The population prevalence of multimorbidity (the existence of at least 2 or more long-term conditions LTCs in an individual) is increasing among young adults, particularly in minority ethnic groups ...and individuals living in socioeconomically deprived areas. In this study, we applied a data-driven approach to identify clusters of individuals who had an early onset multimorbidity in an ethnically and socioeconomically diverse population. We identified associations between clusters and a range of health outcomes. Using linked primary and secondary care data from the Clinical Practice Research Datalink GOLD (CPRD GOLD), we conducted a cross-sectional study of 837,869 individuals with early onset multimorbidity (aged between 16 and 39 years old when the second LTC was recorded) registered with an English general practice between 2010 and 2020. The study population included 777,906 people of White ethnicity (93%), 33,915 people of South Asian ethnicity (4%), and 26,048 people of Black African/Caribbean ethnicity (3%). A total of 204 LTCs were considered. Latent class analysis stratified by ethnicity identified 4 clusters of multimorbidity in White groups and 3 clusters in South Asian and Black groups. We found that early onset multimorbidity was more common among South Asian (59%, 33,915) and Black (56% 26,048) groups compared to the White population (42%, 777,906). Latent class analysis revealed physical and mental health conditions that were common across all ethnic groups (i.e., hypertension, depression, and painful conditions). However, each ethnic group also presented exclusive LTCs and different sociodemographic profiles: In White groups, the cluster with the highest rates/odds of the outcomes was predominantly male (54%, 44,150) and more socioeconomically deprived than the cluster with the lowest rates/odds of the outcomes. On the other hand, South Asian and Black groups were more socioeconomically deprived than White groups, with a consistent deprivation gradient across all multimorbidity clusters. At the end of the study, 4% (34,922) of the White early onset multimorbidity population had died compared to 2% of the South Asian and Black early onset multimorbidity populations (535 and 570, respectively); however, the latter groups died younger and lost more years of life. The 3 ethnic groups each displayed a cluster of individuals with increased rates of primary care consultations, hospitalisations, long-term prescribing, and odds of mortality. Study limitations include the exclusion of individuals with missing ethnicity information, the age of diagnosis not reflecting the actual age of onset, and the exclusion of people from Mixed, Chinese, and other ethnic groups due to insufficient power to investigate associations between multimorbidity and health-related outcomes in these groups. These findings emphasise the need to identify, prevent, and manage multimorbidity early in the life course. Our work provides additional insights into the excess burden of early onset multimorbidity in those from socioeconomically deprived and diverse groups who are disproportionately and more severely affected by multimorbidity and highlights the need to ensure healthcare improvements are equitable.
Drug survival reflects a drug’s effectiveness, safety, and tolerability. We assessed the drug survival of biologics used to treat psoriasis in a prospective national pharmacovigilance cohort (British ...Association of Dermatologists Biologic Interventions Register (BADBIR)). The survival rates of the first course of biologics for 3,523 biologic-naive patients with chronic plaque psoriasis were compared using survival analysis techniques and predictors of discontinuation analyzed using a multivariate Cox proportional hazards model. Data for patients on adalimumab (n=1,879), etanercept (n=1,098), infliximab (n=96), and ustekinumab (n=450) were available. The overall survival rate in the first year was 77%, falling to 53% in the third year. Multivariate analysis showed that female gender (hazard ratio (HR) 1.22; 95% confidence interval (CI): 1.09–1.37), being a current smoker (HR 1.19; 95% CI: 1.03–1.38), and a higher baseline dermatology life quality index (HR 1.01; 95% CI: 1.00–1.02) were predictors of discontinuation. Presence of psoriatic arthritis (HR 0.82; 95% CI: 0.71–0.96) was a predictor for drug survival. As compared with adalimumab, patients on etanercept (HR 1.63; 95% CI: 1.45–1.84) or infliximab (HR 1.56; 95% CI: 1.16–2.09) were more likely to discontinue therapy, whereas patients on ustekinumab were more likely to persist (HR 0.48; 95% CI: 0.37–0.62). After accounting for relevant covariates, ustekinumab had the highest first-course drug survival. The results of this study will aid clinical decision making when choosing biologic therapy for psoriasis patients.
Palmoplantar pustulosis (PPP) is a severe inflammatory skin disorder characterized by eruptions of painful, neutrophil-filled pustules on the palms and soles. Although PPP has a profound effect on ...quality of life, it remains poorly understood and notoriously difficult to treat.
We sought to investigate the immune pathways that underlie the pathogenesis of PPP.
