Prevalence, Incidence, and Mortality of Raynaud’s Phenomenon, Sjögren’s Syndrome, and Scleroderma: an umbrella review of systematic reviews

Objectives: To comprehensively review systematic reviews of prevalence, incidence, and mortality of Raynaud’s, Sjögren’s, and Scleroderma, and to identify any research gaps.Methods: An umbrella review of English language systematic reviews was undertaken using PubMed and Embase (OVID) covering the period 2000-2023 (PROSPERO CRD42023434865). The estimate and its corresponding 95% confidence interval were reported when available from each systematic review. The quality of systematic reviews was assessed using the Scottish Intercollegiate Guidelines Network (SIGN) tool. A narrative synthesis was undertaken.Results: 17 systematic reviews were identified, of which one was for Raynaud’s, five for Sjögren’s and 11 for Scleroderma. There were some high-quality systematic reviews for Sjögren’s and mortality of Scleroderma. However, there were only low-quality systematicreviews of prevalence and incidence of Raynaud’s and Scleroderma. Furthermore, there were no systematic reviews for the mortality of Raynaud’s. For Raynaud’s, the pooled prevalence was 4850 per 100,000; pooled annual incidence was 250 per 100,000. For Sjögren’s, prevalence was 60-70 per 100,000; annual incidence was 6.92 per 100,000 and the pooled standardised mortality ratio ranged from 1.38-1.48. For Scleroderma, pooled prevalence ranged from 17.6-23 per 100,000; annual incidence was 1.4 per 100,000; and the pooled standardised mortality ratio ranged from 2.72-3.53.Conclusion: The outcomes of Raynaud’s were less-well described compared to Sjögren’s and Scleroderma. There was a lack of high-quality systematic reviews for the prevalence and incidence of Raynaud’s and Scleroderma. Therefore, further studies and systematic reviews with rigorous case definitions, assessing different ethnic groups are warranted in this area

Strategies for using topical corticosteroids in children and adults with eczema.

