Scholarly Activity

OBJECTIVES: Understanding patient priorities in nonsegmental vitiligo is essential for developing therapies that address unmet needs. This study used a modified Outcome-Driven Innovation approach to quantify unmet need by considering patients' perspectives on the importance of, and their satisfaction with, treatment attributes.

METHODS: A cross-sectional survey of 522 patients with nonsegmental vitiligo in the United States quantified the relative importance participants placed on 26 treatment attributes. Participants also rated their satisfaction with how well available treatments performed on those attributes. K-means clustering was used to segment participants based on priorities.

RESULTS: Three segments, focusing on efficacy, administration and dosing, or safety, were identified. The two most underserved attributes, identified by >10% of participants as important for which satisfaction was low, were improvement in emotional well-being from repigmentation (15.6% of participants) and access to systemic therapy (15.1% of participants). Participants with ≥5% body surface area affected, including the face, more often identified efficacy and systemic treatment that targets the entire body as unmet needs than did those reporting facial involvement only.

CONCLUSIONS: These findings highlight substantial unmet needs in nonsegmental vitiligo treatment, underscoring the importance of developing systemic therapies that align with patients' priorities to deliver meaningful repigmentation that improves emotional well-being.

Vitiligo is a chronic autoimmune depigmenting disease characterized by loss of pigment in the skin, hair, or both. As treatment options evolve, particularly with the emergence of oral Janus kinase inhibitors and dual Janus kinase 3/tyrosine kinase expressed in hepatocellular carcinoma family kinase inhibitor, it is essential to assess population-level safety events in patients with vitiligo. This retrospective cohort study examined patients aged ≥ 12 years with vitiligo in the United States, comparing them with age-, sex-, and race-matched controls to evaluate patient demographics, baseline comorbidities, medication histories, vitiligo prevalence and incidence across demographic groups, and incidence rates of safety events following vitiligo diagnosis. This study used records dated 1 January 2016 to 30 September 2023 from the Optum Market Clarity United States Electronic Health Record database. This study included 15 047 patients with vitiligo and 75 231 matched controls. In both cohorts, the median age was 51 years and 56.3% of patients were female. Compared with controls, patients with vitiligo had a higher baseline proportion of autoimmune and inflammatory diseases (e.g., autoimmune thyroiditis, psoriasis, alopecia areata, and atopic dermatitis), infections, malignancies, hypothyroidism, allergic rhinitis, and hearing loss; they were also more likely to have used treatments for dermatologic conditions and immunosuppressive medications. Post diagnosis, higher incidence rates of autoimmune and inflammatory conditions (e.g., alopecia areata, systemic sclerosis, pernicious anemia, autoimmune thyroiditis, and psoriasis), infections, hearing-related events, and skin cancer were observed in the vitiligo cohort compared with the non-vitiligo cohort. Furthermore, vitiligo incidence and prevalence rates were numerically higher in Asian and Hispanic populations than in other racial and ethnic groups. However, the observed results should be interpreted with caution considering the limitations of the dataset. These findings provide valuable insight into the epidemiology of and safety considerations for patients with vitiligo in the United States, informing future clinical and therapeutic strategies.

