A one year quality of life and sexual health observational study in adult Asian psoriasis patients.

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Genital involvement and sexual dysfunction are common amongst patients with psoriasis. However, the effects of genital psoriasis on quality of life (QOL) and sexual health of psoriasis patients are not well understood.

We performed an observational study on adult Asian psoriasis patients attending psoriasis subspecialty clinics in a tertiary dermatology centre in Singapore over 1 year. Participants underwent clinical examination of the whole-body surface, with particular attention to the genitalia and questionnaires to evaluate QOL and psychosexual health were administered.

A total of 62 patients participated. Most participants were male (82.3%) with a mean age of 41.7 years (SD 12.5). The mean Psoriasis Area and Severity Index (PASI) score was 7.0 (SD 4.3) with a mean Dermatology Life Quality Index (DLQI) score of 9.8 (SD 6.7), indicating moderately impaired QOL. Higher PASI scores were associated with increasing QOL impairment on DLQI (p = 0.021). The commonest site involved was the suprapubic region (61.3%).

Males in whom genital psoriasis prevented sexual intercourse or diminished their libido reported more sexual dysfunction. Females reported a greater severity impact of genital psoriasis in terms of symptoms and embarrassment (p = 0.038) yet were less likely to be on treatment (37.5% vs. 45.0%).

Perceived efficacy of treatment was low, and younger patients fared poorly on the Patient Health Questionnaire-9 depression questionnaire (p = 0.047). Clinicians should proactively evaluate for and treat genital psoriasis, as patients may be reluctant to discuss their genital rashes if not prompted, leading to under-recognition and undertreatment.

How was the study conducted?

Design: Population-based cohort study using linked health administrative data.

Population: Adults age 66+ with psoriasis or psoriatic arthritis using systemic treatments in Ontario, Canada.

Study period: Between April 1, 2002 and December 31, 2020.

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Background:
Systemic treatments for psoriatic disease affect the immune system and may increase infection risk. Older adults are at high risk for infection, and the relative safety of systemic treatments for them is unknown.

Objective:
This study examined the association of systemic treatments for psoriatic disease with rates of serious infection among older adults.

Methods:
We conducted a cohort study used linked population-based health administrative data from 2002 to 2021 in Ontario, Canada.

Results:
Of 11,641 new users of systemic therapy, 53% were female, with a median age of 71. Over 4.8 years of follow-up, there were 1,967 serious infections. Serious infection rates per 100 person-years were 2.7 for methotrexate, 2.5 for other older drugs, 2.2 for anti-TNF biologics, 1.4 for other biologics, and 8.9 for tofacitinib. Methotrexate, older drugs, and anti-TNF biologics were not linked to serious infections, while other biologics had lower rates and tofacitinib had higher rates.

Conclusion:
Biologics targeting IL-12, IL-23, or IL-17 were associated with a lower rate of serious infection among older adults with psoriatic disease. These biologics may have important safety benefits for older adults with higher infection risk.

Patient's perspective on the Impact of psoriasis on their quality of life after 1 year of Ilumya  / Ilumetri (tildrakizumab)

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Background:
Tildrakizumab showed high efficacy and safety for treating moderate-to-severe psoriasis in clinical trials. The development of biologics to treat psoriasis has allowed us to aim for increasingly ambitious objectives. However, patients' and physicians' perspectives on therapeutic goals and satisfaction concerning treatments may sometimes differ.

Objectives:
To analyze the efficacy and safety of tildrakizumab and the impact of the psoriasis improvement regarding the physicians' and patients' point of view, in daily practice, after 1 year of treatment.

Methods:
A prospective multicentric study was conducted in patients who were initiated with tildrakizumab for moderate-to-severe psoriasis. Assessments of psoriasis and its impact on patients' lives were performed at tildrakizumab initiation and after 6 and 12 months of treatment.

