Gallic Acid Alleviates Psoriasis Keratinization and Inflammation by Regulating BRD4 Expression.

Psoriasis is a chronic non-contagious autoimmune disease. Gallic acid is a natural compound with potential health benefits, including antioxidant, anticancer, antiviral and antibacterial properties. Nevertheless, the influence of gallic acid on psoriasis has not been fully determined. This investigation aimed to discover the effect of gallic acid on psoriasis. Thirty-one pairs of psoriatic skin tissues and healthy adult human skin tissues were collected. Human keratinocytes (HaCaT cells) were transfected with interleukin 17A (IL-17A) to create the psoriatic keratinocyte model. The content of bromodomain-containing protein 4 (BRD4) microRNA was assessed using qRT-PCR testing. The content of BRD4 was detected by Western blotting. Cell migration was evaluated by conducting a wound healing assay. Cell proliferation was determined using an EdU assay. Apoptosis was detected by the TUNEL assay. The contents of interferon gamma (IFN-γ), IL-6, IL-8 and IL-17 were detected by ELISA. BRD4 was up-regulated in psoriatic skin tissues and in the IL-17A group compared to the healthy adult human skin tissues and the control group. Silencing BRD4 inhibited cell migration, proliferation and inflammatory response but induced apoptosis in IL-17A-treated HaCaT cells. Conversely, BRD4 over-expression promoted cell migration, proliferation and inflammatory response but suppressed apoptosis in IL-17A-treated HaCaT cells. Gallic acid repressed cell migration, proliferation and inflammatory response but indu-ced apoptosis in HaCaT cells transfected with IL-17A by down-regulating BRD4. Gallic acid represses cell migration, proliferation and inflammatory response but induces apoptosis in IL-17A-transfected HaCaT cells by down-regulating BRD4.

Functional Genomics and Insights into the Pathogenesis and Treatment of Psoriasis.

Psoriasis is a lifelong, systemic, immune mediated inflammatory skin condition, affecting 1-3% of the world's population, with an impact on quality of life similar to diseases like cancer or diabetes. Genetics are the single largest risk factor in psoriasis, with Genome-Wide Association (GWAS) studies showing that many psoriasis risk genes lie along the IL-23/Th17 axis. Potential psoriasis risk genes determined through GWAS can be annotated and characterised using functional genomics, allowing the identification of novel drug targets and the repurposing of existing drugs. This review is focused on the IL-23/Th17 axis, providing an insight into key cell types, cytokines, and intracellular signaling pathways involved. This includes examination of currently available biological treatments, time to relapse post drug withdrawal, and rates of primary/secondary drug failure, showing the need for greater understanding of the underlying genetic mechanisms of psoriasis and how they can impact treatment. This could allow for patient stratification towards the treatment most likely to reduce the burden of disease for the longest period possible.

Management of Psoriasis Patients with Serious Infectious Diseases.

The management of patients affected by moderate-to-severe psoriasis may be challenging, in particular in patients with serious infectious diseases [tuberculosis (TB), hepatitis B and C, HIV, COVID-19]. Indeed, these infections should be ruled out before starting and during systemic treatment for psoriasis. Currently, four conventional systemic drugs (methotrexate, dimethyl fumarate, acitretin, cyclosporine), four classes of biologics (anti-tumour necrosis factor alpha, anti-interleukin (IL)12/23, anti-IL-17s, and anti-IL-23], and two oral small molecules (apremilast, deucravacitinib) have been licensed for the treatment of moderate-to-severe psoriasis. Each of these drugs is characterized by a unique safety profile which should be considered before starting therapy. Indeed, some comorbidities or risk factors may limit their use. In this context, the aim of this manuscript was to evaluate the management of patients affected by moderate-to-severe psoriasis with serious infectious diseases.

Switching patterns of biological drugs in patients with psoriasis and psoriatic arthritis: insight from the VALORE database network.

