A case report of bullous pemphigoid following secukinumab therapy for a patient with psoriasis.

Aim: Bullous pemphigoid induced by secukinumab in treatment of psoriasis is rare.Methods: We report a 49-year-old man with psoriasis who developed bullous pemphigoid during treatment with secukinumab.Results: Scattered tense vesicles with itching appeared all over the body after the fourth treatment. Bullous pemphigoid was confirmed by pathological examination and direct immunofluorescence. The patient was treated with topical corticosteroids, oral nicotinamide and minocycline hydrochloride. The lesions of bullous pemphigoid improved significantly after 7 days of treatment.Conclusions: Bullous pemphigoid is a rare adverse event following administration of secukinumab.

Discovery and preclinical evaluation of KYS202004A, a novel bispecific fusion protein targeting TNF-α and IL-17A, in autoimmune disease models.

The treatment of autoimmune and inflammatory diseases often requires targeting multiple pathogenic pathways. KYS202004A is a novel bispecific fusion protein designed to antagonize TNF-α and IL-17A, pivotal in the pathophysiology of autoimmune and inflammatory diseases. Our initial efforts focused on screening for optimal structure by analyzing expression levels, purity, and binding capabilities. The binding affinity of KYS202004A to TNF-α and IL-17A was evaluated using SPR. In vitro, we assessed the inhibitory capacity of KYS202004A on cytokine-induced CXCL1 expression in HT29 cells. In vivo, its efficacy was tested using a Collagen-Induced Arthritis (CIA) model in transgenic human-IL-17A mice and an imiquimod-induced psoriasis model in cynomolgus monkeys. KYS202004A demonstrated significant inhibition of IL-17A and TNF-α signaling pathways, outperforming the efficacy of monotherapeutic agents ixekizumab and etanercept in reducing CXCL1 expression in vitro and ameliorating disease markers in vivo. In the CIA model, KYS202004A significantly reduced clinical symptoms, joint destruction, and serum IL-6 concentrations. The psoriasis model revealed that KYS202004A, particularly at a 2  mg/kg dose, was as effective as the combination of ixekizumab and etanercept. This discovery represents a significant advancement in treating autoimmune and inflammatory diseases, offering a dual-targeted therapeutic approach with enhanced efficacy over current monotherapies.

CD169+ Skin Macrophages Function as a Specialized Subpopulation in Promoting Psoriasis-like Skin Disease in Mice.

Skin macrophages are critical to maintain and restore skin homeostasis. They serve as major producers of cytokines and chemokines in the skin, participating in diverse biological processes such as wound healing and psoriasis. The heterogeneity and functional diversity of macrophage subpopulations endow them with multifaceted roles in psoriasis development. A distinct subpopulation of skin macrophages, characterized by high expression of CD169, has been reported to exist in both mouse and human skin. However, its role in psoriasis remains unknown. Here, we report that CD169+ macrophages exhibit increased abundance in imiquimod (IMQ) induced psoriasis-like skin lesions. Specific depletion of CD169+ macrophages in CD169-ditheria toxin receptor (CD169-DTR) mice inhibits IMQ-induced psoriasis, resulting in milder symptoms, diminished proinflammatory cytokine levels and reduced proportion of Th17 cells within the skin lesions. Furthermore, transcriptomic analysis uncovers enhanced activity in CD169+ macrophages when compared with CD169- macrophages, characterized by upregulated genes that are associated with cell activation and cell metabolism. Mechanistically, CD169+ macrophages isolated from IMQ-induced skin lesions produce more proinflammatory cytokines and exhibit enhanced ability to promote Th17 cell differentiation in vitro. Collectively, our findings highlight the crucial involvement of CD169+ macrophages in psoriasis development and offer novel insights into the heterogeneity of skin macrophages in the context of psoriasis.

Behcet's-like disease induced by secukinumab in a patient with psoriasis: a case report and literature review.

