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Introduction We evaluated the anti-interleukin-36 receptor antibody spesolimab in patients with moderate-to-severe palmoplantar pustulosis (PPP). Methods This phase IIb trial comprised a loading dose period to week (W) 4, then maintenance dosing to W52. Patients were randomised 2:1:1:1:2 to subcutaneous spesolimab 3000 mg to W4 then 600 mg every 4 weeks (q4w), spesolimab 3000 mg to W4 then 300 mg q4w, spesolimab 1500 mg to W4 then 600 mg q4w, spesolimab 1500 mg to W4, 300 mg q4w to W16 then 300 mg every 8 weeks (q8w), or placebo switching to spesolimab 600 mg q4w at W16. The primary efficacy endpoint was percentage change from baseline in Palmoplantar Pustular Area and Severity Index (PPP ASI) at W16. Secondary endpoints included a Palmoplantar Pustular Physician’s Global Assessment (PPP PGA) score of 0/1. Safety (including adverse events [AEs], local tolerability) was assessed. Results 152 patients were treated. The primary endpoint was not met; mean differences for spesolimab versus placebo ranged from − 14.6% (95% confidence interval [CI]: − 31.5%, 2.2%) to − 5.3% (95% CI: − 19.1%, 8.6%); none reached significance. At W16, 23 (21.1%) and two (4.7%) patients in the combined spesolimab and placebo groups, respectively, achieved PPP PGA 0/1 (mean difference 16.4%; 95% CI: 3.8%, 25.7%), increasing to 59 (54.1%; combined spesolimab) and 12 (27.9%; placebo switch to spesolimab) patients at W52. Non-Asian patients had significant improvements in the primary endpoint (mean difference − 17.7%; nominal P  = 0.0394) and PPP PGA 0/1 at W16 with spesolimab versus placebo. Rates of AEs and AE-related discontinuations were similar for spesolimab and placebo. Local tolerability events and injection-site reactions were more frequent with spesolimab than placebo. Conclusion The primary objective to demonstrate a non-flat dose–response relationship and proof-of-concept was not achieved; improvements with spesolimab occurred in secondary endpoints and in non-Asian patients, indicating potential modest benefits. Spesolimab was generally well tolerated (ClinicalTrials.gov NCT04015518). Plain Language Summary A clinical trial of spesolimab for patients with palmoplantar pustulosis . Palmoplantar pustulosis (PPP) is a painful, difficult-to-treat skin disease that is found on patients’ palms and the soles of their feet. In this clinical trial, we studied an injected medicine called spesolimab for treating patients with PPP. Patients were split into five groups; four groups received different doses of spesolimab and one received placebo (an injection without spesolimab). After 16 weeks, patients receiving placebo switched to spesolimab. We measured the body area affected by PPP and how severe PPP was at week 16. Patients’ doctors also assessed skin affected by PPP. At 16 weeks of treatment, there was no significant difference between spesolimab and placebo in terms of the PPP-affected area and severity. However, more patients had clear or almost clear skin with spesolimab than placebo. Among non-Asian patients, more showed an improvement in their PPP with spesolimab than with placebo; this was not the case with Asian patients. Patients taking spesolimab or placebo reported side effects, of which the most common were colds, aches and headaches. More patients receiving spesolimab reported a reaction at the injection site compared with placebo. We monitored patients for up to 1 year, and results remained similar. We showed that spesolimab may have a modest effect on the body area affected by PPP, as well as the severity of PPP, and did not seem to cause more side effects than placebo, except for reactions at the injection site.