We applied bulk and single-cell RNA sequencing (RNA-Seq) methods to the analysis of skin biopsy samples and peripheral blood mononuclear cells. We validated our results by flow cytometry and immune fluorescence microscopy
Bulk RNA-Seq of patient skin detected an unexpected signature of T-cell activation, with a significant overexpression of several TH2 genes typically upregulated in atopic dermatitis. To further explore these findings, we carried out single-cell RNA-Seq in peripheral blood mononuclear cells of healthy and affected individuals. Memory CD4+ T cells of PPP patients were skewed toward a TH17 phenotype, a phenomenon that was particularly significant among cutaneous lymphocyte-associated antigen–positive skin-homing cells. We also identified a subset of memory CD4+ T cells that expressed both TH17 (KLRB1/CD161) and TH2 (GATA3) markers, with pseudotime analysis suggesting that the population was the result of TH17 to TH2 plasticity. Interestingly, the GATA3+/CD161+ cells were overrepresented among the peripheral blood mononuclear cells of affected individuals, both in the single-cell RNA-Seq data set and in independent flow cytometry experiments. Dual-positive cells were also detected in patient skin by immune fluorescence microscopy.
PPP is associated with complex T-cell activation patterns and may explain why biologic drugs that target individual T helper cell populations have shown limited therapeutic efficacy.
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Group 2 innate lymphoid cells (ILC-2s) regulate immune responses to pathogens and maintain tissue homeostasis in response to cytokines. Positive regulation of ILC-2s through ICOS has been recently ...elucidated. We demonstrate here that PD-1 is an important negative regulator of KLRG1
ILC-2 function in both mice and humans. Increase in KLRG1
ILC-2 cell numbers was attributed to an intrinsic defect in PD-1 signaling, which resulted in enhanced STAT5 activation. During
infection, a significant expansion of KLRG1
ILC-2 subsets occurred in
mice and, upon adoptive transfer,
KLRG1
ILC-2s significantly reduced worm burden. Furthermore, blocking PD-1 with an antibody increased KLRG1
ILC-2 cell number and reduced disease burden. Therefore, PD-1 is required for maintaining the number, and hence function, of KLRG1
ILC-2s.
Biologic therapies can be highly effective for the treatment of severe psoriasis, but response for individual patients can vary according to drug. Predictive biomarkers to guide treatment selection ...could improve patient outcomes and treatment cost-effectiveness.
We sought to test whether HLA-C*06:02, the primary genetic susceptibility allele for psoriasis, predisposes patients to respond differently to the 2 most commonly prescribed biologics for psoriasis: adalimumab (anti–TNF-α) and ustekinumab (anti–IL-12/23).
This study uses a national psoriasis registry that includes longitudinal treatment and response observations and detailed clinical data. HLA alleles were imputed from genome-wide genotype data for 1326 patients for whom 90% reduction in Psoriasis Area and Severity Index score (PASI90) response status was observed after 3, 6, or 12 months of treatment. We developed regression models of PASI90 response, examining the interaction between HLA-C*06:02 and drug type (adalimumab or ustekinumab) while accounting for potentially confounding clinical variables.
HLA-C*06:02–negative patients were significantly more likely to respond to adalimumab than ustekinumab at all time points (most strongly at 6 months: odds ratio OR, 2.95; P = 5.85 × 10−7), and the difference was greater in HLA-C*06:02–negative patients with psoriatic arthritis (OR, 5.98; P = 6.89 × 10−5). Biologic-naive patients who were HLA-C*06:02 positive and psoriatic arthritis negative demonstrated significantly poorer response to adalimumab at 12 months (OR, 0.31; P = 3.42 × 10−4). Results from HLA-wide analyses were consistent with HLA-C*06:02 itself being the primary effect allele. We found no evidence for genetic interaction between HLA-C*06:02 and ERAP1.
This large observational study suggests that reference to HLA-C*06:02 status could offer substantial clinical benefit when selecting treatments for severe psoriasis.
Background Atopic eczema (AE) is characterized by skin barrier and immune dysfunction. Null mutations in filaggrin (FLG), a key epidermal barrier protein, strongly predispose to AE; however, the ...precise role of FLG deficiency in AE pathogenesis remains incompletely understood. Objectives We sought to identify global proteomic changes downstream of FLG deficiency in human epidermal living skin–equivalent (LSE) models and validate findings in skin of patients with AE. Methods Differentially expressed proteins from paired control (nontargeting control short hairpin RNA shNT) and FLG knockdown (FLG knockdown short hairpin RNA shFLG) LSEs were identified by means of proteomic analysis (liquid chromatography–mass spectrometry) and Ingenuity Pathway Analysis. Expression of key targets was validated in independent LSE samples (quantitative RT-PCR and Western blotting) and in normal and AE skin biopsy specimens (immunofluorescence). Results Proteomic analysis identified 17 ( P ≤ .05) differentially expressed proteins after FLG knockdown, including kallikrein-7 (KLK7; 2.2-fold), cyclophilin A (PPIA; 0.9-fold), and cofilin-1 (CFL1, 1.3-fold). Differential protein expression was confirmed in shNT/shFLG LSEs; however, only KLK7 was transcriptionally dysregulated. Molecular pathways overrepresented after FLG knockdown included inflammation, protease activity, cell structure, and stress. Furthermore, KLK7 (1.8-fold) and PPIA (0.65-fold) proteins were differentially expressed in lesional biopsy specimens from patients with AE relative to normal skin. Conclusions For the first time, we show that loss of FLG in the absence of inflammation is sufficient to alter the expression level of proteins relevant to the pathogenesis of AE. These include proteins regulating inflammatory, proteolytic, and cytoskeletal functions. We identify PPIA as a novel protein with levels that are decreased in clinically active AE skin and show that the characteristic upregulation of KLK7 expression in patients with AE occurs downstream of FLG loss. Importantly, we highlight disconnect between the epidermal proteome and transcriptome, emphasizing the utility of global proteomic studies.
