic infiltration of the esophageal mucosa. Historically, pharmacologic options have been limited to proton pump inhibitors and swallowed topical corticosteroids, neither of which have been approved by the US Food and Drug Administration for the treatment of EoE. The goal of therapy is ultimately to avoid irreversible stricturing disease. Despite the rising prevalence of EoE, there have been few therapeutic advancements until recently. Some newer topical corticosteroid preparations are being studied, including a budesonide suspension (TAK-721), orodispersible tablet formulations of budesonide and fluticasone (APT-1011), and mometasone and ciclesonide preparations. Also in various stages of clinical trials are potential disease-modifying biologics such as dupilumab, cendakimab, lirentelimab, benralizumab, and mepolizumab. Some of these medications have proven efficacious for other atopic conditions and show incredible promise for the treatment of eosinophilic gastrointestinal diseases. Further studies will be needed to determine long-term treatment outcomes for each of these drugs.

Treatment for eosinophilic esophagitis.

PURPOSE OF REVIEW: To summarize current dietary and pharmacologic approaches in the treatment of eosinophilic esophagitis (EoE). RECENT FINDINGS: Studies comparing dietary approaches in EoE treatment support empiric elimination diets as the preferred approach to dietary EoE treatment, with no data to support use of currently available allergy tests to guide specific food elimination diets. Swallowed topical corticosteroid therapy is the current standard of care in pharmacologic EoE treatment, with similar effectiveness of fluticasone and budesonide, but their discontinuation results in return of both EoE symptoms and disease. A number of nonsteroid-based therapies are currently under investigation for the treatment of EoE, which are focused on targeting disease at a cellular level. SUMMARY: EoE can be treated with diet or medications. Empiric elimination is presently the preferred dietary approach. Swallowed steroids is the standard of care to treat EoE with medication; however, there are several promising drugs currently undergoing clinical trials.

Mechanical Skin Injury Promotes Food Anaphylaxis by Driving Intestinal Mast Cell Expansion.

Mast cell (MC) mediator release after crosslinking of surface-bound IgE antibody by ingested antigen underlies food allergy. However, IgE antibodies are not uniformly associated with food allergy, and intestinal MC load is an important determinant. Atopic dermatitis (AD), characterized by pruritis and cutaneous sensitization to allergens, including foods, is strongly associated with food allergy. Tape stripping mouse skin, a surrogate for scratching, caused expansion and activation of small intestinal MCs, increased intestinal permeability, and promoted food anaphylaxis in sensitized mice. Tape stripping caused keratinocytes to systemically release interleukin-33 (IL-33), which synergized with intestinal tuft-cell-derived IL-25 to drive the expansion and activation of intestinal type-2 innate lymphoid cells (ILC2s). These provided IL-4, which targeted MCs to expand in the intestine. Duodenal MCs were expanded in AD. In addition to promoting cutaneous sensitization to foods, scratching may promote food anaphylaxis in AD by expanding and activating intestinal MCs.

Impact of Gastroesophageal Reflux Disease on Mucosal Immunity and Atopic Disorders.

Atopic disorders and gastroesophageal reflux disease (GERD) are some of the most common medical conditions treated by primary care physicians and specialists alike. The observation that atopic disorders, like asthma, allergic rhinitis and sinusitis, food allergies, atopic dermatitis, contact dermatitis, and eosinophilic esophagitis are common comorbidities in patients with GERD raises the question of the nature of the relationship that may exist between GERD and atopic disorders. In this article, we review the pathophysiology of GERD, its effect on the immune system, the effect of acid-blocking medications on allergic responses, as well as several common atopic conditions that have been associated with GERD including asthma, chronic rhinosinusitis (CRS), allergic rhinitis (AR), atopic dermatitis (AD), contact dermatitis (CD), food allergies, proton pump inhibitor (PPI)-responsive esophageal eosinophilia (PPI-REE), and eosinophilic esophagitis (EoE). In each condition, the evidence of a causal link is not definitive. Although the relationship between asthma and GERD remains controversial, evidence suggests that a subset of asthma patients with documented GERD may experience improved asthma control following appropriate treatment of GERD. The relationship of GERD to allergic rhinitis and chronic sinusitis is weak; however, studies support the concept that treatment of frequent episodes of GERD can have a positive effect on rhinitis and sinusitis overall. The relationship between allergic sensitization and GERD is likely bidirectional. GERD may induce changes in the mucosal immune system that may favor the development of food allergy and allergic sensitization to aeroallergens; however, the underlying mechanisms have not been established.