Background: Chronic urticaria (CU) appears to be of autoimmune origin in about half of all patients, since several autoreactive immunoglobulin Gs (IgGs), such as anti-FcεRIα and anti-IgE, are detected in the sera of such patients. However, whether autoreactive IgE is associated with CU remains unclear. In this study, we attempted to identify autoreactive IgE antibodies in sera from patients with CU. Methods: Sera were collected from 67 normal subjects, 85 patients with CU and 28 patients with atopic dermatitis (AD). An autologous serum skin test (ASST) was performed on 27 of the CU patients. Autoreactive IgE and IgG levels against self-antigens were measured using enzyme-linked immunosorbent assays. The basophils were activated with dsDNA, and the CD63 expression level was examined using a fluorescence-activated cell sorter. Results: The anti-dsDNA IgE levels were significantly higher in patients with CU and AD than in normal subjects, but no differences in the anti-dsDNA IgG levels were seen. The levels of thioredoxin-, peroxiredoxin- and thyroglobulin-reactive IgE and IgG were not significantly higher in the CU patients than in the other 2 groups. There was no significant difference in the levels of anti-dsDNA IgE between ASST-positive and ASST-negative patients. The basophils from 2 out of 9 CU patients exhibited degranulation in response to dsDNA. Conclusions: Our data suggest that anti-dsDNA IgE is involved in the pathogenesis of some cases of CU.

Introduction Long-term safety data are critical for evaluating therapies for psoriasis. Ixekizumab has demonstrated efficacy and is well tolerated for the treatment of moderate-to-severe plaque psoriasis. We examined the safety and tolerability of up to 5 years of ixekizumab therapy in patients with psoriasis. Methods Integrated safety data were analyzed from 13 ixekizumab clinical studies. Rates of treatment-emergent adverse events (TEAEs), serious AEs (SAEs) and AEs of special interest were analyzed for the 12-week induction period in the combined pivotal studies, and for all pooled studies by year(s) of therapy and overall, reported as exposure-adjusted incidence rates (IRs) per 100 patient-years (p-y) and/or frequencies. Results Total ixekizumab exposure was 17,003.4 p-y ( N  = 5898); 2749 patients had ≥ 4 years of exposure. When compared across years of exposure, rates for AEs remained largely stable or declined, including TEAEs leading to discontinuation (3.8/100 p-y in year 1, declining to 2.0/100 p-y in year 5); SAEs (range 6.2–7.0/100 p-y); serious infections (range 1.3–1.7/100 p-y); nonmelanoma skin cancer (ranging from 0.5/100 p-y in year 1 to 0.2/100 p-y in years 4–5); other malignancies (range 0.4–0.6/100 p-y); inflammatory bowel disease including ulcerative colitis and Crohn’s disease (IR 0.2/100 p-y); and major adverse cardiovascular events (MACE) (range 0.3–0.7/100 p-y). Candidiasis was reported in 327 patients (IR 1.9/100 p-y), with the majority identified as mucocutaneous. The rate of injection site reactions was 15.5/100 p-y during year 1 and 2.0–2.3/100 p-y by years 3–5. Conclusions The decrease in rates of TEAEs and the stable rates of SAEs, other malignancies and MACE during up to 5 years of ixekizumab dosing are consistent with previous reports describing a favorable safety profile of ixekizumab following shorter durations of exposure. Funding Eli Lilly and Company.

Introduction Palmoplantar pustulosis (PPP) is a pruritic, painful, chronic dermatitis that greatly impacts functioning and quality of life and can be difficult to treat. Approved treatment options for PPP are limited, and many patients do not fully respond to current treatments. Methods This was a randomized, double-blind, placebo-controlled, phase 2 study in Japanese patients with moderate to severe PPP and inadequate response to topical treatment. Patients were randomized 1:1 to receive apremilast 30 mg twice daily or placebo for 16 weeks followed by an extension phase where all patients received apremilast through week 32. PPP Area and Severity Index (PPPASI), modified PPPASI (which evaluates pustules and vesicles separately), and Palmoplantar Severity Index (PPSI) total scores and subscores (erythema, pustules/vesicles, and desquamation/scales) were evaluated over 32 weeks of apremilast treatment. Achievement of ≥ 50% improvement in PPPASI (PPPASI-50) was evaluated at week 16 among baseline demographic and clinical characteristic subgroups. Results At week 16, improvements in total score and subscores for PPPASI, modified PPASI, and PPSI, as well as rates of PPPASI-50 were at least moderately greater with apremilast than placebo. Mean PPPASI total score decreased by − 68.3% from baseline to week 32 with continued apremilast treatment. At week 32, mean change from baseline in PPPASI/modified PPPASI subscores ranged from − 58.5% to − 77.0% with apremilast. At week 32, PPSI total score for physician and patient assessments decreased by − 51.3% and − 40.0%, respectively, with continued apremilast treatment. PPPASI-50 response at week 16 was greater with apremilast versus placebo in most demographic and baseline characteristic subgroups. Conclusions Improvements in all PPPASI and PPSI total scores and subscores observed with apremilast over 16 weeks were maintained through 32 weeks in patients with moderate to severe PPP and inadequate response to topical treatment. Rates of PPPASI-50 response at week 16 were mostly consistent across patient subgroups. ClinicalTrials.gov NCT04057937.

