Dietary treatment modulates mast cell phenotype, density, and activity in adult eosinophilic oesophagitis.

BACKGROUND: Mast cells (MCs) are abundant in the inflammatory infiltrate in eosinophilic oesophagitis (EoE), but decrease with disease remission. However, their phenotype, role in the pathophysiology of the disease, and modulation after effective dietary therapy are still unclear. OBJECTIVE: To define the phenotype of oesophageal MCs, their modulation through dietary therapy, and their association with clinical manifestations of EoE. METHODS: Oesophageal mucosal samples from 10 adult patients with EoE obtained before and after effective six-food elimination diet (SFED) therapy, as well as from 10 control subjects were analysed. Eosinophil and MC density were quantified. Gene expression of chemoattractants for eosinophils (CCL11, CCL24, and CCL26), MCs (SCF), and their receptors (CCR3 and SCFR, respectively) were assessed by means of qPCR. Gene and protein expression of specific MC proteases (CPA3, CMA, and TPSB2) were evaluated with qPCR and immunofluorescence. Clinical manifestations and atopic background were recorded. RESULTS: MC density was significantly increased in EoE compared with controls, decreasing after dietary treatment (18.6 to 1.44 cells/hpf, respectively; P < 0.001). The MCTC subtype predominated in the oesophageal mucosa (90%) in both patients with EoE and controls. Gene expression of MC-related proteases, eotaxins, and SCF were up-regulated in patients with EoE, but significantly decreased after therapy, regardless of atopic background. Epithelial peaks of MCs and eosinophils were significantly associated (ρ = 0.80) in EoE and correlated with the symptom score (ρ = 0.78). Gene expression of MC proteases and eotaxins also correlated with the symptom score (P < 0.05). CONCLUSIONS AND CLINICAL RELEVANCE: MC and its proteases seem to play a relevant role in the pathophysiology and symptoms of EoE, which can be reversed after effective dietary treatment.

Eosinophilic esophagitis is characterized by a non-IgE-mediated food hypersensitivity.

Eosinophilic esophagitis (EoE) is a chronic disease characterized clinically by symptoms of esophageal dysfunction and histologically by eosinophil-predominant inflammation. EoE is frequently associated with concomitant atopic diseases and immunoglobulin E (IgE) sensitization to food allergens in children as well as to aeroallergens and cross-reactive plant allergen components in adults. Patients with EoE respond well to elemental and empirical food elimination diets. Recent research has, however, indicated that the pathogenesis of EoE is distinct from IgE-mediated food allergy. In this review, we discuss the individual roles of epithelial barrier defects, dysregulated innate and adaptive immune responses, and of microbiota in the pathogenesis of EoE. Although food has been recognized as a trigger factor of EoE, the mechanism by which it initiates or facilitates eosinophilic inflammation appears to be largely independent of IgE and needs to be further investigated. Understanding the pathogenic role of food in EoE is a prerequisite for the development of specific diagnostic tools and targeted therapeutic procedures.

Eosinophilic Esophagitis: An Evidence-Based Approach to Therapy.

In recent years, several randomized controlled trials and meta-analyses have evaluated the efficacy of the various therapeutic options available for treating patients with eosinophilic esophagitis, including dietary modifications, proton pump inhibitors, topical corticosteroids, and endoscopic esophageal dilation. Proton pump inhibitors are currently considered the first-line treatment for eosinophilic esophagitis, achieving histological remission and improvement of symptoms in 50.5% and 60.8% of patients, respectively. The efficacy of topical corticosteroids in eosinophilic esophagitis has been assessed in several trials. Meta-analyses summarizing results indicate that budesonide and fluticasone propionate are significantly superior to placebo, both in decreasing eosinophil densities in the esophageal mucosa and in relieving symptoms. However, owing to differences in drug delivery, viscous budesonide seems to be the best pharmacological therapy for eosinophilic esophagitis. Results for dietary modifications have been mixed depending on the type of diet prescribed. Thus, while exclusive amino acid-based elemental diets are the most effective in inducing histological remission of eosinophilic esophagitis (90.8%), their severe drawbacks limit their implementation in clinical practice. Allergy testing-based food elimination provides a suboptimal remission rate of 45.5%, although this is lower in adults than in children (32.2% vs 47.9%, respectively). In addition, the various available studies are highly heterogeneous. Empirical 6-food elimination diets were shown to be the best diet-based therapy, with a homogeneous remission rate of 72%. Simpler, more convenient empirical schemes have also been evaluated. The aim of this review is to provide an evidence-based overview on the efficacy of the options available for treatment of eosinophilic esophagitis along with a practical management algorithm.