Dibutyl-phthalate exposure from mesalamine medications and serum thyroid hormones in men.

BACKGROUND: Dibutyl phthalate (DBP) is an endocrine disruptor and used in some medication coatings, such as mesalamine for treatment inflammatory bowel disease (IBD). OBJECTIVES: To determine whether high-DBP from some mesalamine medications alters thyroid function. METHODS: Seventy men with IBD, without thyroid disease or any radiation history participated in a crossover-crossback prospective study and provided up to 6 serum samples (2:baseline, 2:crossover, 2:crossback). Men on non-DBP mesalamine (background exposure) at baseline crossed-over to DBP-mesalamine (high exposure) then crossed-back to non-DBP mesalamine (B1HB2-arm) and vice versa for men on DBP-mesalamine at baseline (H1BH2-arm). Serum concentrations of total triiodothyronine (T3), total thyroxine (T4), free triiodothyronine (FT3), free thyroxine (FT4), thyroid-stimulating hormone (TSH) and thyroid peroxidase antibody (TPOAb), and thyroglobulin antibody (TgAb). RESULTS: After crossover in B1HB2-arm (26 men, 134 samples), T3 decreased 10% (95% confidence interval (CI): 14%,-5%), T3/T4 ratio decreased 8% (CI: 12%,-3%), TPOAb, and TgAb concentrations decreased, 11% (-20%, -2%) and 15% (-23%, -5%), respectively; after crossback, they increased. When men in the H1BH2-arm (44 men, 193 samples) crossed-over, T3 decreased 7% (CI: -11%, -2%) and T3/T4 ratio decreased 6% (CI: -9%, -2%). After crossback, only TgAb increased and FT4 decreased. CONCLUSIONS: High-DBP novel exposure or removal from chronic high-DBP exposure could alter elements of the thyroid system, and most probably alters the peripheral T4 conversion to T3 and thyroid autoimmunity, consistent with thyroid disruption. After exposure removal, these trends were mostly reversed.

Every-other-day Dosing of Oral Viscous Budesonide Is not Effective in the Management of Eosinophlic Esophagitis.

BACKGROUND: Eosinophilic esophagitis (EoE) is a clinicopathologic disorder characterized histologically by esophageal eosinophilia. Oral viscous budesonide (OVB) is an effective treatment with remission rates reported between 55% and 87%; however, topical corticosteroids are associated with increased risk of candidal esophagitis and adrenal suppression. Attempts to decrease the daily dose of topical steroids have resulted in disease relapse. The objective of this study was to determine whether or not reducing the frequency of OVB administration would be effective in controlling esophageal eosinophilia in children and adolescents. METHODS: Data were obtained by retrospective chart review of patients at Boston Children's Hospital diagnosed with EoE, based on endoscopic findings of >15 eosinophils per high power field (eos/HPF) on esophageal biopsies while on acid blockade. Patients with histologic evidence of response (<15 eos/HPF) while on daily OVB had been offered the option of maintenance therapy based on a Monday-Wednesday-Friday (MWF) dosing regimen. Changes in peak esophageal eosinophil counts over time were examined. RESULTS: Eight male patients ages 5 to 18 years attained clinical response while receiving daily OVB and were subsequently maintained on a MWF OVB dosing regimen for 3 to 7 months. All 8 patients showed an increase in peak esophageal eosinophils, with 7 of 8 (88%) experiencing disease relapse. In fact, the distribution of peak esophageal eosinophils after MWF dosing was not statistically different from peak levels at diagnosis (P = 0.95). CONCLUSIONS: An MWF dosing regimen of OVB was not effective at maintaining histologic response in children and adolescents with EoE. Larger prospective studies are warranted to confirm these results.

