Wiedemeyer K, Del Castillo Velasco-Herrera M, Billington J
… +17 more, Cheema S, Wong K, Sousa-Squiavinato ACM, Vermes I, Anderson E, Khan M, Clarke EL, Merchant W, Weigelt MA, Billings SD, Arends MJ, Alomari AK, Monteagudo C, Ferreira I, Brenn T, van der Weyden L, Adams DJ
BACKGROUND: Keloid is a chronic inflammatory skin disease, which is marked by abnormal fibroproliferative scar, without effective treatments. Many factors are involved in keloid formation, primarily highly activated infl...BACKGROUND: Keloid is a chronic inflammatory skin disease, which is marked by abnormal fibroproliferative scar, without effective treatments. Many factors are involved in keloid formation, primarily highly activated inflammatory, wound tension, and hereditary susceptibility. Collagen signaling plays important roles in various diseases, including tumors and fibrotic diseases, but its function in keloid inflammation remains unknown. We aimed to study the roles and mechanisms of collagen signaling in the inflammation development during keloid formation. METHODS: Normal and keloid keratinocytes and fibroblasts were isolated from fresh normal skin and keloid tissues. Picrosirius red staining, Western Blotting, Q-PCR, co-immunoprecipitation, APEX2-mediated proximity biotinylation, Elisa, immunohistochemistry, and immunofluorescence assays were used to discover the roles of collagen-DDR1 signaling in the inflammation development. Human Keloid samples were subcutaneously transplanted to nude mice to building keloid xenograft model. The therapeutic potential of DDR1 inhibitor (7rh) and ARF6 inhibitor (NAV-2729) was examined in the keloid inflammation development. RESULTS: Both phosphorylated NFκB and STAT3 were obviously elevated in keloid tissues. Collagen I accounted for the vast majority of collagens in keloids. Collagen I signaling promoted keloid inflammation amplifier activation by DDR1. DDR1 and ARF6 were upregulated in keloid tissues, and the levels of both were positively correlated. In keloid dermal tissues, elevated DDR1 was mainly expressed in fibroblasts. Collagen I-DDR1 signaling activated NFκB and STAT3 signaling. DDR1 inhibitor (7rh) restrained keloid inflammation development and growth in keloid xenograft model. Mechanistically, DDR1 interacted with ARF6, which promoted the transport of DDR1 to plasma membrane and amplified collagen I-induced DDR1 signaling, then facilitated DDR1 binding to STAT3, leading to STAT3 phosphorylation. The combined inhibition of DDR1 and ARF6 synergistically inhibited keloid inflammation amplifier. CONCLUSIONS: Collectively, these findings reveal the molecular basis of collagen I-DDR1 signaling activating NFκB and STAT3 signaling and expose the role of ARF6-DDR1 axis in promoting keloid inflammation development, indicating that DDR1 and ARF6 may serve as innovative therapeutic targets in keloid.