Results:
At baseline, psoriasis deeply affected patients' lives, with 42% showing signs of clinical depression and 34.6% experiencing genital involvement with significant impact on their sex life. After 1 year, tildrakizumab was, overall, effective and safe, even in difficult-to-treat areas. Psoriasis Area Severity Index score decreased from 13.6 to 2.3, SF12-mental component score improved from 41 to 48.7 and Dermatology Life Quality Index dropped from 10.4 to 2.5. Despite these improvements, some patients remained dissatisfied, expressing concerns about relapse and persistence of mental impact of the disease over the long term.

Conclusions:
Tildrakizumab confirmed its efficacy and safety for the treatment of moderate-to-severe psoriasis. However, despite good control of their disease, some patients remained dissatisfied, over the long time, raising the issue of the cumulative mental impact of a disease left with no effective treatment for too long before the initiation of an effective treatment. These findings suggest that early treatment of psoriasis with effective therapies is important not only to target tissue-resident memory T cells, as indicated by recent studies, but also to potentially address patients' cicatricial memory of their disease.

This study looked at the effects of different seasons in patients with psoriasis.

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Psoriasis is a chronic inflammatory skin condition driven by immune system dysfunction, genetic predisposition and environmental factors. Patients with psoriasis experience a well-known clinical phenomenon of ‘winter severity and summer relief’, in which seasonal environmental factors play critical roles in the onset and progression of psoriasis.

These factors include temperature, humidity, infection, light exposure and psychological stress. Seasonal changes in temperature and humidity can compromise skin barrier function and exacerbate inflammatory responses, thereby worsening psoriasis symptoms.

Notably, during the winter, decreased light exposure leads to reduced vitamin D (VD) levels, reaching their lowest levels from late winter to early spring. This decline in VD levels is associated with increased disease activity, greater disease severity and more frequent flare-ups in patients with psoriasis.

During the winter, influenza and Streptococcus pneumoniae infections are more prevalent, which can further exacerbate psoriasis symptoms. Moreover, the environmental conditions in winter can trigger or intensify feelings of depression, which may adversely affect psoriasis through the brain–skin axis. In this comprehensive review, we thoroughly examined the influence of seasonal environmental factors on the incidence, recurrence and severity of psoriasis.

By clarifying these complex relationships, we aimed to support the future development of more personalised and effective treatment and management strategies for patients with psoriasis.

Results of a one-year  trial utilising high-resolution peripheral quantitative computed tomography in patients with psoriatic arthritis using Cosentyx (secukinumab).

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Objectives:
This study aimed to ascertain the effect of secukinumab on erosion and enthesiophyte progression in psoriatic arthritis (PsA) by high-resolution peripheral quantitative computed tomography (HR-pQCT).

Methods:
This was a phase 4, double-blind, randomized, placebo-controlled trial. Patients with active PsA and ≥ 1 erosion in the metacarpophalangeal joints (MCPJ) 2-4 were randomised in a 1:1 ratio to subcutaneous secukinumab or placebo. HR-pQCT of the MCPJ 2-4 were performed at baseline, week 24 and week 48 The primary outcome was the changes in the volume of erosions on MCPJ 2-4 measured by HR-pQCT at 24 and 48 weeks.

Results:
Forty patients (age: 51.9±13.4 years, 20 [50%] male, disease duration: 4.7±6.7years) were recruited. Thirty-four patients who completed study treatment were included in the per-protocol analysis. At baseline, week 24 and week 48, the secukinumab group showed a significant reduction in erosion volume, whereas no changes were observed in the placebo group (change in the secukinumab group: -0.1 (-0.5, 0.0) vs: 0.0 (-0.2, 0.4) in the placebo group, p=0.004). A similar trend was observed for enthesiophyte volume changes in the secukinumab group, while no differences were noted in the placebo group (change in the secukinumab group: -0.1 (-0.8, 0.0) vs 0.0 (-0.4, 1.3) in the placebo group, p=0.067). GEE results showed that the odds ratio (OR) for enthesiophyte progression in the secukinumab group was 0.264 (95% CI: 0.080-0.878, p=0.030), while the OR for partial erosion healing in the secukinumab group was 2.882 (95% CI: 1.130 to 7.349, p=0.027).

Conclusions:
Secukinumab demonstrates a potential benefit in facilitating partial erosion repair and preventing enthesiophyte progression in PsA.

