036 The accumulation of calcipotriol-induced tissue resident memory T cells counterbalances its anti-inflammatory properties in a model of psoriasiform dermatitis

Generalized pustular psoriasis is a rare and severe systemic inflammatory disease characterized by skin erythema and visible sterile pustules. Associated with hereditary and external factors, it can be life-threatening and requires specialized diagnosis and treatment. A 6-year-old male with disseminated dermatosis of 7 months evolution, initially appearing in the retroauricular region with erythematous scaly plaques and pustular lesions, spreading to various body segments, accompanied by intense pruritus, fever, and tachycardia. Histopathological examination reported psoriasiform dermatitis with lymphocytes, plasma cell aggregates, and neutrophils forming microabscesses in the stratum corneum, compatible with a diagnosis of pustular psoriasis. Treatment included methotrexate at 12 mg/m²/week, folic acid, 1% methylprednisolone aceponate cream, 0.005% calcipotriol, urea-based emollient at 10%, and antihistamines. Generalized pustular psoriasis in pediatrics requires comprehensive care, considering not only dermatological aspects but also psychosocial factors. Successful management of pediatric cases, as described, highlights the importance of a personalized approach tailored to each patient's needs to achieve long-term satisfactory outcomes.

We often experience sustained improvement, even after discontinuation of treatment in psoriasis lesions treated with topical vitamin D3 (VD3) or the combination of topical corticosteroids and VD3. However, the underlying mechanisms of these sustained effects remain unclear. We explored mechanisms for the sustained effects of maxacalcitol (MCT) and combined MCT/betamethasone butyrate propionate (BBP) ointments using a murine psoriasiform dermatitis model induced by imiquimod (IMQ). IMQ was applied once daily to the shaved backs of mice for 6 days to induce psoriasiform dermatitis. MCT, BBP, combined MCT/BBP ointment, or their vehicles were treated for 3 days prior to IMQ application. IMQ was reapplied after 1, 2, or 3 weeks from the first IMQ application to investigate the sustained effects of their ointments. In the first application of IMQ, the administration of MCT, BBP, or MCT/BBP ointment improved clinical and pathological manifestations and reduced Th17-related cytokines. Treatment with MCT or MCT/BBP showed an increase in IL-10 mRNA expression and a higher count of Foxp3+ cells within the skin, but not in those with BBP. The induction of IL-10 by MCT and MCT/BBP persisted until reapplication of IMQ 2 weeks later, although their effects diminished 3 weeks later. The reduction in Th17-related cytokines was maintained up to 3 weeks later in MCT/BBP, whereas it was not observed 2 weeks later in MCT. In conclusion, MCT and MCT/BBP showed long-term effects by induction of regulatory T cells and IL-10. Additionally, MCT/BBP downregulated Th17-related cytokines, which could contribute to the sustained improvement after discontinuation observed in clinical practice.

BackgroundMultiple Sclerosis (MS) is an immune-mediated, demyelinating disease of the central nervous system. Although psoriasis and psoriasiform dermatitis are reported in MS patients, the prevalence of the diseases is uncertain globally and unstudied in Australia. This study aims to determine the frequency of psoriasis in a clinic-based cohort of Australian MS patients.MethodsA survey was conducted on 204 consecutive MS patients aged 18 and over who attended a tertiary MS clinic in Northern Sydney from July 2018 to December 2022.ResultsA total of 204 patients were examined, comprising 137 female (67.2%) and 67 male (32.8%). The mean age was 48.8 years (SD = 13.6). Psoriasis was identified in 13.7% (28/204; 95% CI: 9.63% to 19.20%).DiscussionThe frequency of psoriasis in MS is high and may be underestimated, given that many more patients have symptoms without signs. This implies an immunopathological link between the two conditions and is worthy of further study.