Seasonal distribution of initial diagnosis and clinical recrudescence of eosinophilic esophagitis: a systematic review and meta-analysis.

BACKGROUND: The association between seasonality and diagnosis and/or recrudescence of eosinophilic esophagitis (EoE) remains unclear, with some studies demonstrating a higher diagnostic rate in those months with a higher aeroallergen load while others rule out this association. METHODS: We performed a systematic search of the MEDLINE, EMBASE, and SCOPUS databases for studies on the seasonality of the initial diagnosis or recrudescence (i.e., food bolus impaction) of EoE. Summary estimates, including 95% confidence intervals, were calculated for seasonal variation in diagnosis or incidence of food bolus impaction. A random-effects meta-regression model was made using aggregate-level data to compare seasonality in EoE diagnosis and recrudescence. Publication bias risks were assessed by means of funnel plot analysis. RESULTS: Of 1078 references found, data were finally collected from 18 studies which included a total of 16,846 EoE patients. Of all new cases of EoE diagnosed per year, 27.1% were diagnosed in spring and 21.5% in winter. No overall statistical differences in the annual seasonal distribution of newly diagnosed EoE cases were observed in the random-effects meta-regression model (P = 0.132). Similarly, a homogenous distribution of episodes of EoE recrudescence throughout the year was noted, with no significant differences between seasons (P = 0.699). No significant publication bias was found. CONCLUSIONS: This systematic review found no significant variations in the seasonal distribution of either the diagnosis or clinical recrudescence of EoE throughout the year.

Advances in knowledge on microscopic colitis: From bench to bedside.

Microscopic colitis (MC) is a general term that describes a family of chronic inflammatory bowel diseases, including lymphocytic colitis (LC) and collagenous colitis (CC). The two forms are characterized by chronic watery diarrhea with normal or near normal endoscopic colonic appearance and specific histopathological abnormalities.Data from recent epidemiological studies reported the diagnosis of MC from several different regions in the world, providing that it can be a worldwide condition. The etiopathogenesis of MC still remains unknown but it is generally accepted that MC is a multifactorial disease, probably secondary to an abnormal immune reaction in predisposed individuals, triggered by different luminal factors (infections, drugs, autoimmunity and/or bile acids). Furthermore, some studies show that the epithelial barrier function in the colonic mucosa of MC patients is also impaired. Several mucosal factors of intestinal inflammation have been studied in MC, postulating that an aberrant T-lymphocyte response may lead to a chronic gut inflammatory condition, with the infiltration of colonic mucosa by different proportion of subset of T-lymphocytes. Little is known about the specific inflammatory mediators in MC pathogenesis, but a predominant Th1 type cytokine profile has been demonstrated. Currently, a number of medical treatments have been studied in MC patients, following mainly an empirical treatment approach. Further studies are needed in order to obtain prospective and more evidence-based data. In the future, it will be possible to develop causal treatment approaches after better understanding the molecular mechanisms behind the origin of the disease.

Propofol administration is safe in adult eosinophilic esophagitis patients sensitized to egg, soy, or peanut.