Psoriasis is an immune-mediated inflammatory disease (IMID) impacting more than 40 million people globally and characterized by skin plaques, elevated systemic levels of inflammatory cytokines, and psychosocial burden. Many patients remain undertreated. Available topical and oral treatments are typically less effective than biologic therapies and have safety considerations that may limit long-term use. Tyrosine kinase 2 (TYK2), a Janus kinase (JAK) enzyme, is a validated target in psoriasis and is also being investigated for other IMIDs. TYK2 mediates signaling of interleukin (IL)-23 and IL-17, central proinflammatory cytokines whose dysregulation contributes to chronic inflammation associated with psoriasis, and IL-12 and type I interferons (IFNs). Therefore, selective inhibition of TYK2 offers more targeted immunomodulation vs. broader immunosuppression associated with JAK 1/2/3 inhibition. Envudeucitinib (formerly ESK-001) is a next-generation, oral, allosteric TYK2 inhibitor under investigation for the treatment of psoriasis and systemic lupus erythematosus. Envudeucitinib selectively binds to the unique regulatory domain (JAK homology 2 [JH2]) of TYK2 to induce a conformational change that prevents ATP from binding the catalytic domain (JAK homology 1 [JH1]), thereby inactivating TYK2. This approach avoids adverse events associated with classic JAK inhibition. In preclinical and phase 1 studies, oral administration of envudeucitinib twice daily achieved maximal (90% inhibitory concentration [IC(90)]) TYK2 inhibition over 24 h, highlighting a level of sustained target engagement that distinguishes envudeucitinib from other oral immunomodulators. Envudeucitinib decreased type I IFN gene signatures in whole blood and pSTAT1 in T cells. These findings were corroborated in a phase 2 study in adults with moderate-to-severe plaque psoriasis; envudeucitinib showed maximal TYK2 inhibition at higher doses (40-80 mg daily), patients demonstrated significant and increasing efficacy responses through week 52, and the safety profile was favorable. The efficacy and safety of envudeucitinib are being further evaluated in the ongoing phase 3 ONWARD studies. Psoriasis, an inflammatory disease that develops when the immune system is overactive in the skin, impacts more than 40 million people globally. Patients with psoriasis have red, scaly, itchy skin plaques and high levels of inflammatory molecules in the blood. Many patients do not receive adequate treatment, highlighting the need for more effective and safer oral therapies. We describe how a new potential oral medicine for psoriasis, envudeucitinib, works. Envudeucitinib targets the tyrosine kinase 2 (TYK2) protein that is involved in the inflammation process associated with psoriasis. When taken twice daily, envudeucitinib achieved strong and sustained inhibition of TYK2 for a full 24 h, which is a distinguishing feature of this therapy. Selective reduction of TYK2 activity, while avoiding effects on other related proteins, may allow for more targeted adjustment of inflammatory signaling associated with psoriasis and may translate to clinical benefit. In early studies, envudeucitinib taken orally twice daily markedly reduced TYK2 activity and the levels of other inflammatory molecules over a 24-h period. These findings were confirmed in a phase 2 study in patients with psoriasis, where envudeucitinib again reduced TYK2 activity. Patients with psoriasis taking envudeucitinib had significant improvements in their skin after 12 weeks of treatment, and these improvements were sustained or continued to improve through 52 weeks of treatment without notable side effects. In summary, envudeucitinib is a new potential oral medication for psoriasis that reduces inflammation with an acceptable safety profile.

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

OBJECTIVE: The 52-week, phase 3b/4 PSORIATYK SCALP (NCT05478499) trial evaluated deucravacitinib efficacy and safety in scalp psoriasis, including patients with more limited overall psoriasis. Here, we report week 16 results.

METHODS: Adults with moderate to severe scalp psoriasis and body surface area involvement ≥ 3% were randomized 1:2 to placebo (n = 51) or deucravacitinib 6 mg once daily (n = 103) through week 16. The primary efficacy endpoint was scalp-specific Physician Global Assessment score of 0/1; key secondary endpoints were Psoriasis Scalp Severity Index 90, scalp-specific numeric rating scale itch score, and static Physician Global Assessment (sPGA) 0/1.

RESULTS: In the overall population, scalp-specific Physician Global Assessment score of 0/1 (48.5% vs 13.7%; P < .0001), Psoriasis Scalp Severity Index 90 (38.8% vs 2.0%; P < .0001), and mean change from baseline in scalp-specific numeric rating scale itch (-3.2 vs -0.7; P < .0001) were superior with deucravacitinib versus placebo. In the sPGA ≥ 3 subpopulation, sPGA 0/1 was superior with deucravacitinib (51.0% vs 4.3%; P < .0001). Adverse events were comparable between groups.

LIMITATIONS: 16-week analysis.

CONCLUSION: Deucravacitinib was efficacious and well tolerated in patients with moderate to severe scalp psoriasis.

BACKGROUND AND OBJECTIVES: Vitiligo is challenging to treat and may have a substantial impact on quality of life. Despite the exponential growth in the development of new "traditional" vitiligo treatments, many vitiligo patients choose to employ medical products and practices that are used with or instead of standard medical care (complementary and alternative medicine or CAM). In this study, CAMs and camouflage were discussed together and referred to as over-the-counter products (OTCs). Using an observational cross-sectional study, we aimed to investigate the motivations and demographic factors of individuals with vitiligo who use OTCs, to identify the most utilized OTCs in this population, and to assess side effects and perceived efficacy of the utilized OTCs.

METHODS: We performed an international observational cross-sectional study between July 2021 and June 2022. An anonymous digital questionnaire was distributed to adults (aged ≥ 18 years) who had been diagnosed with vitiligo by a healthcare provider via e-mails from the Global Vitiligo Foundation to vitiligo support groups and through postings on the MyVitiligoTeam social media network. Participants were presented with a predefined list of OTC products and an open-ended option was also provided.