ABSTRACTBiologic therapies have transformed the management of atopic dermatitis (AD) and prurigo nodularis (PN), yet paradoxical adverse events such as dupilumab‐induced psoriasiform eruption (DPE) are increasingly recognized. We report a 48‐year‐old Japanese man with long‐standing AD and PN who developed scaly, erythematous plaques on the elbows, hands, and trunk 5 months after initiating dupilumab. While prurigo nodules had markedly improved, the new lesions resembled psoriasis clinically. A biopsy from the elbow revealed features consistent with psoriasiform dermatitis—regular acanthosis, thickened granular layer, and perivascular lymphocytic infiltration without neutrophils—suggesting DPE rather than true psoriasis. Topical vitamin D3 and corticosteroids were ineffective, prompting a switch to tralokinumab, an IL‐13–specific inhibitor. Following this transition, psoriasiform lesions on the trunk and hands resolved, and PN did not recur. However, plaques on both elbows persisted for over a year and remained after tralokinumab discontinuation. Histologically, these lesions lacked features of psoriasis and were more consistent with PN, suggesting a Th2‐driven relapse mimicking psoriasiform disease. This case highlights the potential of tralokinumab to manage DPE while sustaining PN control but also underscores the heterogeneity of psoriasiform eruptions during type 2 biologic therapy. Not all lesions represent Th1/Th17‐mediated processes; some may reflect residual Th2‐driven disease such as PN with atypical morphology. Histopathological evaluation is essential for distinguishing true paradoxical reactions from overlapping or relapsing dermatoses and for guiding optimal treatment selection in patients receiving targeted immunomodulators.

ABSTRACTPsoriasis is a chronic inflammatory skin disease characterized by abnormal differentiation and hyperproliferation of epidermal keratinocytes. Autophagy plays a critical role in regulating the functions of immune cells, endothelial cells, and especially keratinocytes, contributing to the pathogenesis of psoriasis. However, the role of chaperone-mediated autophagy (CMA) in psoriatic keratinocytes has not been fully explored. Our study, for the first time, revealed that defective CMA is present in imiquimod (IMQ)-induced psoriasiform lesions. Importantly, activation of CMA significantly attenuated IMQ-induced phenotypes both in vitro and in vivo, including reduced skin lesion severity, decreased keratinocyte proliferation and differentiation, and lower cytokine secretion. Mechanistically, toll-like receptor 7 (TLR7), containing a specific KFERQ-like motif, is a substrate for CMA-mediated degradation. This process modulates IMQ-TLR7 signal activation in keratinocytes. CMA deficiency in psoriasis leads to increased TLR7 levels, which, in turn, enhances TLR7-NF-κB signaling pathway activation, ultimately contributing to dysregulated keratinocyte proliferation, differentiation, and cytokine secretion. This study provides novel evidence that defective CMA is present in IMQ-induced psoriasiform lesions and that CMA activation can attenuate IMQ-induced phenotypes by modulating TLR7 signaling in keratinocytes. These findings highlight the potential of CMA as a therapeutic target for psoriasis.

Metformin Treatment Protects Mice from Glucose-Promoted Psoriasiform Dermatitis through Enrichment of Akkermansia muciniphila with Modulation of Bacterial Tryptophan Metabolites.

LB1163 Psoriasiform dermatitis after keratinocyte-restricted deletion of centrosomal protein Cep43

OASL activates MAPK to drive psoriatic pathogenesis: Astilbin targeting this axis improves metabolic-inflammation crosstalk.

ABSTRACTTumor necrosis factor‐alpha inhibitors (TNFi) are used to treat various autoimmune diseases but can induce paradoxical psoriasiform dermatitis (PD) in a subset of patients. This retrospective chart review aimed to identify risk factors impacting PD severity in 70 pediatric patients at a single center. Forty patients (57.1%) discontinued their initial TNFi: 12/40 (30.0%) switched to another TNFi, with 4/12 (33.3%) experiencing PD recurrence, while 25/40 (62.5%) switched medication classes. Female sex was associated with increased use of high‐potency topical steroids (p = 0.01), suggesting more severe disease. Juvenile idiopathic arthritis (p = 0.02), older age (p < 0.01), and concomitant immunomodulator use (p = 0.04) were associated with a longer latency period before PD development.