A crossover-crossback prospective study of dibutyl-phthalate exposure from mesalamine medications and serum reproductive hormones in men.

BACKGROUND: Phthalates, such as dibutyl phthalate (DBP), are endocrine disruptors used in some medication coatings e.g., mesalamine to treat inflammatory bowel disease (IBD). OBJECTIVES: Taking advantage of different mesalamine formulations with/without DBP, we assessed whether DBP from mesalamine (>1000x background) altered serum hormones. METHODS: Men (N=73) with IBD participated in a crossover-crossback prospective study and provided up to 6 serum samples (2:baseline, 2:crossover, 2:crossback). Men on non-DBP mesalamine (background) at baseline crossed-over for 4 months to DBP-mesalamine (high) and then crossed-back for 4 months to non-DBP mesalamine (B1HB2-arm) and vice versa for men on DBP-mesalamine at baseline (H1BH2-arm). We divided H1BH2-arm at the median (H1<3yrs or H1≥3yrs). We estimated crossover and crossback % changes in serum reproductive hormones using multivariable linear mixed effect models. RESULTS: When B1HB2-arm (26 men,134 samples) crossed-over, luteinizing hormone decreased 13.9% (95% confidence interval(CI): -23.6,-3.0) and testosterone, inhibin-B, and follicle-stimulating hormone (FSH) marginally decreased; after crossback all increased 8-14%. H1BH2-arm, H1≥3yrs (25 men,107samples) had no changes at crossover or crossback whereas in H1BH2-arm,H1<3yrs (22 men,100 samples) after crossover, inhibin-B increased 13.2% (CI: 4.2,22.9), FSH decreased 9.9% (CI: -17.9,-1.1) and after crossback, inhibin-B further increased 11.3%, and FSH marginally increased. CONCLUSIONS: High-DBP exposure may disrupt pituitary-gonadal hormones that largely reversed after exposure removal, but only in men with no or short previous high-exposure history. Paradoxically, men with longer duration of high-DBP exposure, exposure removal did not change hormone levels, suggesting that long-term high-DBP exposure may alter the pituitary-gonadal axis and make it insensitive to exposure changes.

High Prevalence of Eosinophilic Gastrointestinal Disease in Children With Intestinal Failure.

OBJECTIVES: The aim of the present study was to describe the prevalence and clinical features of gastrointestinal (GI) eosinophilic inflammation among pediatric patients with intestinal failure (IF). METHODS: Medical records of all patients studied in our institution's IF program who underwent GI endoscopy over a 15-year period were reviewed, and clinical, pathologic, nutrition, and laboratory data collected. RESULTS: One hundred five patients underwent 208 GI endoscopic procedures with biopsy. The overall prevalence of eosinophilic inflammation, defined as increased eosinophils in at least 1 tissue type on at least 1 endoscopy, was 39 of 105 (37%). The tissue-specific prevalence of eosinophilic inflammation ranged widely, with the colon/rectosigmoid being the most common (18/68, 26%), followed by the esophagus (17/83, 20%), ileum (9/54, 17%), duodenum (4/83, 5%), and stomach (3/83, 4%). Higher peripheral eosinophil count and hematochezia were associated with eosinophilic inflammation in the colon (P = 0.002 and 0.0004, respectively). The use of a strict elemental diet for 3 months before endoscopy was not associated with a decreased frequency of eosinophilic inflammation in any tissue. CONCLUSIONS: Eosinophilic inflammation is a common histopathological finding in patients with IF. Colonic eosinophilic inflammation is associated with clinical symptoms of GI blood loss, and peripheral eosinophilia, and was not abrogated by a strict elemental diet.

A crossover-crossback prospective study of dibutyl-phthalate exposure from mesalamine medications and semen quality in men with inflammatory bowel disease.