This study looked at the safety and effectiveness of Taltz (ixekizumab) in Japanese patients with psoriasis vulgaris, psoriatic arthritis, generalized pustular psoriasis, and erythrodermic psoriasis.

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We report findings from a post-marketing study conducted from November 2016 to September 2022, which evaluated the safety and effectiveness of ixekizumab in Japanese patients with psoriasis under routine clinical practice for up to 52 weeks, and the incidence of serious infections and malignancies for up to 3 years.

Of 804 patients in this analysis (67.9% male; median age, 54 years; mean disease duration, 11.8 years), 72.9%, 37.7%, 7.8%, and 3.7% had psoriasis vulgaris, psoriatic arthritis, pustular psoriasis, and erythrodermic psoriasis, respectively (subtypes not mutually exclusive).

At 52 weeks, adverse events were reported in 203 patients (25.3%). Serious adverse events were reported in 36 patients (4.5%), including serious infections and infestations (n = 13, 1.6%). The incidence of serious infections and benign, malignant, and unspecified neoplasms was 0.8% (n = 5) and 0.6% (n = 4) respectively, at 3 years.

Overall, 137 patients (17.0%) received Q2/Q2 treatment (160 mg starting dose, followed by 80 mg every 2 weeks from week 12); 550 patients (68.4%) received Q2/Q4 treatment (160 mg starting dose, followed by 80 mg every 2 weeks from weeks 2 to 12 and 80 mg every 4 weeks thereafter); and 117 patients (14.6%) discontinued before week 12 or received only one dose after week 12.

A higher proportion of patients in the Q2/Q2 group had psoriatic arthritis (56.9% [n = 78]) compared with the Q2/Q4 group (32.9% [n = 181]). Among patients in the Q2/Q2 versus the Q2/Q4 dose groups, 21 (15.3%) and 141 (25.6%) respectively had adverse events and 2 (1.5%) and 32 (5.8%) respectively had serious adverse events.

The mean Psoriasis Area and Severity Index score and body surface area percentage significantly decreased from baseline to week 52 for all psoriasis subtypes and by Q2/Q2 and Q2/Q4 ixekizumab doses (p < 0.01 or p < 0.001).

Overall, the safety and effectiveness of ixekizumab in real-world settings in Japan were similar to those reported in clinical trials.

This study evaluated treatment response to Skyrizi (risankizumab) and identify potential predictors influencing the treatment response in patients with erythrodermic psoriasis.

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Erythrodermic psoriasis (EP) is a severe and challenging variant of psoriasis that often shows poor drug survival. While risankizumab, an IL-23 inhibitor, has demonstrated efficacy in patients with moderate-to-severe plaque psoriasis, its effectiveness in patients with a history of EP is less explored.

This study aimed to evaluate treatment response to risankizumab and identify potential predictors influencing the treatment response. In this single-center, longitudinal retrospective study, we included 56 patients treated with risankizumab between August 1, 2016, and June 1, 2023, of whom 22 had a history of EP.

Treatment response was assessed using the Psoriasis Area and Severity Index (PASI), and the impact of patient characteristics, including prior biologic exposure and HLA-Cw genotypes, on treatment response was analysed using the Mann–Whitney U test.

Throughout the 100-week follow-up, patients with a history of EP exhibited a poorer treatment response compared to those without such a history. Among patients with a history of EP, those with prior exposure to guselkumab and those treated with more than five biologics demonstrated a decreased response to risankizumab. Additionally, there was a non-significant trend indicating that HLA-Cw1–negative patients responded better to risankizumab.

This case series indicated that risankizumab might be an effective and sustainable treatment option for most patients with a history of EP. However, prior exposure to multiple biologics, particularly those with a similar mode of action targeting IL-23, may reduce its effectiveness. The potential association between HLA-Cw1 genotype and treatment response warrants further investigation.

The study looked at the association between the use of TNF-α inhibitors and an increased risk of fungal infections. 