Psoriasis (PSO) and eczema are inflammatory skin disorders with distinct immune mechanisms. PSO is mainly driven by T helper (Th)17 immune responses, while eczema, notably atopic dermatitis (AD), is Th2 mediated. Spongiotic psoriasiform dermatitis (SD/PSO), a hybrid phenotype of both conditions, lacks precise immunophenotypic characterization and specific treatment strategies. Existing studies have shown that some patients with SD/PSO exhibit a poor response to conventional and single T-cell axis-targeted therapies (such as Th2/Th17 inhibitors), suggesting cross-activation of immune pathways, which urgently requires more targeted intervention strategies. To characterize the immunological and differentiation profiles of SD/PSO, clarify its differences from classical PSO and AD, and identify alternative therapies for conventional therapy-resistant patients. Four patients with SD/PSO were evaluated. Histopathological analysis and tyramide signal amplification-based multiplex immunofluorescence assay were performed to assess immune profiles and keratinocyte differentiation profiles. In four patients with SD/PSO, conventional therapies showed inadequate response. Three patients experienced lesion exacerbation with interleukin (IL)-17A inhibitors. Immunomarker analysis revealed mixed Th17/Th2 activation: Th17 markers (IL-17A, IL-23, IL-36A/G) were comparably elevated to PSO, while IL-4 levels matched AD and IL-13 exhibited moderate-level expression (between PSO and AD). SD/PSO lesions exhibited PSO-like epidermal differentiation with Janus kinase-signal transducer and activator of transcription (JAK-STAT) hyperactivation and JAK inhibitor treatment induced significant clinical improvement. SD/PSO represents a mixed AD-PSO immunophenotype with PSO-like differentiation patterns, characterized by coactivated Th17/Th2 pathways and JAK-STAT hyperactivation. JAK inhibitors effectively treat patients with SD/PSO by suppressing multi-T-cell axis-targeted inflammatory signals and blocking epidermal hyperproliferation, establishing JAK-STAT inhibition as a targeted strategy. Larger studies are needed to validate results and explore combination therapies.

Background: Psoriasis, an inflammatory skin disorder, involves pyroptosis-a pro-inflammatory cell death process. However, cell-specific pyroptosis dynamics and immune microenvironment interactions remain unclear. Objective: To investigate cell-type-specific pyroptosis patterns in psoriasis and their immunoregulatory mechanisms. Methods: We integrated 21 transcriptomic datasets (from 2007 to 2020) obtained from the GEO database and two single-cell RNA sequencing datasets to quantify pyroptotic activity using Gene Set Variation Analysis and AUCell algorithms. Immune cell infiltration profiles were evaluated via CIBERSORT, while cell-cell communication networks were analyzed by CellChat. In vitro and in vivo experiments were performed to validate key findings. Results: Our analysis revealed that psoriasis patients exhibited significantly elevated levels of pyroptosis compared to healthy controls, with pyroptotic activity reflecting treatment responses. Notably, monocyte-derived macrophages (MDMs) in psoriatic lesions displayed markedly heightened pyroptotic activity. In vitro experiments confirmed that MDMs derived from psoriasis patients overexpressed pyroptosis-related molecules (Caspase 1 and Caspase 4) as well as pro-inflammatory cytokines (TNFα, IL6, IL1β) when compared to healthy controls. Furthermore, these cells showed increased expression of CXCL16, which might potentially activate Th17 cells through CXCR6 signaling, thereby driving skin inflammation. Inhibition of monocyte migration in an imiquimod-induced psoriasiform dermatitis model significantly alleviated skin inflammation and reduced the proportion of M1 macrophages and Th17 cells in lesional skin. Conclusions: This study revealed that MDMs in psoriatic lesions exhibited a hyperactive pyroptotic state, which contributed to disease progression through CXCL16-mediated remodeling of the immune microenvironment. These findings highlight pyroptosis as a potential therapeutic target for psoriasis.

Delgocitinib is a novel Janus kinase (JAK) inhibitor available in a cream formulation of 0.25% and 0.5% ointment. It is a pan-JAK inhibitor and has been approved for treating atopic dermatitis. Some other conditions where delgocitinib has been successfully used are chronic hand eczema, psoriasiform dermatitis, cutaneous T-cell pseudolymphoma, alopecia areata, and vitiligo among many other conditions. Nasopharyngitis, eczema, and headache were the common adverse events reported. Although a newer molecule, delgocitinib has the potential to treat many common inflammatory skin conditions. Due to the dearth of non-steroidal preparations, delgocitinib can be an additional treatment option for various conditions.