Purpose: The incidence of cutaneous paradoxical reactions associated with IL-17 inhibitors has gained attention in recent literature. Our report aims to investigate the characteristics of one rare paradoxical reaction, presenting as Behcet's disease.Methods: We reported one case of Behcet's-like disease induced by secukinumab in a patient with psoriasis. This patient, a young woman with a long history of psoriasis, showed significant improvement in her psoriatic condition after receiving four doses of secukinumab. Unexpectedly, she developed symptoms such as high fever, painful oral and genital ulcers, facial maculopapules, and erythema nodosum-like lesions on her lower limbs. Despite neutrophilia, there was no evidence of infection found in her laboratory tests. Histological analysis of a skin biopsy highlighted subcutaneous panniculitis and a mixed inflammatory cell infiltrate in the dermis. The patient was consequently diagnosed with secukinumab-induced Behcet's-like disease. Additionally, we have reviewed nine other documented cases of Behcet's-like disease triggered by IL-17 inhibitors.Results: This group showed no significant gender preference, suffering from conditions such as psoriasis, ankylosing spondylitis, and hidradenitis suppurativa. Oral and genital ulcers were prevalent among the paradoxical reactions noted. Marked improvement was observed in all patients upon discontinuation of the IL-17 inhibitors.Conclusions: Our report serves to alert physicians to this uncommon but significant paradoxical effect that may arise with anti-IL-17 treatment.

Deucravacitinib and shikonin combination therapy ameliorates imiquimod-induced psoriasis in mice.

INTRODUCTION: TYK2 inhibitors and traditional natural drugs as promising drugs for psoriasis therapy are receiving increasing attention. They both affect different molecules of JAK/STAT pathway, but it is currently unclear whether their combination will enhance the effect on psoriasis. In this study, we used imiquimod (IMQ)-induced psoriasis mouse model to investigate the therapeutic effects of the combined administration of deucravacitinib (TYK2 inhibitor) and shikonin. METHODS: Aldara cream containing 5% IMQ was used to topically treat the dorsal skin of each mouse for a total of six consecutive days to induce psoriasis. The psoriasis area and severity index (PASI) scores were recorded every day. On the 7th day, skin tissues were taken for histopathological examination and the content of cytokines in skin were evaluated. The frequency of immune cells in peripheral blood, spleen and skin were detected through flow cytometry. RESULTS: Compared to the vehicle control group, the psoriasis symptoms and immune disorder improved significantly in the combination therapy group and deucravacitinib treatment group on the 7th day, and the expressions of p-STAT3 and Ki67 in skin were reduced as well. Moreover, the combined treatment of deucravacitinib and shikonin for psoriasis was superior to the monotherapy group, especially in inhibiting abnormal capillaries proliferation, reducing immune cells infiltration and decreasing the concentration of IL-12p70 in skin. CONCLUSION: The combination of deucravacitinib and shikonin is a promising clinical application.

Metabolic Profiling for Unveiling Mechanisms of Kushenol F against Imiquimod-Induced Psoriasis with UHPLC/MS Analysis.

Psoriasis is a common chronic immune-mediated inflammatory skin disorder. Sophora flavescens Alt. (S. flavescens) has been widely acknowledged in the prevention and treatment of psoriasis. Kushenol F (KSCF) is a natural isopentenyl flavonoid extracted from the root of S. flavescens. We aimed to investigate the effect and mechanism of KSCF on imiquimod (IMQ)-induced psoriasis-like skin lesions in mice. A mouse model of psoriasis was induced with 5% IMQ for 5 days, and the mice were given KSCF dermally for 5 days. Changes in skin morphology, the psoriasis area, the severity index (PASI), and inflammatory factors of psoriasis-like skin lesions were evaluated. Metabolites in the psoriasis-like skin lesions were analyzed with ultra-high-performance liquid chromatography/mass spectrometry followed by a multivariate statistical analysis to identify the differential metabolites and metabolic pathway. The results of the present study confirmed that KSCF significantly reduced PASI scores, epidermal thickening, and epidermal cell proliferation and differentiation. KSCF also reduced the levels of interleukin (IL)-1ß, IL-6, IL-8, IL-17A, IL-22, IL-23, and tumor necrosis factor (TNF)-α in the injured skin tissues while increasing IL-10 content. KSCF significantly regulated metabolites in the skin samples, and a total of 161 significant metabolites were identified. These differential metabolites involved sphingolipid and linoleic acid metabolism and steroid hormone biosynthesis. Collectively, KSCF inhibited the inflammatory response to prevent IMQ-induced psoriasis-like skin lesions in mice by call-backing the levels of 161 endogenous metabolites and affecting their related metabolic pathways. KSCF has the potential to be developed as a topical drug for treating psoriasis symptoms.