BACKGROUND: Switch patterns among different biologics and from originators to biosimilars (and vice versa) can be complex in patients with psoriasis (PsO) and psoriatic arthritis (PsA). OBJECTIVE: The aim of this study was to describe switching patterns of biological drugs in PsO/PsA patients and to explore predictors of multiple switches and switch-back. RESEARCH DESIGN AND METHODS: A large-scale retrospective cohort study was conducted using the Italian VALORE database. Bio-naïve users treated for PsO/PsA during 2010-2022 were included. Time to switch/swap and predictors of multiple switches and switch-back were analyzed. RESULTS: Thirty-thousand seven hundred bio-naïve users were included. At 3 and 5 years of follow-up, patients with at least one switch/swap were 37.1% and 47.8%, respectively. The median time to first switch/swap was significantly shorter (p< 0.001) for TNF-α inhibitors (2,068 days) than anti-IL (2,780 days). At 1 year of follow-up patients starting with IL-23 switched/swapped biological therapy less frequently than those with anti-IL-12/23 and anti-IL-17 (4.9% vs. 8.7% and 9.4%, respectively). Patients starting with anti-IL-12/23 reported a significantly lower risk of multiple switches and switch-back (0.74, 95% CI, 0.67-0.83; 0.58, 95% CI, 0.44-0.77, respectively) than those with TNF-α inhibitors. CONCLUSIONS: Patients with PsO/PsA starting with TNF-α inhibitors switch/swap more rapidly and frequently than those with anti-IL, which are also associated with a reduced risk of multiple switches during follow-up.

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.

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.

The discovery of a novel pyrrolo[2,3-b]pyridine as a selective CDK8 inhibitor offers a new approach against psoriasis.

Currently, the drugs used in clinical to treat psoriasis mainly broadly suppress cellular immunity. However, these drugs can only provide temporary and partial symptom relief, they do not cure the condition and may lead to recurrence or even serious toxic side effects. In this study, we describe the discovery of a novel potent CDK8 inhibitor as a treatment for psoriasis. Through structure-based design, compound 46 was identified as the most promising candidate, exhibiting a strong inhibitory effect on CDK8 (IC50 value of 57 nM) along with favourable inhibition against NF-κB. Additionally, it demonstrated a positive effect in an in vitro psoriasis model induced by TNF-α. Furthermore, this compound enhanced the thermal stability of CDK8 and exerted evident effects on the biological function of CDK8, and it had favourable selectivity across the CDK family and tyrosine kinase. This compound showed no obvious inhibitory effect on CYP450 enzyme. Further studies confirmed that compound 46 exhibited therapeutic effect on IMQ-induced psoriasis, alleviated the inflammatory response in mice, and enhanced the expression of Foxp3 and IL-10 in the dorsal skin in vivo. This discovery provides a new strategy for developing selective CDK8 inhibitors with anti-inflammatory activity for the treatment of psoriasis.

Reactive oxygen species-responsive supramolecular deucravacitinib self-assembly polymer micelles alleviate psoriatic skin inflammation by reducing mitochondrial oxidative stress.

