BACKGROUND:Icotrokinra, a targeted oral peptide, precisely blocks the interleukin-23 receptor. In two phase 3 moderate-to-severe plaque psoriasis trials, ICONIC-ADVANCE 1 (NCT06143878) and ICONIC-ADVANCE 2 (NCT06220604), icotrokinra provided significantly higher skin clearance rates versus placebo at Week 16 and deucravacitinib at Week 16 and 24. OBJECTIVES:Report findings through Week 52 of ICONIC-ADVANCE 1&2. METHODS:ICONIC-ADVANCE 1&2 randomised (2:1:2/4:1:4) adults with moderate-to-severe plaque psoriasis (body surface area ≥10%, Psoriasis Area and Severity Index [PASI] ≥12, Investigator's Global Assessment [IGA] ≥3) to icotrokinra 200 mg, placebo (transition to icotrokinra at Week 16), or deucravacitinib 6 mg once daily (transition to icotrokinra at Week 24). Outcomes assessed through Week 52 included proportions of participants achieving IGA 0/1 (with ≥2-grade improvement from baseline), PASI 90, IGA 0, PASI 100, scalp-specific IGA (ss-IGA) 0/1, patient-reported outcomes (clinically meaningful improvement [CMI; ≥4-point reduction] in Psoriasis Symptoms and Signs Diary [PSSD] itch, PSSD symptom score 0, Dermatology Life Quality Index [DLQI] 0/1), and adverse events (AEs). RESULTS:ICONIC-ADVANCE 1&2 randomised 1505 participants (774/731). Across the studies, skin clearance rates among icotrokinra-randomised participants increased through Week 24 and were durable through Week 52, with ∼70%-75% exhibiting clear/almost clear skin (IGA 0/1, PASI 90) and ∼50% demonstrating completely clear skin (IGA 0, PASI 100) during Weeks 24-52. Among participants achieving clear/almost clear skin at Week 16, ∼85%-90% maintained response at Week 52. Response rates for ss-IGA 0/1 and patient-reported outcomes were also durable through Week 52. Participants who transitioned from placebo or deucravacitinib to icotrokinra exhibited increasing response rates that were comparable to icotrokinra-randomised participants through Week 52. The AE profile of icotrokinra was similar to placebo through Week 16 and showed lower AE rates than deucravacitinib through Week 24; no safety signals were observed through Week 52. CONCLUSIONS:Once-daily icotrokinra provided robust, durable skin clearance and symptom improvement, with no safety signals, through Week 52 in adults with moderate-to-severe plaque psoriasis. Participants transitioning from placebo or deucravacitinib to icotrokinra achieved similar increased response rates to icotrokinra-randomised participants through Week 52. Findings support icotrokinra as a systemic therapy with long-term robust disease control and a favourable safety profile.

Mas-related G protein-coupled receptor X2 (MRGPRX2) levels are elevated in patients with atopic dermatitis (AD). EP262, a small-molecule MRGPRX2 receptor antagonist, significantly diminished AD development in humanized mouse models of AD. In the EASE study, the safety, tolerability, and pharmacodynamics of EP262 were compared with placebo in patients with AD. Patients aged 18–80 years with AD, 3

Mas-related G protein-coupled receptor X2 (MRGPRX2) levels are elevated in patients with atopic dermatitis (AD). EP262, a small-molecule MRGPRX2 receptor antagonist, significantly diminished AD development in humanized mouse models of AD. In the EASE study, the safety, tolerability, and pharmacodynamics of EP262 were compared with placebo in patients with AD. Patients aged 18–80 years with AD, 3

Chronic hand eczema (CHE) is a relatively common skin disease that is associated with substantial personal and societal burden, including work disability and psychosocial impairment. The etiopathogenesis of CHE is heterogeneous and multifactorial, and although it is an area of active research, it remains incompletely understood. Methods to investigate the etiopathogenesis of CHE have largely been adopted from other skin diseases to examine gene expression, proteomics, and skin barrier integrity. Tape stripping has emerged as a practical and noninvasive method to study differences in transcriptomics that is less painful and more convenient than the gold standard, skin punch biopsy. Studies have suggested broad activation of immune pathways in CHE, including key Th1, Th2, Th17, and Th22 cytokines. In parallel, there are indications of broad skin barrier dysfunction in CHE including downregulation of barrier proteins. There is a dearth of high-quality evidence on etiopathological differences between CHE subtypes, and this remains an area of research need to identify new targets for treatment.