BACKGROUND: Sedation might improve tolerability and adherence to endoscopic procedures in patients with eosinophilic esophagitis (EoE). Propofol administration is often contraindicated in patients with hypersensitivity to egg, soy, or peanut. OBJECTIVE: To investigate the safety of propofol administration for procedural sedation in EoE patients sensitized/allergic to egg, soy, peanut. METHODS: A retrospective observational study in adult EoE patients undergoing esophagogastroduodenoscopy with propofol sedation was conducted between January 2009 and March 2013. Food-specific serum IgE and skin prick tests for egg, soy, peanut, and cross-reactant foods were performed in all patients. RESULTS: Sixty EoE adult patients, mostly on food elimination diets (91%), were evaluated (age: 28 years (14-56), male gender (90%)). Atopy was present in 88% of patients, being the most prevalent comorbidities rhinoconjunctivitis (78%) and asthma (67%). Fifty-two patients (86%) were sensitized to either egg, soy, or peanut. Eighteen patients (28%) had a history of allergic reactions to egg, legumes, and nuts and strictly avoided these foods. A total of 404 upper endoscopies were performed under propofol sedation. No allergic adverse events were reported, except a transient bronchospasm after orotracheal intubation in an asthmatic adolescent receiving multiple drugs for anesthesia, in whom no sensitization to either propofol or its lipid vehicle was confirmed. CONCLUSIONS: Propofol was safely administered for procedural sedation in a large series of adult EoE patients multisensitized to egg, soy, peanut, showing one-third clinical allergy to these foods.

Tolerance of a cow's milk-based hydrolyzed formula in patients with eosinophilic esophagitis triggered by milk.

BACKGROUND: Cow's milk protein, a major food trigger for EoE in both children and adults, should be continuously avoided once identified as such. This study evaluates tolerance of a cow's milk-based extensively hydrolyzed formula (eHF) with regard to disease remission maintenance in adult patients with milk-triggered EoE. METHODS: Seventeen adult patients in whom cow's milk was consecutively demonstrated to trigger EoE after an empiric six-food elimination diet-based study protocol and who subsequently maintained disease remission were prospectively recruited. They were given 400 ml of a cow's milk-based eHF daily for 8 weeks. Intraepithelial peak eosinophil and blood eosinophil counts, esophageal-related symptoms, serum total and specific IgE to major milk proteins, and eosinophil cationic protein were monitored before and after eHF intake. RESULTS: Thirteen male and four female patients aged 17-56 completed the study protocol. 15 patients (88.24%) achieved and maintained EoE remission, while an infiltration of ≥15 eosinophils/hpf reappeared in the remaining two patients. No differences in age, gender, symptoms, and endoscopic appearance at baseline conditions or personal/family allergic background were observed between those patients who tolerated the eHF and those who did not. Symptom scores did not significantly change after eHF intake and were significantly lower than those documented at baseline conditions or after cow's milk challenge. No differences were documented in blood eosinophil counts or serum markers after eHF intake. CONCLUSION: Most adult patients with EoE triggered by cow's milk tolerate a cow's milk-based eHF, thus providing them with a safe, economical alternative to cow's milk.

Single nucleotide polymorphisms in ADAM17, IL23R and SLCO1C1 genes protect against infliximab failure in adults with Crohn's disease.

BACKGROUND: To predict primary failure of infliximab (IFX) therapy in Crohn's disease (CD) and to identify patients who maintain long-term effectiveness to IFX is currently not feasible. Some genetic variations are proposed as potential biomarkers. AIM: We assessed a set of single nucleotide polymorphisms (SNPs) in genes related to the IFX mechanism of action and the presence of HLA-DQA1 * 05 allele on the primary response and long-term durability in CD patients. METHODS: A multi-centre cross-sectional study of IFX-exposed adult patients with CD was undertaken. Treatment persistence and time to failure were co-primary endpoints. DNA from the 131 patients was genotyped. Association between SNPs and clinical variables with IFX persistence was assessed. RESULTS: Failure to IFX was documented in 65 (49.6%) out of 131 patients. IFX persistence was associated either with carrying the TT genotype in ADAM17 rs10929587 (ORa=0.2; 95%CI=0.1-0.8; p = 0.021), or the CC genotype in SLCO1C1 rs3794271 (ORa=0.2; 95%CI=0.1-0.7; p = 0.008), according to multivariate logistic regression. In contrast, previous bowel resection increased the risk of IFX failure (ORa=2.8; 95%CI=1.1-7.3; p = 0.025). Cox regression analysis confirmed these findings and also identified IL23R rs10489629-TT (HRa 0.41; 95%CI=0.22-0.75; p = 0.004) and concomitant immunosuppressants (HRa 0.46; 95%CI=0.27-0.77; p = 0.003) as protection from IFX failure. However, no association between HLA-DQA1 * 05 allele and persistence of IFX therapy was found, with similar failure rates among carriers and non-carriers (52.8% vs. 47.4%, respectively; p = 0.544). CONCLUSIONS: SNPs rs10929587-TT in ADAM17, rs10489629-TT in IL23R and rs3794271-CC in SLCO1C1, together with no previous bowel surgery and concomitant immunosuppression, were identified as protection from failure to IFX.