Introduction: The new topical formula is urgent needed to meet clinical needs for majority mild patients with psoriasis. Deucravacitinib exerts outstanding anti-psoriatic capacity as an oral TYK2 inhibitor; however, single therapy is insufficient to target the complicated psoriatic skin, including excessive reactive oxygen species (ROS) and persistent inflammation. To address this need, engineered smart nano-therapeutics hold potential for the topical delivery of deucravacitinib. Methods: hydrophobic Deucravacitinib was loaded into polyethylene glycol block-polypropylene sulphide (PEG-b-PPS) for transdermal delivery in the treatment of psoriasis. The oxidative stress model of HaCaT psoriasis was established by TNF-α and IL-17A in vitro. JC-1 assay, DCFH-DA staining and mtDNA copy number were utilized to assess mitochondrial function. 0.75% Carbopol®934 was incorporated into SPMs to produce hydrogels and Rhb was labeled to monitor penetration by Immunofluorescence. In vivo, we established IMQ-induced psoriatic model to evaluate therapeutic effect of Car@Deu@PEPS. Results: Deu@PEPS exerted anti-psoriatic effects by restoring mitochondrial DNA copy number and mitochondrial membrane potential in HaCaT. In vivo, Car@Deu@PEPS supramolecular micelle hydrogels had longer retention time in the dermis in the IMQ-induced ROS microenvironment. Topical application of Car@Deu@PEPS significantly restored the normal epidermal architecture of psoriatic skin with abrogation of splenomegaly in the IMQ-induced psoriatic dermatitis model. Car@Deu@PEPS inhibited STAT3 signaling cascade with a corresponding decrease in the levels of the differentiation and proliferative markers Keratin 17 and Cyclin D1, respectively. Meanwhile, Car@Deu@PEPS alleviated IMQ-induced ROS generation and subsequent NLRP3 inflammasome-mediated pyroptosis. Conclusion: Deu@PEPS exerts prominent anti-inflammatory and anti-oxidative effects, which may offers a more patient-acceptable therapy with fewer adverse effects compared with oral deucravacitinib.

Biologics for Psoriasis.

Biologic therapies targeting tumor necrosis factor alpha (TNF-α) (infliximab, adalimumab, certolizumab, etanercept), the p40 subunit shared by IL-12 and IL-23 (ustekinumab), the p19 subunit of IL-23 (guselkumab, tildrakizumab, risankizumab), IL-17A (secukinumab, ixekizumab), IL-17-RA (brodalumab) and both IL-17A and IL-17F (bimekizumab) have revolutionized the treatment of psoriasis. In both the short and long term, risankizumab had highest Psoriasis Area and Severity Index 90 scores compared to other oral and injectable biologics. IL-23 inhibitors had lowest rates of short-term and long-term adverse events and most favorable long-term risk-benefit profile compared to IL-17, IL-12/23, and TNF-α inhibitors.

Paradoxical Psoriasis.

Cytokine blocking therapies have revolutionized the management of psoriasis and atopic dermatitis but can lead to the development of paradoxic psoriasis (PP). Patients treated with biologics should be closely monitored for the development of PP and other paradoxical eruptions (including inflammatory joint disease, inflammatory bowel disease, eczematous eruptions, lupus like eruptions, sarcoidal eruptions, and others) and occasionally the development of cutaneous T-cell lymphoma. Further understanding the immunologic mechanism of these processes will ultimately drive our understanding of and ability to predict and manage PPs.

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.

Low rates of vaccination among atopic dermatitis, alopecia areata, psoriasis, and psoriatic arthritis patients on biologics.

Biologics and Janus kinase (JAK) inhibitors are immunomodulating and immunosuppressing medications utilized to treat atopic dermatitis (AD), psoriasis (PSO), psoriatic arthritis (PsA), and alopecia areata (AA). Special recommendations must be considered when prescribing vaccinations in this population, as the pneumococcal and herpes zoster vaccine are recommended to patients ≥ 19-years-old (rather than ≥ 65-years-old and ≥ 50-years-old as in the general population, respectively), along with a yearly influenza and up to date COVID-19 vaccination. Additionally, TNF-α and JAK-inhibitors may increase the risk of latent Hepatitis B virus (HBV) reactivation among high-risk patients. Prior to prescribing these medications, a quantitative HepB Surface Antibody (HepB SA) test is performed to determine immunity. This study utilized the SlicerDicer function on EPIC Medical Records to search for any patient ≥ 19-years-old prescribed a biologic or JAK inhibitor for AD, PSO, PsA, or AA between 10/2003 and 10/2023 at a large tertiary institution. Vaccination rates among patients on biologics and JAK inhibitors were low, with rates being significantly lower in patients 19-64 years-old, compared to those ≥ 65 years-old for most disease states (p < 0.01). Among AD, PSO/PsA, and AA patients, on average, 9.39% were vaccinated for influenza, 6.76% for herpes zoster, 16.56% for pneumococcal pneumonia, and 63.98% for COVID-19. Only 3.16% of patients were adequately vaccinated for HepB after an abnormal HepB SA test. Here, extremely low rates of vaccination among patients on biologics and JAK inhibitors at our institution were highlighted, emphasizing the imperative need for ensuring vaccination in this group.

