small molecules

2026-08-10 | Efficacy and safety of Janus kinase and TYK2 inhibitors in the treatment of generalized pustular psoriasis and palmoplantar pustulosis: a systematic review.

Pustular psoriasis (PP), including generalized pustular psoriasis (GPP) and palmoplantar pustulosis (PPP), is a rare and severe inflammatory dermatosis distinct from plaque psoriasis and associated with significant unmet therapeutic needs. Although advances in immunopathogenesis have identified key cytokine and signaling pathways, evidence-based treatment options remain limited. This systematic review evaluates the efficacy and safety of emerging Janus kinase (JAK) and tyrosine kinase (TYK) inhibitors in the management of PP. This systematic review was conducted in accordance with PRISMA 2020 guidelines. PubMed/Medline, Ovid-Embase, and Web of Science were searched from inception to November 15th, 2025, to identify all English-language clinical studies evaluating JAK or TYK inhibitors in patients with GPP or PPP. Methodological quality and risk of bias were independently assessed using National Institutes of Health quality assessment tools and the Murad et al. criteria. Of 2,259 records identified, 33 clinical studies (177 patients with GPP or PPP) met the predefined eligibility criteria. TYK inhibitors were evaluated in three studies of deucravacitinib (n = 11), which showed variable efficacy across reports: improvements in PASI/PPPASI, symptoms, and quality of life in some patients, and discontinuation due to insufficient response in others, with no serious adverse events reported. JAK inhibitors were evaluated in 30 studies involving 166 patients and were associated with improvements in disease severity, quality of life, and physician-assessed outcomes. Favorable responses were reported in observational studies, while rapid clinical improvement was frequently described in case-based evidence. Overall, treatment was generally well tolerated, although interpretation is limited by the predominance of uncontrolled studies and heterogeneous data. Available evidence indicates that JAK and TYK inhibitors may provide clinical benefit in GPP and PPP, particularly in refractory cases, with generally acceptable safety profiles. However, conclusions are limited by small, heterogeneous studies, and well-designed randomized controlled trials with longer follow-up are needed to establish long-term efficacy and safety.

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2026-08-06 | Safety and Efficacy of Deucravacitinib in Japanese Patients With Moderate to Severe Plaque Psoriasis: 5-Year Analysis of the Phase 3 POETYK PSO-1, PSO-4, and Long-Term Extension Trials.

Deucravacitinib, an oral, selective tyrosine kinase 2 inhibitor, is approved in multiple countries for the treatment of moderate to severe plaque psoriasis, as well as generalized pustular and erythrodermic psoriasis in Japan. Deucravacitinib 6 mg once daily was efficacious and well tolerated through 3 years in the pooled population of Japanese patients in the POETYK PSO-1 and PSO-4 trials who entered the ongoing open-label POETYK long-term extension trial. Safety and efficacy of deucravacitinib were evaluated through 5 years (256 weeks; data cutoff September 2, 2024) in Japanese patients who received continuous deucravacitinib in PSO-1 or PSO-4 or who crossed over from placebo to deucravacitinib at Week 16 in PSO-1. Safety was evaluated via adverse event (AE) exposure-adjusted incidence rates (EAIRs); efficacy was evaluated via endpoints including ≥ 75% reduction from baseline in the Psoriasis Area and Severity Index (PASI 75) and static Physician Global Assessment (sPGA) score of 0/1 (clear/almost clear). At data cutoff, 136 patients had received at least one deucravacitinib dose; 77.2% had > 48 months and 39.7% had > 60 months of total deucravacitinib exposure. EAIRs per 100 person-years were 182.1 (any AEs), 6.9 (serious AEs), 3.0 (discontinuations due to AEs), 1.6 (serious infections), 1.6 (herpes zoster events), 0.5 (major adverse cardiovascular events), and 1.4 (malignancies). Clinical responses (as observed) were maintained over 5 years in PSO-1 patients receiving continuous deucravacitinib treatment from baseline (PASI 75: Year 1, 88.9%; Year 5, 85.7%; sPGA 0/1: Year 1, 74.1%; Year 5, 71.4%); results were consistent regardless of imputation method (modified nonresponder imputation, treatment failure rule). Year 1 response rates were also maintained through Year 5 in PSO-4 patients and in PSO-1 patients who crossed over from placebo. These findings support the long-term safety and durable efficacy profile of deucravacitinib through 5 years in Japanese patients with psoriasis.

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2026-07-30 | Combination of Low-Dose Methotrexate and Cyclosporine in a Patient with Generalized Pustular Psoriasis: A Case Report

Generalized pustular psoriasis (GPP) is a rare and life-threatening chronic inflammatory skin disease characterized by sterile pustules and systemic inflammation, associated with substantial disease burden due to frequent flares. Limited guidelines and suboptimal treatment outcomes have led to various therapeutic approaches, including combination therapy. This case report aims to describe the use of low-dose methotrexate and cyclosporine combination in a GPP patient and evaluate the clinical response achieved. A 40-year-old woman presented with painful pustules distributed throughout the entire body accompanied by a burning sensation. She had undergone methotrexate therapy for 1 year before self-cessation due to insignificant improvement. Dermatological examination revealed generalized multiple pustules on an erythematous base, some confluent and covered by scales. Histopathological examination showed abundant neutrophils in the superficial epidermal layer along with focal neutrophils and mild spongiosis, supporting the diagnosis of GPP. The patient was given methotrexate 7.5 mg weekly and cyclosporine 100 mg daily for 5 weeks, showing significant clinical improvement, then maintained with methotrexate 7.5 mg weekly monotherapy. Combination therapy for GPP, particularly methotrexate and cyclosporine, has demonstrated faster and better clinical responses compared to monotherapy, with response rates of 70–90%. Cyclosporine provides rapid disease control, while methotrexate offers sustained immunomodulation. Both agents carry risks of adverse effects, necessitating careful dose selection and close monitoring. This case report demonstrates that low-dose methotrexate and cyclosporine combination is effective in managing refractory GPP with significant clinical improvement after 5 weeks of therapy, making it a promising therapeutic option for severe and refractory GPP cases.