Clinical features and immune mechanisms directly linked to the altered liver function in patients with rheumatoid arthritis.

BACKGROUND: The aim of this study was to explore the impact of arthritis on liver function using different approaches in vivo and in vitro. METHODS: A cross-sectional study was performed on 330 non-obese/non-T2DM subjects: 180 RA patients, 50 NAFLD non-RA patients, and 100 healthy donors (HDs). A longitudinal study was conducted on 50 RA patients treated with methotrexate for six months. Clinical and laboratory parameters and markers of liver disease were collected. Mechanistic studies were carried out in both the CIA mouse model and hepatocytes treated with anti-citrullinated protein antibodies (ACPAs). RESULTS: RA patients have an increased risk of suffering from liver disease independent of obesity or T2DM. This risk was associated with factors such as insulin resistance, autoantibodies, inflammation, and component C3. Methotrexate treatment for six months was associated with liver abnormalities in those newly-diagnosed patients having CV risk factors. ACPAs induced a defective hepatocyte function, promoting IR and inflammation. The induction of arthritis in mice caused the infiltration of immune cells in the liver and increased inflammatory, apoptotic, and fibrotic processes. CONCLUSION: RA patients may experience mild to moderate liver inflammation due to the infiltration of T, B cells, and macrophages, and the action of ACPAs. This is independent of obesity or diabetes and linked to systemic inflammation, and disease activity levels. The negative effects of methotrexate on liver function could be restricted to the concomitant presence of cardiovascular risk factors.

Decoding clinical and molecular pathways of liver dysfunction in Psoriatic Arthritis: Impact of cumulative methotrexate doses.

BACKGROUND: The occurrence of liver abnormalities in Psoriatic Arthritis (PsA) has gained significant recognition. Identifying key factors at the clinical and molecular level can help to detect high-risk patients for non-alcoholic fatty liver disease in PsA. OBJECTIVES: to investigate the influence of PsA and cumulative doses of methotrexate on liver function through comprehensive in vivo and in vitro investigations. METHODS: A cross-sectional study involving 387 subjects was conducted, 200 patients with PsA, 87 NAFLD-non-PsA patients, and 100 healthy donors (HDs), age and sex-matched. Additionally, a retrospective longitudinal study was carried out, including 83 PsA patients since initiation with methotrexate. Detailed clinical, and laboratory parameters along with liver disease risk were analyzed. In vitro, experiments with hepatocyte cell line (HEPG2) were conducted. RESULTS: PsA patients present increased liver disease risk associated with the presence of cardiometabolic comorbidities, inflammatory markers, onychopathy, and psoriasis. The treatment with PsA serum on hepatocytes encompassed inflammatory, fibrotic, cell stress, and apoptotic processes. At the molecular level, methotrexate impacts liver biology, although the cumulative doses did not affect those alterations, causing any potential damage to liver function at the clinical level. Finally, anti-PDE-4 or anti-JAK decreased the inflammatory profile induced by PsA serum on hepatocytes. CONCLUSION: 1)This study identifies the complex link between liver disease risk, comorbidities, and disease-specific features in PsA patients. 2)Methotrexate dose in PsA patients had no significant effect on liver parameters, confirmed by hepatocyte in vitro studies. 3)Anti-PDE-4 and anti-JAK therapies show promise in reducing PsA serum-induced hepatocyte activation, potentially aiding liver complication management.