Atopic dermatitis (AD) is a prevalent disease worldwide and is associated with systemic comorbidities representing a significant burden on patients, their families, and society. Therapeutic options ...for AD remain limited, in part because of a lack of well-characterized animal models. There has been increasing interest in developing experimental approaches to study the pathogenesis of human AD in vivo, in vitro, and in silico to better define pathophysiologic mechanisms and identify novel therapeutic targets and biomarkers that predict therapeutic response. This review critically appraises a range of models, including genetic mutations relevant to AD, experimental challenge of human skin in vivo, tissue culture models, integration of “omics” data sets, and development of predictive computational models. Although no one individual model recapitulates the complex AD pathophysiology, our review highlights insights gained into key elements of cutaneous biology, molecular pathways, and therapeutic target identification through each approach. Recent developments in computational analysis, including application of machine learning and a systems approach to data integration and predictive modeling, highlight the applicability of these methods to AD subclassification (endotyping), therapy development, and precision medicine. Such predictive modeling will highlight knowledge gaps, further inform refinement of biological models, and support new experimental and systems approaches to AD.
It is unknown why some patients with psoriasis experience long-term effectiveness with their first biologic monotherapy. Our aim was to compare the baseline demographic, disease, genotypic, clinical ...and lifestyle characteristics of patients with psoriasis registered in the British Association of Dermatologists Biologics and Immunomodulators Register and the aligned Biomarkers and Stratification to Optimise outcomes in Psoriasis study who were designated as ‘super responders’ (SRs), defined as patients on their first biologic with more than 5 years continuous biologic monotherapy, or ‘super nonresponders’ (SNRs), defined as patients on their first biologic who had discontinued at least two biologics in their first year of treatment, to biologic therapy. Female sex, shorter study follow-up, higher Dermatology Life Quality Index, high frequency of adalimumab, less frequency of ustekinumab at registration, and higher number of comorbidities were associated with SNRs compared with SRs.
Wounding induces a calcium wave and disrupts the calcium gradient across the epidermis but mechanisms mediating calcium and downstream signalling, and longer‐term wound healing responses are ...incompletely understood. As expected, live‐cell confocal imaging of Fluo‐4‐loaded normal human keratinocytes showed an immediate increase in Ca2+i at the wound edge that spread as a calcium wave (8.3 µm/s) away from the wound edge with gradually diminishing rate of rise and amplitude. The amplitude and area under the curve of Ca2+i flux was increased in high (1.2 mM) Ca2+o media. 18α‐glycyrrhetinic acid (18αGA), a gap‐junction inhibitor or hexokinase, an ATP scavenger, blocked the wound‐induced calcium wave, dependent in part on Ca2+o. Wounding in a high Ca2+o increased nuclear factor of activated T‐cells (NFAT) but not NFkB activation, assessed by dual‐luciferase receptor assays compared to unwounded cells. Treatment with 18αGA or the store‐operated channel blocker GSK‐7975A inhibited wound‐induced NFAT activation, whereas treatment with hexokinase did not. Real‐time cell migration analysis, measuring wound closure rates over 24 h, revealed that 18αGA essentially blocked wound closure whereas hexokinase and GSK‐7975A showed relatively minimal effects. Together these data indicate that while both gap‐junction communication and ATP release from damaged cells are important in regulating the wound‐induced calcium wave, long‐term transcriptional and functional responses are dominantly regulated by gap‐junction communication.
In this study, we analysed specific parameters of the wound‐induced calcium wave in human keratinocytes and delineated the relative the contribution of extracellular ATP signalling, gap‐junctional communication, and extracellular calcium influx providing insight into the mechanisms of wave transmission. By inhibiting the specific components contributing to wave transmission, we established that gap‐junctional communication and store‐operated calcium entry regulated wound‐induced nuclear factor of activated T‐cells transcriptional activation and keratinocyte migration to close the wound. Gap‐junctional communication exerted the most profound effect and completely prevented wound closure with relatively small contributions from extracellular ATP.
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