Dand N, Rayinda T, Silz E
… +15 more, Thomas LF, Saklatvala JR, McSweeney SM, Ung CY, Christou E, Lewis F, Kettunen J, Huilaja L, Brumpton BM, Hveem K, Løset M, Tasanen K, McGrath JA, Simpson MA, Tziotzios C
Br J Dermatol
· 2026 Mar · PMID 41850335
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BACKGROUND: Lichen sclerosus (LS) is a common and highly debilitating chronic inflammatory dermatosis that primarily affects genital skin in both females and males. Despite the utility of large genetic studies to reveal...BACKGROUND: Lichen sclerosus (LS) is a common and highly debilitating chronic inflammatory dermatosis that primarily affects genital skin in both females and males. Despite the utility of large genetic studies to reveal pathogenic mechanisms and suggest novel therapeutic targets, the genetic basis of LS remains largely unstudied. OBJECTIVE: To identify genomic loci at which common genetic variation influences LS susceptibility and establish associated pathogenic mechanisms. METHODS: Sex-stratified genome-wide association studies of genital LS were performed in three European biobanks (UK Biobank, the Trøndelag Health Study [HUNT] and FinnGen). LS cases were primarily identified via linked electronic health records from primary and/or secondary care. In total 6,681 female cases and 407,255 controls were included, with 970 male cases and 331,484 controls. GWAS were combined through fixed-effect meta-analysis. Further analyses to identify putative causal variants and genes were performed, including statistical fine-mapping, functional annotation and assessment of colocalization with gene expression quantitative trait loci (eQTLs). RESULTS: The MHC Class II allele HLA-DRB1*12:01 was strongly associated with LS susceptibility in females (OR=2.54, 95%CI=2.28-2.83, P=8.3×10-63) and males (OR=2.30, 95%CI=1.73-3.07, P=1.3×10-8). We found genome-wide significant associations (P<5.0×10-8) at another 12 loci in females, including a potentially causal protein-altering variant in IGFLR1 (rs140952221; OR=0.71, 95% CI=0.67-0.74, P=2.1×10-11). Colocalization with established eQTLs in skin and immune tissues highlighted dysregulated expression of CD247, IL2RB and ALDH2 amongst potential LS pathomechanisms. Evidence was observed for shared genetic effects between the sexes, albeit with diluted effect sizes in males (β=0.42, 95%CI=0.21-0.64, P=9.7×10-5). One further risk locus, at chromosome 5p13.2 was revealed by combined-sex meta-analysis. CONCLUSIONS: This study provides new insight into the pathogenesis of LS by identifying common genetic variation contributing to disease risk and implicating immune-inflammatory and metabolic pathways as potential future drug targets.
BACKGROUND: Chronic spontaneous urticaria (CSU) poses a significant burden on both patient and caregiver. Currently treatments for CSU are inadequate for some patients. TLL-018, an oral TYK2/JAK1 inhibitor, is under inve...BACKGROUND: Chronic spontaneous urticaria (CSU) poses a significant burden on both patient and caregiver. Currently treatments for CSU are inadequate for some patients. TLL-018, an oral TYK2/JAK1 inhibitor, is under investigation for CSU treatment. OBJECTIVES: To evaluate the efficacy and safety of TLL-018 for treating moderate-to-severe CSU in patients who had an inadequate response to antihistamines. METHODS: In this multicenter, double-blind, randomized, placebo-controlled, parallel-group pilot study (NCT05373355), patients with CSU who showed an inadequate response to antihistamines received either 10 mg or 30 mg of TLL-018, or placebo orally twice daily. After 4 weeks, patients on placebo were switched to 20 mg of TLL-018, and continuing treatment for an additional 8 weeks. The primary endpoint was safety, while secondary endpoints included efficacy measures, such as weekly Urticaria Activity Score (UAS7) ≤ 6, UAS7 = 0, and a Dermatology Life Quality Index of 0 or 1 at weeks 4 and 12. RESULTS: The study involved of 41 patients. At week 4, the ANCOVA versus change from placebo of UAS7/weekly Itch Severity Score/weekly Hive Severity Score were -11.5/-8.0/-3.8 in the 10-mg groups and -16.0/-9.0/-7.0 in the 30-mg groups. At week 12, the percentages achieving UAS7 ≤ 6 and UAS7 = 0 were 53.8%/38.5%, 71.4%/64.3%, and 61.5%/53.8% in the placebo-to-20 mg, the 10-mg, and the 30-mg TLL-018 groups, respectively. Common treatment-emergent adverse events included elevated serum creatine kinase and blood lipid levels, hyperglycemia, and urinary occult blood. CONCLUSIONS: TLL-018 was well-tolerated and effective in treating moderate-to-severe CSU in patients who had an inadequate response to antihistamines.