RESULTS: Of the 224 respondents, half were aged 45-64, most were female (69.6%), and the majority were White (56.3%). A total of 41.1% of participants used OTCs, either exclusively (19.2%) or with prescribed therapies (22%), while 58.9% used only prescribed therapies. The top reasons for using OTCs were dissatisfaction with conventional therapy, concerns about side effects, inconvenience, and cost. The most commonly used OTCs were camouflage, Vitamin B12, Vitamin D, zinc, ginkgo biloba, and vitamin C. Camouflage was reported as the most helpful OTC. Mild side effects were reported by 6.3% of users.

CONCLUSION: This study highlights the widespread use of OTCs in managing vitiligo, emphasizing the need for healthcare providers to be familiar with commonly used OTCs. Patients using OTCs raised concerns about conventional treatments, which should be considered in management discussions and drug development. Camouflage was the most beneficial OTC in this study, and it should be included in management plans. A better understanding of OTCs could improve treatment strategies and patient satisfaction.

IMPORTANCE: There is no international consensus on defining vitiligo severity or relapse. Current measures (such as body surface area) quantify depigmentation but do not fully capture the broader clinical and psychosocial effects of the disease.

OBJECTIVE: To develop internationally agreed-upon definitions and criteria for vitiligo severity and relapse as part of the International Consensus on Definition of Severity and Relapse in Vitiligo study.

EVIDENCE REVIEW: This global, mixed-methods consensus study used a multistep approach, including comprehensive literature review, qualitative study, 2 rounds of electronic Delphi surveys, and a final consensus meeting. To ensure adequate diversity and inclusivity and to capture a broad range of experiences, perspectives, social contexts, and representation, a recruitment framework (encompassing variation in age, sex, and skin phototypes) was predefined.

FINDINGS: In total, 91 people from 5 continents expressed interest in participating. Experts (dermatologists, trialists, methodologists, nurses, psychologists, journal editors, and researchers) and people with vitiligo from diverse ethnic backgrounds and skin phototypes took part. During the first electronic Delphi survey round, 85 people participated and 81 participated in round 2 (response rate of 95% in each survey round). Consensus was reached that even though measurement of body surface area remains a necessary and adequate starting point for assessing vitiligo severity, this measure alone is insufficient to capture disease burden. The final consensus meeting included 44 participants (response rate of 54%). Twelve criteria for upgrading severity were recommended, encompassing both clinical aspects of vitiligo and its psychosocial effects. The major criteria for vitiligo include spread or active disease, involvement of highly visible or high-impact areas, psychological distress, stigmatization, lack of self-acceptance, and overall burden. The minor criteria for vitiligo include darker skin tones, younger age, involvement of scalp/facial hair, increased risk of sunburn, impact on career or school, and perceived loss of personal or cultural identity. No consensus was reached on the extent of pigment loss. Relapse was defined as loss of pigmentation in previously repigmented lesions (repigmentation had occurred either spontaneously or with treatment).

CONCLUSION AND RELEVANCE: This global, mixed-methods consensus study established internationally agreed-upon severity criteria for vitiligo. This consensus aims to bridge the gap between physician assessment and patient experience; improve the relevance and consistency of the severity classification in clinical care, research, and regulatory frameworks; and help close the remaining gaps in the diagnosis and classification of vitiligo.

Conventional type 1 dendritic cells (cDC1s) are specialized for cross-presenting tumor antigens and determining the efficacy of immunotherapies, including immune checkpoint blockade and adoptive cell therapy. However, their rarity and tumor-induced dysfunction severely limit CD8 T cell priming and represent a central bottleneck to therapeutic efficacy. While strategies such as anti-DEC-205-mediated antigen delivery and Flt3L-driven DC expansion can enhance host DC function, their reliance on functional cDC1s remains a significant constraint. We developed Tim-3-targeted vaccines by conjugating tumor antigens or neoantigens to anti-Tim-3 antibodies. These vaccines delivered antigens to both cDC1s and cDC2s, and elicited robust, durable CD8 T cell responses. Remarkably, Tim-3-targeted vaccines endowed cDC2s with efficient cross-presentation capacity that matched that of cDC1s. In tumor-bearing mice or in CD11c-β-catenin(active) mice, which model β-catenin-driven DC dysfunction, Tim-3-targeted vaccination restored cross-priming and counteracted tumor- and DC-mediated immunosuppression. In Batf3(-/-) mice lacking cDC1s, anti-Tim-3-based vaccines still elicited significant CD8 T cell cross-priming and tumor control-albeit both were reduced compared to wild-type mice- demonstrating that cDC1s contribute to but are not essential for Tim-3-targeted vaccine-induced CD8 T cell priming and anti-tumor efficacy. Strikingly, a single dose of anti-Tim-3-neoantigen vaccination eradicated large established MC38 tumors in a CD8 T cell-dependent manner. Together, these data identify Tim-3-targeted vaccines as a next-generation cancer vaccine platform that broadens DC engagement, reduces reliance on cDC1s, and overcomes tumor- and DC-mediated immunosuppression, addressing key limitations of current DC-based cancer vaccines.