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TNF-α inhibitors, including infliximab, adalimumab and etanercept, are used to treat various inflammatory diseases, such as arthritis, psoriasis and ankylosing spondylitis. However, these treatments may predispose patients to fungal infections, including histoplasmosis, candidiasis and aspergillosis.

In this study, we systematically reviewed case reports to critically examine the correlations between anti-TNF-α therapies and the occurrence of invasive and superficial fungal infections.

Infliximab was the most commonly used TNF-α inhibitor (50.65%). The highest number of fungal infections during anti-TNF34 α therapy was reported in the USA (84.25%). The conditions treated primarily included rheumatoid arthritis. A total of 517 invasive fungal infections were identified, including histoplasmosis, invasive candidiasis and aspergillosis, with histoplasmosis being the most common.

Most studies were conducted in higher-income countries, highlighting the critical lack of research on the use of immunobiologicals in relation to fungal diseases in African countries, which requires further attention.

Logistic regression analysis revealed significant associations between adalimumab use and increased risks of candidiasis, coccidioidomycosis, onychomycosis and pityriasis versicolor. For etanercept, significant associations were found with aspergillosis, coccidioidomycosis, cryptococcosis, dermatophytosis, invasive candidiasis, pityriasis versicolor and onychomycosis. Infliximab use was significantly associated with coccidioidomycosis, onychomycosis, aspergillosis, cryptococcosis, histoplasmosis and invasive candidiasis.

The data presented in this study clearly demonstrate an association between the use of TNF-α inhibitors and an increased risk of fungal infections. It is imperative that healthcare professionals maintain a high level of vigilance when managing patients on these medications. Regular monitoring and proactive management strategies are essential to mitigate risks and ensure patient safety.

This research suggests there is no link genetic link between psoriasis and diabetes.

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Epidemiological studies proposed a bidirectional link between psoriasis (Ps) and diabetes mellitus (DM); their causal relationship remains inadequately explored.

We obtained summary statistics of genome-wide association analyses for Type 1 diabetes mellitus (T1DM), Type 2 diabetes mellitus (T2DM), and Ps from individuals of European ancestry by accessing the UK Biobank and FinnGen datasets. Inverse-variance weighted (IVW) method was utilized as the primary method.

Additional analyses included debiased IVW (dIVW), constrained maximum likelihood with model averaging, robust adjusted profile score, Mendelian randomization (MR)–Egger, weighted median, and weighted mode. Moreover, sensitivity tests were conducted, including Cochran’s Q, MR pleiotropy residual sum, and outlier analyses.

Eventually, bidirectional MR was conducted to examine the possibility of a causal link between Ps and DM. No significant causal associations were indicated between DM and Ps. Moreover, there was no causal link between Ps and T1DM. Although certain positive correlations were identified between Ps and T2DM, aggregate evidence remains insufficient to establish a causal relationship.

The results demonstrated no evidence of horizontal pleiotropy between genetic variants. Furthermore, a leave-one-out test validated the stability and robustness of this correlation. Our study identifies no genetic causal effect of Ps on DM and of DM on Ps in European ancestry.

Additional research is warranted to verify the presence of an association between Ps and DM in diverse populations.

This study aims to clarify three points [1] Do d-ROM levels correlate with GPP severity? [2] Do d-ROM levels correlate with GPP severity during pregnancy, given that d-ROM levels are known to increase from the middle to late stages of pregnancy? [3] Is 4-HNE involved in the increase in oxidative stress in GPP?

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Reactive oxygen species (ROS) are involved in the pathogenesis of generalised pustular psoriasis (GPP), but this involvement has not been fully elucidated.

We performed the diacron-reactive oxygen metabolite (d-ROM) test and the biological antioxidant potential (BAP) test on sera from nine patients with active GPP who were hospitalised and treated at our hospital, including three patients with pustular psoriasis of pregnancy (PPP).

The serum d-ROM and BAP levels were evaluated before treatment and at 1 month of treatment. We also performed immunostaining of 4-hydroxy-2-nonenal (4-HNE) in skin tissues. In the GPP patients, the average d-ROM levels were significantly reduced at 1 month of treatment (reduced to 343.0 ± 82.1 U.Carr from 423.2 ± 95.0 U.Carr, p = 0.005).

