Efficacy and safety of anakinra and canakinumab in PSTPIP1-associated inflammatory diseases: a comprehensive scoping review.

Introduction: This scoping review explores the effectiveness of IL-1 pathway inhibitors in managing PSTPIP1-associated inflammatory diseases (PAID). These diseases are marked by abnormal IL-1 pathway activation due to genetic mutations. Methods: Our methodology adhered to a pre-published protocol and involved a thorough search of MEDLINE and EMBASE databases up to February 2022, following the Joanna Briggs Institute Reviewer's Manual and the PRISMA Extension for Scoping Reviews. The review included studies reporting on IL-1 pathway inhibitor use in PAID patients. Results: From an initial pool of 5,225 articles, 36 studies involving 43 patients were selected. The studies predominantly used observational designs and exhibited diversity in patient demographics, treatment approaches, and outcomes. Anakinra and canakinumab demonstrated promise in treating sterile pyogenic arthritis, pyoderma gangrenosum, and acne (PAPA) and PSTPIP1-associated myeloid-related-proteinemia inflammatory (PAMI) syndromes, with scant data on other syndromes. Notably, there was a paucity of information on the adverse effects of these treatments, necessitating cautious interpretation of their safety profile. Conclusion: Current evidence on IL-1 pathway inhibitors for PAID is primarily from observational studies and remains limited. Rigorous research with larger patient cohorts is imperative for more definitive conclusions. Collaborative efforts among specialized research centers and international health initiatives are key to advancing this field.

Scalp and serum profiling of frontal fibrosing alopecia reveals scalp immune and fibrosis dysregulation with no systemic involvement.

BACKGROUND: Frontal fibrosing alopecia (FFA) is a progressive, scarring alopecia of the frontotemporal scalp that poses a substantial burden on quality of life. Large-scale global profiling of FFA is lacking, preventing the development of effective therapeutics. OBJECTIVE: To characterize FFA compared to normal and alopecia areata using broad molecular profiling and to identify biomarkers linked to disease severity. METHODS: This cross-sectional study assessed 33,118 genes in scalp using RNA sequencing and 350 proteins in serum using OLINK high-throughput proteomics. Disease biomarkers were also correlated with clinical severity and a fibrosis gene set. RESULTS: Genes differentially expressed in lesional FFA included markers related to Th1 (IFNγ/CXCL9/CXCL10), T-cell activation (CD2/CD3/CCL19/ICOS), fibrosis (CXCR3/FGF14/FGF22/VIM/FN1), T-regulatory (FOXP3/TGFB1/TGFB3), and Janus kinase/JAK (JAK3/STAT1/STAT4) (Fold changes [FCH]>1.5, FDR<.05 for all). Only one protein, ADM, was differentially expressed in FFA serum compared to normal (FCH>1.3, FDR<.05). Significant correlations were found between scalp biomarkers (IL-36RN/IL-25) and FFA severity, as well as between JAK/STAT and fibrosis gene-sets (r>.6; P <.05). LIMITATIONS: This study was limited by a small sample size and predominantly female FFA patients. CONCLUSION: Our data characterize FFA as an inflammatory condition limited to scalp, involving Th1/JAK skewing, with associated fibrosis and elevated T-regulatory markers, suggesting the potential for disease reversibility with JAK/STAT inhibition.

Mild atopic dermatitis lacks systemic inflammation and shows reduced nonlesional skin abnormalities.