BACKGROUND: Eczema is a common skin condition. Although topical corticosteroids have been a first-line treatment for eczema for decades, there are uncertainties over their optimal use. OBJECTIVES: To establish the effectiveness and safety of different ways of using topical corticosteroids for treating eczema. SEARCH METHODS: We searched databases to January 2021 (Cochrane Skin Specialised Register; CENTRAL; MEDLINE; Embase; GREAT) and five clinical trials registers. We checked bibliographies from included trials to identify further trials. SELECTION CRITERIA: Randomised controlled trials in adults and children with eczema that compared at least two strategies of topical corticosteroid use. We excluded placebo comparisons, other than for trials that evaluated proactive versus reactive treatment. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods, with GRADE certainty of evidence for key findings. Primary outcomes were changes in clinician-reported signs and relevant local adverse events. Secondary outcomes were patient-reported symptoms and relevant systemic adverse events. For local adverse events, we prioritised abnormal skin thinning as a key area of concern for healthcare professionals and patients. MAIN RESULTS: We included 104 trials (8443 participants). Most trials were conducted in high-income countries (81/104), most likely in outpatient or other hospital settings. We judged only one trial to be low risk of bias across all domains. Fifty-five trials had high risk of bias in at least one domain, mostly due to lack of blinding or missing outcome data. Stronger-potency versus weaker-potency topical corticosteroids Sixty-three trials compared different potencies of topical corticosteroids: 12 moderate versus mild, 22 potent versus mild, 25 potent versus moderate, and 6 very potent versus potent. Trials were usually in children with moderate or severe eczema, where specified, lasting one to five weeks. The most reported outcome was Investigator Global Assessment (IGA) of clinician-reported signs of eczema. We pooled four trials that compared moderate- versus mild-potency topical corticosteroids (420 participants). Moderate-potency topical corticosteroids probably result in more participants achieving treatment success, defined as cleared or marked improvement on IGA (52% versus 34%; odds ratio (OR) 2.07, 95% confidence interval (CI) 1.41 to 3.04; moderate-certainty evidence). We pooled nine trials that compared potent versus mild-potency topical corticosteroids (392 participants). Potent topical corticosteroids probably result in a large increase in number achieving treatment success (70% versus 39%; OR 3.71, 95% CI 2.04 to 6.72; moderate-certainty evidence). We pooled 15 trials that compared potent versus moderate-potency topical corticosteroids (1053 participants). There was insufficient evidence of a benefit of potent topical corticosteroids compared to moderate topical corticosteroids (OR 1.33, 95% CI 0.93 to 1.89; moderate-certainty evidence). We pooled three trials that compared very potent versus potent topical corticosteroids (216 participants). The evidence is uncertain with a wide confidence interval (OR 0.53, 95% CI 0.13 to 2.09; low-certainty evidence). Twice daily or more versus once daily application We pooled 15 of 25 trials in this comparison (1821 participants, all reported IGA). The trials usually assessed adults and children with moderate or severe eczema, where specified, using potent topical corticosteroids, lasting two to six weeks. Applying potent topical corticosteroids only once a day probably does not decrease the number achieving treatment success compared to twice daily application (OR 0.97, 95% CI 0.68 to 1.38; 15 trials, 1821 participants; moderate-certainty evidence). Local adverse events Within the trials that tested 'treating eczema flare-up' strategies, we identified only 26 cases of abnormal skin thinning from 2266 participants (1% across 22 trials). Most cases were from the use of higher-potency topical corticosteroids (16 with very potent, 6 with potent, 2 with moderate and 2 with mild). We assessed this evidence as low certainty, except for very potent versus potent topical corticosteroids, which was very low-certainty evidence.  Longer versus shorter-term duration of application for induction of remission No trials were identified. Twice weekly application (weekend, or 'proactive therapy') to prevent relapse (flare-ups) versus no topical corticosteroids/reactive application Nine trials assessed this comparison, generally lasting 16 to 20 weeks. We pooled seven trials that compared weekend (proactive) topical corticosteroids therapy versus no topical corticosteroids (1179 participants, children and adults with a range of eczema severities, though mainly moderate or severe). Weekend (proactive) therapy probably results in a large decrease in likelihood of a relapse from 58% to 25% (risk ratio (RR) 0.43, 95% CI 0.32 to 0.57; 7 trials, 1149 participants; moderate-certainty evidence). Local adverse events We did not identify any cases of abnormal skin thinning in seven trials that assessed skin thinning (1050 participants) at the end of treatment. We assessed this evidence as low certainty. Other comparisons  Other comparisons included newer versus older preparations of topical corticosteroids (15 trials), cream versus ointment (7 trials), topical corticosteroids with wet wrap versus no wet wrap (6 trials), number of days per week applied (4 trials), different concentrations of the same topical corticosteroids (2 trials), time of day applied (2 trials), topical corticosteroids alternating with topical calcineurin inhibitors versus topical corticosteroids alone (1 trial), application to wet versus dry skin (1 trial) and application before versus after emollient (1 trial). No trials compared branded versus generic topical corticosteroids and time between application of emollient and topical corticosteroids. AUTHORS' CONCLUSIONS: Potent and moderate topical corticosteroids are probably more effective than mild topical corticosteroids, primarily in moderate or severe eczema; however, there is uncertain evidence to support any advantage of very potent over potent topical corticosteroids. Effectiveness is similar between once daily and twice daily (or more) frequent use of potent topical corticosteroids to treat eczema flare-ups, and topical corticosteroids weekend (proactive) therapy is probably better than no topical corticosteroids/reactive use to prevent eczema relapse (flare-ups). Adverse events were not well reported and came largely from low- or very low-certainty, short-term trials. In trials that reported abnormal skin thinning, frequency was low overall and increased with increasing potency. We found no trials on the optimum duration of treatment of a flare, branded versus generic topical corticosteroids, and time to leave between application of topical corticosteroids and emollient. There is a need for longer-term trials, in people with mild eczema

Molecular Networks in FGF Signaling: Flotillin-1 and Cbl-Associated Protein Compete for the Binding to Fibroblast Growth Factor Receptor Substrate 2