Real-world use of mycophenolate mofetil in inflammatory bowel disease: Results from the ENEIDA registry.

BACKGROUND: Studies to evaluate the use of mycophenolate mofetil (MMF) in inflammatory bowel disease (IBD) are limited after the appearance of biological treatments. AIMS: Our primary objective was to evaluate the effectiveness and safety of MMF in IBD. METHODS: IBD patients who had received MMF were retrieved from the ENEIDA registry. Clinical activity as per the Harvey-Bradshaw Index (HBI), partial Mayo score (pMS), physician global assessment (PGA) and C-reactive protein (CRP) were reviewed at baseline, at 3 and 6 months, and at final follow-up. Adverse events and causes of treatment discontinuation were documented. RESULTS: A total of 83 patients were included (66 Crohn's disease, 17 ulcerative colitis), 90% of whom had previously received other immunosuppressants. In 61% of patients systemic steroids were used at initiation of MMF, and in 27.3% biological agents were co-administered with MMF. Overall clinical effectiveness was observed in 64.7% of the population. At the end of treatment, 45.6% and 19.1% of subjects showed remission and clinical response, respectively. MMF treatment was maintained for a median of 28.9 months (IQR: 20.4-37.5). CONCLUSION: Our study suggests, in the largest cohort to date, that MMF may be an effective alternative to thiopurines and methotrexate in IBD.

Esophageal manifestations of celiac disease.

Celiac disease (CD) may often be associated with various motor disorders affecting the different segments of the digestive tract, including the esophagus. Although it has not been universally reported, some available evidences indicate that pediatric and adult celiac patients could manifest a higher frequency of esophagitis and gastroesophageal reflux disease-related symptoms compared to nonceliac patients. In addition, several published studies have consistently shown the efficacy of a gluten-free diet in rapidly controlling esophageal symptoms and in preventing their recurrence. Since the participation of gluten in the esophageal symptoms of CD seems clear, its intimate mechanisms have yet to be elucidated, and several hypothesis have been proposed, including the specific immune alterations characterizing CD, the reduction in nutrient absorption determining the arrival of intact gluten to distal gastrointestinal segments, and various dysregulations in the function of gastrointestinal hormones and peptides. Recent studies have suggested the existence of a possible relationship between CD and eosinophilic esophagitis, which should be more deeply investigated.

Boerhaave's syndrome as the primary manifestation of adult eosinophilic esophagitis. Two case reports and a review of the literature.

Eosinophilic esophagitis (EoE) has been associated with an increased risk of esophageal mucosal tears induced by vomiting to dislodge impacted food or following endoscopic procedures. However, Boerhaave's syndrome or transmural perforation of the organ resulting from vomiting induced to dislodge impacted food has rarely been reported. In this article, we present two male adult patients with long-term esophageal symptoms who suffered from Boerhaave's syndrome after the impaction of food in the esophagus. Both patients required surgical management because of clinical and radiological signs of perforation. This rare complication of EoE has been documented in 11 other reports, predominantly affecting young men in whom EoE had not been previously diagnosed, despite the majority having esophageal symptoms and a history of atopy. There are only two published cases of esophageal perforation that presented in children, which were managed conservatively. Our two patients and 4 out of the 11 described in literature required surgery because of esophageal perforation. Our two cases involved closure of the perforation, while in three published reports, perforation resulted in a partial or complete esophagectomy. No cases have been published on Boerhaave's syndrome caused by EoE that ended in fatalities. It is important to note that esophageal perforation caused by vomiting is a potentially severe complication of EoE that is being increasingly described in literature. Therefore, patients with non-traumatic Boerhaave's syndrome should be assessed for EoE, especially if they are young men who have a prior history of dysphagia and allergic manifestations.

Esophageal microbiome in active eosinophilic esophagitis and changes induced by different therapies.