Inhibition of CTSC contributes to psoriasis inflammation and keratinocyte hyperproliferation by NF-κB signaling pathway.

Psoriasis pathogenesis involves dysregulated immune responses, yet the role of protein prenylation (particularly PGGT1B-mediated geranylgeranylation) in macrophage-driven inflammation remains poorly understood. This study aims to explore the role and molecular mechanism of protein geranylgeranyltransferase type I subunit beta (PGGT1B) in the development of psoriasis. Myeloid cell-specific PGGT1B gene knockout mice were generated, and a mouse psoriasis model was established with imiquimod to study the role and mechanism of PGGT1B gene downregulation-induced macrophage activation in the pathogenesis of psoriasis. Bone marrow-derived macrophages (BMDMs) from wild-type and PGGT1B knockout mice were cultured and stimulated with resiquimod (R848) to simulate the immune microenvironment of psoriasis. In addition, the differentially expressed genes induced by PGGT1B knockout were analyzed using RNA-seq, and bioinformatics analysis was carried out to study the possible biological process of PGGT1B regulation. Finally, PMA-THP-1 was co-cultured with HaCaT cells to study the effect of PGGT1B deletion in macrophages on the proliferation and differentiation of keratinocytes. Bone marrow PGGT1B deficiency aggravated the psoriasis-like lesions induced by imiquimod in mice. In BMDMs with PGGT1B deficiency, the NF-κB signaling pathway was over-activated by R848, and the expressions of proinflammatory cytokines IL-1β, IL-6, and TNF-α were significantly increased. Activation of cell division cycle 42 (CDC42) may mediate the activation of the NF-κB pathway in PGGT1B-deficient BMDMs. PGGT1B deletion can promote the proliferation and inhibit the differentiation of HaCaT cells. Reduced PGGT1B levels can increase the expression of CDC42, which further activates NLRP3 inflammation in macrophages through NF-κB signaling, further aggravating the inflammatory state of psoriasis. Psoriasis-like lesions induced by IMQ are aggravated when PGGT1B expression is reduced in mouse bone marrow cells. A possible mechanism for this is that PGGT1B-deficient macrophages migrate to the epidermis more easily during psoriasis, which leads to the activation of Cdc42, NF-κB signaling, and NLRP3 inflammatory corpuscles.

Antisense oligonucleotides targeting IRF4 alleviate psoriasis

Durvalumab has demonstrated significant efficacy in several types of malignancies, while large-scale real-world safety studies remain limited. This study aimed to systematically evaluate the safety of durvalumab through data mining of the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS). We extracted reports of durvalumab as the primary suspected drug from the FAERS database (January 2017 to June 2024). Four disproportionality analysis algorithms were used to detect signals between durvalumab and adverse events (AEs). Durvalumab was recorded in 10,120 reports as the primary suspected drug. Of these, 43.6% of AEs occurred during the first month of treatment, with a median onset time of 40 days (IQR: 14–99 ). Among 181 potential signals, 64 were unexpected preferred terms not listed in the prescribing information, including cytokine release syndrome (CRS), pulmonary tuberculosis, radiation esophagitis, oesophageal fistula, oesophageal perforation, pleural effusion, pneumothorax, cerebral infarction, biliary tract infection, cholecystitis, psoriasiform dermatitis, portal vein thrombosis, acute cholangitis and pericarditis malignant. Serious adverse events accounted for 93.3% of cases. Males exhibited a significantly higher risk of experiencing serious outcomes compared to females (OR = 1.83, 95% CI: 1.52–2.19, P < 0.001). Older age groups demonstrated an elevated risk of severe outcomes relative to those under 65 years (65–74 years: OR = 1.52, 95% CI: 1.15-2.00, P = 0.003; ≥75 years: OR = 1.40, 95% CI: 1.02–1.92, P = 0.038). This study comprehensively assessed the safety of durvalumab and discovered potential new adverse event signals, which may provide critical support for risk identification and monitoring of durvalumab.