The Generalised Pustular Psoriasis Area and Severity Index (GPPASI) score correlated with d-ROM levels (r = 0.57, p = 0.10), suggesting that those levels reflect the disease severity. In normal pregnancy, d-ROM values are known to increase from mid-term to late-term. The d-ROM values increased when GPP worsened in the case of PPP.

Immunohistochemical staining of 4-HNE was positive for subcorneal pustules, neutrophils, and for the cytoplasm of epidermal keratinocytes, especially in upper epidermal layers. Our findings indicate that 4-HNE may play an important role in GPP and PPP.

Multi-omics studies have revealed altered expression of circadian clock genes and proteins which are associated with an increased risk of Psoriatic Arthritis (PsA)

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Background:
Circadian rhythms have been shown to play a significant role in the etiology and progression of immune-related morbidities, including cancer and autoimmune diseases. As an autoimmune disorder, psoriatic arthritis (PsA) has been underexplored in the context of circadian rhythms. This study aimed to explore the relationship between circadian rhythm and PsA.

Methods:
We conducted a Summary-data–based Mendelian randomization (SMR) analysis, obtaining summary data on gene methylation, expression, and protein abundance levels of circadian clock-related genes (CRGs) from European ancestry individuals, with a total of 1749 genes selected from the GeneCards database using “biological clock” as the search term. The discovery cohort was obtained from the GWAS catalog database, and the replication cohort was obtained from the FinnGen database. Candidate genes related to circadian rhythm and PsA were identified through research, and their pharmacological potential and molecular docking were further validated as drug targets.

Results:
After integrating multi-omics data, we identified 11 methylation sites in three genes (HLA-DQB1, ITPR3, and GABBR1) of CRGs that were causally related to PsA, and the effects produced were not consistent. The three gene expressions of CRGs (IL4, HLA-DQB1, and OPI-AIS5) were related to PsA. At the protein level, we identified three proteins (GCKR, STAT3, and CSNK2B) of CRGs related to PsA. The top 20 drug candidates underwent drug prediction screening, resulting in the identification of 12 compounds that demonstrated effective outcomes with three (HLA-DQB1, STAT3, and IL-4) specific therapeutic targets through molecular docking.

Conclusion:
This study suggests altered expression of circadian clock genes and proteins, including HLA-DQB1, ITPR3, GABBR1, IL4, OIP5-AS1, GCKR, CSNK2B, and STAT3, as factors contributing to the increased risk of PsA.

Efficacy and Safety of oral TYK2 Inhibitor, ICP-488, in patients with moderate to severe plaque psoriasis: A phase II, randomised, double-blinded, placebo-controlled trial.

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The study results demonstrated that ICP-488 is highly effective in treating psoriasis patients at both 6 mg QD and 9 mg QD doses. Moreover, ICP-488 exhibited favorable safety and tolerability profiles, reinforcing its potential as a valuable treatment option for moderate-to-severe psoriasis patients.

A total of 129 psoriasis patients were randomized into three groups to receive once daily oral doses of ICP-488 at 6 mg, 9 mg, or placebo for twelve weeks. The primary endpoint was the percentage of subjects who achieved at least a 75% improvement from baseline in the Psoriasis Area and Severity Index score (PASI 75) at week 12. 

At week 12, the percentage of patients achieving PASI 75 was significantly superior in the ICP-488 6 mg QD group (77.3%) and the 9 mg QD group (78.6%) than that of the placebo group (11.6%) (P<0.0001); the percentages of subjects achieving PASI 90 and sPGA of 0 (clear) or 1 (almost clear) were also significantly higher in the ICP-488 6 mg QD group (36.4%, 70.5%) and 9 mg QD group (50.0%, 71.4%) compared to the placebo group (0%, 9.3%)(P<0.0001). All treatment emergent adverse events (TEAEs) and treatment-related adverse events (TRAEs) and were mild or moderate.