BACKGROUND: Molecular studies in atopic dermatitis (AD) are largely restricted to patients with moderate-to-severe disease. OBJECTIVE: Our aim was to evaluate skin and blood abnormalities in mild, moderate, and severe AD. METHODS: Skin and blood samples were obtained from 61 patients with AD (20 with mild or limited disease, 17 with moderate disease, and 24 with severe disease) and 20 healthy subjects. Immune and barrier markers were measured in lesional, nonlesional, and healthy skin by quantitative real-time PCR and immunohistochemistry, and in blood by using the OLINK proteomic assay. RESULTS: Cellular markers of epidermal hyperplasia and T-cell/dendritic cell infiltration were increased in AD tissues of all patients in all severity groups versus in those of controls, whereas downstream TH2 cell-, TH22 cell-, TH1 cell-, and TH17 cell-related mediators demonstrated incremental elevations with increasing disease severity, in both lesional and nonlesional skin. Whereas the levels of the TH2 (IL13, CCL17, and CCL26) and TH22 (IL-22) cytokines were significantly elevated in both AD lesional and nonlesional skin of all patients regardless of the severity of their disease, patients with mild or limited AD showed increases in their levels of TH1 cell (IFNG, CXCL9, and CXCL10) and TH17 cell (IL-17A, CCL20, and CXCL1) markers in lesional but not nonlesional skin. Regulatory T-cell-related mediators (IL-10 and FOXP3) were comparably upregulated in all groups, without displaying the severity-based gradient in other immune axes. Unsupervised clustering aligned samples along a severity spectrum, where nonlesional mild or limited AD skin clustered with the samples from healthy controls. Furthermore, whereas the blood profiles of patients with moderate and severe AD showed gradual increases in the levels of TH1 cell-, TH2 cell-, and TH17 cell-related and atherosclerosis and/or cardiovascular risk (CCL7, FGF21, and IGFBP1) proteins, the blood profiles of patients with mild or limited AD lacked significant differences from those of the controls. CONCLUSION: Mild and limited AD show high levels of TH2/TH22 cell activation that is primarily localized to skin lesions and lacks the systemic inflammation of moderate and severe disease.

Single-cell transcriptome analysis of human skin identifies novel fibroblast subpopulation and enrichment of immune subsets in atopic dermatitis.

BACKGROUND: Atopic dermatitis (AD) is a prevalent inflammatory skin disease with a complex pathogenesis involving immune cell and epidermal abnormalities. Despite whole tissue biopsy studies that have advanced the mechanistic understanding of AD, single cell-based molecular alterations are largely unknown. OBJECTIVE: Our aims were to construct a detailed, high-resolution atlas of cell populations and assess variability in cell composition and cell-specific gene expression in the skin of patients with AD versus in controls. METHODS: We performed single-cell RNA sequencing on skin biopsy specimens from 5 patients with AD (4 lesional samples and 5 nonlesional samples) and 7 healthy control subjects, using 10× Genomics. RESULTS: We created transcriptomic profiles for 39,042 AD (lesional and nonlesional) and healthy skin cells. Fibroblasts demonstrated a novel COL6A5+COL18A1+ subpopulation that was unique to lesional AD and expressed CCL2 and CCL19 cytokines. A corresponding LAMP3+ dendritic cell (DC) population that expressed the CCL19 receptor CCR7 was also unique to AD lesions, illustrating a potential role for fibroblast signaling to immune cells. The lesional AD samples were characterized by expansion of inflammatory DCs (CD1A+FCER1A+) and tissue-resident memory T cells (CD69+CD103+). The frequencies of type 2 (IL13+)/type 22 (IL22+) T cells were higher than those of type 1 (IFNG+) in lesional AD, whereas this ratio was slightly diminished in nonlesional AD and further diminished in controls. CONCLUSION: AD lesions were characterized by expanded type 2/type 22 T cells and inflammatory DCs, and by a unique inflammatory fibroblast that may interact with immune cells to regulate lymphoid cell organization and type 2 inflammation.

Scoping Review on the Use of Drugs Targeting JAK/STAT Pathway in Atopic Dermatitis, Vitiligo, and Alopecia Areata.

INTRODUCTION: The JAK/STAT signaling pathway is involved in the immune-mediated inflammatory skin diseases atopic dermatitis (AD), vitiligo, and alopecia areata (AA), and represents a potential target when developing treatments. So far, no drugs targeting this pathway have been approved for the treatment of dermatological diseases. We reviewed the use of drugs blocking the JAK/STAT pathway in the aforementioned diseases. METHODS: An a priori protocol was published. We used Joanna Briggs Institute Reviewer's Manual methodology to conduct the review and PRISMA Extension for Scoping Review (PRISMA-ScR) to report results. MEDLINE, EMBASE, CINAHL, Scopus, and Web of Science databases were searched in a three-step approach on April 2019 by two researchers. RESULTS: Ninety-six mainly multicenter observational studies were included (66, 10, and 20 studies on AA, vitiligo, and AD, respectively). Tofacitinib and ruxolitinib were mainly used for the three diseases, and also upadacitinib, abrocitinib, baricitinib, cerdulatinib, delgocitinib, gusacitinib for AD, and baricitinib, PF-06700841, and PF-06651600 for AA. All patients with AD improved, whereas patients with vitiligo and patients with AA showed varied responses, including unresponsive cases. The safety profiles were similar for all drugs and diseases, mainly comprising mild or no adverse events. CONCLUSIONS: Evidence on the efficacy and safety of drugs targeting the JAK/STAT pathway for the treatment of patients with AD, vitiligo, or AA is increasing but is still of low quality.