BACKGROUND:Patients with psoriasis affecting a low percentage of their body surface area (BSA) are under-represented in clinical studies and may face substantial disease burden if high-impact sites are affected. OBJECTIVES:To evaluate in a phase IIIb randomized placebo-controlled study (SPECTREM; NCT06039189) the efficacy and safety of guselkumab in participants with low BSA (2-15%), moderate [Investigator's Global Assessment (IGA) = 3] plaque psoriasis involving one or more high-impact site (scalp, face, genitals, intertriginous areas). METHODS:Eligible participants were randomized 2 : 1 to receive guselkumab 100 mg or placebo at week 0 and week 4, then every 8 weeks. The primary endpoint was the proportion of participants achieving IGA 0/1 (cleared/minimal) at week 16. Major secondary endpoints included the proportion of participants achieving ≥ 90% improvement in Psoriasis Area and Severity Index (PASI 90), IGA 0 and 100% improvement in PASI (PASI 100); mean percentage improvements from baseline to week 16 in BSA and PASI; and proportions of participants achieving site-specific IGA or Physician's Global Assessment (PGA) 0/1 among those with scalp, facial, genital or intertriginous site-specific IGA/PGA ≥ 3 at baseline. RESULTS:Among the 338 randomized participants (guselkumab, n = 225; placebo, n = 113), mean (SD) baseline BSA was 7.6% (3.7) and PASI was 9.0 (3.8). At week 16, all primary and major secondary endpoints were met, with guselkumab demonstrating superiority vs. placebo (all P < 0.001) in the proportions of participants achieving IGA 0/1 (74.2% vs. 12.4%), IGA 0 (40.4% vs. 3.5%), PASI 90 (52.9% vs. 6.2%) and PASI 100 (32.4% vs. 2.7%), and mean percentage improvement from baseline in BSA (80.6% vs. 6.1%) and PASI (82.6% vs. 13.7%). Site-specific IGA/PGA 0/1 response rates for guselkumab vs. placebo were as follows: scalp 75.0% (n = 114/152) vs. 14.5% (n = 11/76); face 87.8% (n = 79/90) vs. 28.6% (n = 12/42); genital 78.0% (n = 64/82) vs. 37.5% (n = 15/40) and intertriginous 86.5% (n = 96/111) vs. 28.8% (n = 15/52). In the guselkumab and placebo groups, respectively, 37.8% and 39.8% experienced one or more adverse event; no new safety signals were identified. CONCLUSIONS:Through week 16, guselkumab was effective and well tolerated in participants with low BSA, moderate plaque psoriasis with involvement of high-impact sites. Statistically significant improvements across multiple clearance measures, irrespective of baseline BSA, support the effectiveness of guselkumab across a broad range of patients.