A subset of peripheral sensory neurons expressing specific Mas-related G-protein-coupled receptors and transient receptor potential channels mediate pruritogen-induced chemical itch. However, the molecular mechanisms that regulate the excitability of these cells, and consequently itch sensation, are poorly understood. TWIK-related spinal cord K + channel (TRESK) is a background K + channel that modulates the resting membrane potential, action potential firing, and neuronal excitability, and it has been involved in somatosensation and pain transduction. Here, we demonstrate that this channel contributes to pruritic transduction and it is a potential target for treating chronic itch pathologies. TRESK channel coexpress with Mas-related G-protein-coupled receptor A3, MrgprC11 and MrgprD in mouse sensory neurons, and with MrgprX1 in human ones. Genetic ablation of TRESK enhances firing of MrgprA3-expressing pruriceptors and acute itch in response to intradermal injection of chloroquine, while the response to histamine, BAM8-22, or leukotriene C4 remains unaffected. TRESK deletion also exacerbates chronic itch in mouse models of allergic contact dermatitis, dry skin, and imiquimod-induced psoriasiform dermatitis, resulting in a significantly increased scratching behavior that develops earlier and is more robust. Moreover, pharmacologically enhancing TRESK function diminishes both acute and chronic itch in wild-type mice but not in TRESK knockout (KO) animals. In summary, our data indicate that TRESK plays a role in regulating the excitability of a subset of sensory neurons that mediate histaminergic-independent itch. Enhancing the channel function with specific activators represents a promising antipruritic therapeutic approach that can be combined with other compounds for the treatment of nonhistaminergic itch, which currently lack adequate treatment options.

Cytotoxic-T-lymphocyte-antigen-4 (CTLA-4), a member of the immunoglobulin superfamily, is an essential negative regulator of immune responses that is constitutively expressed on both regulatory (Treg) and activated T cells. To date, heterozygous germline variants in CTLA4, leading to haploinsufficiency, have been associated with several immunological disorders, including hypogammaglobulinemia, multi-organ autoimmunity, lymphoproliferative disorders, and enlarged lymphoid organs. Indeed, CTLA4 carriers display highly heterogeneous clinical manifestations with a phenotypic spectrum ranging from asymptomatic carrier status to fatal autoimmunity. Here, we describe a family with autoimmune phenotypes (Hashimoto thyroiditis, psoriasiform dermatitis, celiac disease/inflammatory bowel disease, and rheumatoid arthritis), segregating across three different generations due to a recurrent missense variant [c.436G>A, p.(Gly146Arg)] in the CTLA4 gene. Interestingly, the proband showed prominent neurological manifestations, including seizures, hydrocephalus, and demyelination, which are less frequently reported in individuals with pathogenic variants in CTLA4. A detailed literature review of neurologic features that have been reported so far in CTLA4 carriers is also provided.

Dihydromyricetin (DMY), a flavonoid, belongs to a class of natural compounds and possesses anti-inflammatory properties. The objective of this research is to investigate the effects and mechanism of DMY in mice induced by imiquimod (IMQ). Here, DMY ointment was topically applied to evaluate the effect of DMY on psoriasis, while the results showed DMY improved clinical phenotype of IMQ-induced psoriasiform dermatitis. Histological evaluation revealed decreases in keratinocyte hyperplasia and immune cell infiltration in mice after DMY administration. Besides, DMY treatment could attenuate psoriasiform inflammation as showed in the decreased expression of inflammation mediators such as IL-17a, IL-23a, TNF-α, IL-6, IL-1β, IL-12a, CXCL2, and S100A8 in the skin of mice. Mechanistically, DMY reduced the polarization of macrophages towards the pro-inflammatory M1 phenotype by inhibiting the TLR4/NF-κB pathway, importantly, which subsequently regulated the differentiation of T helper (Th) 1 and Th17 cell subsets, leading to the relief of immune inflammatory response in psoriasis. In conclusion, the research reveals that DMY markedly attenuated IMQ-induced psoriasis in mice and provides that DMY have great potential for treatment of psoriasis.