IntroductionThere are numerous new systemic treatments for atopic dermatitis in various stages of development and most are being compared with placebo rather than active comparators. In order to understand the relative efficacy and safety of existing and new treatments for atopic dermatitis, robust mixed comparisons (ie, direct and indirect) would be beneficial. To address this gap, this protocol describes methods for a systematic review and network meta-analysis of systemic treatments for atopic dermatitis.Methods and analysisWe will update the search of a previous systematic review, including searches of the Cochrane Central Register of Controlled Trials, MEDLINE, Embase, Latin American and Caribbean Health Science Information database and the Global Resource of EczemA Trials database in addition to clinical trial protocol registries. Title, abstract and full paper screening as well as data extraction will be conducted in duplicate by independent researchers. Primary outcomes include efficacy with regards to clinician-reported signs and patient-reported symptoms and safety with regards to withdrawal from treatment due to adverse events and the occurrence of serious adverse events. Secondary outcomes will include change in quality of life and itch severity. Where possible and appropriate, network meta-analysis will be performed for each outcome using a random-effects model within a Bayesian framework. If appropriate, the review will be transitioned to a living review with continuous updating of the analysis.Ethics and disseminationDissemination in a peer-reviewed scientific journal is planned.PROSPERO registration numberCRD42018088112; Pre-results.

IMPORTANCE Most clinical trials assessing systemic immunomodulatory treatments for patients with atopic dermatitis are placebo-controlled. OBJECTIVE To compare the effectiveness and safety of systemic immunomodulatory treatments for patients with atopic dermatitis in a systematic review and network meta-analysis. DATA SOURCES The Cochrane Central Register of Controlled Trials, MEDLINE, Embase, Latin American and Caribbean Health Science Information database, Global Resource of Eczema Trials database, and clinical trial registries were searched from inception to October 28, 2019. STUDY SELECTION English-language randomized clinical trials of 8 weeks or more of treatment with systemic immunomodulatory medications for moderate to severe atopic dermatitis were included. Titles, abstracts, and articles were screened in duplicate. Of 10 324 citations, 39 trials were included. DATA EXTRACTION AND SYNTHESIS Data were extracted in duplicate, and the review adhered to Preferred Reporting Items for Systematic Reviews and Meta-analyses for Network Meta-Analyses guidelines. Random-effects bayesian network meta-analyses were performed and certainty of evidence was assessed using Grading of Recommendations Assessment, Development and Evaluation criteria. MAIN OUTCOMES AND MEASURES Prespecified outcomes were change in signs of disease, symptoms, quality of life, itch, withdrawals, and serious adverse events. RESULTS A total of 39 trials with 6360 patients examining 20 medications and placebo were included. Most trials were conducted for adults receiving up to 16 weeks of therapy. Dupilumab, 300 mg every 2 weeks, was associated with improvement in the Eczema Area and Severity Index score vs placebo (mean difference, 11.3-point reduction; 95% credible interval [CrI], 9.7-13.1 [high certainty]). Cyclosporine (standardized mean difference, −1.1; 95% CrI, −1.7 to −0.5 [low certainty]) and dupilumab (standardized mean difference, −0.9; 95% CrI, −1.0 to −0.8 [high certainty]) were similarly effective vs placebo in clearing clinical signs of atopic dermatitis and may be superior to methotrexate (standardized mean difference, −0.6; 95% CrI, −1.1 to 0.0 [low certainty]) and azathioprine (standardized mean difference, −0.4; 95% CrI, −0.8 to −0.1 [low certainty]). Several investigational medications for atopic dermatitis are promising, but data to date are limited to small early-phase trials. Safety analyses were limited by low event rates. CONCLUSIONS AND RELEVANCE Dupilumab and cyclosporine may be more effective for up to 16 weeks of treatment than methotrexate and azathioprine for treating adult patients with atopic dermatitis. More studies directly comparing established and novel treatments beyond 16 weeks are needed and will be incorporated into future updates of this review.

Recently, we identified increased cathepsin X expression in H. pylori-infected gastric mucosa. Here, we describe further up-regulation in gastric cancer and report on the role of inflammatory cytokines required for cathepsin X up-regulation in H. pylori-infected gastric mucosa, as well as on consequences for cellular invasion. Biopsy specimens were taken from the antrum, corpus and cardia of H. pylori-infected and non-infected patients. Gastric cancer samples were obtained from patients undergoing gastric surgery. Cathepsin X was detected in gastric mucosa by quantitative real-time RT-PCR, western blotting and immunohistochemistry. Induction of cathepsin X expression in epithelial and inflammatory cells caused by H. pylori infection was tested in in vitro contact and non-contact co-cultures of AGS cells and monocytic cells. Patients with H. pylori gastritis showed significantly higher cathepsin X mRNA (2.5-fold) and protein (1.6-fold) expression than H. pylori-negative patients. Cathepsin X was also up-regulated in gastric cancer (3-12-fold) compared to non-neoplastic mucosa. Cathepsin X was predominantly expressed by macrophages in the mucosal stroma and in glands of the antral mucosa. In addition, tumour cells stained for cathepsin X in 26 (68%) patients with gastric carcinoma. In general, staining was significantly more common (20 vs. 6 patients) and more intense (3.55 vs. 0.83) in intestinal type gastric cancer than in the diffuse type. In vitro cell culture experiments revealed that intercellular signalling between pathogenicity island (PAI)-positive H. pylori-infected epithelial cells and macrophages via soluble factors in the culture medium seems to be responsible for increased expression of cathepsin X in monocytes. Using antisense oligonucleotides, cathepsin X up-regulation was directly associated with higher invasiveness in vitro. Although no correlation of cathepsin X expression and TNM stage was found, our study demonstrates that cathepsin X plays a role not only in the chronic inflammation of gastric mucosa but also in the tumourigenesis of gastric cancer.