Blood MALT1 expression could help predict treatment outcomes in psoriasis patients, especially in those receiving biologics.

INTRODUCTION: Mucosa-associated lymphoid tissue 1 (MALT1) modulates T helper cell differentiation, pro-inflammatory cytokine production, and epidermal hyperplasia to participate in the pathology of psoriasis. This study aimed to explore the correlation of blood MALT1 with treatment outcomes in psoriasis patients. METHODS: MALT1 was detected in peripheral blood mononuclear cells by reverse transcription-quantitative polymerase chain reaction in 210 psoriasis patients before starting or converting to a new therapy, 50 disease controls, and 50 healthy controls. The psoriasis area severity index (PASI) score was evaluated at month (M)1, M3, and M6 in psoriasis patients. RESULTS: MALT1 was increased in psoriasis patients versus disease controls and healthy controls (both p < .001); and positively related to body mass index (p = .019) and PASI score (p < .001) in psoriasis patients. PASI75 rate at M1, M3, and M6 was 22.9%, 46.2%, and 71.0%, respectively; while PASI90 rate at M1, M3, and M6 was 3.8%, 29.0%, and 50.5%, respectively, in psoriasis patients. PASI75/90 rates at M1, M3, and M6 were increased in psoriasis patients receiving biologics versus those without (all p < .05). Pretreatment MALT1 was higher in psoriasis patients who achieved PASI75 (p = .001) and PASI90 (p < .001) at M6 compared to those who did not achieve that. Subgroup analyses discovered that pretreatment MALT1 had a stronger ability to predict PASI75 and 90 realizations in psoriasis patients receiving biologics (area under the curve [AUC]: 0.723 and 0.808) versus those without (AUC: 0.594 and 0.675). CONCLUSION: Blood MALT1 measurement may assist in predicting outcomes in psoriasis patients, especially in those receiving biologics.

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.

Choosing the right biologic treatment for moderate-to-severe plaque psoriasis: the impact of comorbidities.

INTRODUCTION: Psoriasis is a chronic inflammatory skin disease often associated with several comorbidities, such as psoriatic arthritis, inflammatory bowel disease, obesity, diabetes mellitus or cardiovascular diseases, infections, or cancer, among others. With the progressive aging of the population, a growing number of patients with psoriasis can be expected to present multiple comorbidities. Currently, there is a wide range of biological treatments available for moderate to severe psoriasis, including tumor necrosis alpha (TNF) inhibitors, IL12/23 inhibitor, IL17 inhibitors, and IL23 inhibitors. AREAS COVERED: This review aims to describe the specific characteristics of these drugs in relation to psoriasis comorbidities, in order to facilitate decision-making in clinical practice. EXPERT OPINION: Some of the biological treatments can influence comorbidities, in some cases even improving them. Therefore, comorbidities are a key factor when deciding on one biological treatment over another. The development of new drugs is expanding the therapeutic arsenal for psoriasis. A high level of expertise in the field with a detailed knowledge of the characteristics of every drug is imperative to provide personalized medicine.

Psoriatic arthropathy in patients with previous neoplasia: a case series of four patients treated with secukinumab and literature review.