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2026-07-27 | Treatment Patterns and Pathways of Systemic Drug Therapy in Patients With Plaque, Erythrodermic, and Generalized Pustular Psoriasis: A Retrospective Cohort Study in Japan.

Systemic psoriasis treatment options have rapidly expanded in Japan, including the approval of tyrosine kinase 2 and interleukin-36 receptor inhibitors in 2022. However, contemporary real-world treatment patterns across plaque, erythrodermic, and generalized pustular psoriasis remain incompletely characterized. Using a Japanese hospital-based insurance claims database (Medical Data Vision Co. Ltd.), we conducted a retrospective cohort study for patients with these psoriasis subtypes who initiated systemic drug therapy between 2020-2023 and had a ≥ 12-month observation period. Overall, 3965 patients with plaque psoriasis, 80 with erythrodermic psoriasis, and 128 with generalized pustular psoriasis were included (median age, 62-66 years). Most patients initiated systemic therapy with a single drug. A phosphodiesterase 4 inhibitor was the most frequently prescribed index treatment for plaque psoriasis (48.8%), whereas a vitamin A derivative was most commonly prescribed for erythrodermic and generalized pustular psoriasis (42.5% and 42.2%, respectively), suggesting a distinctive Japan-specific prescription pattern. The median proportion of days covered for index treatment was nearly 100% across all subtypes. Among the index treatments, biologics generally showed longer time to discontinuation than oral medications. Elderly patients were more likely to receive a phosphodiesterase 4 inhibitor or a vitamin A derivative as index treatment than younger patients, and biologics were more commonly selected for patients with psoriatic arthritis than for those without. Early uptake of tyrosine kinase 2 inhibitor was observed in 2023. Over a median observation period of approximately 30 months, > 85% of patients received three or fewer lines of systemic drug therapy and approximately 50% remained on at least one systemic drug therapy throughout the study period. This first comprehensive Japanese claims database analysis of multiple psoriasis subtypes provides an updated real-world treatment landscape in Japan and helps address an important evidence gap arising from rapidly evolving systemic treatment options and limited contemporary real-world data.

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2026-07-10 | Upadacitinib Successfully Treated Dupilumab-Associated Generalized Pustular Psoriasis in a Pediatric Patient with Atopic Dermatitis: A Case Report.

Atopic dermatitis (AD) and psoriasis are both T-cell-mediated inflammatory skin diseases. While dupilumab effectively treats moderate-to-severe AD, paradoxical psoriasiform eruptions, including rare cases of generalized pustular psoriasis (GPP), have been reported. These reactions often show poor response to conventional therapies, presenting significant therapeutic challenges. We present a case of a 6-year-old child with AD who developed GPP following dupilumab therapy and was successfully treated with upadacitinib. A 6-year-old girl with a 5-year history of AD was initiated on dupilumab therapy after an inadequate response to antihistamine treatment. Although initial symptoms improved, the patient rapidly developed GPP-like skin lesions throughout the body on day 11. Despite treatment with high-dose corticosteroids and cyclosporine, the patient experienced recurrent generalized pustules and developed erythrodermic psoriasis-like manifestations. Subsequently, upadacitinib was added at a dose of 15 mg every other day, following which the skin lesions gradually improved and completely resolved within 1 month. During the subsequent 6-month follow-up period on continued medication, no recurrence of skin lesions or adverse events was reported. This case provides a reference for the efficacy and safety of upadacitinib in a pediatric patient with AD who developed secondary GPP following dupilumab therapy. Upadacitinib may represent a valuable therapeutic option for dupilumab-associated paradoxical psoriasis (including GPP) in AD patients. Prospective studies are needed to establish its long-term safety and efficacy in this patient population.

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proteins

2025-03-23 | LL37 complexed to double-stranded RNA induces RIG-I-like receptor signalling and Gasdermin E activation facilitating IL-36γ release from keratinocytes.