BACKGROUND: Phthalates are widely used chemicals with ubiquitous exposure. Dibutyl-phthalate (DBP), a male reproductive toxicant in animals, is understudied in humans. Some mesalamine medications used to treat inflammatory bowel disease (IBD) have DBP in their coating, whereas other mesalamine formulations do not. OBJECTIVES: Taking advantage of differences in mesalamine formulations, we investigated whether high-DBP exposure from mesalamine medications was associated with decreased semen parameters. METHODS: 73 men with IBD taking mesalamine participated in a crossover-crossback prospective study. Men taking non-DBP containing mesalamine at baseline i.e., background exposure, crossed-over for four months to high-DBP mesalamine and then crossed-back for four months to their non-DBP mesalamine (B1HB2-arm;Background1-High-Background2) and vice versa for men taking high-DBP mesalamine at baseline (H1BH2-arm;High1-Background-High2). Men provided up to six semen samples (2: baseline, 2: crossover and 2: crossback). RESULTS: We estimated crossover, crossback and carryover effects using linear mixed models adjusted for abstinence time, age, season and duration on high-DBP mesalamine at baseline. Semen parameters in B1HB2-arm (26 men, 133 samples) decreased after high-DBP mesalamine exposure (crossover versus baseline), especially motility parameters, and continued to decrease further even after crossback to non-DBP mesalamine (crossback versus crossover). The cumulative carryover effect of high-DBP (crossback versus baseline) was a decrease of % total sperm motility by 7.61(CI:-13.1, -2.15), % progressive sperm motility by 4.23(CI:-8.05, -0.4) and motile sperm count by 26.0% (CI:-46.2%, 1.7%). However, H1BH2-arm (47 men, 199 samples) had no significant change during crossover or crossback. CONCLUSIONS: Men newly exposed to high-DBP mesalamine for four months had a cumulative reduction in several semen parameters, primarily sperm motility, that was more pronounced and statistically significant even after exposure ended for four months.

Urinary phthalate metabolite concentrations among men with inflammatory bowel disease on mesalamine therapy.

BACKGROUND: Phthalates, a family of compounds used in a variety of consumer products, are reproductive and developmental toxicants in experimental animals. One of these phthalates, dibutyl phthalate (DBP), is an inactive ingredient in the coating of Asacol. AIM: To determine if men with inflammatory bowel disease taking Asacol have higher urinary concentrations of monobutyl phthalate (MBP), a metabolite of DBP, compared to the general population in the United States. METHODS: Five patients at the Massachusetts General Hospital Crohn's and Colitis Center, taking at least 800 mg of Asacol three times a day, provided one spot urine sample. Urinary MBP and other phthalate metabolite concentrations were measured by using online solid phase extraction coupled with isotope dilution high-performance liquid chromatography tandem mass spectrometry. RESULTS: In four of the five men, the urinary concentrations of MBP (9888 ng/mL, 12,308 ng/mL, 10,124 ng/mL, and 41,590 ng/mL) and of a minor DBP metabolite, mono(3-carboxypropyl) phthalate (MCPP, 116.4 ng/mL, 163.4 ng/mL 72.6 ng/mL, 5604 ng/mL) were orders of magnitude higher than the background concentrations among the US general population. One subject missed his morning Asacol dose and had urinary MBP concentrations (17.5 ng/mL) similar to background levels. CONCLUSION: We confirmed that men with inflammatory bowel disease taking Asacol have urinary concentrations of MBP and MCPP much higher than background levels.

Comparison of 2 delivery vehicles for viscous budesonide to treat eosinophilic esophagitis in children.

