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Psoriasis is a chronic, immune‐mediated disorder characterized by immune regulation disorders and abnormal keratinocyte proliferation. Deucravacitinib (Deu), a selective oral Tyrosine Kinase 2 (TYK2) inhibitor, shows promise in treating psoriasis but may cause systemic side effects and fail to address persistent localized thickened lesions. Herein, a self‐locking microneedle (MN) patch with a polyvinyl alcohol (PVA) inner ring loaded with Deu is developed, designed to penetrate the transdermal barriers and dissolve rapidly, downregulating the IL‐23/IL‐17 pathway and serve as the first line of defense against the spread of skin‐originated inflammation. Additionally, Calcipotriol (Cal), a vitamin D derivative, is incorporated into a methacrylated hyaluronic acid (HAMA) backing layer and outer ring that mimics occlusive administration, maintaining localized skin surface retention for prolonged anti‐proliferative therapy. The Deu@Cal MN demonstrates satisfactory adhesiveness due to swelling‐mediated mechanical interlocking via the outer ring, ensuring targeted drug release at lesion site. Besides its effectiveness in alleviating both skin inflammation and proliferation, it inhibits the differentiation of Th17 cells in the spleen, suggesting potential to reduce systemic inflammation. These findings offer a new therapeutic approach for treating psoriasis and other autoimmune and inflammatory conditions. [ABSTRACT FROM AUTHOR]

This study systematically reviews existing data on the efficacy of Tyrosine Kinase 2 (TYK2) inhibitors in comparison to placebo or standard treatments for therapeutic benefit and improving quality of life in dermatological diseases. Seventeen records representing 13 clinical trials, one matching‐adjusted indirect comparison, and one case study were included. Results indicate that Deucravacitinib is superior to placebo, Apremilast and Adalimumab in treating adult patients with moderate‐to‐severe plaque psoriasis and superior to placebo in the treatment of adults with systemic lupus erythematosus. Comparative investigations on Brepocitinib and Ropsacitinib were more limited. Oral Brepocitinib demonstrated superiority over placebo in managing alopecia areata, and hidradenitis suppurativa. Topical Brepocitinib exhibited superiority over placebo in treating atopic dermatitis, but not plaque psoriasis. Ropsacitinib demonstrated superiority over placebo in the management of plaque psoriasis. Brepocitinib and Ropsacitinib had more side effects than Deucravacitinib. [ABSTRACT FROM AUTHOR]

Introduction: Palmoplantar pustular psoriasis (PPPP) is a chronic inflammatory skin disorder characterized by sterile pustules on the palms and soles, significantly impacting patients' quality of life. The pathogenesis of PPPP involves intricate interactions between immune dysregulation, environmental triggers, and genetic predisposition. The treatment of PPPP is challenging, and there is a need for effective and safe treatment options for patients. Objective: We evaluated the efficacy and safety of deucravacitinib, a novel oral selective allosteric inhibitor of tyrosine kinase 2 (TYK2), in treating refractory PPPP. Material and methods: A retrospective analysis was conducted on five patients treated with deucravacitinib 6 mg/day, with clinical assessments at weeks 0, 4, and 16. Results: While initial worsening was observed in most patients, three showed improvement by week 16. One patient improved with the addition of methotrexate. Treatment was discontinued in two patients after week 16. Adverse effects were primarily viral and bacterial infections, and no serious adverse events occurred. Conclusion: Current therapeutic options for PPPP are limited, necessitating exploration of novel treatments. Deucravacitinib's mechanism of action, targeting TYK2, could show promise in PPPP management. However, its efficacy and safety in this specific condition require further investigation through larger, randomized controlled trials. [ABSTRACT FROM AUTHOR]