BACKGROUND: Current treatment pathways for moderate-to-severe psoriasis in the United Kingdom and the Republic of Ireland direct initiation of targeted biologic immunomodulators when conventional systemic drugs are ineff...BACKGROUND: Current treatment pathways for moderate-to-severe psoriasis in the United Kingdom and the Republic of Ireland direct initiation of targeted biologic immunomodulators when conventional systemic drugs are ineffective or not tolerated. Starting biologics early in the treatment pathway may modify the disease course and improve short- and long-term outcomes. OBJECTIVE: To compare the effectiveness and risk of incident comorbid conditions over five years between initiating a biologic as the first systemic treatment and the standard-of-care (beginning with conventional non-biologic systemic therapy with possible subsequent switch to biologics). METHODS: This study applied the target trial emulation framework using data from the British Association of Dermatologists Biologics and Immunomodulators Register (BADBIR) from September 2007 to December 2024. Adults (≥18 years) with moderate-to-severe psoriasis (baseline Psoriasis Area and Severity Index [PASI] ≥10) and no prior systemic therapy were included. Five-year trajectories of PASI and Dermatology Life Quality Index (DLQI) were modelled using mixed-effects repeated-measures models (MMRM). The probability of complete skin clearance (PASI = 0) and the risk of developing long-term comorbidities (cardiovascular, hepatic, neoplastic, metabolic, mental health, musculoskeletal disorder conditions, and incident psoriatic arthritis) were estimated using marginal structural models with stabilised inverse probability weighting to adjust for baseline and time-varying confounding. RESULTS: We included 3,702 patients, 3,368 followed standard-of-care, and 334 initiated a biologic as first-line systemic therapy. At 5 years, mean PASI from MMRM was 4.7 (95% confidence interval [CI] 4.0-5.4) for standard-of-care and 2.0 (1.2-2.7) for biologic initiators; DLQI was 5.6 (4.2-7.0) and 3.5 (1.3-5.7), respectively. Cumulative rate of achieving PASI 0 was 32.2% versus 58.6%, with higher likelihood of PASI 0 for biologic initiators (hazard ratio [HR] 2.85, 95% CI 2.34-3.47). The cumulative risk of chronic comorbidities was lower among biologic initiators (47.5% vs 54.3%; HR 0.72, 95% CI 0.58-0.89), with lower risks of mental disorders (HR 0.64, 95%CI 0.44-0.94) and hepatic disorders (HR 0.54, 95%CI 0.38-0.76). CONCLUSION: Initiating biologics as the first systemic therapy was associated with better clinical outcomes compared with standard stepwise approaches. These results support reconsideration of existing pathways to allow earlier use of biologics.
BACKGROUND: The incidence of both melanoma and type 2 diabetes (T2D) is increasing. Recent studies suggest that T2D is associated with a more advanced melanoma stage at diagnosis, but its impact on melanoma prognosis rem...BACKGROUND: The incidence of both melanoma and type 2 diabetes (T2D) is increasing. Recent studies suggest that T2D is associated with a more advanced melanoma stage at diagnosis, but its impact on melanoma prognosis remains unclear. OBJECTIVES: To examine the impact of T2D on sex- and stage-specific melanoma recurrence, melanoma-specific mortality, and overall mortality. METHODS: This population-based cohort study included all Danish patients diagnosed with melanoma between 2004 and 2022, excluding those with prior cancer or type 1 diabetes. The impact of T2D on melanoma recurrence, melanoma-specific mortality, and overall mortality was assessed by stage (AJCC stage I-II [localised], stage III [locoregional], and stage IV [metastatic]) and stratified on sex. Cumulative incidence proportions and risk differences (RD) were estimated. Furthermore, regression analyses using competing risk models to estimate adjusted hazard ratios (aHR) were applied, adjusting for age, comorbidity, calendar year, and stage at diagnosis. Patients were from date of melanoma diagnosis and followed until death, emigration, or the end of the study period (December 31, 2024). RESULTS: This study included 30,365 individuals diagnosed with melanoma; 14,343 were males (1,195 with T2D) and 16,022 were females (816 with T2D), with higher event frequencies in males than females. Among males with localised melanoma, T2D was associated with higher 5-year risks of recurrence (15.0% vs 8.3%, aHR 1.30, 95% CI 1.08-1.56) and melanoma-specific mortality (8.5% vs 4.2%, aHR 1.28, 1.00-1.64). Among women with localised melanoma, the T2D associated risk differences were less pronounced and no associations was observed after adjustment: Recurrence aHR: 1.04 (0.78-1.38), and Melanoma-specific mortality aHR: 1.10 (0.75-1.61). For both sexes with either locoregional or metastatic melanoma, T2D had no prognostic impact. CONCLUSION: T2D was associated with poorer prognosis among males with localised melanoma, whereas no prognostic impact was observed among females or patients with more advanced disease. These findings indicate the need for closer follow-up of males with early-stage melanoma and T2D, and for further studies to clarify underlying mechanisms and the potential benefits of optimised diabetes management.