ESK-001 is an investigational next-generation tyrosine kinase 2 (TYK2) inhibitor that is designed to correct immune dysregulation across a spectrum of diseases driven by proinflammatory mediators, including IL-23, IL-17, and type 1 interferon (IFN).

ESK-001's selective targeting is designed to deliver maximal inhibition while minimizing off-target binding and effects.

ESK-001 is currently being investigated for the oral treatment of plaque psoriasis and systemic lupus erythematosus (SLE). Potential future indications include psoriatic arthritis, inflammatory bowel disease, and other chronic inflammatory conditions.

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Safety summary:
ESK-001 (40 mg BID) remained generally safe and well-tolerated over 52 weeks; majority of
TEAEs were mild-to-moderate in severity and self-limited; no safety signals to date

Efficacy summary:
40 mg BID patients showed high levels of response throughout the study
PASI-75 (77.5%), PASI-90 (61.3%) and PASI-100 (38.8%) (mNRI) scores at Week 52
80% of ≥PASI-75 responders at Week 12 in STRIDE maintained or improved their response at Week 52; 62% improved response over 52 weeks of treatment
Rapid and sustained improvement in DLQI 0/1 and itch

ESK-001 pivotal program status:
Onward Phase 3 development program in plaque psoriasis ongoing, with over 600 patients enrolled to date.

Johnson & Johnson have announced new icotrokinra (JNJ-2113) data from its comprehensive Phase 3 clinical program and the start of the first-ever head-to-head study in plaque psoriasis.

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Standout combination of complete skin clearance and favorable safety profile in a once daily pill could shift treatment paradigm

Nearly half of patients with moderate-to-severe plaque psoriasis (PsO) treated with investigational icotrokinra achieved completely clear skin (IGA 0) at Week 24 in Phase 3 ICONIC-LEAD

Topline results from Phase 3 ICONIC-ADVANCE 1&2 studies show icotrokinra achieved co-primary endpoints and showed superiority to deucravacitinib in moderate-to-severe plaque PsO

These results pave the way to initiate the first-ever head-to-head study seeking to demonstrate the superiority of a pill versus injectable biologic in moderate-to-severe plaque PsO.

UCB have released Bimzelx (bimekizumab) 5 year data.

• Sustained complete skin clearance over five years: In a subset of 153 patients from the second extension of BE BRIGHT, 67.7% of patients with moderate-to-severe plaque psoriasis (PSO) treated with BIMZELX® (bimekizumab-bkzx) achieved PASI100 at five years
     
  
• Durable and broad efficacy across patient subgroups at four years: Consistently high rates of complete or near-complete skin clearance seen at four years regardless of baseline weight or baseline cardiometabolic comorbidities such as hypertension, hyperglycemia or elevated BMI
     
  
• High response rates in patients at risk of psoriatic arthritis at three years: Data showed 68.7–71.6% of PSO patients at risk of developing psoriatic arthritis (PsA) achieved complete skin clearance, generally consistent with the overall treated group. Similar results were seen in all patients with PSO, including those with PsA at baseline
     
  
• Dual inhibition: BIMZELX® is the first and only approved medicine designed to selectively inhibit both interleukin 17A (IL-17A) and interleukin 17F (IL-17F)
  

Sotyktu (deucravacitinib) in plaque psoriasis four year safety and efficacy results.

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Background:
Deucravacitinib, an oral, selective, allosteric tyrosine kinase 2 (TYK2) inhibitor, is approved in multiple countries for treatment of adults with moderate to severe plaque psoriasis who are candidates for systemic therapy.

Objectives:
To evaluate the safety and efficacy of deucravacitinib through 4 years in the Phase 3 POETYK PSO-1, PSO-2 and long-term extension (LTE) trials in psoriasis.

Methods:
PSO-1 and PSO-2 (parent trials) randomized patients 1:2:1 to oral placebo, deucravacitinib 6 mg once daily (QD) or apremilast 30 mg twice daily. At 52 weeks, patients enrolled in the LTE trial received open-label deucravacitinib 6 mg QD. Safety was evaluated in patients who received ≥1 dose of deucravacitinib at any time. Clinical and patient-reported outcomes (PASI, PGA and DLQI) were analysed in patients who received continuous deucravacitinib from Day 1 of the parent trials and enrolled in the LTE trial.