Background It is reported that treatment of palmoplantar pustulosis (PPP) with guselkumab has greater improvement in clinical responses in terms of palmoplantar pustulosis area severity index (PPPASI) score. Here, we present the effect of guselkumab (100 and 200 mg) on PPP‐related serum proteins and their association with clinical responses. Objectives To analyze the effects of guselkumab treatment on PPP‐related circulating serum proteins up to Week 72 and evaluate their association with clinical responses. Methods Serum cytokines (interleukin [IL]‐17A, IL‐17F, IL‐22, tumour necrosis factor‐alpha, interferon‐gamma) and 184 inflammation/immune activation‐related serum proteins were evaluated. Baseline cytokine levels for patients with PPP were compared with healthy controls (HCs) to detect differentially expressed serum proteins using Welch's t‐test. Correlation with individual PPPASI scores was assessed to explore associations with disease severity. Guselkumab treatment‐associated pharmacodynamic (PD) effects were evaluated as fold changes in cytokine levels compared with baseline. Results Baseline serum IL‐17A, IL‐17F and IL‐22 levels were elevated in PPP patients (n = 159) compared with HCs (n = 25) and were significantly correlated with baseline PPPASI disease scores. Serum cytokines were reduced following guselkumab treatment, with maximal reduction at Week 72 for both doses (all p < 0.01). Lower levels of IL‐17A, IL‐17F and IL‐22 were associated with PPPASI improvement at Week 72. Olink platform analysis identified a decrease in chemokine ligand‐19 and IL‐6 levels with guselkumab compared with placebo. However, the difference between the treatment groups was not significant. The biomarker effect of guselkumab 100 versus 200 mg groups was comparable, suggesting the PD effect is plateaued and higher than 200 mg is unlikely to increase biomarker changes. Conclusions Targeting IL‐23 with guselkumab in PPP led to a progressive reduction in IL‐17A, IL‐17F and IL‐22 in serum, and lower serum levels of these Th17/Th22 cytokines were associated with better PPPASI response after treatment. Clinical Trials.gov identifier NCT02641730.

Synthetic pyrrole–imidazole (PI) polyamides bind to the minor groove of double-helical DNA with high affinity and specificity, and inhibit the transcription of corresponding genes. We examined the effects of a transforming growth factor (TGF)-β1-targeted PI polyamide (Polyamide) on hypertrophic skin scars in rats. Hypertrophic scars were created dorsally in rats by incisions. FITC-labeled Polyamide was injected to investigate its distribution in the skin. Expression of TGF-β1, connective tissue growth factor (CTGF), collagen type1, and fibronectin mRNAs was evaluated by reverse transcription PCR analysis. The extent of fibrosis and the expression of TGF-β1 were evaluated histologically and immunohistochemically. Polyamide was distributed in almost all nuclei of skin cells. Expression of TGF-β1 mRNA reached a peak at 3 days after skin incision. Expression of CTGF and extracellular matrix mRNAs was increased continuously even after the peak induction of TGF-β1 mRNA. Injection of Polyamide completely inhibited both the development of scars and the induction of growth factors and extracellular matrix mRNAs. The treatment also markedly inhibited fibrotic changes and reduced the numbers of vimentin-positive spindle-shaped fibroblasts. Injection of Polyamide also reduced established hypertrophic scars in rats. Thus, TGF-β1-targeted PI polyamide should be a feasible gene silencer for hypertrophic scars and keloids.