Ramamurthy Srinivasan M, Ali F, Grover S
… +12 more, Nikookam Y, Vincent R, Abbott RA, Gan A, Hunt W, Cheng V, Rosenbach M, Parker E, Tan E, de Berker D, Niebel D, Tso S
Dereure O, Bernard P, Chosidow O
… +32 more, Ingen-Housz-Oro S, Machet L, Duvert-Lehembre S, Maillard H, Abasq C, Sassolas B, Acquitter M, Konstantinou MP, Chaby G, Caux F, Le Roux-Villet C, Prost C, Avenel-Audran M, Delaporte E, Jeudy G, Mahé A, Montaudie H, Picard-Dahan C, Quereux G, Richard MA, Bourgault-Villada I, Jullien D, Lepelletier C, Fichel F, Sanchez M, Rouanet J, Labeille B, Mahé E, Pham-Ledard A, Herman F, Picot MC, Joly P
BACKGROUND: Superpotent topical corticosteroids (STS) are highly effective in bullous pemphigoid (BP), but prolonged use is associated with practical limitations and a risk of relapse. OBJECTIVE: To evaluate whether comb...BACKGROUND: Superpotent topical corticosteroids (STS) are highly effective in bullous pemphigoid (BP), but prolonged use is associated with practical limitations and a risk of relapse. OBJECTIVE: To evaluate whether combining short-term STS with methotrexate (MTX) could maintain efficacy, reduce relapses, and preserve safety compared with prolonged STS alone. METHODS: In this multicentre, randomised, open-label, non-inferiority trial, adults with BP were assigned to receive either STS (clobetasol propionate) for one month plus low-dose MTX as maintenance (MTX + STS arm), or prolonged STS alone (STS arm). The primary endpoint was 9-month overall survival (OS), with a predefined non-inferiority margin of 15%. Secondary outcomes included relapse-free survival (RFS) and severe adverse events (SAE). RESULTS: Among 266 randomised patients (mean age 80.8 years), 9-month OS was 86.5% in the MTX + STS arm and 83.5% in the STS arm (p=0.498; hazard ratio [HR] 0.80, 95% CI 0.40-1.50). The lower limit of the 90% confidence interval for the difference in survival rates (-4.6%) remained within the predefined non-inferiority margin, meeting the primary endpoint. Among the 87.4% of patients who achieved disease control within 28 days, relapse occurred in 31 patients in the MTX + STS arm and 52 in the STS arm, corresponding to a 9-month RFS of 68.4% (95% CI 59.3-78.8) versus 47.4% (95% CI 37.7-59.5), respectively (p=0.042). SAE were more frequent in the MTX + STS arm than in the STS arm (mean number per patient per month 0.40 [95% CI 0.23-0.57] vs 0.19 [95% CI 0.01-0.36], p=0.005). LIMITATIONS: The study was open-label, did not include a validated disease activity score and was conducted in a selected BP population managed under clinical trial conditions. CONCLUSION: Maintenance therapy with low-dose MTX is non-inferior to prolonged STS in terms of survival and is associated with a reduced risk of relapse, at the cost of increased toxicity.
Amitay-Laish I, Mitsunaga K, Ortiz-Romero PL
… +10 more, de Masson A, Morsia E, Sanches JA, Enz PA, Nikolaou V, Jonak C, Porkert S, Leshem YA, Avitan-Hersh E, Hodak E