Chronic spontaneous urticaria (CSU) is a mast cell-driven inflammatory disease characterized by recurrent wheals and/or angioedema with an unpredictable course and substantial global prevalence. Beyond its visible skin m...Chronic spontaneous urticaria (CSU) is a mast cell-driven inflammatory disease characterized by recurrent wheals and/or angioedema with an unpredictable course and substantial global prevalence. Beyond its visible skin manifestations, CSU may impose a profound and multifaceted burden on patients, families, healthcare systems, and society. This narrative review synthesizes current evidence on the overall burden of CSU, encompassing epidemiology, clinical manifestations, humanistic impact, cumulative life course impairment, and economic costs. CSU markedly disrupts quality of life through sleep disturbance, pruritus, emotional distress, psychiatric comorbidity, impaired social and occupational functioning, and stigma, with effects extending to children, caregivers, and family members. Disease burden is further amplified by angioedema, concomitant inducible urticaria, delayed diagnosis, suboptimal treatment, and persistent uncertainty regarding disease recurrence, even during periods of symptom control. Indirect and direct economic costs-including healthcare utilization, absenteeism, and presenteeism-are substantial and vary across regions, influenced by healthcare systems and access to effective therapies. The review highlights the importance of comprehensive, patient-centred burden assessment using validated patient-reported outcome measures, alongside disease activity evaluation, to inform individualized management strategies. Addressing the hidden and cumulative burden of CSU requires timely diagnosis, personalized and phenotype-based treatment, integration of psychosocial care, and improved access to effective therapies in order to meaningfully restore quality of life and long-term well-being.
BACKGROUND: Vitiligo is a chronic depigmentation disorder caused by selective melanocyte loss. Autoreactive CD8+ T cells are known contributors, but impaired melanocyte-keratinocyte adhesion due to E-cadherin dysfunction...BACKGROUND: Vitiligo is a chronic depigmentation disorder caused by selective melanocyte loss. Autoreactive CD8+ T cells are known contributors, but impaired melanocyte-keratinocyte adhesion due to E-cadherin dysfunction has also been implicated. OBJECTIVES: This study aimed to identify the key adhesion molecules mediating melanocyte-basement membrane interactions and to investigate their modulation in response to vitiligo-associated factors, including IFNγ and mechanical stress. METHODS: Primary human epidermal melanocytes (PHEMs) and ex vivo human skin tissues were exposed to IFNγ and mechanical stress. To identify key molecules involved in melanocyte adhesion, we integrated RNA sequencing data from prior studies with antibody array profiling. The involvement of focal adhesion-associated proteins in melanocyte-basement membrane attachment was further assessed by confocal imaging of vitiligo patient skin, revealing a reduction in these molecules. RESULTS: Exposure to interferon gamma (IFNγ) and mechanical stress reduced focal adhesion kinase (FAK) and integrin β1 (ITGβ1) expression in melanocytes and ex vivo human skin, increasing melanocyte detachment. Both molecules were also decreased in basal keratinocytes and melanocytes from the skin of vitiligo patients compared to healthy controls. Pre-treatment with the JAK inhibitor baricitinib, used in vitiligo therapy, reduced melanocyte detachment through a cathepsin L (CTSL)-dependent mechanism. CONCLUSIONS: IFNγ and mechanical stress contribute to melanocyte detachment from the basement membrane via CTSL, FAK, and ITGβ1 regulation. These findings highlight the importance of melanocyte-basement membrane adhesion in vitiligo pathogenesis and offer insight into the Koebner phenomenon in disease progression.
Arham AGA, Sharma A, Thomas LF
… +11 more, Ramessur R, Debik J, Denos M, Hoff M, Videm V, Paternoster L, Smith C, Åsvold BO, Giskeødegård GF, Brumpton BM, Løset M
BACKGROUND: Psoriasis is recognized as a systemic inflammatory disease associated with metabolic dysregulation. Understanding these metabolic changes may reveal biomarkers to elucidate disease mechanisms and predict como...BACKGROUND: Psoriasis is recognized as a systemic inflammatory disease associated with metabolic dysregulation. Understanding these metabolic changes may reveal biomarkers to elucidate disease mechanisms and predict comorbidities. While previous studies have identified psoriasis-associated metabolites, findings are often limited by sample sizes and lack validation. OBJECTIVES: To identify circulating metabolites associated with psoriasis, including disease severity and psoriatic arthritis. Further, we investigated whether the metabolic signature was disease-specific compared to other immune-mediated inflammatory diseases (IMIDs). METHODS: We performed a cross-sectional analysis of 470,352 White/European individuals from the UK Biobank (n=453,428) and HUNT (n=16,924). Nuclear Magnetic Resonance spectroscopy was used to quantify metabolite levels, covering lipoprotein fractions and subfractions, fatty acids, and small-molecular metabolites. For each metabolite, we performed multivariable linear regression adjusting for age, sex, BMI, smoking status, and use of lipid-lowering medications. RESULTS: The metabolomic profile of psoriasis was largely consistent across the two populations. In the model adjusted for age and sex, 123 metabolic measures were associated with psoriasis. After full adjustment, only Glycoprotein acetyls (GlycA) remained associated with psoriasis (coefficient [95% CI]: 0.09 [0.07-0.11] in UK Biobank and 0.11 [0.06-0.17] in HUNT). In HUNT, severe psoriasis exhibited more pronounced metabolic alterations compared to non-severe psoriasis. Across both populations, phenylalanine levels were highly elevated in psoriatic arthritis compared to cutaneous psoriasis (0.44 [0.29-0.60] in UK Biobank and 0.47 [0.28-0.67] in HUNT). In comparisons across IMIDs, atopic dermatitis and cutaneous-limited psoriasis exhibited milder metabolic alterations, and psoriasis in HUNT showed a distinct lipoprotein profile. CONCLUSIONS: This large-scale study confirms metabolic alterations in individuals with psoriasis and highlights phenylalanine as a potential biomarker for joint involvement in psoriasis. The distinct metabolomic profile of psoriasis relative to other IMIDs suggests a potentially unique systemic profile. These findings offer a foundation for advancing biomarker research and mechanistic studies for psoriasis.