Eosinophilic esophagitis (EoE) is a chronic, immune-mediated inflammatory esophageal disease triggered by food antigens. Cumulative evidence supports the implication of microbiota and the innate immune system in the pathogenesis of EoE. Changes in the esophageal microbiome were investigated by applying 16S rRNA gene sequencing on esophageal biopsies of adult patients with active EoE at baseline (n = 30), and after achieving remission with either proton pump inhibitors (PPI, n = 10), swallowed topical corticosteroids (STC, n = 10) or food-elimination diets (FED, n = 10). Ten non-EoE biopsies were also characterized as controls. Compared to controls, no differences in alpha (intra-sample) diversity were found in EoE microbiota overall. However, it decreased significantly among patients who underwent FED. As for beta (inter-sample) diversity, non-EoE controls separated from EoE baseline samples. Post-treatment samples from patients treated with PPI and FED had a more similar microbiota composition, while those receiving STC were closer to controls. Differential testing of microbial relative abundance displayed significant changes for Filifactor, Parvimonas and Porphyromonas genera. Analysis of predicted functions indicated alterations in metabolic pathways and abundance of sulphur-cytochrome oxidoreductases. Our findings demonstrate changes in microbiota associated with EoE, as well as a treatment effect on the microbiome.

Endoscopic, bioptic, and manometric findings in eosinophilic esophagitis before and after steroid therapy: a case series.

BACKGROUND AND AIM: Eosinophilic esophagitis can be associated with a wide range of endoscopic patterns. The aim of the present case series report is to describe and classify endoscopic appearances before and after corticoid therapy in relation to histopathology and manometry. PATIENTS AND METHODS: In 30 patients (m : f, 27 : 3; mean age 36.2 years) with eosinophilic esophagitis, endoscopic findings were prospectively classified according to luminal diameter and mucosal pattern. Manometric and bioptic histopathologic findings were also recorded. Endoscopy was repeated following a 3-month course of steroid therapy. RESULTS: In total, 20 % of patients showed a concentric esophageal stricture, and in 57 % simultaneous contraction rings were visible. Mucosal alterations consisted of granular mucosa (20 %), longitudinal furrows (33 %) and transversal undulations (3 %). Lower esophageal sphincter dysfunction and distal esophageal dysfunctional manometry were seen in 73 % and 57 % of cases, respectively. Following steroids, the esophagus showed a normal caliber in 97 % of patients, and 63 % of patients had normal mucosa. CONCLUSIONS: The most frequent findings were narrowing of the esophageal lumen, which returned to normal following steroid treatment to a larger extent than mucosal alterations.

Systematic review: health-related quality of life in children and adults with eosinophilic oesophagitis-instruments for measurement and determinant factors.

BACKGROUND: Several measures have been used to assess the health-related quality of life (HRQoL) of patients with eosinophilic oesophagitis (EoE). AIMS: To systematically review these HRQoL measures, to appraise measurement properties of specific instruments and to evaluate determinant factors influencing HRQoL in paediatric and adult EoE patients. METHODS: We searched the PubMed, Embase, Scopus, Web of Science (WOS) and PsycINFO databases for documents providing original information on the development of measurement tools and/or evaluation of HRQoL outcomes in EoE patients of all ages. RESULTS: Of the 596 references identified, data was collected from 34 studies (with only 16 of them being published as full papers) including a total of 1,689 individual patients. Three disease-specific HRQoL measures in EoE covering different aspects of patients' lives and developed in English, were scored positive regarding measurement properties. The PedsQL inventory (including parent and child report forms) and the Peds-QoL EoE module were the generic and specific instruments respectively used in children, while the SF-36 and EoE-QoL-A were the most used questionnaires in adults. Patients with EoE show an impaired HRQoL compared to controls, which greatly depends on symptom severity and disease duration. Severity of endoscopic features and female gender may also determine an impaired HRQoL. The effect of treatments on HRQoL requires further assessment. CONCLUSIONS: HRQoL is a relevant outcome that should be considered in clinical practice and research of EoE. Further validation studies in several languages and populations are required to support the use of disease-specific HRQoL measures.