Gene amplified in squamous cell carcinoma (SCC) 1 (GASC1), also known as KDM4C/JMJD2C, encodes a histone demethylase that specifically demethylates lysine residues (H3K9, H3K36, and H1.4K26) and plays a crucial role in the regulation of gene expression as well as in heterochromatin formation. GASC1 is located at human chromosome 9p23–24, where frequent genomic amplification is observed in human esophageal cancer, and its aberrant expression is detected in a variety of human cancers, such as breast, colon, and prostate. Therefore, it is highly likely that GASC1 contributes to the genesis and/or development of cancer. However, there is a lack of direct evidence of GASC1 having an oncogenic function. In this study, we aimed to clarify the role of GASC1 in the skin SCC carcinogenesis. For this purpose, we generated Gasc1-heterozygous mice (Gasc1 ⁺/⁻) with reduced expression of Gasc1. On the basis of our results, Gasc1 ⁺/⁻ mice displayed a significantly lower incidence and multiplicity of both benign and malignant tumors induced by the two-stage skin carcinogenesis protocol than wild-type mice. In addition, the volume of carcinoma was significantly lower in Gasc1 ⁺/⁻ mice. Consistent with these observations, knocking down of Gasc1 resulted in reduced cell viability of SCC cells in vitro. Our findings clearly demonstrated that GASC1 has an oncogenic role in skin carcinogenesis.

Psoriasis is a common human skin disease whereby abnormal production of inflammatory mediators is believed to play an important role in its pathogenesis. The IL12B gene, which encodes the shared IL-12p40 subunit in two cytokines, IL-12 and IL-23, and the IL23R gene, which encodes a subunit of the receptor for IL-23, were identified as psoriasis-susceptibility genetic factors in recent candidate gene and genome-wide association studies of Chinese and Europeans. Since there are significant differences in the incidence of psoriasis between Europeans and Japanese suggesting a genetic ethnic effect, we examined the association of IL12B and IL23R gene polymorphisms with psoriasis in a cohort of Japanese. In this study, we genotyped two SNPs (rs3212227 and rs6887695) in the IL12B gene and one SNP (rs11209026) in the IL23R gene using 560 Japanese psoriasis cases and 560 controls and compared our results with those previously published for Europeans and Asians. Our study showed significant associations between psoriasis and both IL12B gene SNPs, rs3212227 (odds ratio (OR) = 1.35, P  = 4.94E-04) and rs6887695 (OR = 1.32, P  = 2.00E-03), but no significant association between psoriasis and the IL23R SNP, rs11209026. Furthermore, a significant haplotype association was found for the IL12B gene protective haplotype C-C (OR = 0.71, P  = 1.84E-04) in Japanese, as previously elucidated in the studies of European ancestry.

This study revealed that the absence of histamine in histidine decarboxylase gene-knockout (HDC−/−) mice resulted in delayed cutaneous wound healing and that exogenously administered histamine compensated this process. With the overproduction of histamine in HDC gene-transgenic mice, the healing was accelerated compared to the HDC+/+ mice. These results indicate that histamine positively accelerated the cutaneous wound healing. Macrophage recruitment and angiogenesis at the wound edge were specifically impaired in HDC−/− mice, and histamine-treated wounds in HDC−/− mice demonstrated increased macrophage recruitment and angiogenesis. The amount of basic fibroblast growth factor (bFGF) in protein level at the wound edge was higher in HDC+/+ mice, especially on the 3rd and 5th day of wound healing compared to those in HDC−/− mice. Topically administered SU5402, a specific antagonist to fibroblast growth factor receptor-1 tyrosine kinase, to the wound surface suppressed the wound healing in HDC+/+ mice but not in HDC−/− mice. Moreover, SU5402 reduced macrophage recruitment and angiogenesis in HDC+/+ mice. From these observations, it was concluded that the accelerated wound-healing activity of histamine was mediated by the activity of bFGF, which leads to angiogenesis, and macrophage recruitment in the wound-healing process.

Spitz nevus is an important differential diagnosis of malignant melanoma, especially in young adults. This case provides a significant information about unusual dermoscopic features of adult Spitz nevus, which may reflect changes over the years. Spitz nevus is an important differential diagnosis of malignant melanoma, especially in young adults. This case provides a significant information about unusual dermoscopic features of adult Spitz nevus, which may reflect changes over the years.