Aim: In the global phase 3 POETYK PSO-1 and PSO-2 trials, significantly greater proportions of deucravacitinib-treated patients met the coprimary endpoints (PASI 75, sPGA 0/1) at Week 16 versus placebo or apremilast-treated patients. This analysis evaluated onset of action and maintenance of response in patients randomized to deucravacitinib and placebo only. Methods: Adults with moderate to severe plaque psoriasis at baseline were randomized 1:2:1 to oral placebo, deucravacitinib, or apremilast. Onset of action was determined through changes from baseline in mean PASI, BSA, BSA × sPGA, and DLQI. Maintenance of response was assessed using PASI 75, PASI 90, PASI 100, sPGA 0/1, and sPGA 0 response rates through Week 52 in patients who were treated continuously with deucravacitinib, crossed over from placebo to deucravacitinib at Week 16, or received deucravacitinib and achieved PASI 75 by Week 24. Results: Deucravacitinib showed significantly higher increases in mean percent change from baseline in PASI versus placebo by Week 1. Significant improvement versus placebo was observed in all other efficacy measures by Week 8. Efficacy with deucravacitinib was maintained through Week 52. Conclusion: Deucravacitinib displayed efficacy as early as 1 week and clinical responses were maintained over 52 weeks in patients with moderate to severe plaque psoriasis. [ABSTRACT FROM AUTHOR]

Background: Deucravacitinib is a selective oral tyrosine kinase 2 (TYK2) inhibitor recently approved for psoriasis. Objectives: We aimed to evaluate the real-world effectiveness and safety of deucravacitinib for psoriasis. Methods: We analyzed 33 Japanese patients with psoriasis (23 with plaque psoriasis, eight with psoriatic arthritis, and two with erythrodermic psoriasis) from January 2023 to October 2023. All patients received deucravacitinib 6 mg daily until week 16. Results: At week 8, 12, or 16, the achievement rate of PASI 75 was 60.9%, 73.9%, or 78.3%, that of PASI 90 was 13.0%, 39.1%, or 52.2%, that of PASI 100 was 0%, 8.7%, or 13.0%, that of absolute PASI ≤2 was 34.8%, 65.2%, or 78.3%, respectively. The achievement rate of dermatology life quality index 0/1 at week 16 was 42.9%. Fourteen patients (42%) complained pruritus. Peak pruritus-numerical rating scale in patients with pruritus decreased by median [interquartile] 71.4 [50–80] % of baseline at week 2. Adverse events occurred in 18.2% of patients, which were mild and manageable. Conclusions: Deucravacitinib for patients with psoriasis was well-tolerated and gave favorable therapeutic effects in the real-world practice. Deucravacitinib treatment rapidly reduced pruritus. [ABSTRACT FROM AUTHOR]

Psoriasis (Ps) is a debilitating immune-mediated chronic skin condition. It affects about 1–3% of the world population, with an 8–11% prevalence in Northern European populations. Tyrosine kinase 2 (TYK2) is a newly identified target for Ps. An independent non-coding genetic association with Ps has been identified ~400 kb upstream of TYK2. The variants making up the credible Ps Single-Nucleotide Polymorphism (SNP) set were identified in their genomic context with the potential to influence TYK2 expression by interacting with regulatory elements involved in gene regulation. Previous evidence from our laboratory has suggested that credible SNP sets in intronic regions can be distal regulators of the genes of interest through long-range chromatin interactions. We hypothesise that SNPs at ILF3 are distal regulators of TYK2 expression via long-range chromatin interactions and Ps risk. The dysregulation of the TYK2 pathway in Ps may be mediated by a combination of GWAS risk SNPs at ILF3 and TYK2 and downstream genes. We investigated this by employing functional genomics and molecular biology methods. We developed a CD4 T cell model system with Jurkat-dCAS9-VP64 and Jurkat-dCAS9-KRAB cells using CRISPR activation and CRISPR inhibition of the risk variants rs892086 and rs7248205, selected from the latest Ps GWAS SNP set for their long-range interaction and light Linkage Disequilibrium (R2 > 0.8), respectively. Using CRISPR activation, we demonstrate here that these risk SNPs, although distal to TYK2, do indeed regulate the TYK2 gene. Investigations into annotating the TYK2 pathway using RNA-seq analysis revealed differentially regulated genes, including VEGFA, C1R, ADORA1, GLUD2, NDUFB8, and FCGR2C, which are thought to be implicated in Ps. These genes were observed to be associated with conditions such as psoriatic arthritis, atopic dermatitis, and systemic sclerosis when compared using published databases, which confirms their relevance and importance in inflammatory conditions. With the developed cell model systems using CRISPR technology and differential gene regulation, we demonstrate here that these genes have the potential to define the TYK2/Ps pathway and our understanding of the disease biology. [ABSTRACT FROM AUTHOR]