Background Allergic asthma causes substantial morbidity and constitutes a public health burden, which increases with asthma severity. There is evidence that allergy immunotherapy (AIT) prevents the progression of allergic rhinitis (AR) to asthma. However, evidence is missing on the potential of AIT to prevent progression from milder to more severe asthma. Methods This population‐based cohort study utilized healthcare data (2005 to 2014) from a statutory health insurance in Germany. The severity of asthma was classified according to the treatment steps recommended by the global initiative for asthma (GINA). The effect of AIT on the transition between the GINA steps was analyzed using multivariable Cox regression models adjusted for age and sex. Results From the total cohort of 1,739,440 patients, 39,167 individuals aged 14 years or older were classified as having incident asthma during the observation period and were included in the study. From these, 4111 patients (10.5%) received AIT. AIT exposure was associated with a significantly decreased likelihood of asthma progression from GINA step 1 to GINA step 3 (HR 0.87; 95% CI 0.80‐0.95) and GINA step 3 to GINA step 4 (HR 0.66; 95% CI 0.60‐0.74). GINA medication for step 2 and step 5 was rarely prescribed. Conclusions This observational study in a real‐world setting indicates that patients with allergic asthma who receive AIT are less likely to experience progression of asthma severity than asthma patients not receiving AIT.

This study highlights the significant burden of AR. Despite the established benefits of AIT to treat AR and prevent asthma, this study suggests significant undertreatment. Future research is necessary to develop and implement adequate measures to increase guideline adherence.

BackgroundClose, continuous and efficient collaboration between different professions and sectors of care is necessary to provide patient-centered care for individuals with mental disorders. The lack of structured collaboration between in- and outpatient care constitutes a limitation of the German health care system. Since 2012, a new law in Germany (§64b Social code book (SGB) V) has enabled the establishment of cross-sectoral and patient-centered treatment models in psychiatry. Such model projects follow a capitation budget, i.e. a total per patient budget of inpatient and outpatient care in psychiatric clinics. Providers are able to choose the treatment form and adapt the treatment to the needs of the patients. The present study (EVA64) will investigate the effectiveness, costs and efficiency of almost all model projects established in Germany between 2013 and 2016.Methods/designA health insurance data-based controlled cohort study is used. Data from up to 89 statutory health insurance (SHI) funds, i.e. 79% of all SHI funds in Germany (May 2017), on inpatient and outpatient care, pharmaceutical and non-pharmaceutical treatments and sick leave for a period of 7 years will be analyzed. All patients insured by any of the participating SHI funds and treated in one of the model hospitals for any of 16 pre-defined mental disorders will be compared with patients in routine care. Sick leave (primary outcome), utilization of inpatient care (primary outcome), utilization of outpatient care, continuity of contacts in (psychiatric) care, physician and hospital hopping, re-admission rate, comorbidity, mortality, disease progression, and guideline adherence will be analyzed. Cost and effectivity of model and routine care will be estimated using cost-effectiveness analyses. Up to 10 control hospitals for each of the 18 model hospitals will be selected according to a pre-defined algorithm.DiscussionThe evaluation of complex interventions is an important main task of health services research and constitutes the basis of evidence-guided advancement in health care. The study will yield important new evidence to guide the future provision of routine care for mentally ill patients in Germany and possibly beyond.Trial registrationThis study was registered in the database “Health Services Research Germany” (trial number: VVfD_EVA64_15_003713).

Background: The diagnosis of eosinophilic esophagitis (EoE) and differentiation from gastroesophageal reflux disease (GERD) is potentially challenging and is based upon clinical signs and endoscopic and histological features. In order to alert the endoscopist to consider EoE in patients with esophageal symptoms before performing esophagogastroduodenoscopy, we aimed to identify a set of clinical and laboratory markers for predicting EoE. Methods: The study included 43 patients with either EoE (n = 23) or GERD (n = 20). The diagnosis of EoE was based on International Consensus Criteria. Age, gender, weight loss, history of atopy, dysphagia, history of food impaction, proton pump inhibitor (PPI) refractory heartburn, odynophagia, peripheral eosinophilia, and serum IgE were analyzed. Each symptom or sign was classified as ‘0’ (absent, normal) or ‘1’ (present, elevated), individually analyzed and statistically evaluated among the two groups of patients. Logistic regression analysis was carried out to identify a clinically applicable marker constellation to differentiate EoE from GERD. Results: Univariate analysis identified 6 out of the 10 variables to be significant between both groups. A stepwise procedure of logistic regression led to a model in which 3 out of the initial 10 items were found to be relevant for differentiating GERD and EoE. Derived from this model, an optimal differentiation was achieved by using the following simplified equation: peripheral eosinophilia + history of food impaction + PPI refractory heartburn leading to a maximal value of 3 (1 + 1 + 1). Based on a cut-off value of ≧2, sensitivity and specificity for diagnosing EoE were 91 and 100%, respectively. Conclusion: A defined set of markers including two clinical features and one laboratory parameter is highly predictive of EoE and thus allows physicians to distinguish EoE from GERD even before upper gastrointestinal endoscopy is performed.

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