OBJECTIVE: Psoriasis and psoriatic arthritis (PsA) are closely linked to cancer, as supported by the literature. Systemic treatments for psoriasis and PsA, namely non-biological disease-modifying anti-rheumatic drugs (DMARDs), have been associated with increased cancer risk in both conditions. New, more effective biological DMARDs (bDMARDs) do not seem to be associated with higher overall cancer risk compared to those not receiving bDMARDs, opening up possibilities for treating patients with previous or ongoing oncological disease alongside psoriasis and PsA. However, limited literature exists on treating PsA patients with cancer with bDMARDs. This study aims to assess the safety of secukinumab, a bDMARD, in patients with PsA and concurrent cancer. Here, we describe a case series of four patients with PsA treated with bDMARD secukinumab and review the literature on the subject. CASE SERIES: We assessed the laboratory parameters and clinical characteristics of 4 patients with PsA treated with the bDMARD secukinumab and followed up until 30 months. Three patients had oncological disease in remission, while one had active neoplasia. No cancer progression was observed during the treatment of these patients with secukinumab. CONCLUSIONS: In conclusion, our case series, consisting of four PsA patients with concurrent neoplasia treated with secukinumab, showed no evidence of cancer progression and represents the first case of PsA described in the literature treated during active oncological disease, lending support to the safety of secukinumab for the treatment of patients with PsA and concomitant neoplasia.

Detection of significant liver fibrosis in Chinese psoriasis patients receiving methotrexate: a comparison between transient elastography and liver histology.

INTRODUCTION: Methotrexate (MTX) is effective for treating psoriasis and psoriatic arthritis, but its potential hepatoxicity remains a concern. Liver biopsy, the gold standard for detecting MTX-induced liver injury, is invasive and carries considerable risk. Transient elastography (TE) offers a non-invasive alternative for detecting advanced liver fibrosis. This study investigated the performance of TE in detecting MTX-induced liver fibrosis among Chinese psoriasis patients, compared with liver biopsy. METHODS: This study included adult patients with clinical psoriasis. Liver stiffness measurement using TE was performed in patients receiving MTX. Exclusion criteria were known liver cirrhosis, positive viral hepatitis carrier status, or conditions influencing TE performance. Liver biopsy was performed when liver stiffness was ≥7.1 kilopascals (kPa) or when the total cumulative dose (TCD) of MTX was ≥3.5 g. RESULTS: A total of 228 patients were screened; among 34 patients who met the inclusion criteria, nine (26.5%) had significant liver fibrosis (Roenigk grade ≥3a). The area under the receiver operating characteristic curve was 0.76 (95% confidence interval=0.59-0.93; P=0.021), indicating that TE had satisfactory performance in detecting liver fibrosis. A cut-off value of 7.1 kPa of liver stiffness yielded 100% sensitivity and 68% specificity. Liver fibrosis was not correlated with the TCD of MTX or the duration of MTX use; it was significantly correlated with obesity and diabetes status (body mass index ≥30 kg/m2, waist circumference ≥138 cm, and glycated haemoglobin level ≥7.8%). CONCLUSION: Transient elastography is reliable and superior to the TCD for detecting liver fibrosis in Chinese psoriasis patients receiving MTX. Liver biopsy should be reserved for high-risk patients or patients with liver stiffness ≥11.7 kPa on TE.

Geniposide ameliorates psoriatic skin inflammation by inhibiting the TLR4/MyD88/NF-κB p65 signaling pathway and MMP9.

Psoriasis is an incurable immune-mediated disease affecting the skin or the joints. There are continuing studies on drugs for psoriasis prevention and treatment. This research found that Geniposide (GE) significantly thinned IMQ mice's skin lesions, reduced the scales, and lowered the presence of inflammatory cells in the pathology in a dose-dependent manner. GE inhibited IL-23, IL-22, IL-17A, IL-12, IL-6, and TNF-α levels in psoriatic mice serum. AKT1, TNF, TLR4, MMP9, MAPK3, and EGFR were selected as the top 6 targets of GE against psoriasis via network pharmacology, and GE-TLR4 has the most robust docking score value by molecular docking. Taken together, GE significantly inhibited TLR4 and MMP9 protein expression and influenced MyD88/NF-κB p65 signaling pathway. Finally, TLR4 was verified as the critical target of GE, which engaged in immunomodulatory activities and reduced MMP9 production in LPS and TAK-242-induced HaCaT cells. GE had a medium affinity for TLR4, and the KD value was 1.06 × 10-5 M. GE is an effective treatment and preventative strategy for psoriasis since it impacts TLR4.