A pediatric case of dupilumab-induced pustular psoriasis.

Dupilumab is a novel treatment agent for moderate to severe atopic dermatitis (AD) with few adverse effects. Drug-induced psoriasiform lesions are rare.We report a 4-year-old boy with AD who developed pustular psoriasis during treatment with dupilumab.Pustular psoriasis appeared within 1 week of treatment and worsened in the second week. After stopping dupilumab administration, topical corticosteroids (desonide and mometasone furoate creams) and oral desloratadine without relief. Pustular psoriasis was confirmed by pathological examination, and thiamphenicol was administered. After 2 weeks of treatment, the lesions nearly resolved without recurrence in 1-year follow-up.Dupilumab-induced pustular psoriasis is rare in children.

Sensory ASIC3 channel exacerbates psoriatic inflammation via a neurogenic pathway in female mice.

Psoriasis is an immune-mediated skin disease associated with neurogenic inflammation, but the underlying molecular mechanism remains unclear. We demonstrate here that acid-sensing ion channel 3 (ASIC3) exacerbates psoriatic inflammation through a sensory neurogenic pathway. Global or nociceptor-specific Asic3 knockout (KO) in female mice alleviates imiquimod-induced psoriatic acanthosis and type 17 inflammation to the same extent as nociceptor ablation. However, ASIC3 is dispensable for IL-23-induced psoriatic inflammation that bypasses the need for nociceptors. Mechanistically, ASIC3 activation induces the activity-dependent release of calcitonin gene-related peptide (CGRP) from sensory neurons to promote neurogenic inflammation. Botulinum neurotoxin A and CGRP antagonists prevent sensory neuron-mediated exacerbation of psoriatic inflammation to similar extents as Asic3 KO. In contrast, replenishing CGRP in the skin of Asic3 KO mice restores the inflammatory response. These findings establish sensory ASIC3 as a critical constituent in psoriatic inflammation, and a promising target for neurogenic inflammation management.

Orientin alleviates the inflammatory response in psoriasis like dermatitis in BALB/c mice by inhibiting the MAPK signaling pathway.

BACKGROUND: Psoriasis, a chronic inflammatory condition of the skin, is characterized by an atypical proliferation of epidermal keratinocytes and immune cell infiltration. Orientin is a flavonoid monomer with potent anti-inflammatory activities. However, the therapeutic effects of orientin on psoriasis and the underlying mechanisms have not been elucidated. OBJECTIVE: To investigate the therapeutic effect of orientin on psoriasis and the underlying mechanisms using network pharmacology and experimental studies. METHODS: A psoriasis-like mouse model was established using imiquimod (IMQ). Lipopolysaccharide (LPS) was used to stimulate the RAW264.7 and HaCaT cells in vitro. The therapeutic effects of orientin and the underlying mechanism were analyzed using histopathological, immunohistochemical, quantitative real-time polymerase chain reaction, enzyme-linked immunosorbent assay, flow cytometry, and western blotting analyses. RESULTS: Orientin ameliorated skin lesions and suppressed keratinocyte proliferation and immune cell infiltration in the IMQ-induced psoriasis-like mouse model. Additionally, orientin inhibited the secretion of the pro-inflammatory factors interleukin (IL)-1ß, tumor necrosis factor (TNF)-α, IL-6, IL-8, IL-17, and IL-23 in the psoriasis-like mouse model and LPS-induced RAW264.7 and HaCaT cells. Furthermore, orientin mitigated the LPS-induced upregulation of reactive oxygen species and downregulation of IL-10 and glutathione levels. Orientin alleviated inflammation by downregulating the MAPK signaling pathway. CONCLUSION: Orientin alleviated psoriasis-like dermatitis by suppressing the MAPK signaling pathway, suggesting that orientin is a potential therapeutic for psoriasis.

