European Guidelines (S3) on diagnosis and management of mucous membrane pemphigoid, initiated by the European Academy of Dermatology and Venereology - Part II.

This guideline has been initiated by the task force Autoimmune Blistering Diseases of the European Academy of Dermatology and Venereology, including physicians from all relevant disciplines and patient organizations. It is a S3 consensus-based guideline that systematically reviewed the literature on mucous membrane pemphigoid (MMP) in the MEDLINE and EMBASE databases until June 2019, with no limitations on language. While the first part of this guideline addressed methodology, as well as epidemiology, terminology, aetiology, clinical presentation and outcome measures in MMP, the second part presents the diagnostics and management of MMP. MMP should be suspected in cases with predominant mucosal lesions. Direct immunofluorescence microscopy to detect tissue-bound IgG, IgA and/or complement C3, combined with serological testing for circulating autoantibodies are recommended. In most patients, serum autoantibodies are present only in low levels and in variable proportions, depending on the clinical sites involved. Circulating autoantibodies are determined by indirect IF assays using tissue substrates, or ELISA using different recombinant forms of the target antigens or immunoblotting using different substrates. The major target antigen in MMP is type XVII collagen (BP180), although in 10-25% of patients laminin 332 is recognized. In 25-30% of MMP patients with anti-laminin 332 reactivity, malignancies have been associated. As first-line treatment of mild/moderate MMP, dapsone, methotrexate or tetracyclines and/or topical corticosteroids are recommended. For severe MMP, dapsone and oral or intravenous cyclophosphamide and/or oral corticosteroids are recommended as first-line regimens. Additional recommendations are given, tailored to treatment of single-site MMP such as oral, ocular, laryngeal, oesophageal and genital MMP, as well as the diagnosis of ocular MMP. Treatment recommendations are limited by the complete lack of high-quality randomized controlled trials.

European guidelines (S3) on diagnosis and management of mucous membrane pemphigoid, initiated by the European Academy of Dermatology and Venereology - Part I.

This guideline on mucous membrane pemphigoid (MMP) has been elaborated by the Task Force for Autoimmune Blistering Diseases of the European Academy of Dermatology and Venereology (EADV) with a contribution of physicians from all relevant disciplines and patient organizations. It is a S3 consensus-based guideline encompassing a systematic review of the literature until June 2019 in the MEDLINE and EMBASE databases. This first part covers methodology, the clinical definition of MMP, epidemiology, MMP subtypes, immunopathological characteristics, disease assessment and outcome scores. MMP describes a group of autoimmune skin and mucous membrane blistering diseases, characterized by a chronic course and by predominant involvement of the mucous membranes, such as the oral, ocular, nasal, nasopharyngeal, anogenital, laryngeal and oesophageal mucosa. MMP patients may present with mono- or multisite involvement. Patients' autoantibodies have been shown to be predominantly directed against BP180 (also called BPAG2, type XVII collagen), BP230, laminin 332 and type VII collagen, components of junctional adhesion complexes promoting epithelial stromal attachment in stratified epithelia. Various disease assessment scores are available, including the Mucous Membrane Pemphigoid Disease Area Index (MMPDAI), the Autoimmune Bullous Skin disorder Intensity Score (ABSIS), the 'Cicatrising Conjunctivitis Assessment Tool' and the Oral Disease Severity Score (ODSS). Patient-reported outcome measurements (PROMs), including DLQI, ABQOL and TABQOL, can be used for assessment of quality of life to evaluate the effectiveness of therapeutic interventions and monitor disease course.

Incidence of eosinophilic esophagitis in the Netherlands continues to rise: 20-year results from a nationwide pathology database.