Expanding the systemic treatment options for patients with psoriasis, deucravacitinib, an oral, selective, allosteric tyrosine kinase 2 inhibitor is approved in the United States, European Union, China, Japan, Taiwan, Korea, and other countries for the treatment of adults with moderate to severe plaque psoriasis who are candidates for systemic therapy. Evidence suggests the comparative efficacy of systemic therapies may be different in Asian versus White patients. This systematic review and network meta‐analysis (NMA) evaluated the clinical efficacy associated with deucravacitinib and other biologic or non‐biologic systemic treatments for moderate to severe plaque psoriasis in Asian populations. Electronic databases were searched to identify randomized trials of the interventions of interest. Multinomial random effects models adjusting for baseline placebo risk were used to estimate Psoriasis Area and Severity Index (PASI) responses at weeks 10–16. Of 8596 studies identified, 20 were included in the NMA. The estimated PASI 75 and 90 (95% credible interval) response rates for deucravacitinib were estimated to be 66% (49%–80%) and 40% (24%–58%) in Asian populations, notably higher than placebo (6% [4%–9%] and 1% [0.8–2%]) and apremilast (24% [12%–40%] and 9% [4%–20%]). No statistically significant difference was observed in PASI 75 and 90 responses between deucravacitinib and adalimumab, certolizumab pegol, infliximab, ustekinumab, and tildrakizumab. Deucravacitinib demonstrated robust efficacy in the Asian population, with PASI 75 and 90 responses comparable to some biologics. Deucravacitinib provides a convenient oral therapy with efficacy similar to several biologic therapies. [ABSTRACT FROM AUTHOR]

Abstract Introduction Despite advancements in the treatment of psoriasis (PsO), there are few head-to-head studies assessing comparative effectiveness of the newest therapies approved to treat PsO. Our objective was to assess the comparative clinical effectiveness of risankizumab and deucravacitinib in patients with moderate-to-severe PsO. Methods This placebo-anchored matching-adjusted indirect comparison (MAIC) analysis utilized data from UltIMMa-1/2 risankizumab and POETYK PSO-1/2 deucravacitinib trials. Individual patient data from UltiMMA-1/2 were weighted via propensity score to match POETYK PSO-1/2 published summary data. Rate differences between risankizumab and deucravacitinib were assessed for Psoriasis Area and Severity Index (PASI) 75/90/100, the Static Physician Global Assessment (sPGA = 0 or 0/1), and the Dermatology Life Quality Index (DLQI) 0/1. Results At 16 weeks, risankizumab-treated patients demonstrated statistically significantly higher rates of skin clearance and greater improvement in quality of life (QoL) compared to those treated with deucravacitinib. Across all outcomes, risankizumab demonstrated a lower number needed to treat compared to deucravacitinib. Limitations are potential bias due to unobserved/unmeasurable differences and limited generalizability of the results. Conclusions This indirect comparison demonstrates that risankizumab has higher rates of skin clearance and greater improvements in QoL than deucravacitinib. This study will help inform healthcare providers in their treatment and management strategy of PsO.