The Interleukin-36 (IL-36) cytokine family have emerged as important players in mounting an inflammatory response at epithelial barriers and tailoring appropriate adaptive immune responses. As members of the Interleukin-1 superfamily, IL-36 cytokines lack a signal peptide for conventional secretion and require extracellular proteolysis to generate bioactive cytokines. Although the IL-36 family plays an important role in the pathogenesis of plaque and pustular psoriasis, little is known about the release mechanisms of these cytokines from keratinocytes and the physiological stimuli involved. Nucleic acid released from damaged or dying keratinocytes initiates early inflammatory signals that result in the breaking of tolerance associated with psoriasis pathogenesis onset. Cathelicidin peptide, LL37 binds to DNA or double-stranded RNA (dsRNA) and activates a type I Interferon responses in plasmacytoid dendritic cells and keratinocytes. Here, we demonstrate that LL37 binds to dsRNA and induces IL-36γ release from human primary keratinocytes. LL37/dsRNA complexes activate RIG-I-like Receptor signalling, resulting in Caspase-3 and Gasdermin E (GSDME) cleavage. Subsequent GSDME pore formation facilitates IL-36γ release. This response is magnified by priming with psoriasis-associated cytokines, IL-17A and IFNγ. IL-36γ release in this manner is largely independent of cell death in primary keratinocytes and lacked extracellular proteolysis of IL-36γ. Conversely, transfection of keratinocytes directly with dsRNA synthetic analogue, Poly(I:C) induces NLRP1 inflammasome activation, which facilitates IL-36γ expression and release in a GSDMD-dependent manner. Inflammasome-associated cell death also enables extracellular processing of IL-36γ by the release of keratinocyte-derived proteases. These data highlight the distinct responses triggered by dsRNA sensors in keratinocytes. Depending on the inflammatory context and magnitude of the exogenous threat, keratinocytes will release IL-36γ coupled with cell death and extracellular cleavage or release the inactive pro-form, which requires subsequent processing by neutrophil proteases to unleash full biological activity, as occurring in psoriatic skin. Cytoplasmic sensing of dsRNA in keratinocytes mediates IL-36γ release via caspase activity and GSDM pore formation Keratinocytes release IL-36γ upon stimulation with intracellular dsRNA alone or complexed to the psoriasis-associated cathelicidin anti-microbial peptide LL37. Left: Transfected dsRNA triggers NLRP1 inflammasome assembly and IL-1β release, which can enhance IL-36γ expression, resulting in IL-36γ release and extracellular cleavage by released proteases. Right: LL37/dsRNA complexes activate a MDA5-MAVS pathway facilitating the release of IL-36γ through Caspase-3 activation and GSDME pore formation.

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2024-09-25 | The role of interleukin-36 in health and disease states.

The interleukin (IL)-1 superfamily upregulates immune responses and maintains homeostasis between the innate and adaptive immune systems. Within the IL-1 superfamily, IL-36 plays a pivotal role in both innate and adaptive immune responses. Of the four IL-36 isoforms, three have agonist activity (IL-36α, IL-36β, IL-36γ) and the fourth has antagonist activity (IL-36 receptor antagonist [IL-36Ra]). All IL-36 isoforms bind to the IL-36 receptor (IL-36R). Binding of IL-36α/β/γ to the IL-36R recruits the IL-1 receptor accessory protein (IL-1RAcP) and activates downstream signalling pathways mediated by nuclear transcription factor kappa B and mitogen-activated protein kinase signalling pathways. Antagonist binding of IL-36Ra to IL-36R inhibits recruitment of IL-1RAcP, blocking downstream signalling pathways. Changes in the balance within the IL-36 cytokine family can lead to uncontrolled inflammatory responses throughout the body. As such, IL-36 has been implicated in numerous inflammatory diseases, notably a type of pustular psoriasis called generalized pustular psoriasis (GPP), a chronic, rare, potentially life-threatening, multisystemic skin disease characterised by recurrent fever and extensive sterile pustules. In GPP, IL-36 is central to disease pathogenesis, and the prevention of IL-36-mediated signalling can improve clinical outcomes. In this review, we summarize the literature describing the biological functions of the IL-36 pathway. We also consider the evidence for uncontrolled activation of the IL-36 pathway in a wide range of skin (e.g., plaque psoriasis, pustular psoriasis, hidradenitis suppurativa, acne, Netherton syndrome, atopic dermatitis and pyoderma gangrenosum), lung (e.g., idiopathic pulmonary fibrosis), gut (e.g., intestinal fibrosis, inflammatory bowel disease and Hirschsprung's disease), kidney (e.g., renal tubulointerstitial lesions) and infectious diseases caused by a variety of pathogens (e.g., COVID-19; Mycobacterium tuberculosis, Pseudomonas aeruginosa, Streptococcus pneumoniae infections), as well as in cancer. We also consider how targeting the IL-36 signalling pathway could be used in treating inflammatory disease states.

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2024-05-17 | Dermal adipogenesis protects against neutrophilic skin inflammation

The skin’s immune response to danger signals involves rapid recruitment of neutrophils, but their excessive accumulation leads to inflammatory skin diseases, such as psoriasis, and how skin resident cells tolerate neutrophilic inflammation is poorly understood. Dermal white adipose tissue (dWAT) is an emerging component of the skin's immune barrier, but its role in controlling skin inflammation remains under-studied. Here, using an imiquimod-induced psoriasis mouse model, we observed a dynamic coupling between dermal adipogenesis, neutrophil infiltration and regression. During the early inflammatory phase, dWAT repopulates with PDGFRA+ preadipocytes that secrete CXCL1 and SAA3, attracting and activating CXCR2+ neutrophils. These neutrophils further activate preadipocytes through IL1β-IL1R signaling, establishing a self-sustaining inflammatory loop. Prolonged activation of pAds triggers PPARγ-dependent adipogenesis, leading to the formation of early adipocytes that secrete lipids exerting potent anti-inflammatory activity against myeloid cells, thereby aiding in inflammation resolution. Inhibition of adipogenesis, via targeted inhibition of PPARγ, through either pharmacological or genetic approaches, disrupts the formation of early adipocytes and prevents neutrophil regression and inflammation resolution. Analysis of human psoriatic cells identified a dFB subpopulation enriched with preadipocyte, IL1-pathway, and inflammatory gene signatures. Furthermore, transcriptomic analyses revealed a negative correlation between neutrophil-related inflammatory response with dermal adipogenesis response in generalized pustular psoriasis. Together, this study highlights the distinct roles of adipogenic fibroblasts and early adipocytes in initiating and resolving skin inflammation and suggests that promoting the differentiation of proinflammatory fibroblasts into anti-inflammatory early adipocytes could open avenues for the treatment of neutrophil-related inflammatory skin diseases, such as psoriasis and ulcers.