Results:
In total, 1519 patients received ≥1 dose of deucravacitinib, with cumulative exposure of 4392.8 person-years (PY) through the data cut-off of 1 November 2023. Exposure-adjusted incidence rates (EAIRs)/100 PY of noted safety measures were comparable or decreased from the 1-year to 4-year cumulative period, respectively, for adverse events (AEs) (229.23, 131.68), serious AEs (including COVID-19) (5.68, 5.01), deaths (0.20, 0.25), discontinuation due to AEs (4.38, 2.20), herpes zoster (0.81, 0.55), malignancies (1.02, 0.89), major adverse cardiovascular events (0.30, 0.32) and venous thromboembolism (0.20, 0.07). In patients who received continuous deucravacitinib (n = 513), clinical and patient-reported outcome rates were well maintained from 1 year through 4 years (e.g. PASI 90, 1 year, 45.6% [95% CI, 41.3%–50.0%], 4 years, 47.5% [42.6%–52.4%]; DLQI 0/1, 1 year, 51.5% [47.1%–55.9%], 4 years, 49.4% [44.4%–54.4%]).

Conclusions:
Deucravacitinib demonstrated a consistent safety profile and durable efficacy through 4 years of treatment in patients with moderate to severe plaque psoriasis.

This study suggests TYK2 inhibitor could be used in a topical manner on psoriasis therapy.

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Introduction:
Tyrosine kinase 2 (TYK2)-dependent cytokine signalling is integral to the pathogenesis of psoriasis. While BMS-986165, a highly selective TYK2 inhibitor, has recently been approved for oral treatment of psoriasis, its therapeutic potential via topical application remains unexplored.

Objectives:
We aim to investigate the efficacy of topically applying TYK2 inhibitor in psoriasis and to elucidate the underlying mechanisms driving the therapeutic effects of this delivery approach.

Methods:
1.5% BMS-986165 ointment was applied topically to the back skin of imiquimod (IMQ)-induced psoriatic mice. To identify potential target cells influenced by the topical TYK2 inhibitor, we performed single cell RNA sequencing (scRNA-seq) and flow cytometry on mouse lesions. The role of TYK2 in vitro was assessed by silencing its expression or administering BMS-986165 in human keratinocytes (KCs). Mechanistic insights into TYK2 function in KCs were further investigated using RNA-seq, dual luciferase reporter assay and ChIP-qPCR.

Results:
External use of 1.5% BMS-986165 ointment significantly ameliorated the IMQ-induced psoriasis-like dermatitis. Importantly, topical TYK2 inhibitor attenuated proinflammatory capability of KCs. In vitro, TYK2 inhibition suppressed the transcription of nerve growth factor receptor (NGFR) by disrupting the AKT-SP1 signalling pathway. This impairment hindered the activation of activator protein 1 (AP1), thereby weakening the proinflammatory potential of KCs.

Conclusion:
This study reveals a novel therapeutic potential for selective TYK2 inhibitor in topical manner on psoriasis therapy, which might prompt the development of topical treatment for psoriasis. Crucially, our findings provide an underexplored regulatory mechanism of TYK2 inhibitor in psoriasis.

The aim of this study was to assess drug survival and the efficacy of biologics for psoriasis in smokers compared with non-smokers.

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Background:
Smoking is a modifiable risk factor that increases the likelihood of developing psoriasis and the severity of the disease. In recent years, biological therapies have transformed the management of psoriasis. There is conflicting evidence about whether smoking affects the efficacy of biologics. The aim of this study was to assess drug survival and the efficacy of the first biologic for psoriasis in smokers compared with non-smokers.

Methods:
This was a retrospective cohort study using data from the Australasian Psoriasis Registry. Participants with psoriasis who met Pharmaceutical Benefits Scheme eligibility criteria for a biologic (n = 395) were included. Associations between smoking and drug survival or Psoriasis Area and Severity Index (PASI) response were assessed using univariable and multivariable Cox Proportional Hazards regression, controlling for confounders including sex, obesity, psoriatic arthritis, biologic class and baseline PASI.