Intermittent fasting alleviates IMQ-induced psoriasis-like dermatitis via reduced γδT17 and monocytes in mice.

Psoriasis is a chronic immune mediated inflammatory skin disease with systemic manifestations. It has been reported that caloric restriction could improve severity of psoriasis patients. However, the mechanism of intermittent fasting effects on psoriasis has not been investigated. Caloric restriction is known to reduce the number of circulating inflammatory monocytes in a CCL2-dependent manner. However, it is still unknown whether caloric restriction can improve psoriasis by regulating monocytes through CCL2. In this study, we used imiquimod (IMQ)-induced psoriasis-like mouse model to explore the effects and the mechanisms of intermittent fasting on psoriasis-like dermatitis. We found that intermittent fasting could significantly improve IMQ-induced psoriasis-like dermatitis, and reduce the number of γδT17 cells and IL-17 production in draining lymph nodes and psoriatic lesion via inhibiting proliferation and increasing death of γδT17 cells. Furthermore, intermittent fasting could significantly decrease monocytes in blood, and this was associated with decreased monocytes, macrophages and DC in psoriasis-like skin inflammation. Reduced monocytes in circulation and increased monocytes in BM of fasting IMQ-induced psoriasis-like mice is through reducing the production of CCL2 from BM to inhibit monocyte egress to the periphery. Our above data shads light on the mechanisms of intermittent fasting on psoriasis.

Cornuside alleviates psoriasis-like skin lesions in mice by relieving inflammatory effects.

Psoriasis is a chronic inflammatory skin disease substantially affecting the quality of life, with no complete cure owing to its complex pathogenesis. Cornuside, a major bioactive compound present in Cornus officinalis Sieb. et Zucc., which is a well-known traditional Chinese medicine with a variety of biological and pharmacological activities, such as anti-apoptotic, antioxidant, and anti-inflammatory properties. However, its effects on psoriasis remain unclear. Our preliminary analysis of network pharmacology showed that cornuside may be involved in psoriasis by regulating the inflammatory response and IL-17 signaling pathway. Thus, we investigated the protective role and mechanism of cornuside in the pathogenesis of psoriasis in an imiquimod (IMQ)-induced psoriasis mouse model. In-vivo experiments demonstrated that cornuside-treated mice had reduced skin erythema, scales, thickness, and inflammatory infiltration. The Psoriasis Area Severity Index score was significantly lower than that of the IMQ group. Flow cytometry analysis indicated that cornuside effectively inhibited Th1- and Th17-cell infiltration and promoted aggregation of Th2 cells in skin tissues. Cornuside also inhibited the infiltration of macrophages to the skin. Furthermore, in-vitro experiments indicated that cornuside also decreased the polarization of M1 macrophages and reduced the levels of associated cytokines. Western blotting demonstrated that cornuside suppressed the phosphorylation of c-Jun N-terminal kinase (JNK) and extracellular receptor kinase (ERK) in bone marrow-derived macrophages. Our findings indicate that cornuside has a protective effect against IMQ-induced psoriasis by inhibiting M1 macrophage polarization through the ERK and JNK signaling pathways and modulating the infiltration of immune cells as well as the expression of inflammatory factors.

Immune Checkpoint Inhibitor-Induced Psoriasis: Diagnosis, Management, and a Review of Cases.