Drugs targeting the JAK/STAT pathway for the treatment of immune-mediated inflammatory skin diseases: protocol for a scoping review.

INTRODUCTION: The Janus kinase and Signal Transducer and Activator of Transcription protein (JAK/STAT) pathway is known to be involved in inflammatory and neoplastic skin diseases, like psoriasis, atopic dermatitis, alopecia areata, vitiligo and melanoma. Improved knowledge of the components of this pathway has allowed the development of drugs, which act by inhibiting the pathway, blocking specific components. This offers new therapeutic opportunities. Although evidence on the use of JAK/STAT blockades in dermatological diseases is growing, none have been approved for use in treating skin diseases. The aim of this study is to develop an a priori protocol to broadly review the available evidence on the use of drugs targeting the JAK/STAT pathway in the treatment of dermatological diseases. METHODS AND ANALYSIS: For the conduction of the scoping review protocol, we will employ an established scoping review methodology described in the Joanna Briggs Institute manual. This methodology outlines a five-stage approach: (1) identify the research question; (2) identify relevant studies; (3) select studies; (4) chart the data and (5) collate, summarise and report the results, with an optional consultation exercise. Finally, we will use the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews to present the results. ETHICS AND DISSEMINATION: Since this is a review of the literature, ethics approval is not indicated. We will disseminate the findings from this study in publications in peer-reviewed journals as well as presentations at relevant national and international conferences.

Evolution of international collaborative research efforts to develop non-Cochrane systematic reviews.

This research-on-research study describes efforts to develop non-Cochrane systematic reviews (SRs) by analyzing demographical and time-course collaborations between international institutions using protocols registered in the International Prospective Register of Systematic Reviews (PROSPERO) or published in scientific journals. We have published an a priori protocol to develop this study. Protocols published in scientific journals were searched using the MEDLINE and Embase databases; the query terms "Systematic review" [Title] AND "protocol" [Title] were searched from February 2011 to December 2017. Protocols registered at PROSPERO during the same period were obtained by web scraping all non-Cochrane records with a Python script. After excluding protocols that had a fulfillment or duplication rate of less than 90%, they were classified as published "only in PROSPERO", "only in journals", or in "journals and PROSPERO". Results of data and metadata extraction using text mining processes were curated by two reviewers. These Datasets and R scripts are freely available to facilitate reproducibility. We obtained 20,814 protocols of non-Cochrane SRs. While "unique protocols" by reviewers' institutions from 60 countries were the most frequent, a median of 6 (2-150) institutions from 130 different countries were involved in the preparation of "collaborative protocols". The highest Ranked countries involved in overall protocol production were the UK, the U.S., Australia, Brazil, China, Canada, the Netherlands, Germany, and Italy. Most protocols were registered only in PROSPERO. However, the number of protocols published in scientific journals (924) or in both PROSPERO and journals (807) has increased over the last three years. Syst Rev and BMJ Open published more than half of the total protocols. While the more productive countries were involved in "unique" and "collaborative protocols", less productive countries only participated in "collaborative protocols" that were mainly published in PROSPERO. Our results suggest that, although most countries were involved in solitary production of protocols for non-Cochrane SRs during the study period, it would be useful to develop new strategies to promote international collaborations, especially with less productive countries.

A Scoping Review Protocol to Explore the Use of Interleukin-1-Targeting Drugs for the Treatment of Dermatological Diseases: Indications, Mechanism of Action, Efficacy, and Safety.

INTRODUCTION: The interleukin (IL)-1 pathway has been identified as being involved in inflammatory and neoplastic skin diseases such as psoriasis, atopic dermatitis, neutrophilic dermatosis, melanoma, and squamous cell carcinoma. Drugs developed to target the IL-1 pathway are currently used to treat these pathologies, and although they are becoming more selective, they are not exempt from adverse events and high costs. Integrating the best research evidence with clinical experience and patient needs has been shown to improve care, health, and cost outcomes. This is because evidence-based guidelines rank interventions according to cost-effectiveness. However, evidence on this topic is scarce for several reasons. First, although randomized clinical trials currently provide the best evidence, they are not always available. Second, there are no secondary scientific studies that summarize the use of IL-1-targeting agents in dermatology. We therefore sought to develop an a priori protocol for broadly reviewing the available evidence on the use of IL-1-targeting drugs in the treatment of dermatological diseases. METHODS: We used the latest methodology to perform a scoping review as described in the Joanna Briggs Institute manual. RESULTS/DISCUSSION: Developing and applying a methodology for evidence synthesis promotes reproducibility and increases the validity of secondary scientific investigations, making it the optimal strategy for scientifically synthesizing a broad field such as the indications for and the mechanisms of action, efficacies, safety, and costs of IL-1-targeting drugs in the treatment of dermatological diseases. Quantitative synthesis facilitates the detection of knowledge gaps and the identification of new questions that can be addressed through systematic reviews. We present an a priori protocol for exploring the available evidence on this topic.