Results:
The prevalence of current smoking was 24.6% and former smoking was 18.5%. On univariable analysis, smokers were 34% more likely to discontinue treatment compared with non-smokers (p = 0.039), were 27% less likely to attain PASI90 (p = 0.037) and 33% less likely to attain PASI100 (p = 0.038). On multivariable analysis, the association between smoking and reduced drug survival was no longer statistically significant. Multiple factors, including obesity, female sex, psoriatic arthritis and higher PASI scores, were risk factors for drug discontinuation.

Conclusions:
This analysis illustrated that multiple factors are involved in drug survival, and smoking was not an independent risk factor for drug discontinuation. This study provides a rationale for future studies examining the effect of lifestyle modification on the efficacy of biological therapies in psoriasis.

This cohort aimed to explore the association between metabolic syndrome (MetS) and radiographic features (peripheral and axial) in psoriatic arthritis (PsA).

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Objectives:
Metabolic syndrome (MetS) is a known comorbidity of psoriatic arthritis (PsA) and is associated with PsA disease activity. We aimed to explore the association between MetS and radiographic features (peripheral and axial) in PsA.

Methods:
We included patients with PsA followed at our prospective observational cohort for the period between 1978 and 2024. We identified patients with MetS on longitudinal follow-up and used generalized estimating equations (GEE) analysis to define the radiographic features independently associated with MetS, adjusting for age, sex, PsA disease duration, calendar decade, and use of targeted disease modifying anti-rheumatic drugs.

Results:
The study population consisted of 1422 patients, out of which 400 (28.1%) had MetS at baseline (clinic entry) and 836 (58.79%) ever had a record of MetS (per the harmonized definition by Alberti et al.) over a median [interquartile range] follow-up duration of 10.59 [4.52, 18.28] years. The mean (standard deviation [SD]) age of our cohort at baseline was 44.43 (12.98) years, with 789 (55.5%) patients identifying as male. Mean (SD) body mass index was 28.79 (6.36) kg/m2. In the GEE analysis, MetS was not significantly associated with axial disease or radiographic damage to peripheral joints, assessed as the presence of syndesmophytes or sacroiliitis and the radiographic damaged joint count, respectively. On the other hand, MetS was significantly associated with calcaneal spurs, diffuse idiopathic skeletal hyperostosis, and degenerative disc disease.

Conclusion:
MetS is associated with degenerative and metabolic changes in the spine and entheses, but not with radiographic damage in PsA.

This retrospective analysis aimed to establish criteria to accurately approximate Generalized pustular psoriasis (GPP) prevalence in Germany.

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Background and Objectives: Generalized pustular psoriasis (GPP) is a rare, chronic, potentially life-threatening skin disease. We aimed to establish criteria to accurately approximate GPP prevalence in Germany.

Methods: A retrospective analysis of the WIG2 health claims database (1/1/2016–31/12/2020) was conducted. Patients aged ≥ 12 years continuously enrolled in their statutory health insurance with one inpatient or confirmed outpatient diagnosis code for GPP (International Classification of Diseases, 10th Revision [ICD-10] L40.1) were included. Scenarios with increasingly strict criteria were used to identify the GPP population.

Results: From 2016–2020, 5,236 potential GPP cases were identified based on a recorded GPP diagnosis. The scenario of ≥ 1 GPP diagnosis yielded the highest prevalence (336–390 patients/million) followed by > 1 GPP diagnosis in ≥ 2 quarters (189–288 patients/million); scenarios resulting in the lowest prevalence were diagnosis in ≥ 2 quarters AND two independent diagnoses (17–28/million) and diagnosis in ≥ 2 quarters AND two independent diagnoses or diagnosis by a specialist AND potential flare (58–61 patients/million).

Conclusions: This study suggests that diagnosis in ≥ 2 quarters by a specialist or two independent physicians may be the most clinically robust and reliable criteria for estimating GPP prevalence; therefore, 50–100 patients/million may represent a reasonable prevalence estimate range for Germany.