BACKGROUND: Vitiligo is a multi-factorial autoimmune skin disorder often triggered by environmental exposures. Although the exposome has gained attention, no systematic review has fully assessed its role in vitiligo.

OBJECTIVE: We aimed to evaluate evidence linking exposomal factors to vitiligo onset and progression, focusing on quantifiable associations and study quality.

METHODS: A systematic search of PubMed and Embase (inception to 25 August, 2024) followed PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) 2020 guidelines and was registered in PROSPERO (CRD42024529828). Eligible studies reported associations between environmental exposures and vitiligo onset, flares, or progression. Observational studies, case series, clinical trials, and pharmacovigilance reports were included. Findings were synthesized narratively.

RESULTS: Of 8377 records, 496 studies met inclusion criteria. Drug-associated vitiligo, particularly from immune checkpoint inhibitors, was the most robustly supported association (7-25% in patients with melanoma). Phenol-based chemicals were consistently linked to melanocyte toxicity. Coronavirus disease 2019 infection modestly increased risk (hazard ratio ≈ 1.11), while vaccination did not. Other factors such as stress (n = 113), trauma, sunburn, smoking, diet, and sleep were frequently cited but supported by lower-level evidence. Study heterogeneity, a lack of standardized outcomes, and the predominance of observational designs limited meta-analysis and causal inference.

CONCLUSIONS: These findings highlight the environmental triggers of vitiligo onset and progression. Drugs, chemicals, and infections are key triggers; lifestyle factors require further study.

The loss of major histocompatibility complex class I (MHC-I) molecules has been proposed as a mechanism for cancer immune evasion. Nevertheless, the mechanism is poorly understood. We report here that membrane-associated RING-CH-type finger 8 (MARCHF8), upregulated by human papillomavirus (HPV), ubiquitinates and degrades MHC-I in HPV-positive head and neck cancer (HPV+ HNC). Inhibiting MARCHF8 restores MHC-I levels on HPV+ HNC cells, suppresses tumor growth, and increases the infiltration of natural killer (NK) and T cells in the tumor microenvironment. Furthermore, Marchf8 knockout markedly increases cross talk between cytotoxic NK cells and CD8(+) T cells with macrophages and enhances the tumor-killing activity of CD8(+) T cells. Interestingly, Marchf8 knockout, in combination with anti-PD-1 treatment, further enhances tumor suppression and increases NK and T cell infiltration in mice bearing immune checkpoint inhibitor-refractory tumors. Our findings suggest that MARCHF8 could be a promising target for immunotherapy for HPV+ HNC patients.