Abstract Background Psoriasis, a chronic, immune-mediated, inflammatory disease, affects 2‒3% of the population. Tyrosine kinase 2 (TYK2) mediates cytokine signaling involved in adaptive [interleukin (IL)-12, IL-23] and innate (type-I interferons) immune responses; IL-23–driven T-helper (Th)17 pathways play a key role in chronic inflammation in psoriasis. In a phase 2 trial, deucravacitinib, an oral, selective, allosteric TYK2 inhibitor, reduced IL-23/Th17 and type-I interferon pathway expression in the skin of patients with moderate to severe plaque psoriasis, reductions that were accompanied by clinical improvement of psoriatic lesions. Objectives The aim of this study was to identify biomarkers of psoriatic disease in serum from patients enrolled in the phase 2 trial and to assess the effects of deucravacitinib on those biomarkers. Methods Serum biomarkers from Olink proteomics and other quantitative assays were evaluated for a pharmacodynamic response to deucravacitinib treatment and correlation with psoriasis disease activity measures. Results Serum biomarkers associated with the IL-23/Th17 pathway [IL-17A, IL-17C, IL-19, IL-20, beta-defensin, and peptidase inhibitor 3 (PI3)] were upregulated in patients with psoriasis versus healthy controls. Deucravacitinib treatment reduced IL-17A (adjusted mean change from baseline at Day 85; 12 mg once daily versus placebo; −0.240 versus −0.067), IL-17C (−14.850 versus −1.664), IL-19 (−96.445 versus −8.119), IL-20 (−0.265 versus −0.064), beta-defensin (−65,025.443 versus −7553.961), and PI3 (−14.005 versus −1.360) expression. Reductions in serum biomarker expression occurred in a dose- and time-dependent manner, with significant reductions from baseline seen with deucravacitinib doses ≥ 3 mg twice daily (P ≤ 0.05). Biomarker expression correlated with disease activity measures such as Psoriasis Area and Severity Index (PASI) at baseline. Biomarker expression also correlated with PASI scores at Week 12. Conclusion IL-23/Th17 pathway expression in the serum of patients with psoriasis is an indicator of disease activity and response to deucravacitinib treatment. Trial registration number NCT02931838.

Introduction Psoriasis and atopic dermatitis are chronic, immune-mediated skin disorders that are disqualifying for entrance into the military. Both conditions can cause difficulty wearing body armor and other protective equipment when poorly controlled, limiting a service member's ability to train and deploy worldwide. In addition, these conditions may be exacerbated by military service because of increased exposure to austere environments, extreme temperatures, stress, skin injury, bug bites, and vaccinations Service members have limited treatment options because of restrictions on systemic medications that can be used while deployed. Newer systemic medications—in particular, biologics and oral immunomodulators—have evolved to be both extremely effective and safe. We review more recent treatment options for psoriasis and atopic dermatitis in the context of DoD's regulations guiding entry and retention of personnel with psoriasis and eczema and make recommendations regarding updating DoD policy for systemic treatment options. Materials and Methods A literature search was performed using PubMed, Embase, and Ovid with the last search done in the fall of 2023 from all years to date. These articles were further screened based on inclusion and exclusion criteria. In total, 25 articles were included in this review. An Internet search was also performed on the DoD's regulations guiding entry and retention of personnel with psoriasis and eczema. In addition, we examined medical requirements for deployment to the U.S. Central Command and U.S. European Command. Results Currently, U.S. Central Command and U.S. European Command do not allow the use of medications with special storage and handling requirements on deployments. Newer biologics are safe and efficacious but require refrigeration, although other immunomodulators like deucravacitinib and apremilast are oral pills and do not have cold-storage requirements. However, the use of biologics in austere environments may be feasible because of increased intervals between dosing and the ability to store refrigerated medical supplies in most deployed environments. For military service members with psoriasis, risankizumab and deucravacitinib are excellent options given their favorable safety and efficacy profiles. Of the biologics available for atopic dermatitis, dupilumab is the safest and effective systemic medication available. The Janus kinase inhibitors have also demonstrated excellent efficacy in treating atopic dermatitis, but more safety data are needed because of potential adverse events to include heart-related events, blood clots, and cancers. Conclusions Systemic treatments have evolved to become highly specific for both eczema and psoriasis. These newer biologics and immunomodulators may be compatible with use in the deployed setting, especially those that have long dosing intervals and proven efficacy and safety. Of the biologics, dupilumab and risankizumab offer the best efficacy, safety, and dosing intervals for atopic dermatitis and psoriasis, respectively. Deucravcitinib is a recently FDA-approved oral immunomodulator for psoriasis that has an excellent safety profile and efficacy. Allowing the use of these medications on deployments will enable more people with moderate to severe psoriasis and eczema to join and remain in the military while receiving effective treatment. [ABSTRACT FROM AUTHOR]