Fibroblast growth factor receptor substrate 2 (FRS2α) is a signaling adaptor protein that regulates downstream signaling of many receptor tyrosine kinases. During signal transduction, FRS2 can be both tyrosine and threonine phosphorylated and forms signaling complexes with other adaptor proteins and tyrosine phosphatases. We have here identified flotillin-1 and the cbl-associated protein/ponsin (CAP) as novel interaction partners of FRS2. Flotillin-1 binds to the phosphotyrosine binding domain (PTB) of FRS2 and competes for the binding with the fibroblast growth factor receptor. Flotillin-1 knockdown results in increased Tyr phosphorylation of FRS2, in line with the inhibition of ERK activity in the absence of flotillin-1. CAP directly interacts with FRS2 by means of its sorbin homology (SoHo) domain, which has previously been shown to interact with flotillin-1. In addition, the third SH3 domain in CAP binds to FRS2. Due to the overlapping binding domains, CAP and flotillin-1 appear to compete for the binding to FRS2. Thus, our results reveal a novel signaling network containing FRS2, CAP and flotillin-1, whose successive interactions are most likely required to regulate receptor tyrosine kinase signaling, especially the mitogen activated protein kinase pathway

A communal catalogue reveals Earth's multiscale microbial diversity

Our growing awareness of the microbial world's importance and diversity contrasts starkly with our limited understanding of its fundamental structure. Despite recent advances in DNA sequencing, a lack of standardized protocols and common analytical frameworks impedes comparisons among studies, hindering the development of global inferences about microbial life on Earth. Here we present a meta-analysis of microbial community samples collected by hundreds of researchers for the Earth Microbiome Project. Coordinated protocols and new analytical methods, particularly the use of exact sequences instead of clustered operational taxonomic units, enable bacterial and archaeal ribosomal RNA gene sequences to be followed across multiple studies and allow us to explore patterns of diversity at an unprecedented scale. The result is both a reference database giving global context to DNA sequence data and a framework for incorporating data from future studies, fostering increasingly complete characterization of Earth's microbial diversity.Peer reviewe

A communal catalogue reveals Earth’s multiscale microbial diversity

Our growing awareness of the microbial world’s importance and diversity contrasts starkly with our limited understanding of its fundamental structure. Despite recent advances in DNA sequencing, a lack of standardized protocols and common analytical frameworks impedes comparisons among studies, hindering the development of global inferences about microbial life on Earth. Here we present a meta-analysis of microbial community samples collected by hundreds of researchers for the Earth Microbiome Project. Coordinated protocols and new analytical methods, particularly the use of exact sequences instead of clustered operational taxonomic units, enable bacterial and archaeal ribosomal RNA gene sequences to be followed across multiple studies and allow us to explore patterns of diversity at an unprecedented scale. The result is both a reference database giving global context to DNA sequence data and a framework for incorporating data from future studies, fostering increasingly complete characterization of Earth’s microbial diversity

HLA class I and II diversity contributes to the etiologic heterogeneity of non-Hodgkin lymphoma subtypes

A growing number of loci within the human leukocyte antigen (HLA) region have been implicated in non-Hodgkin lymphoma (NHL) etiology. Here, we test a complementary hypothesis of "heterozygote advantage" regarding the role of HLA and NHL, whereby HLA diversity is beneficial and homozygous HLA loci are associated with increased disease risk. HLA alleles at class I and II loci were imputed from genome-wide association studies (GWAS) using SNP2HLA for: 3,617 diffuse large B-cell lymphomas (DLBCL), 2,686 follicular lymphomas (FL), 2,878 chronic lymphocytic leukemia/small lymphocytic lymphomas (CLL/SLL), 741 marginal zone lymphomas (MZL), and 8,753 controls of European descent. Both DLBCL and MZL risk were elevated with homozygosity at class I HLA-B and -C loci (OR DLBCL=1.31, 95% CI=1.06-1.60; OR MZL=1.45, 95% CI=1.12-1.89) and class II HLA-DRB1 locus (OR DLBCL=2.10, 95% CI=1.24-3.55; OR MZL= 2.10, 95% CI=0.99-4.45). Increased FL risk was observed with the overall increase in number of homozygous HLA class II loci (p-trend<0.0001, FDR=0.0005). These results support a role for HLA zygosity in NHL etiology and suggests that distinct immune pathways may underly the etiology of the different NHL subtypes

Atopic eczema in primary care: evidence update and implications for practice

Most people with eczema have mild or moderate disease, and most are treated in primary care.1 This article aims to support health professionals in helping patients get control of eczema in time-limited consultations. Recent updated National Institute for Health and Care Excellence (NICE) guidance on atopic eczema highlighted changes to advice regarding bath emollients and advice on how to wash.2 While a fuller update is awaited, the evidence behind this is presented here, along with a summary of other recent research on eczema