Lung adenocarcinoma (LUAD), the most common subtype of non-small cell lung cancer (NSCLC), frequently relies on epigenetic plasticity to support growth, stress adaptation, and therapeutic escape. Among the chromatin mechanisms enabling this plasticity, histone variant exchange is central. Incorporation of specific variants reshapes DNA accessibility and transcriptional programs, underpinning cancer cell adaptability. VPS72, a histone chaperone shared by the SRCAP and TIP60 complexes, mediates ATP-dependent deposition of the H2A.Z-H2B dimer into regulatory chromatin, thereby promoting proliferation, lineage state, immune evasion, and treatment tolerance transcriptional programs. H2A.Z deposition is linked to aggressive malignancy; however, the contribution of VPS72 itself to LUAD progression remains undefined. Given its central role in H2A.Z loading, the VPS72-H2A.Z axis may represent a key epigenetic driver and potentially targetable vulnerability. TCGA LUAD datasets were analyzed to profile VPS72 expression, genomic correlates, and functional relevance. VPS72 was significantly upregulated relative to normal tissue and associated with greater genomic instability, higher tumor mutational burden, stronger hypoxia signatures, earlier clinical detectability, and reduced overall survival. High VPS72 expression was also observed in female patients and ever-smokers, indicating exposure-linked modulation. Functional evaluation in LUAD models showed that genome-wide CRISPR and RNAi screens identified VPS72 as a major fitness gene. shRNA-mediated VPS72 depletion reduced proliferation and Ki-67 expression, reduced colony formation, impaired migration and invasion, and abrogated anchorage-independent growth. Transcriptional profiling revealed that VPS72 loss strongly repressed MYC- and E2F-driven cell-cycle programs and disrupted metabolic pathways, including heme biosynthesis, mitochondrial respiration, calcium signaling, and hypoxia adaptation. Although H2A.Z itself is not directly targetable, VPS72 role in its deposition creates a druggable interface. To exploit this, we developed cell-permeable peptides that block the VPS72-H2A.Z interaction, which phenocopied VPS72 knockdown by inducing apoptosis and suppressing LUAD cell growth in a dose-dependent manner. Collectively, these findings identify VPS72 as a central epigenetic regulator and therapeutically actionable vulnerability in LUAD. Disrupting the VPS72-H2A.Z axis attenuates oncogenic transcriptional programs and malignant behaviors, offering a promising strategy to overcome epigenetic plasticity and treatment resistance in aggressive NSCLC.

Introduction: Hand involvement in atopic dermatitis (AD) causes particular physical and psychological burden and has limited treatment options. Tralokinumab showed efficacy and safety in moderate-to-severe AD. ADHAND (NCT05958407) is a phase 3b randomized, 32-week trial of AD patients with moderate-to-severe hand involvement (HandAD). To investigate the efficacy and safety of tralokinumab treatment during the 16-week double-blind period in HandAD patients. Methods: 235 patients were randomized 2:1 to receive tralokinumab 300 mg or placebo (PBO) Q2W. Inclusion criteria were: Investigator's Global Assessment for Atopic Hand Eczema (IGA-AHE) score 3 or 4; Hand Eczema Symptom Diary (HESD) itch score ≥4; inadequate response to topical medications; AD involvement of ≥1 location other than hands/wrists. The primary endpoint was the proportion achieving IGA-AHE 0/1 at Week 16. Key secondary endpoints included proportions achieving Hand Eczema Severity Index (HECSI)-90/-75, and ≥4-point reductions in HESD itch/pain scores at Week 16. Results: At Week 16, significantly more patients receiving tralokinumab (40.0% of 156 [95% CI: 31.3;49.4]) vs PBO (10.6% of 79 [5.0;20.9]) achieved IGA-AHE 0/1. The proportions of participants achieving HECSI-90/-75 were 41.7% [33.0;50.9] / 64.1% [55.3;72.0]. ≥4-point reductions in HESD itch and HESD pain were observed in nearly half of patients receiving tralokinumab. Rates of reported adverse events (AEs), serious AEs, and AEs leading to withdrawal from trial were low and similar between tralokinumab and PBO. Conclusions: Tralokinumab demonstrated superior efficacy vs PBO across all primary and key secondary endpoints at 16 weeks, with an overall frequency of AEs consistent with PBO, in HandAD patients, offering tralokinumab as a potentially valuable treatment option for this hard-to-treat population.