Immune checkpoint inhibitors (ICIs) are effective antitumor agents but are associated with immune-related adverse events. ICI-induced psoriasis commonly presents in patients with a history of psoriasis but may occur de novo, and it has a significant physical and psychosocial impact. ICI-induced and non-ICI-induced psoriasis are likely mediated by similar cytokines, and similar treatments are employed. Topical treatment often suffices, and when needed, several systemic treatments appear to be effective without impacting antitumor response. Development of psoriasis may indicate a superior response to ICIs. Thus, recognition and management of ICI-induced psoriasis is essential to avoid ICI interruption and maximize therapeutic potential.

Interferon-Alpha Induces Psoriatic Inflammation in Mice by Phosphorylating FOXO3.

Psoriasis is a chronic, immune-mediated inflammatory skin disease characterized by epidermal thickening and inflammatory cell infiltration. Excessive proliferation of keratinocytes and resistance to apoptosis lead to thickening of the epidermis. Plasmacytoid dendritic cells are involved in the occurrence of psoriasis mainly by secreting interferon-alpha (IFN-α). IFN-α is a glycoprotein with antiviral, antitumor, and immunomodulatory effects, but its role in psoriasis remains unclear. In this investigation, a mild psoriatic phenotype was observed in mice upon topical application of IFN-α cream, and the inflammation was exacerbated when combined with imiquimod (IMQ). Immunohistochemical analyses demonstrated that IFN-α induces psoriatic inflammation in mice by stimulating phosphorylation of forkhead box O3, consistent with the involvement of this protein in cell proliferation, apoptosis, and inflammation. Our results suggested that topical IFN-α caused psoriatic inflammation and that the psoriatic inflammation was exacerbated by the combination of IFN-α and IMQ, possibly due to the dysfunction of forkhead box O3.

Membranous lupus nephritis secondary to secukinumab therapy: A case report and literature review.

The interleukin (IL)-17 axis is involved in many inflammatory and autoimmune diseases. Secukinumab, an IL-17 inhibitor, has been approved for psoriasis treatment. There are accumulating cases of lupus erythematosus induced by IL-17 inhibition. Lupus nephritis after IL-17 inhibition has not been reported. We report the case of a 57-year-old man who developed membranous lupus nephritis after secukinumab treatment for psoriasis. Anti-SSA and PM-Scl antibodies were positive. dsDNA, anti-Smith, and anti-histone antibodies were negative, and serum complement was low. Secukinumab was discontinued, while tacrolimus was initiated, subsequently switched to cyclosporin, belimumab, glucocorticosteroid, and hydroxychloroquine with a good response. The relationship between lupus erythematosus and IL-17 inhibition requires further research.

Decreased HMGCS1 inhibits proliferation and inflammatory response of keratinocytes and ameliorates imiquimod-induced psoriasis via the STAT3/IL-23 axis.

Psoriasis is an immuno-inflammatory disease characterized by excessive keratinocyte proliferation, requiring extensive lipids. 3-hydroxy-3-methylglutaryl-coenzyme A synthase 1 (HMGCS1) is an essential enzyme in the mevalonate pathway, involved in cholesterol synthesis and the inflammatory response. However, the role of HMGCS1 in psoriasis has remained elusive. This study aims to elucidate the mechanism by which HMGCS1 controls psoriasiform inflammation. We discovered an increased abundance of HMGCS1 in psoriatic lesions when analyzing two Gene Expression Omnibus (GEO) datasets and confirmed this in psoriatic animal models and psoriatic patients by immunohistochemistry. In a TNF-α stimulated psoriatic HaCaT cell line, HMGCS1 was found to be overexpressed. Knockdown of HMGCS1 using siRNA suppressed the migration and proliferation of HaCaT cells. Mechanistically, HMGCS1 downregulation also reduced the expression of IL-23 and the STAT3 phosphorylation level. In imiquimod-induced psoriatic mice, intradermal injection of HMGCS1 siRNA significantly decreased the expression of HMGCS1 in the epidermis, which in turn led to an improvement in the Psoriasis Area and Severity Index score, epidermal thickening, and pathological Baker score. Additionally, expression levels of inflammatory cytokines IL-23, IL1-ß, chemokine CXCL1, and innate immune mediator S100A7-9 were downregulated in the epidermis. In conclusion, HMGCS1 downregulation improved psoriasis in vitro and in vivo through the STAT3/IL-23 axis.