BACKGROUND: The incidence of eosinophilic esophagitis (EoE) has increased rapidly. Most epidemiologic data were gathered in single-center studies over a short timeframe, possibly explaining the heterogeneous incidences. AIM: The aim of this study was to retrospectively estimate the Dutch nationwide incidence of EoE over the last 20 years. METHODS: The Dutch pathology registry (PALGA) was queried to identify pathology reports describing esophageal eosinophilia from 1996 to 2016. Cases were eligible if EoE was confirmed by the pathologist. Using the annual Dutch population data, the incidence of EoE was calculated. KEY RESULTS: The search yielded 11 288 reports of which 5080 described esophageal eosinophilia. Eosinophilic esophagitis was diagnosed in 2161 patients, 1574 (73%) males and 365 (17%) children. The incidence increased from 0.01 (95% CI 0-0.02) in 1996 to 2.07 (95% CI 2.05-2.23) per 100 000 inhabitants in 2015. The incidence was higher in males than in females, 3.02 (95% CI 2.66-3.41) vs 1.14 (95% CI 0.93-1.38), odds ratio (OR) 2.66 (95% CI 2.10-3.36) and higher in adults than in children, 2.23 (95% CI 1.99-2.49) vs 1.46 (95% CI 1.09-1.91), OR 1.78 (95% CI 1.32-2.40). Incidence of EoE increased more than 200-fold, whereas endoscopy rates only tripled, from 30 in 1996 to 105 per 100 000 inhabitants in 2015. We observed no seasonal variation. CONCLUSIONS AND INFERENCES: In the last decades, the Dutch EoE incidence has increased tremendously and still continues to rise. This expansion is only partially driven by increased endoscopy rates.

Elemental diet decreases inflammation and improves symptoms in adult eosinophilic oesophagitis patients.

BACKGROUND: Eosinophilic oesophagitis (EoE) is a chronic disease, driven by food allergens. Elemental diets are effective for the management of children with EoE, but studies on the effect of elemental diets in adults are scarce and poor palatability challenges dietary adherence. AIM: To assess the effects of an elemental diet (Neocate, Nutricia, Utrecht, the Netherlands) on the inflammation, symptoms and endoscopic signs in adult EoE patients. METHODS: In this prospective study, 21 patients with active EoE, confirmed by biopsies showing ≥15 eosinophils per microscopic high power field (HPF) and symptoms of oesophageal dysfunction were included. Patients underwent endoscopy before and 4 weeks after diet. Histological disease activity (peak eosinophil count/HPF), and endoscopic signs were scored by physicians. Symptoms and adherence to the diet were evaluated by questionnaires. Serum total IgE levels and total eosinophil counts were determined and the expression of inflammatory cytokines was analysed by qPCR. RESULTS: In total, 17 (81%) of the patients completed the diet, of whom 12 (71%) showed complete histological response (≤15 eosinophils/HPF) and 4 (24%) showed partial histological response (≥50% reduction of baseline eosinophil count). Peak eosinophil counts decreased significantly after the diet from 40 to 9 per HPF (P ≤ 0.001). A marked improvement in endoscopic signs was observed. Symptoms decreased significantly in all subjects, and 15 patients (88%) became completely asymptomatic (P ≤ 0.001). In 14 patients (82%), blood eosinophil count and serum IgE decreased (P ≤ 0.05). CONCLUSION: Elemental diet reduces eosinophilic inflammation and induces clinical remission in adult patients with eosinophilic oesophagitis.

The Endoscopic Reference Score shows modest accuracy to predict histologic remission in adult patients with eosinophilic esophagitis.

BACKGROUND: The relationship between the severity of endoscopic signs scored according to the Endoscopic Reference Score (EREFS) and histopathologic signs of eosinophilic esophagitis (EoE) has not been sufficiently explored. We aimed to determine if the EREFS system predicts histopathologic activity in EoE patients. METHODS: We included 69 patients with EoE (age 35 [IQR 29-48] years; 80% male) who, between 2006 and 2014, underwent esophagogastroduodenoscopy (EGD) during which high-quality endoscopic images were taken and esophageal biopsy specimens were obtained. Per EGD, three or more depersonalized images were scored by an expert endoscopist, and histopathologic signs were scored by a pathologist with gastrointestinal expertise; both in a blinded fashion. The predictive values of endoscopic signs for disease activity (peak eosinophil count) were calculated. In addition, we measured the utility of the EREFS in the follow-up of 35 EoE patients. KEY RESULTS: Individual endoscopic signs did not correspond to the peak eosinophil count or other histopathologic signs. Although the composite fibrotic signs score, inflammatory signs score, and total EREFS correlated weakly to moderately with the peak eosinophil count, none of these scores had both high positive and negative predictive values for histopathologic disease activity. In the follow-up of 35 patients, lower peak eosinophil counts were not associated with a decrease in endoscopic abnormalities. CONCLUSIONS & INFERENCES: In adult patients with EoE, the EREFS system correlates with peak eosinophil counts, but their predictive value for disease activity is insufficient for clinical use. Therefore, biopsies remain indispensable for the assessment of disease activity.

Disease duration determines health-related quality of life in adult eosinophilic esophagitis patients.