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2023-11-01 | Metabolomics Reveals Molecular Signatures for Psoriasis Biomarkers and Drug Targets Discovery

Purpose: Psoriasis is a chronic, multi-system skin disease that can be influenced by immunological, environmental, and genetic factors. Plasma metabolomic analysis can provide a great deal of information on potential diagnostic biomarkers, pathogenesis and personalized treatment. However, the role of metabolites in psoriasis is unknown. Patients and Methods: We performed an untargeted metabolomic analysis of plasma based on high-resolution liquid chromatography mass spectrometry from 10 plaque psoriasis patients and 10 healthy controls. Results: A total of 301 differential metabolites were detected, of which 10 metabolites were possible potential biomarkers, including vitamins, amino acids, and lipids. At the same time, KEGG pathway enrichment analysis was performed for all detected differential metabolites, and it was found that protein digestion and absorption, amino acid metabolism and lipid metabolism may be jointly involved in regulating the pathogenesis of psoriasis. In addition, the proteins ESR1, OPRM1 and HSD11B1 were identified as possible potential topical therapeutic targets for psoriasis through analysis of the metabolite-protein interaction network. Conclusion: In this study, we identified 10 differential metabolites as possible potential combinatorial biomarkers for the diagnosis of psoriasis. 12 metabolic pathways were significantly enriched that may be closely related to the occurrence and development of psoriasis. Three proteins, ESR1, OPRM1, and HSD11B1, were identified as possible potential therapeutic targets for psoriasis. Keywords: psoriasis, metabolomics, biomarker, KEGG pathway, therapeutic target

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2023-08-18 | Low-dose Interleukin-2 For Psoriasis Therapy Based on the Regulation of Th17/Treg Cell Balance in Peripheral Blood

The imbalance between regulatory T (Treg) cells and efficient T cells plays an important role in psoriasis. Low-dose interleukin (IL)-2 can preferentially activate Treg cells and ameliorate the imbalance of Treg/efficient T cells. This study focused on the status of circulating CD4+ T subsets and the clinical efficacy of low-dose IL-2 therapies in psoriasis. This retrospective study included peripheral blood samples obtained from 45 psoriatic patients and 40 healthy controls. The 45 psoriatic patients received three cycles of subcutaneous low-dose IL-2 treatment (0.5 million IU/day for 2 weeks) combined with conventional therapies. Inflammatory indices, CD4+ T-lymphocyte subsets, and cytokines were measured in all patients before and after treatment. The percentage of Treg cells was dramatically decreased in the psoriasis group compared to the healthy group, and the percentage of Treg cells negatively correlated with the disease indices and the Psoriasis Area and Severity Index (PASI) (P < 0.001). The Th17/Treg ratio was significantly increased in the psoriasis group compared to the healthy group, and the Th17/Treg ratio positively correlated with disease indices and PASI (P < 0.001). Low-dose IL-2 treatment significantly amplified the percentage of Treg cells and restored the Th17 and Treg immune balance in psoriasis (P < 0.001). Low-dose IL-2 combination therapy effectively improved the clinical manifestations of psoriasis but decreased the inflammatory indicators of the disease activity, with no apparent side effects. Thus, low-dose IL-2 provides a new strategy for the treatment of psoriasis.

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antibodies

2026-08-05 | INDIVIDUAL ARTICLE: Generalized Pustular Psoriasis: A Contemporary Review of Diagnosis, Pathophysiology, and IL-36 Pathway-Directed Management.

Emerging epidemiologic, clinical, and real-world data establish GPP as a distinct disease entity associated with high rates of hospitalization, multisystem involvement, and increased mortality. Accurate diagnosis requires recognition of characteristic cutaneous findings together with laboratory and clinical evidence of systemic involvement, and exclusion of key mimickers such as acute generalized exanthematous pustulosis, as well as recognition of patient-reported systemic symptoms such as fever, malaise, and joint pain. Advances in pathophysiologic understanding have identified dysregulated innate immune signaling centered on the interleukin-36 (IL-36) pathway as the primary driver of neutrophilic inflammation and pustule formation. Randomized clinical trials, real-world evidence, and meta-analyses consistently demonstrate that IL-36 receptor blockade achieves rapid and reliable control of acute GPP flares and provides a rational strategy for flare prevention. In contrast, off-label biologic therapies targeting IL-17, IL-23, or tumor necrosis factor-α show more variable and often delayed efficacy, particularly for acute disease control. Contemporary evidence supports a paradigm shift toward disease-specific, pathway-directed management of GPP, with IL-36 pathway inhibition positioned as the cornerstone of modern therapy.  .

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2026-08-01 | Effectiveness and Safety of Spesolimab in Adolescents and Adults with Generalized Pustular Psoriasis

Purpose: Generalized pustular psoriasis (GPP) is a rare, severe, and potentially life-threatening inflammatory skin disease characterized by widespread erythema, pustules and systemic involvement. Evidence-based treatment guidelines for adolescents with GPP remain limited. Spesolimab, a parenteral humanized monoclonal antibody targeting the interleukin-36 receptor, has emerged as a novel therapeutic option; however, data on its use in adolescents are scarce. Here, we aimed to evaluate the effectiveness of spesolimab in treating GPP episodes in adolescents and compared their outcomes with those in adults. Patients and Methods: We analyzed the management of GPP episodes with spesolimab in two adolescent and four adult patients in our unit and conducted a literature review involving 25 patients. Clinical outcomes included response to treatment, pustule resolution, and infection management. Spesolimab achieved rapid and sustained symptom control in all patients, including those with coexisting plaque psoriasis. Results: Twenty-two patients (71.0%) experienced complete pustule resolution within 1 week, and all 31 patients achieved complete pustule resolution by week 4. Treatment responses in adolescents were comparable to those in adults. Infections were identified as key exacerbating factors and managed accordingly. Conclusion: IL-36R inhibitors, such as spesolimab, are potentially effective and safe treatment for both adolescent and adult patients with GPP. Future studies should explore the long-term efficacy of spesolimab and its application strategy of sustained disease control. Keywords: spesolimab, IL-36 receptor antagonist, pustular psoriasis, drug therapy