Evaluating characteristics of PROSPERO records as predictors of eventual publication of non-Cochrane systematic reviews: a meta-epidemiological study protocol.

BACKGROUND: Epidemiology and the reporting characteristics of systematic reviews (SRs) and meta-analyses (MAs) are well known. However, no study has analyzed the influence of protocol features on the probability that a study's results will be finally reported, thereby indirectly assessing the reporting bias of International Prospective Register of Systematic Reviews (PROSPERO) registration records. OBJECTIVE: The objective of this study is to explore which factors are associated with a higher probability that results derived from a non-Cochrane PROSPERO registration record for a systematic review will be finally reported as an original article in a scientific journal. METHODS/DESIGN: The PROSPERO repository will be web scraped to automatically and iteratively obtain all completed non-Cochrane registration records stored from February 2011 to December 2017. Downloaded records will be screened, and those with less than 90% fulfilled or are duplicated (i.e., those sharing titles and reviewers) will be excluded. Manual and human-supervised automatic methods will be used for data extraction, depending on the data source (fields of PROSPERO registration records, bibliometric databases, etc.). Records will be classified into published, discontinued, and abandoned review subgroups. All articles derived from published reviews will be obtained through multiple parallel searches using the full protocol "title" and/or "list reviewers" in MEDLINE/PubMed databases and Google Scholar. Reviewer, author, article, and journal metadata will be obtained using different sources. R and Python programming and analysis languages will be used to describe the datasets; perform text mining, machine learning, and deep learning analyses; and visualize the data. We will report the study according to the recommendations for meta-epidemiological studies adapted from the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement for SRs and MAs. DISCUSSION: This meta-epidemiological study will explore, for the first time, characteristics of PROSPERO records that may be associated with the publication of a completed systematic review. The evidence may help to improve review workflow performance in terms of research topic selection, decision-making regarding team selection, planning relationships with funding sources, implementing literature search strategies, and efficient data extraction and analysis. We expect to make our results, datasets, and R and Python code scripts publicly available during the third quarter of 2018.

The differential impact of scientific quality, bibliometric factors, and social media activity on the influence of systematic reviews and meta-analyses about psoriasis.

Researchers are increasingly using on line social networks to promote their work. Some authors have suggested that measuring social media activity can predict the impact of a primary study (i.e., whether or not an article will be highly cited). However, the influence of variables such as scientific quality, research disclosures, and journal characteristics on systematic reviews and meta-analyses has not yet been assessed. The present study aims to describe the effect of complex interactions between bibliometric factors and social media activity on the impact of systematic reviews and meta-analyses about psoriasis (PROSPERO 2016: CRD42016053181). Methodological quality was assessed using the Assessing the Methodological Quality of Systematic Reviews (AMSTAR) tool. Altmetrics, which consider Twitter, Facebook, and Google+ mention counts as well as Mendeley and SCOPUS readers, and corresponding article citation counts from Google Scholar were obtained for each article. Metadata and journal-related bibliometric indices were also obtained. One-hundred and sixty-four reviews with available altmetrics information were included in the final multifactorial analysis, which showed that social media and impact factor have less effect than Mendeley and SCOPUS readers on the number of cites that appear in Google Scholar. Although a journal's impact factor predicted the number of tweets (OR, 1.202; 95% CI, 1.087-1.049), the years of publication and the number of Mendeley readers predicted the number of citations in Google Scholar (OR, 1.033; 95% CI, 1.018-1.329). Finally, methodological quality was related neither with bibliometric influence nor social media activity for systematic reviews. In conclusion, there seems to be a lack of connectivity between scientific quality, social media activity, and article usage, thus predicting scientific success based on these variables may be inappropriate in the particular case of systematic reviews.