Background: Lebrikizumab (LEB), a high-affinity IL-13 inhibitor, demonstrated stability of response up to 2 years as monotherapy treatment in adults&adolescents (≥ 40 kg) with moderate-to-severe atopic dermatitis (AD) from the pivotal phase 3 trials (ADvocate1, NCT04146363; ADvocate2, NCT04178967; ADjoin, NCT04392154). Methods: Here, we assessed the stability of response up to 3 years of LEB treatment in responder patients at Week (W) 16 after the induction with LEB Q2W, who were re-randomized to LEB Q2W or Q4W for 36W maintenance period in ADvocate1 and 2, and continued the same treatment (LEB Q2W, n = 82; LEB Q4W, n = 99) in ADjoin, the LEB long-term extension study up to 3 years. Response at W16 was defined as IGA 0/1 or EASI 75 without rescue medication in ADvocate1 and 2. Topical rescue medications were permitted during the analysis period (in W16-152). This analysis reported the proportion of LEB-treated patients who maintained EASI 75 (in W16 EASI 75 responders) and absolute EASI ≤ 7 response (in W16 EASI ≤ 7 responders), at individual level, in ≥ 80% of attended visits from W16-152. Pruritus Numeric Rating Scale (PNRS) was collected up to W104. Proportion of LEB-treated patients who achieved PNRS ≥ 3-point improvement among W16 EASI 75 responders, and maintained the PNRS response in ≥ 80% of attended visits from W16-104 was reported. Observed data was analyzed regardless of rescue medication use or discontinuation from treatment. Results: A stable EASI 75 response from W16-152 was reported in 92.9% of patients receiving LEB Q4W and 92.7% for LEB Q2W. A stable EASI ≤ 7 response from W16-152 was achieved for 96.8%, receiving LEB Q4W and 97.3% for LEB Q2W. In patients with baseline PNRS ≥ 3, achieving EASI 75 and PNRS ≥ 3-point improvement at W16, a stable PNRS ≥ 3-point improvement from W16-104 was achieved by 93.8% (N = 65) of patients receiving LEB Q4W and 88.7% (N = 62) for LEB Q2W. During ADjoin (W52-152) the use of low-moderate and high potency topical corticosteroids (TCS) was 9.1% (n = 9) in both TCS potency categories for LEB Q4W, whereas for LEB Q2W was 4.9% (n = 4) and 6.1% (n = 5), respectively. Conclusions: LEB provides long-term stability in skin response and itch relief with no or minimal fluctuations measured by EASI 75, EASI <7 and PNRS.

Rationale: Roflumilast cream demonstrated efficacy and safety for atopic dermatitis (AD) in ≥2-year-olds in randomized, vehicle-controlled, 4-week, phase 3 trials (INTEGUMENT-1/2; INTEGUMENT-PED). A phase 3, open-label extension (OLE) trial (INTEGUMENT-OLE [NCT04804605]) investigated long-term outcomes. Methods: Patients who completed INTEGUMENT-1/2 or INTEGUMENT-PED (parent studies) could enroll in INTEGUMENT-OLE; roflumilast cream 0.15%/0.05% (≥6/2–‍5 years) was applied once daily for ≤52 weeks. Patients achieving Validated Investigator Global Assessment for AD (vIGA-AD) 0 (clear) at/after OLE week 4 transitioned to proactive twice-weekly (BIW) application, which was continued as long as ‘disease control’ (vIGA-AD 0/1 [clear/almost clear] and adequate AD sign/symptom control) was maintained. vIGA-AD, Eczema Area and Severity Index (EASI), mean body surface area affected (BSA), and safety were assessed. Results: At OLE week 52, vIGA-AD 0/1 rates were 55.7% (117/210) and 63.1% (234/371) for INTEGUMENT-1/2 and INTEGUMENT-PED groups, respectively; mean EASI (10.45 to 2.79; 12.18 to 2.59) and mean BSA (14.8% to 3.7%; 22.3% to 4.9%) decreased from parent-study baseline. At/after OLE week 4, 19.8% (130/658) and 30.2% (170/562) of patients in respective groups transitioned to BIW application with median durations of ‘disease control’ of 281 and 238 days (Kaplan-Meier estimates). Treatment-related adverse events were reported for 4.7% and 2.5% of patients from INTEGUMENT-1/2 and INTEGUMENT-PED, respectively, and application-site pain adverse events for <1% of patients overall. Conclusions: Roflumilast cream was well tolerated and provided long-term decreases in AD signs/symptoms for patients aged ≥2 years, supporting the use of roflumilast cream for long-term AD control, including proactive BIW application, without topical corticosteroids.

Rationale: APG777 is the first half-life-extended anti-IL-13 antibody to be evaluated in atopic dermatitis (AD). As AD is often associated with comorbid type 2 inflammatory diseases, we evaluated APG777 in patients with AD with and without evidence of asthma and sinonasal conditions in the phase 2 APEX Part A study (NCT06395948). Methods: Adults (N=123) with moderate-to-severe AD were randomized 2:1 to APG777 (720mg Day 1, Week 2; 360mg Weeks 4, 12) or placebo. For this post-hoc, as-observed analysis, treatment comparisons in participants with and without evidence of type 2 comorbidities at baseline were assessed by the percentage achieving 75% improvement in the Eczema Area and Severity Index (EASI-75) at Week 16. Results: Treatment with APG777 led to an overall EASI-75 response rate of 74.7% (n=56/75) at Week 16 (vs. 26.3% [n=10/38] placebo; p<0.001). Among participants with a history of asthma and/or sinonasal conditions, 71.1% (n=27/38) of APG777-treated participants achieved EASI-75 at Week 16 (vs. 36.8% [n=7/19] placebo). Similarly, among participants without a history of asthma and sinonasal conditions, more APG777- vs. placebo-treated participants achieved EASI-75 (78.4% [n=29/37] vs. 15.8% [3/19]). EASI-75 response rates were also greater with APG777 vs. placebo for subgroups with baseline BEC≥300 cells/μL (71.1% vs. 19.0%), BEC<300 cells/μL (78.4% vs. 35.3%), IgE≥100 IU/mL (76.4% vs. 32.0%), and IgE<100 IU/mL (70.0% vs. 15.4%). No new safety signals were detected in patients with or without asthma and sinonasal conditions. Conclusions: Treatment with APG777 was well-tolerated and provided clinically meaningful improvements in AD signs and symptoms, regardless of coexisting type 2 inflammatory conditions.