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2026-07-03 | Management of Generalized Pustular Psoriasis Flare with Intravenous Spesolimab Followed by Long-Term Treatment with Subcutaneous Spesolimab: A Case Report.

This case report describes the clinical course and treatment of generalized pustular psoriasis (GPP) flare with intravenous (i.v.) spesolimab, an anti-IL-36R antibody, and subsequent long-term disease management with subcutaneous (s.c.) spesolimab. A 72-year-old female patient had an ongoing GPP flare for 1 month before presenting to the hospital for flare and related multiorgan failure. She was successfully treated with 2 infusions of 900 mg i.v. spesolimab 1 week apart. She then initiated therapy with 300 mg s.c. spesolimab every 4 weeks for the long-term treatment of GPP. Rapid and significant improvement of skin and systemic symptoms was observed within 1 week of receiving i.v. spesolimab. However, the severity of the patient's prolonged flare deteriorated her functional status, and she required rehabilitation post-discharge. At follow-ups, s.c. spesolimab demonstrated favorable efficacy and tolerability, with no flare recurrence. Mild superficial desquamation reappeared in the days before consecutive spesolimab doses, with complete skin recovery achieved post-dose. This case underscores the serious complications arising from untreated flare and the need for long-term management of chronic GPP. The patient's ongoing post-flare symptoms highlight the chronicity of GPP, and continuous targeted treatment with spesolimab improved both her symptoms and quality of life.

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2026-06-29 | Case Report: Successful treatment of refractory generalized pustular psoriasis with xeligekimab: a report of two cases.

Generalized pustular psoriasis (GPP) is a severe, relapsing skin disorder characterized by widespread erythema and sterile pustules. Classical systemic therapies often yield suboptimal results. Xeligekimab is a novel, fully human anti-interleukin-17A (anti-IL-17A) monoclonal antibody recently approved in China for plaque psoriasis. Its efficacy in GPP has not been previously reported. This report presents two cases of refractory GPP successfully treated with xeligekimab. Both patients- a 25-year-old male and a 70-year-old male had long-standing GPP that was unresponsive to conventional systemic therapies including acitretin and methotrexate. After receiving a single 200 mg dose of xeligekimab, both patients exhibited rapid and significant clinical improvement within 3 to 4 days. Remarkably, one patient remained in remission at the 3-month follow-up after only one injection. This is the first report to suggest that xeligekimab is a potent and promising therapeutic option for inducing rapid and sustained remission in patients with GPP.

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2026-06-25 | Monotherapy with Biologics for Generalized Pustular Psoriasis: A Systematic Review of Comparative Interventional Studies with an Exploratory Network Meta-Analysis.

Background-Generalized pustular psoriasis (GPP) is a rare and severe inflammatory skin disorder-and evidence regarding relative impact of treatments thereof is currently scant. Objective-We aimed to systematically review and narratively synthesize comparative interventional therapies for GPP and secondarily explore their relative effectiveness through exploratory network meta-analyses (NMAs). Methods-Comprehensive searches were performed in PubMed and EMBASE to identify comparative interventional studies that investigated the impact of biologics in GPP. Bayesian NMAs were conducted only for exploratory analyses. Results-Eleven studies met our inclusion criteria and data from 4 of the 11 were used for NMAs. Methodological heterogeneity was evident; the various biologics demonstrated effectiveness in treating GPP. Inhibitors of interleukin (IL)-36 (e.g., spesolimab) resulted in rapid pustular clearance within one week and sustained reductions in flare occurrence. Inhibitors targeting IL-17, IL-23, TNF, and IL-12/23 also demonstrated high response rates, durable disease control, and improvements in quality of life among diverse patient populations. Results from our exploratory NMAs revealed patterns of relative effectiveness with IL-17 and IL-36 inhibitors that are consistent with the existing literature. However, methodological limitations across the four studies deterred us from making conclusive inferences. Conclusions-Biologic therapies provide significant clinical benefit in patients with GPP. Our narrative syntheses highlight the need for future quantitative syntheses.

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oligonucleotides

2024-08-19 | RNA-binding proteins potentially regulate alternative splicing of immune/inflammatory-associated genes during the progression of generalized pustular psoriasis.