OBJECTIVES: Oral viscous budesonide (OVB) using Splenda as a delivery vehicle has become an attractive therapeutic option for children with eosinophilic esophagitis (EoE). Many families are wary of giving the artificial sweetener in high doses to their children. The aim of the present study was to determine whether OVB mixed with Neocate Nutra, a hypoallergenic nutritional supplement, is at least as efficacious as OVB mixed with Splenda at healing EoE. METHODS: Our institutional review board approved a retrospective chart review of patients with well-documented EoE treated with OVB at the Boston Children's Hospital Eosinophilic Gastrointestinal Disorder program between June 2008 and June 2013. Primary outcome measured was histologic response defined as change in peak eosinophil count to <15 eosinophils per high-power field (eos/HPF) after at least 10 weeks of OVB therapy. RESULTS: A total of 46 children were treated with OVB mixed with Splenda, and 14 were treated with OVB mixed with Neocate Nutra. The 2 groups were not significantly different in their demographic (race, age, sex) or clinical (initial eosinophil count, proton pump inhibitor use, or concomitant dietary elimination) characteristics. On follow-up endoscopy, 30 of 46 patients on Splenda and 13 of 14 patients on Neocate Nutra achieved histologic response. Mean pretreatment and posttreatment peak eosinophil counts for the children taking Neocate Nutra were 62 eos/HPF ([high-power field] range 20-120 eos/HPF) and 9 eos/HPF (range 0-100 eos/HPF), respectively. Mean pretreatment and posttreatment peak eosinophil counts for the Splenda group were 59.5 eos/HPF (range 20-180 eos/HPF) and 25.5 eos/HPF (range 0-200 eos/HPF), respectively. The odds ratio (OR) of success with Neocate Nutra as compared with Splenda was 6.93 (95% CI 0.83-57.91, P = 0.0728), demonstrating the noninferiority of Neocate Nutra. CONCLUSIONS: We demonstrate that OVB mixed with Neocate Nutra is at least as effective as OVB mixed with Splenda at treating children with EoE. Neocate Nutra is an innovative, effective, and palatable mixing agent to create a viscous budesonide slurry for families who prefer not to use the standard recipe with Splenda.

Distinct microbiome in pouchitis compared to healthy pouches in ulcerative colitis and familial adenomatous polyposis.

BACKGROUND: Pouchitis occurs in up to 50% of patients with ulcerative colitis (UC) undergoing ileal pouch anal anastomosis (IPAA). Pouchitis rarely occurs in patients with familial adenomatous polyposis (FAP) who undergo IPAA. Our aim was to compare mucosal and luminal flora in patients with UC-associated pouchitis (UCP), healthy UC pouches (HUC), and healthy FAP pouches (FAP). METHODS: Nineteen patients were enrolled in this cross-sectional study (nine UCP, three HUC, seven FAP). Patients with active pouchitis were identified using the Pouchitis Disease Activity Index (PDAI). Ileal pouch mucosal biopsies and fecal samples were analyzed with a 16S rDNA-based terminal restriction fragment length polymorphism (TRFLP) approach. Pooled fecal DNA from four UCP and four FAP pouches were sequenced for further speciation. RESULTS: TRFLP data revealed statistically significant differences in the mucosal and fecal microbiota between each group of patients. UCP samples exhibited significantly more TRFLP peaks matching Clostridium and Eubacterium genera compared to HUC and FAP pouches and fewer peaks matching Lactobacillus and Streptococcus genera compared to FAP. DNA Sanger sequencing of a subset of luminal samples revealed UCP having more identifiable sequences of Firmicutes (51.2% versus 21.2%) and Verrucomicrobia (20.2% versus 3.2%), and fewer Bacteroidetes (17.9% versus 60.5%) and Proteobacteria (9.8% versus 14.7%) compared to FAP. CONCLUSIONS: The pouch microbial environment appears to be distinctly different in the settings of UC pouchitis, healthy UC, and FAP. These findings suggest that a dysbiosis may exist in pouchitis which may be central to understanding the disease.

Self-management of older adolescents with inflammatory bowel disease: a pilot study of behavior and knowledge as prelude to transition.

OBJECTIVE: Patients gradually assume responsibility for self-management. This study sought to determine whether adolescents with inflammatory bowel disease (IBD) have developed key skills of self-management prior to the age at which many transfer to adult care. PATIENTS AND METHODS: Adolescents aged 16 to 18 years old in the Children's Hospital Boston IBD database (94 total) received a mailed survey assessing knowledge and confidence of their own health information and behaviors. RESULTS: Respondents (43%) could name medication and dose with confidence but had very poor knowledge of important side effects. Most patients deferred responsibility mostly or completely to parents for scheduling appointments (85%), requesting refills (75%), or contacting provider between visits (74%). CONCLUSIONS: Older adolescents with IBD have good recall of medications but not of side effects. Parents remain responsible for the majority of tasks related to clinic visits and the acquisition of medications.