Introduction: Despite advancements in the treatment of psoriasis (PsO), there are few head-to-head studies assessing comparative effectiveness of the newest therapies approved to treat PsO. Our objective was to assess the comparative clinical effectiveness of risankizumab and deucravacitinib in patients with moderate-to-severe PsO. Methods: This placebo-anchored matching-adjusted indirect comparison (MAIC) analysis utilized data from UltIMMa-1/2 risankizumab and POETYK PSO-1/2 deucravacitinib trials. Individual patient data from UltiMMA-1/2 were weighted via propensity score to match POETYK PSO-1/2 published summary data. Rate differences between risankizumab and deucravacitinib were assessed for Psoriasis Area and Severity Index (PASI) 75/90/100, the Static Physician Global Assessment (sPGA = 0 or 0/1), and the Dermatology Life Quality Index (DLQI) 0/1. Results: At 16 weeks, risankizumab-treated patients demonstrated statistically significantly higher rates of skin clearance and greater improvement in quality of life (QoL) compared to those treated with deucravacitinib. Across all outcomes, risankizumab demonstrated a lower number needed to treat compared to deucravacitinib. Limitations are potential bias due to unobserved/unmeasurable differences and limited generalizability of the results. Conclusions: This indirect comparison demonstrates that risankizumab has higher rates of skin clearance and greater improvements in QoL than deucravacitinib. This study will help inform healthcare providers in their treatment and management strategy of PsO. [ABSTRACT FROM AUTHOR]

Translational medicine provides insight into novel drugs and predicts unwanted effects. In well-characterized pathways (e.g., cytokine-Janus kinase [JAK]-signal transducers and activators of transcription [STAT]), a variety of in vitro assessments were used to estimate selectivity of effects on different potential targets (i.e., JAK1, JAK2, JAK3, and tyrosine kinase 2 [TYK2]). Several approved drugs were characterized as selective for the JAK family. These assessments are challenged by a lack of compounds that only inhibit one JAK family member. Deucravacitinib is a first-in-class, oral, selective, allosteric inhibitor of TYK2, a kinase required for IL-12, IL-23, and Type I interferon signaling. Unlike deucravacitinib, which selectively binds to the TYK2 regulatory domain, JAK1,2,3 inhibitors target the catalytic domain, contributing to nonselective targeting of JAK1,2,3. Cytokines associated with JAK1,2,3 signaling are required for both immune and nonimmune functions. A similar laboratory abnormality profile was observed in clinical trials using JAK1,2,3 inhibitors that has not been observed with deucravacitinib. In vitro testing of JAK1,2,3 inhibitors has relied upon assays of signal transduction, such as those measuring STAT phosphorylation, for estimates of potency and selectivity. These assay systems can be effective in estimating in vivo efficacy; however, they may not provide insight into downstream outcomes of receptor signaling, which may be more relevant for evaluating safety aspects. Assay systems assessing functional outcomes from cells may yield a more useful translational evaluation. Here, deucravacitinib was assessed for potency and selectivity versus three representatives of the JAK inhibitor class (tofacitinib, baricitinib, and upadacitinib) based on functional assays. JAK inhibitors had suppressive activity against JAK2-dependent hematopoietic colony-forming assays modeling thrombopoiesis, erythropoiesis, and myelopoiesis; however, deucravacitinib did not. Deucravacitinib had limited potency against NK cells, cytotoxic T cells, Thelper cells, and regulatory T cells activated by JAK1/JAK3-dependent common gamma chain cytokines. These data are consistent with the biologic role of JAK1,2,3 and pharmacodynamic changes in clinical laboratory abnormalities. Against TYK2-dependent cytokines, deucravacitinib selectively inhibited Type I interferon stimulation of monocytes and dendritic cells and was a more potent inhibitor than JAK inhibitors. IL-12 and IL-23 functional outputs were similarly potently inhibited by deucravacitinib. Results are consistent with deucravacitinib selectively inhibiting TYK2. [ABSTRACT FROM AUTHOR]