Generalized pustular psoriasis (GPP) is a rare but severe form of psoriasis. However, the pathogenesis of GPP has not been fully elucidated. Although RNA-binding proteins (RBPs) and the alternative splicing (AS) process are essential for regulating post-transcriptional gene expression, their roles in GPP are still unclear. We aimed to elucidate the regulatory mechanisms to identify potential new therapeutic targets. Here, We analyzed an RNA sequencing (RNA-seq) dataset (GSE200977) of peripheral blood mononuclear cells (PBMCs) of 24 patients with GPP, psoriasis vulgaris (PV), and healthy controls (HCs) from the Gene Expression Omnibus (GEO) database. We found that the abnormal alternative splicing (AS) events associated with GPP were mainly "alt3p/alt5p", and 15 AS genes were differentially expressed. Notably, the proportions of different immune cell types were correlated with the expression levels of regulatory alternatively spliced genes (RASGs): significant differences were observed in expression levels of DTD2, NDUFAF3, NBPF15, and FBLN7 in B cells and ARFIP1, IPO11, and RP11-326L24.9 in neutrophils in the GPP samples. Furthermore, We identified 32 differentially expressed RNA-binding proteins (RBPs) (18 up-regulated and 14 down-regulated). Co-expression networks between 14 pairs of differentially expressed RBPs and RASGs were subsequently constructed, demonstrating that these differentially expressed RBPs may affect the progression of GPP by regulating the AS of downstream immune/inflammatory-related genes such as LINC00989, ENC1 and MMP25-AS1. Our results were innovative in revealing the involvement of inflammation-related RBPs and RASGs in the development of GPP from the perspective of RBP-regulated AS.

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2023-05-01 | 845 Long non-coding RNA-GDA-1 regulates keratinocyte proliferation and psoriasis inflammation by regulating forkhead box m1 via the STAT3/NF-κB signaling pathway

Psoriasis is a chronic inflammatory skin disease associated with multiple comorbidities and complex pathogenesis. Long noncoding RNAs (lncRNAs) play an important regulatory role in many diseases, including psoriasis. In this study, We aimed to investigate the role and mechanism of lncRNA GDA-1 (GDA) in M5-treated psoriatic keratinocytes. GDA expression was significantly upregulated in psoriatic tissues and M5-treated keratinocytes. By silencing and overexpressing GDA in NHEKs and Ker-CT cells, we showed that GDA regulated proliferation and cell cycle, and increased secretion of interleukin-1β, IL-6, chemokine ligands 2 and 20 (CCL2 and CCL20). RNA sequencing after GDA silencing led to identification of a close regulatory relationship between GDA and Forkhead Box M1 (FOXM1). GDA significantly influenced FOXM1 expression at both mRNA and protein levels and activated STAT3/NF-κB signaling pathways. STAT3 and NF-κB inhibition abrogated GDA effects on keratinocyte proliferation and inflammation. In conclusion, our study is the first to report that Lnc-GDA-1 distinctly regulates FOXM1 expression and mediates proliferation and inflammation of psoriatic keratinocytes through the STAT3/NF-κB signaling pathway, which may be a potent target for psoriasis treatment.

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2023-04-17 | 846 LncRNA lnc-SPRR2G-2 contributes to keratinocyte hyperproliferation and inflammation in psoriasis by activating STAT3 pathway and downregulating KHSRP

This study aimed to explore the roles of lnc-SPRR2G-2 in psoriasis. Fluorescencein situhybridization and qRT-PCR were used to detect the localization and expression of lnc-SPRR2G-2. CCK-8, EdU assay and flow cytometry analysis were performed to measure cell proliferation. ELISA assays were used to evaluate the secretion of inflammatory cytokines. Western blot and qRT-PCR analysis were performed to detect expression of molecules related to cell cycle, apoptosis, inflammation and STAT3 signaling pathway. Bioinformatics websites catRAPID and RBPDB were used to predict target proteins of lnc-SPRR2G-2. RNA stability assay was performed to examine mRNA decay of psoriasis-related cytokines. In this study, we found lnc-SPRR2G-2 was significantly upregulated in psoriasis tissues and cell models and mainly localized in the nucleus. Through overexpression and knockdown of lnc-SPRR2G-2, we confirmed its pro-proliferative and pro-inflammatory effects. These phenotypes were associated with STAT3 signaling pathway and could be blocked by STAT3 inhibitor. Moreover, KHSRP was proved to be regulated by lnc-SPRR2G-2 and to control mRNA decay of psoriasis-related cytokines. Here we first reported the function of lnc-SPRR2G-2 and KHSRP in psoriasis and these results suggest that lnc-SPRR2G-2 and KHSRP may be a potential therapeutic target in psoriasis treatment in the future.

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2016-11-21 | Six-transmembrane epithelial antigens of the prostate comprise a novel inflammatory nexus in patients with pustular skin disorders

Pustular skin disorders are a category of difficult-to-treat and potentially life-threatening conditions that involve the appearance of neutrophil-rich pustules. The molecular basis of most pustular skin conditions has remained unknown.We sought to investigate the molecular basis of 3 pustular skin disorders: generalized pustular psoriasis (GPP), palmoplantar pustulosis (PPP), and acute generalized exanthematous pustulosis (AGEP).Microarray analyses were performed to profile genome-wide gene expression of skin biopsy specimens obtained from patients with GPP, PPP, or AGEP and healthy control subjects. Functional enrichment, gene network, and k-means clustering analyses were used to identify molecular pathways dysregulated in patients with these disorders. Immunohistochemistry and immunofluorescence were used to determine protein localization. Quantitative RT-PCR and ELISA were used to determine transcript and secreted cytokine levels. Small interfering RNA was used to decrease transcript levels.Molecules and pathways related to neutrophil chemotaxis emerged as common alterations in patients with GPP, PPP, and AGEP, which is consistent with the pustular phenotypes. Expression of two 6-transmembrane epithelial antigens of the prostate (STEAP) proteins, STEAP1 and STEAP4, was increased in patients' skin and colocalized with IL-36γ around neutrophilic pustules. STEAP1/4 expression clustered with and positively correlated with that of IL-1, the IL-36 family proteins, and CXCL1/8. STEAP4 expression was activated by cytokines and suppressed by inhibition of mitogen-activated protein kinase kinase 1/2, whereas STEAP1 expression appeared less prone to such dynamic regulation. Importantly, STEAP1/4 knockdown resulted in impaired induction of a broad spectrum of proinflammatory cytokines, including IL-1, IL-36, and the neutrophil chemotaxins CXCL1 and CXCL8. STEAP1/4 knockdown also reduced the ability of keratinocytes to induce neutrophil chemotaxis.Transcriptomic changes in 3 pustular skin disorders, GPP, PPP, and AGEP, converged on neutrophil chemotaxis and diapedesis and cytokines known to drive neutrophil-rich inflammatory processes, including IL-1 and members of the IL-36 family. STEAP1 and STEAP4 positively regulate the induction of proinflammatory neutrophil-activating cytokines.