The regulation of the PD-1/PD-L1 pathway in imiquimod-induced chronic psoriasis itch and itch sensitization in mouse.

PD-1/PD-L1 inhibitors have been demonstrated to induce itch in both humans and experimental animals. However, whether the PD-1/PD-L1 pathway is involved in the regulation of chronic psoriatic itch remains unclear. This study aimed to investigate the role of the PD-1/PD-L1 pathway in imiquimod-induced chronic psoriatic itch. The intradermal injection of PD-L1 in the nape of neck significantly alleviated chronic psoriatic itch in imiquimod-treated skin. Additionally, we observed that spontaneous scratching behavior induced by imiquimod disappeared on day 21. Still, intradermal injection of PD-1/PD-L1 inhibitors could induce more spontaneous scratching for over a month, indicating that imiquimod-treated skin remained in an itch sensitization state after the spontaneous scratching behavior disappeared. During this period, there was a significant increase in PD-1 receptor expression in both the imiquimod-treated skin and the spinal dorsal horn in mice, accompanied by significant activation of microglia in the spinal dorsal horn. These findings suggest the potential involvement of the peripheral and central PD-1/PD-L1 pathways in regulating chronic itch and itch sensitization induced by imiquimod.

Geniposide alleviates imiquimod-induced psoriasis-like skin lesions in mice via inhibition of angiogenesis.

In this study, we aimed to evaluate the protective effect of geniposide (GEN) on imiquimod (IMQ)-induced psoriasis-like skin lesions in mice. Firstly, visual changes of psoriatic skin lesions were observed and the severity was recorded using psoriasis area and severity index (PASI) score. Histological changes were assessed by HE staining for epidermal thickness and Masson's staining for collagen fibers. Then, photographs of microvascular inside the skin were taken for macroscopic observation, and microscopic changes associated with angiogenesis were evaluated. Furthermore, expression of angiogenic factors were analyzed by ELISA, immunohistochemistry and immunofluorescence, separately. Lastly, the expression of VEGFR signaling-related proteins was detected by WB. Compared with control, IMQ drove a significant increment of epidermal thicknesses with higher PASI scores and more dermal collagen deposition. IMQ treatment led to abnormal keratinocyte proliferation, increased microvascular inside skin, growing production of angiogenesis-related factors, up-regulated expression of VEGFR1 and VEGFR2, and enhanced phosphorylation of p38. However, GEN significantly ameliorated the psoriatic skin lesions, the epidermal thickness, the formation of collagen fibers, and abnormal keratinocyte proliferation. Importantly, GEN inhibited angiogenesis, the production of angiogenic factors (VEGF-A, Ang-2, TNF-α, and IL-17A), and the proliferation of vascular endothelial cells. Simultaneously, GEN curbed the expression of VEGFR1, VEGFR2, p38, and P-p38 proteins involved in VEGFR signaling. Of note, the suppressive effect of GEN was reversed in the HUVECs with over-expressed VEGFR1 or VEGFR2 related to the cells without transfection. These findings suggest that VEGFR1 and VEGFR2 participate in the anti-angiogenesis of GEN in IMQ-induced psoriasis-like skin lesions in mice.

Determination of the FABP5 expression profile in skin lesions of an IMQ-induced psoriasis mouse model using flow cytometry.

The fatty acid-binding protein 5 (FABP5) is a key player in psoriasis development. Therefore, characterizing the expression profile of FABP5 in various cell types within both layers of psoriatic skin is important. Here, we present a protocol that describes steps for an imiquimod-induced psoriasis mouse model and preparation of epidermal and dermal single-cell suspensions. We then detail procedures to detect the FABP5 expression profile in skin keratinocytes and immune cells using intracellular flow cytometry staining. For complete details on the use and execution of this protocol, please refer to Hao et al.1.