Icotrokinra, a first-in-class targeted oral peptide, precisely blocks the interleukin (IL)-23 receptor and inhibits IL-23 pathway signaling. In phase 3 studies (ICONIC-LEAD, ICONIC-TOTAL, ICONIC-ADVANCE 1 and 2), icotrokinra provided superior skin clearance versus placebo and deucravacitinib in adults and adolescents with moderate-to-severe psoriasis and psoriasis affecting high-impact sites. This analysis evaluates icotrokinra safety through 1 year using pooled data from these four studies. Icotrokinra-randomized participants received 200-mg pills once daily, and placebo-randomized participants crossed over to icotrokinra at week 16; participants randomized to deucravacitinib 6 mg (ICONIC-ADVANCE 1 and 2 only) switched to icotrokinra at week 24. Pooled safety data are summarized for the placebo-controlled period (week 0–16, all studies), active-controlled period (week 0–24, ICONIC-ADVANCE 1 and 2), and through week 52 (all studies). During the placebo-controlled period across all studies, 568 participants received placebo and 1296 received icotrokinra. From week 0 to 24 in the ICONIC-ADVANCE studies, 632 participants received icotrokinra and 634 received deucravacitinib. Through week 52, 2400 icotrokinra-treated participants contributed 1840 participant-years [PY] of follow-up. Through week 16, in the icotrokinra and placebo groups, respectively, exposure-adjusted incidence rates/100 PY of adverse events (AEs; 232 and 269), serious AEs (5.2 and 6.6), infections (91 and 104), and AEs leading to discontinuation (6.6 and 10.0) were comparable between groups. Through week 24, in the ICONIC-ADVANCE studies, rates/100 PY with icotrokinra versus deucravacitinib were as follows: AEs, 204 vs 265; serious AEs, 6.4 vs 7.2; infections, 81 vs 119; AEs leading to discontinuation, 5.7 vs 6.8. Through week 52, event rates/100 PY in icotrokinra-treated participants were as follows: AEs, 167; serious AEs, 4.6; infections, 76; AEs leading to discontinuation, 3.0. In this analysis of 2400 icotrokinra-treated participants with psoriasis followed through 1 year, icotrokinra demonstrated favorable safety; event rates through week 16 were similar to placebo and remained consistent through week 52. NCT06095115, NCT06095102, NCT06143878, NCT06220604. Infographic available for this article.

The gut microbiome of patients with chronic hand eczema (CHE) is different from healthy individuals and enriched in bacteria with immunomodulatory properties. These differences are more important for patients with nonatopic CHE, opening the door to microbiome-based therapeutic strategies in this patient population.Dear Editor, Chronic hand eczema (CHE) is a common, multifactorial and debilitating inflammatory skin disorder.1 A history of atopic dermatitis (AD) is found in only one-third of patients with CHE. Nonatopic CHE presents with distinct immunological features compared with atopic CHE.1,2In recent years, the concept of the 'gut-skin axis' has emerged, in which the gut microbiome could trigger or exacerbate inflammation in the skin by influencing the levels of metabolites, such as short-chain fatty acids (SCFA), bile acids, kynurenine, indoles and trimethylamine N-oxide, that can affect distant sites.3,4 The gut microbiome can also impair intestinal barrier integrity, leading to systemic immune activation through T helper (Th)1 and Th17 pathways.3 Disruption of the gut microbiome, also termed dysbiosis, has been associated with several inflammatory skin diseases, including AD, psoriasis, alopecia areata and hidradenitis suppurativa.4,5 However, composition of the gut microbiome has not yet been investigated in patients with CHE.

Mas-related G protein-coupled receptor X2 (MRGPRX2) levels are elevated in patients with atopic dermatitis (AD). EP262, a small-molecule MRGPRX2 receptor antagonist, significantly diminished AD development in humanized mouse models of AD. In the EASE study, the safety, tolerability, and pharmacodynamics of EP262 were compared with placebo in patients with AD. Patients aged 18–80 years with AD, 3