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2024-12-01 | FC22 Assessment of pustular psoriasis genes in generalized and palmoplantar pustular psoriasis suggest transethnic differences in disease susceptibility, an oligogenic inheritance in both psoriatic subtypes and an involvement of purinergic receptors

Abstract Generalized (GPP) and palmoplantar pustular psoriasis (PPP) are psoriatic subtypes affecting fewer psoriatic patients but often more severely than common psoriasis vulgaris. While several susceptibility genes have been identified in GPP mainly in Africa and Europe, there is currently a lack of established risk factors for PPP. Recently, P2RX7 variants were suggested to contribute to chronic non-bacterial osteomyelitis (CNO), a clinically overlapping disease. In order to estimate the effect sizes of susceptibility variants in GPP and CNO genes, we assessed 195 exome/ genome sequences of GPP and PPP systematically and performed a literature search for published datasets of European pustular psoriasis patients. Depending on the reported state of disease-variants, we compared allele or genotype frequencies to those of controls. In the case of bi-allelic variants, we considered ∼4900 individuals in whom allele dosage could be determined. Meta-analysis in GPP revealed significant effect sizes for IL36RN and MPO variants in European carriers of mono-, but especially of bi-allelic variants [IL36RN: odds ratio (95% confidence interval) = 334.2 (106.5–1599.2); MPO: 73.7 (16.5–328.5)], as expected for a monogenic/ oligogenic disease like GPP. Nine PPP patients (8%) carried a coding variant in either IL36RN or MPO, one additional individual with disease-contributing variants in both IL36RN and MPO suggests that oligogenic inheritance might also be relevant in PPP. Not a single PPP patient, but five GPP patients were identified to carry P2RX7 missense variants predicted/shown to have an impact on the signalling pathway; notably, one of the latter patients carried two variants, suggesting autosomal recessive inheritance. Putative disease variants in AP1S3 were not associated, while SERPINA3 variants were too rare to perform reliable comparisons. We did not analyse CARD14, as there are numerous missense variants and the classification of many missense variants into different ACMG categories is rather arbitrary. Our study indicates a continuum of GPP-PPP-CNO and a significant contribution of IL36RN and MPO variants on disease susceptibility in bi-allelic states and in European GPP patients, less commonly in PPP. The lack of association of pustular psoriasis with BTN3A3 in European patients and with MPO variants in Asian patients suggests transethnic differences in disease susceptibility. The overall allele frequencies of up to 4.5% of variants in AP1S3 and BTN3A3 in certain populations and a considerable frequency of homozygous, healthy carriers of risk alleles in BTN3A3 and AP1S3 render an impact on disease susceptibility less likely. As variants in known disease genes affect &lt;40% of GPP patients and a low percentage in PPP, there is a high need to elucidate the molecular basis of pustular psoriasis, in order to offer more targeted, individualized therapy.

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2024-03-05 | Exosomes: The emerging mechanisms and potential clinical applications in dermatology

Skin tissue, composed of epidermis, dermis, and subcutaneous tissue, is the largest organ of the human body.It serves as a protective barrier against pathogens and physical trauma and plays a crucial role in maintaining homeostasis.Skin diseases, such as psoriasis, dermatitis, and vitiligo, are prevalent and can seriously impact the quality of patient life.Exosomes are lipid bilayer vesicles derived from multiple cells with conserved biomarkers and are important mediators of intercellular communication.Exosomes from skin cells, blood, and stem cells, are the main types of exosomes that are involved in modulating the skin microenvironment.The dysregulation of exosome occurrence and transmission, as well as alterations in their cargoes, are crucial in the complex pathogenesis of inflammatory and autoimmune skin diseases.Therefore, exosomes are promising diagnostic and therapeutic targets for skin diseases.Importantly, exogenous exosomes, derived from skin cells or stem cells, play a role in improving the skin environment and repairing damaged tissues by carrying various specific active substances and involving a variety of pathways.In the domain of clinical practice, exosomes have garnered attention as diagnostic biomarkers and prospective therapeutic agents for skin diseases, including psoriasis and vitiligo.Furthermore, clinical investigations have substantiated the regenerative efficacy of stem cell-derived exosomes in skin repair.In this review, we mainly summarize the latest studies about the mechanisms and applications of exosomes in dermatology, including psoriasis, atopic dermatitis, vitiligo, systemic lupus erythematosus, systemic sclerosis, diabetic wound healing, hypertrophic scar and keloid, and skin aging.This will provide a novel perspective of exosomes in the diagnosis and treatment of dermatosis.

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2024-01-18 | Discovery of natural bispecific antibodies: Is psoriasis induced by a toxigenic Corynebacterium simulans and maintained by CIDAMPs as autoantigens?