BACKGROUND: Eosinophilic esophagitis (EoE) is a chronic inflammatory disease of the esophagus characterized by relapsing symptoms of dysphagia. The quality of life (QoL) of EoE patients is impaired, but risk factors for impaired QoL have not been identified. The chronic nature of the disease, requiring multiple endoscopies and long-term treatments, and its social implications may be important factors underlying the impaired QoL of EoE patients. We aimed to determine which clinical factors influence the QoL in EoE patients. METHODS: In this cross-sectional study, we consecutively included 74 adult patients (age 40.3 ± 13.6years, 23% female) diagnosed with EoE according to current guidelines. Patients filled out the SF-36 health-related QoL questionnaire and a questionnaire for assessing clinical data. Patients' SF-36 scores were compared with norm scores from a reference population of 1742 randomly selected subjects. KEY RESULTS: In EoE patients, vitality (62.1 ± 22.3 vs 68.6 ± 19.3, p = 0.015) and general health (64.4 ± 24.2 vs 70.9 ±20.6, p = 0.024) domains of QoL were decreased, the latter primarily in the 18-25 year age group (50.1 ± 30.5 vs 77.9 ± 17.2, p = 0.006). Disease duration is a risk factor for a low mental component summary score, as identified by univariate regression analysis (OR 1.064 (CI: 1.003-1.128), p = 0.038). CONCLUSIONS & INFERENCES: The QoL is particularly impaired in young adult EoE patients. Disease duration determines the mental QoL. This study offers additional insight into the impact of EoE on patients' lives and emphasizes the importance of early diagnosing and adequately treating EoE.

Birch pollen sensitization with cross-reactivity to food allergens predominates in adults with eosinophilic esophagitis.

EoE patients show variable sensitization patterns to food and aeroallergens. The value of allergy testing in adult EoE patients is unclear. Component-resolved diagnosis (CRD) may offer additional insights into sensitization patterns. The aim of this study was to characterize sensitization patterns in adult EoE patients using CRD. Serum from 76 patients (17 female), age 38.6 ± 1.5 years, was analyzed for reactivity to 112 different allergen components using an immuno-solid-phase allergen chip (ISAC). We observed any sensitization in 59 patients (78%), of which 54 patients were polysensitized. Aeroallergen sensitization, mostly against components of grass or tree pollen, or house dust mite, was observed in 74% of the patients. Birch pollen (rBet v 1) sensitization with cross-reactivity to food allergen components was observed in 30 patients (39%). In conclusion, food sensitizations in EoE patients are mainly caused by cross-reactivity to food allergens after primary birch pollen sensitization. Pollen and food sensitizations may cause or maintain esophageal inflammation in EoE patients. CRD provides more insight into sensitization patterns, identifies additional food allergen sensitizations and might be useful to direct dietary therapy in EoE.

Rapidly increasing incidence of eosinophilic esophagitis in a large cohort.

BACKGROUND: Recent literature has shown increasing incidence and prevalence rates of eosinophilic esophagitis (EoE). However, data are mainly based on small studies and come from centers dedicated to EoE. Aim of this study was to estimate the incidence rates of EoE by using a large database. METHODS: We performed a cross-sectional study of the pathology reports describing esophageal eosinophilia from 1996 through 2010, using the nationwide network and registry of histo- and cytopathology in The Netherlands (PALGA). All histopathology reports nationwide enter this database. We classified cases according to the diagnosis made by the pathologist. Annual incidence rates of EoE were estimated. KEY RESULTS: Our search criteria yielded 8838 positive pathology reports. Eosinophilic esophagitis was diagnosed in 674 patients, of which 74% were men. In another 174 patients, no distinction was made between eosinophilia caused by gastro-esophageal reflux disease or EoE. The incidence of EoE increased considerably over the years, being 0.01 in 1996, 0.01 in 2000, 0.14 in 2005, and 1.31 per 100,000 persons in 2010. Eosinophilic esophagitis was diagnosed in all age groups, but in 2010 the highest incidence was seen in 20-29 years old males, in whom it was estimated to be 3.23 per 100,000 persons. The incidence in children was 0.73 per 100,000 in 2010. No seasonal variation in diagnosis of EoE was observed. CONCLUSIONS & INFERENCES: In this large study, we found robust data on increasing incidence rates of pediatric and adult EoE in the past 15 years. This rapidly increasing incidence has not reached a plateau yet.