IntroductionAtopic dermatitis (AD), a chronic type 2 inflammatory disease, often requires long-term therapeutic intervention. Understanding the long-term safety profile of dupilumab treatment is crucial for clinicians and patients, especially regarding laboratory parameters.MethodsLIBERTY AD OLE, a phase 3, multicenter, open-label extension (OLE) study, evaluated clinical laboratory findings in adults with moderate-to-severe AD treated with dupilumab for up to 5 years.ResultsIn total, 2677 patients entered the OLE study. At the time of database lock, 238 patients completed up to week 272 and 1297 patients completed treatment or the end-of-study visit. There were no clinically meaningful changes from baseline values in mean hematology or serum chemistry parameters. Few laboratory abnormalities were reported as treatment-emergent adverse events (TEAEs), most of which were not serious and did not lead to permanent drug discontinuation. Five serious laboratory-related TEAEs occurred in one patient each (number of patients [nP]/100 patient-years [PY], 0.02): febrile neutropenia, hemolytic anemia, thrombocytopenia, hypokalemia, and hematuria. Six laboratory-related TEAEs led to permanent treatment discontinuation: one case each (nP/100 PY, 0.02) of increased alanine aminotransferase, increased aspartate aminotransferase, increased blood creatine phosphokinase, and increased transaminases and two cases of thrombocytopenia (nP/100 PY, 0.03); although rare, some were related to the study drug. Serious laboratory-related TEAEs and TEAEs leading to study discontinuation were generally lower in our study than in the placebo arm of the 1-year LIBERTY AD CHRONOS study, which was included for comparison. Most of these TEAEs were considered unrelated to the study drug and were recovered/resolved during the study period. No deaths due to laboratory-related TEAEs were reported.ConclusionsTreatment with dupilumab for up to 5 years showed no clinically meaningful changes in mean laboratory parameters. Continuous long-term use of dupilumab in adults with moderate-to-severe AD does not require laboratory testing before initiating or during the treatment.Trial RegistrationClinicalTrials.gov identifiers NCT01949311 and NCT02260986.

BACKGROUND:High-impact site plaque psoriasis is difficult to treat. Icotrokinra, an oral peptide with high specificity for the interleukin (IL)-23 receptor, demonstrated significantly higher rates of high-impact site psoriasis clearance, versus placebo, with no safety signals, through Week (W)16. OBJECTIVES:Report clinical response rates and safety through 1 year of icotrokinra treatment in participants with high-impact site plaque psoriasis. METHODS:Participants (≥12 years of age; psoriasis body surface area ≥1%; Investigator's Global Assessment [IGA] ≥2) with at least moderate scalp, genital or hand/foot psoriasis were randomized (2:1) to once-daily icotrokinra 200 mg (N = 208) or placebo (N = 103), with placebo-to-icotrokinra transition at W16 (N = 92). Rates (using nonresponder imputation) of achieving clear/almost clear (0/1) or clear (0) overall skin (IGA), genital (static Physician's Global Assessment of genitalia [sPGA-G]), hand/foot (hf-PGA) psoriasis and absent/very mild (0/1) or absent (0) scalp psoriasis (scalp-specific-IGA [ss-IGA]), modified Nail Psoriasis Severity Index (mNAPSI) percent improvement and safety were assessed through W52. RESULTS:Eighty-eight per cent (275/311) of participants completed treatment through W52. In icotrokinra-randomized participants, response rates increased through W24 and were durable through W52 for overall psoriasis clearance (IGA 0/1 range: 67%-70%) and across high-impact sites (ss-IGA 0/1: 72%-78%; sPGA-G 0/1: 85%-90%; hf-PGA 0/1: 54%-62%); responses were consistent among placebo-randomized participants after transitioning to icotrokinra. High proportions of icotrokinra-randomized participants achieved complete clearance during W24-52 (IGA 0: 44%-51%; ss-IGA 0: 57%-66%; sPGA-G 0: 73%-84%; hf-PGA 0: 44%-58%). Mean mNAPSI improvement increased from W16 (33%) to W52 (62%). Exposure-adjusted rates of participants with ≥1 adverse event (AE) or serious AE through W16 were similar between icotrokinra and placebo, with no increase in AE rates or occurrence of a safety signal through W52. CONCLUSIONS:Icotrokinra demonstrated high and durable rates of psoriasis clearance across high-impact sites, with a favourable safety profile, through 1 year.