Abstract The high abundance of Corynebacterium simulans in psoriasis skin suggests a contribution to the psoriasis aetiology. This hypothesis was tested in an exploratory study, where western blot (WB) analyses with extracts of heat‐treated C. simulans and psoriasis serum‐derived IgG exhibited a single 16 kDa‐WB‐band. Proteomic analyses revealed ribosomal proteins as candidate C. s. ‐antigens. A peptidomic analysis unexpectedly showed that psoriasis serum‐derived IgG already contained 31 immunopeptides of Corynebacteria ssp., suggesting the presence of natural bispecific antibodies (BsAbs). Moreover, peptidomic analyses gave 372 DECOY‐peptides with similarity to virus‐ and phage proteins, including Corynebacterium diphtheriae phage , and similarity to diphtheria toxin. Strikingly, a peptidomic analysis for human peptides revealed 64 epitopes of major psoriasis autoantigens such as the spacer region of filaggrin, hornerin repeats and others. Most identified immunopeptides represent potential cationic intrinsically disordered antimicrobial peptides (CIDAMPs), which are generated within the epidermis. These may form complexes with bacterial disordered protein regions, representing chimeric antigens containing discontinuous epitopes. In addition, among 128 low‐abundance immunopeptides, 48 are putatively psoriasis‐relevant such as epitope peptides of PGE2‐, vitamin D3‐ and IL‐10‐receptors. Further, 47 immunopeptides originated from tumour antigens, and the endogenous retrovirus HERV‐K. I propose that persistent infection with a toxigenic C. simulans initiates psoriasis, which is exacerbated as an autoimmune disease by CIDAMPs as autoantigens. The discovery of natural BsAbs allows the identification of antigen epitopes from microbes, viruses, autoantigens and tumour‐antigens, and may help to develop epitope‐specific peptide‐vaccines and therapeutic approaches with antigen‐specific regulatory T cells to improve immune tolerance in an autoimmune disease‐specific‐manner.

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2018-05-01 | 037 Neutrophil-derived exosome drives the autoinflammatory responses of generalized pustular psoriasis via activating NOD2 in keratinocytes

Generalized pustular psoriasis (GPP) is a rare, recurrent, and life-threatening disease, characterized by the infiltration of neutrophils into the epidermis to form generalized pustules. Neutrophils are the most abundant leukocytes present in human blood and in the lesional skin of GPP patients. Though short-lived, neutrophils can immediately secrete cytokines, chemokines, and vesicles. Our study aimed to illustrate the functions of neutrophils in the immune disorder of GPP. Herein, we demonstrated that the neutrophil to lymphocyte ratio (NLR) was correlated with the severity of GPP, and decreased dramatically after effective treatment, which indicated that the NLR score could be a marker for the severity and prognosis of GPP, and neutrophil might play a critical role in the pathogenesis of GPP. Besides, keratinocytes co-cultured with GPP neutrophils indirectly produced more CXCL1, CXCL2, CXCL8, CCL20, IL36G, and TNF-α than those in the direct co-culturing system. Further, exosomes derived from GPP neutrophils could enter and activate keratinocytes to secrete the above-mentioned mediators. The proteome profiling of GPP neutrophil exosomes identified olfactomedin 4 (OLFM4) as a critical distinct protein. And neutrophil exosomes with OLFM4 cargo activated keratinocytes to highly produce these chemokines and cytokines via NOD2 and the downstream NF-κb and MAPK signaling pathways. Importantly, the proportion of OLFM4-positive neutrophils was found to be higher in patients with progressive GPP than that in controls. Taken together, these data suggest that neutrophil-derived exosomes enter keratinocytes to stimulate the expression and secretion of CXCLs, IL36G, and TNF-α, resulting in the chemotaxis of more neutrophils, which promotes the autoinflammatory responses in generalized pustular psoriasis.

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2005-12-01 | T Cell-Regulated Neutrophilic Inflammation in Autoinflammatory Diseases

Abstract Previous studies of acute generalized exanthematous pustulosis, a peculiar drug hypersensitivity reaction, suggested that CXCL8-producing T cells regulate sterile, polymorphonuclear neutrophil-rich skin inflammations. In this study, we test the hypothesis of whether CXCL8-producing T cells are present in autoinflammatory diseases like pustular psoriasis and Behçet’s disease. Immunohistochemistry of normal skin revealed few CD4+ and CD8+ T cells, few CXCL8+ cells, and no neutrophilic infiltration, whereas in acute exacerbations of atopic dermatitis, numerous CD4+ T cells but few CD8+ T cells, neutrophils, or CXCL8+ cells were detected. In contrast, a pronounced infiltration of neutrophils and of predominantly CD4+ T cells was observed in skin biopsies from pustular psoriasis, Behçet’s disease, and acute generalized exanthematous pustulosis, with infiltrating T cells strongly positive for CXCL8 and the chemokine receptor CCR6. Skin-derived T cell clones from pustular skin reactions were positive for CCR6 but negative for CCR8 and secreted high amounts of CXCL8 and GM-CSF, often together with IFN-γ and TNF-α after in vitro stimulation. Moreover, some skin-derived T cell clones from Behçet’s disease and from pustular psoriasis predominantly produced CXCL8 and GM-CSF, but failed to secrete IL-5 and IFN-γ. These cells might represent a particular subset as they differ from both Th1 as well as Th2 T cells and are associated with a unique, neutrophil-rich sterile inflammation. Our findings suggest that CXCL8/GM-CSF-producing T cells may orchestrate neutrophil-rich pathologies of chronic autoinflammatory diseases like pustular psoriasis and Behçet’s disease.

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