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.

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.

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.

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 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.

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.

Systematic review with meta-analysis: endoscopic dilation is highly effective and safe in children and adults with eosinophilic oesophagitis.

BACKGROUND: Oesophageal dilation is frequently used as an adjunct treatment to alleviate symptoms that develop from fibrostenotic remodelling in eosinophilic oesophagitis (EoE). Earlier reports described an increased risk of complications associated with dilation. AIM: Perform a systematic review and meta-analysis to assess the efficacy and safety of endoscopic dilation in children and adults with EoE. METHODS: Professional librarians searched MEDLINE, EMBASE, the Cochrane library, Scopus, and Web of Science for articles in any language describing studies of dilation in EoE through December 2016. Studies were selected and data were abstracted independently and in duplicate. Random effects modelling was used to generate summary estimates for clinical improvement and complications (haemorrhage, perforation, hospitalisation, and death). RESULTS: The search resulted in 3495 references, of which 27 studies were included in the final analysis. The studies described 845 EoE patients, including 87 paediatric patients, who underwent a total of 1820 oesophageal dilations. The median number of dilations was 3 (range: 1-35). Clinical improvement occurred in 95% of patients (95% CI: 90%-98%, I2 : 10%, 17 studies). Perforation occurred in 0.38% (95% CI: 0.18%-0.85%, I2 : 0%, 27 studies), haemorrhage in 0.05% (95% CI: 0%-0.3%, I2 : 0%, 18 studies), and hospitalisation in 0.67% (95% CI: 0.3%-1.1%, I2 : 44%, 24 studies). No deaths occurred (95% CI: 0%-0.2% I2 : 0%, 25 studies). CONCLUSIONS: Endoscopic dilation is consistently effective in children and adults with EoE, resulting in improvement in 95% of patients with very low rates (<1%) of major complications.

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.

Systematic review with meta-analysis: diagnostic overlap of microscopic colitis and functional bowel disorders.

BACKGROUND: Microscopic colitis shares certain common clinical manifestations with functional bowel disorders, especially diarrhoea-dominant irritable bowel syndrome (IBS) and functional diarrhoea. However, the exact relationship between microscopic colitis and functional bowel disorders has not been systematically assessed. AIM: To conduct a systematic review and meta-analysis on the diagnostic overlap between functional bowel disorders and microscopic colitis. METHODS: We searched MEDLINE, EMBASE and SCOPUS databases, as well as the abstract books of the major gastroenterology meetings, to investigate the prevalence of microscopic colitis among patients with functional bowel disorders (considering all subtypes of both disorders) and vice versa. Data were pooled with a random-effects model. RESULTS: Of 227 references identified, data were collected from 26 studies and a total of 5,099 adult patients. The pooled prevalence any type of functional bowel disorders in patients who present diagnostic criteria of microscopic colitis was 39.1% (95% CI: 22.8-56.6%; I2 : 97%) and was higher for lymphocytic colitis than for collagenous colitis (40.7% vs. 28.4%, respectively; P = 0.58). The prevalence of microscopic colitis in functional bowel disorders patients was 7% (95% CI: 3.6-11.4%), reaching 9.8% (95% CI: 4.4-17.1%; I2 : 95%) in patients exhibiting diarrhoea-dominant IBS, nonsignificantly higher than microscopic colitis rates among patients with constipation-dominant IBS (1.3%) or mixed-dominant IBS (1.9%). CONCLUSIONS: There is a significant overlap of symptoms between microscopic colitis and functional bowel disorders, especially in diarrhoeal subtypes. The high proportion of microscopic colitis among diarrhoea-dominant functional syndromes should serve as a call for more active diagnosis in selected patients.

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.

Systematic review with meta-analysis: the incidence and prevalence of eosinophilic oesophagitis in children and adults in population-based studies.

BACKGROUND: The recognition of eosinophilic oesophagitis (EoE) has risen sharply, but its current epidemiology is still under debate. AIM: To estimate accurately the prevalence and incidence rates of EoE, by a systematic review and meta-analysis. METHODS: MEDLINE, EMBASE and SCOPUS databases were searched for population-based studies on the epidemiology of EoE. Pooled incidence and prevalence rates, male:female and children:adult ratios, and geographical and temporal variations were calculated with random-effects models. RESULTS: The search yielded 1334 references; the final quantitative summary included 13 population-based studies from North America, Europe and Australia, with the results showing high heterogeneity. The pooled EoE incidence rate was 3.7/100 000 persons/year [95% confidence interval (CI): 1.7-6.5] and was higher for adults (7; 95% CI: 1-18.3) than for children (5.1; 95% CI: 1.5-10.9). The pooled prevalence of EoE was 22.7 cases/100 000 inhabitants (95% CI: 12.4-36), rising to 28.1 (95% CI: 13-49) when studies with a lower risk of bias were considered; prevalence was higher in adults than in children (43.4; 95% CI: 22.5-71.2 vs. 29.5; 95% CI: 17.5-44.7, respectively), and in American compared to European studies. A steady rise in EoE incidence and prevalence rates was observed upon comparison of studies conducted before and after 2008. No significant publication bias was found. CONCLUSIONS: Eosinophilic oesophagitis is an increasingly common diagnosis in North America and Europe. The population-based incidence and prevalence of eosinophilic oesophagitis vary widely across individual studies, probably due to variations in diagnosis and risk of bias of research. More prospective, large-scale, multicenter studies are needed to evaluate reported data.

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.

Current concepts on microscopic colitis: evidence-based statements and recommendations of the Spanish Microscopic Colitis Group.

BACKGROUND: Microscopic colitis (MC) is an underdiagnosed inflammatory bowel disease. AIM: To develop an evidence-based clinical practice guide on MC current concepts. METHODS: Literature search was done on the Cochrane Library, EMBASE and MEDLINE electronic databases, which were consulted covering the period up until March 2015. Work groups were selected for each of the reviewed topics, with the purpose of drafting the initial statements and recommendations. They subsequently underwent a voting process based on the Delphi method. Each statement/recommendation was accompanied by the result of the vote the level of evidence, and discussion of the corresponding evidence. The grade of recommendation (GR) using the GRADE approach was established for diagnosis and treatment recommendations. RESULTS: Some key statements and recommendations are: advancing age increases the risk of developing MC, mainly in females. The symptoms of MC and IBS-D may be similar. If MC is suspected, colonoscopy taking biopsies is mandatory. Treatment with oral budesonide is recommended to induce clinical remission in patients with MC. Oral mesalazine is not recommended in patients with collagenous colitis for the induction of clinical remission. The use of anti-TNF-alpha drugs (infliximab, adalimumab) is recommended for the induction of remission in severe cases of MC that fail to respond to corticosteroids or immunomodulators, as an alternative to colectomy. CONCLUSIONS: This is the first consensus paper on MC based on GRADE methodology. This initiative may help physicians involved in care of these patients in taking decisions based on evidence.

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.