Rationale: Ruxolitinib (Janus kinase [JAK]1/JAK2 inhibitor) cream has demonstrated effectiveness and tolerability in patients with atopic dermatitis (AD) as young as 2 years of age. This analysis of ruxolitinib cream safety in pediatric patients with AD investigated concerns arising from a systemic pan-JAK inhibitor in older adults with rheumatoid arthritis (major adverse cardiovascular events [MACE], malignancy, serious infections, thromboembolic events, and mortality), other AD topical therapies (acne, application site reactions, contact dermatitis, diarrhea, folliculitis, headache, and nausea), and AD (herpes zoster). Methods: Exposure-adjusted incidence rates (EAIRs; number of patients experiencing the event per 100 patient years [PY]) over time were determined in pediatric patients (aged 2−17 y) with AD who applied twice-daily ruxolitinib cream for up to 1 year across 8 clinical trials. Results: Of 461 children and adolescents with AD who applied 1.5% ruxolitinib cream over 304.98 PY, adverse events (AEs) associated with systemic JAK inhibition were not reported (no MACE, thromboembolic events, malignancies, or fatalities) or were infrequent and considered by the investigator as not related to treatment (serious infection EAIR, 0.66). EAIRs associated with other topical AD treatments or AD were low (acne, 0.98; application site reactions, 4.59; contact dermatitis, 1.31; diarrhea, 3.61; folliculitis, 0.66; headache, 3.61; herpes zoster, 0.33; and nausea, 0.98). EAIRs generally remained low over time. Conclusions: AEs associated with systemic JAK inhibition were not reported or rare and considered unrelated to ruxolitinib cream. Rates of AEs associated with other topical therapies or AD were low and stable over time.

Background: The “itch-scratch-inflammation” cycle drives atopic dermatitis (AD) development and persistence. Targeting IL-13 and IL-31 signaling disrupts this cycle and has been clinically validated. ZL-1503, a bispecific antibody with an extended serum half-life, effectively inhibits IL-13 and IL-31 signaling in vitro and in vivo in rodent studies. Method: ZL-1503 was evaluated in a pilot study with three non-human primates (NHP) to assess its long-term effects on IL-31-mediated scratching and IL-13-induced pSTAT6. Baseline scratching was established with IL-31 injection prior to ZL-1503 dosing. Results: An intravenous single dose of ZL-1503 completely inhibited IL-13-mediated pSTAT6 and IL-31-induced scratching for at least 76 days in all three animals. Two out of the three animals exhibited prolonged IL-13-mediated pSTAT6 inhibition for over 118 days, and one out of the 3 animals sustained IL-31-induced scratching inhibition for over 115 days. Pharmacokinetic (PK) analysis of serum samples collected during the study revealed that ZL-1503 exhibited slow clearance, ranging from 1.42 to 2.52 mL/day/kg. ZL-1503 serum exposures correlated very closely with the PD responses. Additionally, in vitro studies showed that binding to one target did not affect ZL-1503's blocking effects on the other target. These findings demonstrate strong PK/PD relationships of ZL-1503 in blocking IL-13 and IL-31 in the NHP model. Conclusion: ZL-1503 exhibited sustained inhibition of inflammatory and pruritogenic pathways in NHP, supporting its progression to IND-enabling studies as a potential treatment for moderate-to-severe AD, and other IL-13 and IL-31-driven diseases.