Clinical significance of colonic intraepithelial lymphocytosis in a pediatric population.

The significance of colonic intraepithelial lymphocytosis has been well described in adults, and is associated with lymphocytic colitis, untreated celiac disease, and medications, among others. Little is known about the meaning of colonic intraepithelial lymphocytosis in the pediatric population; this study examines this finding in a cohort of children. Twenty patients in whom colonic intraepithelial lymphocytosis was a prominent feature were identified from 1999 to 2005. Colonic intraepithelial lymphocytosis was defined as 20 or more intraepithelial lymphocytes per 100 colonocytes present in at least one colonic mucosal biopsy. Each biopsy was examined for numbers of intraepithelial lymphocytes per 100 surface and crypt colonocytes; various architectural, inflammatory, and metaplastic changes were also noted. When available, concurrent duodenal and/or ileal biopsies were examined. Studied clinical parameters included indications for biopsy, clinical follow-up, final diagnosis, comorbidities, autoimmune serologies, and medications. A total of 121 colonic mucosal biopsies were examined in 20 patients who ranged from 1 to 17 years (mean 10.2 years; 40% male). Common indications for endoscopy included diarrhea and abdominal pain. A mean of 29 (+/-22) intraepithelial lymphocytes per 100 enterocytes were seen. Seven patients had colonic intraepithelial lymphocytosis as the only histologic finding. The remaining 13 patients had additional architectural, inflammatory, and metaplastic changes. The mean follow-up period was 14 months (range 1-48 months). Inflammatory bowel disease was diagnosed in 4 of 20 patients and was seen chiefly in biopsies in which colonic intraepithelial lymphocytosis was associated with architectural or inflammatory changes. Common disease associations include celiac disease, lymphocytic colitis, and autoimmune enteropathy. Pediatric colonic intraepithelial lymphocytosis, in the absence of other histologic findings, is associated with various diseases, including celiac disease, lymphocytic colitis, and autoimmune enteropathy. Colonic intraepithelial lymphocytosis in the presence of other inflammatory changes indicates the possibility of idiopathic inflammatory bowel disease. These findings are similar to those seen in adults, with the exception of autoimmune enteropathy.

Transition of adolescents with inflammatory bowel disease from pediatric to adult care: a survey of adult gastroenterologists.

OBJECTIVES: Transition of patients with inflammatory bowel disease (IBD) from pediatric to adult providers requires preparation. Gastroenterologists for adult patients ("adult gastroenterologists") may have expectations of patients that are different from those of pediatric patients. We sought to explore the perspectives of adult gastroenterologists caring for adolescents and young adults with IBD, to improve preparation for transition. MATERIALS AND METHODS: A survey sent to 1132 adult gastroenterologists caring for patients with IBD asked physicians to rank the importance of patient competencies thought necessary in successful transition to an adult practice. Providers reported which problems occurred in patients with IBD transitioning to their own practice. Adult gastroenterologists were asked about medical and developmental issues that are unique to adolescence. RESULTS: A response rate of 34% was achieved. Adult gastroenterologists reported that young adults with IBD often demonstrated deficits in knowledge of their medical history (55%) and medication regimens (69%). In addition, 51% of adult gastroenterologists reported receiving inadequate medical history from pediatric providers. Adult providers were less concerned about the ability of patients to identify previous and current health care providers (19%), or attend office visits by themselves (15%). Knowledge of adolescent medical and developmental issues was perceived as important by adult gastroenterologists; however, only 46% felt competent addressing the developmental aspects of adolescents. CONCLUSIONS: For successful transition, adolescents and young adults with IBD need improved education about their medical history and medications. Pediatric providers need to improve communication with the receiving physicians. In addition, adult providers may benefit from further training in adolescent issues. Formal transition checklists and programs may improve the transition of patients with IBD from pediatric to adult care.