Objectives: Evaluate the efficacy of roflumilast foam 0.3% to improve scalp symptoms and reduce extent of scalp involvement (ESI) in patients with psoriasis involving the scalp and body. Methods: In the phase 3 ARRECTOR/NCT05028582 trial, patients aged ≥ 12 years with psoriasis of the scalp and body (body surface area affected ≤ 25%, ≥ 10% ESI, at least moderate [≥ 3] Scalp-Investigator Global Assessment [S-IGA], at least mild [ ≥ 2] Body-IGA [B-IGA]) applied roflumilast foam 0.3% or vehicle foam once daily for 8 weeks. Co-primary endpoints were S-IGA and B-IGA success (clear/almost clear [0/1] plus ≥ 2-grade improvement). Secondary endpoints included S-IGA 0, ≥ 75% improvement in Psoriasis Scalp Severity Index (PSSI-75), and ESI over time. Results: Significantly higher proportions of patients randomized to roflumilast (n=281) versus vehicle (n=151) achieved S-IGA success (each P<0.0001) at weeks 2 (30.4% vs 11.7%), 4 (53.8% vs 19.5%), and 8 (66.4% vs 27.8%) and S-IGA 0 (9.0% vs 1.5%; 27.5% vs 3.8%; 40.0% vs 9.1%, respectively; each P ≤ 0.0055). Mean ESI decreased more from baseline to week 8 with roflumilast (34.4% to 9.3%) than vehicle (36.0% to 27.3%). The proportion of patients with ESI 0 increased over time with significantly more achieving this endpoint (each P<0.01) with roflumilast versus vehicle at both week 2 (9.8% vs 1.4%) and week 8 (43.0% vs 10.3%). A higher proportion of patients in the roflumilast than vehicle group achieved PSSI-75 at week 8 (70.9% vs 31.3%; P<0.0001). Topical roflumilast was well tolerated and safety was consistent with previous trials. Conclusions: Roflumilast foam 0.3% significantly reduced scalp symptom severity and ESI, compared with vehicle, including complete clearance of plaques on the scalp in many patients. The favorable safety profile and topical formulation make roflumilast foam 0.3% a compelling non-systemic alternative for patients with moderate-to-severe psoriasis involving the scalp and body, who may otherwise receive systemic therapy.

Objectives: Hidradenitis suppurativa (HS), a chronic inflammatory skin disease with debilitating symptoms, significantly impacts patients’ quality of life and work productivity.1 Bimekizumab (BKZ) is a humanised IgG1 monoclonal antibody that selectively inhibits interleukin (IL)-17F in addition to IL-17A.2 This publication demonstrates how long-term BKZ treatment of patients with moderate to severe HS impacts work productivity. Methods: Patients randomised to BKZ from baseline in BE HEARD I&II and who entered their open-label extension (OLE), BE HEARD EXT, were pooled (BKZ Total; OLE set).3,4 Patients completed the Work Productivity and Activity Impairment (WPAI) Questionnaire at various timepoints that included baseline, Week48 and Week96. For the domains, the percentage of overall work impairment, impairment while working (presenteeism), work time missed (absenteeism) and activity impairment were calculated: mean absolute scores are reported; higher scores indicate greater impairment.5 All domains except activity impairment were answered only by patients who were employed. Data are reported as observed case. Results: 556 patients randomised to BKZ at baseline in BE HEARD I&II completed Week48 and entered BE HEARD EXT. BKZ Total patients reported an improved (reduced) mean (SD;n) overall work impairment score over 48 weeks, which was sustained to Week96 (baseline: 29.6%[27.4;338]; Week48: 14.6%[20.4;408]; Week96: 16.0%[20.8;309]). Similarly, improvements in presenteeism (baseline: 28.7%[26.4;338]; Week48: 12.6%[18.1;408]; Week96: 12.5%[17.7;309]) and activity impairment (baseline: 39.9%[28.6;551]; Week48: 16.5%[21.3;555]; Week96: 17.1%[21.8;439]) were also observed. Absenteeism remained consistently low over 96 weeks (baseline: 5.5%[18.8;349]; Week48: 4.8%[17.3;415]; Week96: 5.6%[17.6;314]). Conclusions: In patients with HS treated with bimekizumab, 1-year improvements in work productivity which included overall work impairment, presenteeism and activity impairment, were maintained to 2 years; absenteeism remained low. References: 1. Zouboulis CC et al. 2015;231:184-90; 2. Adams R et al. 2020;11:1894; 3. Kimball AB et al. 2024 (NCT04242446, NCT04242498); 4. BE HEARD EXT: www.clinicaltrials.gov/study/NCT04901195 (NCT04901195); 5. Zhang W et al. 2010;12:R177.