A 70-year old man presented with 20-30 pruritic hyperpigmented, flat papules and annular plaques with squamous borders in the perianal region for 20 years, unresponsive to topical corticosteroids. Histological examinatio...A 70-year old man presented with 20-30 pruritic hyperpigmented, flat papules and annular plaques with squamous borders in the perianal region for 20 years, unresponsive to topical corticosteroids. Histological examination revealed cornoid lamellae, underlying dyskeratosis and a sparse perivascular lymphocytic infiltrate. The diagnosis porokeratosis ptychotropica was made.
King B, Ehst B, Foley P
… +12 more, Reygagne P, Ohyama M, Szepietowski JC, Popmihajlov Z, De Leonardis F, Hippeli L, Treitel M, Johnson B, Gilvary C, Vaile J, Daamen C, Passeron T
BACKGROUND: Alopecia areata (AA) is a common, immune-mediated inflammatory disease characterized by non-scarring hair loss. Tyrosine kinase 2 (TYK2) mediates signaling of select proinflammatory cytokines (e.g. IL-12, IL-...BACKGROUND: Alopecia areata (AA) is a common, immune-mediated inflammatory disease characterized by non-scarring hair loss. Tyrosine kinase 2 (TYK2) mediates signaling of select proinflammatory cytokines (e.g. IL-12, IL-23, and Type I interferons), which may play a role in the pathogenesis of AA. OBJECTIVES: To evaluate the efficacy and safety of deucravacitinib, an oral, selective, allosteric TYK2 inhibitor, in patients with AA. METHODS: Patients were randomized 1:1:1 to oral placebo, deucravacitinib 6 mg once daily (QD), or deucravacitinib 6 mg twice daily (BID). At Week 24, patients randomized to placebo were re-randomized 1:1 to deucravacitinib 6 mg QD or deucravacitinib 6 mg BID until Week 52. The primary efficacy endpoint was change from baseline in Severity of Alopecia Tool (SALT) score at Week 24. Secondary endpoints were proportions of patients achieving ≥50% reduction from baseline in SALT score (SALT50), SALT score ≤20, and Alopecia Areata Investigator Assessment score of 0 (clear) or 1 (almost clear) with ≥2-point improvement from baseline at Week 24. This trial was terminated following database lock at Week 24, but before primary data readout, due to a strategic decision by the sponsor and not as a result of any observed, expected, or perceived efficacy or safety findings with deucravacitinib treatment. Early termination did not affect study power. RESULTS: In total, 94 patients received placebo (n = 31), deucravacitinib 6 mg QD (n = 32), or deucravacitinib 6 mg BID (n = 31). Baseline disease characteristics were balanced across treatment groups. No meaningful difference in change from baseline in SALT score at Week 24 was observed between the deucravacitinib and placebo groups (6 mg QD: adjusted mean difference [95% confidence interval], 1.5 [-6.2, 9.2], P = 0.7010; 6 mg BID: 8.2 [0.2, 16.2], P = 0.0447). Similarly, no differences were observed for any secondary endpoint. No new safety signals were identified. CONCLUSIONS: This trial did not meet the efficacy endpoints and TYK2 inhibition by deucravacitinib may not play a major role in hair regrowth in patients with AA. The safety of deucravacitinib in patients with AA was consistent with the known safety profile of this TYK2 inhibitor.
Ralph N, Goossens A, Carrascosa JM
… +10 more, Goncalo M, Wulf HC, Calzavara-Pinton PG, Rhodes LE, Wilkinson M, Bourke J, Eadie E, Moore E, Christou E, Ibbotson SH
BACKGROUND: Whilst photopatch testing is recognized as the investigation of choice for photoallergic contact dermatitis, changes in potential photoallergen exposure and variables within the photopatch test technique, hav...BACKGROUND: Whilst photopatch testing is recognized as the investigation of choice for photoallergic contact dermatitis, changes in potential photoallergen exposure and variables within the photopatch test technique, have led to challenges in its usage within dermatology. OBJECTIVES: The main objectives of this study were to determine the nature and prevalence of topical photoallergens in Europe and investigate the variable of photoallergen occlusion time before irradiation, on photopatch testing outcomes. METHODS: A prospective multi-centre study of photopatch testing to sunscreens, non-steroidal anti-inflammatory drugs (NSAIDs) and other agents was conducted in 10 centres across seven European countries. A within-subject comparison of a 24h and 48h occlusion period prior to irradiation was included in the study design, to investigate the effect of this variable on photopatch testing outcomes. RESULTS: Of study participants, 28 photoallergic reactions were seen, with 10% (13/132) of participants reacting to sunscreen chemicals and 9% (9/101) to NSAIDs. The most prevalent photoallergens were ketoprofen (n=6), promethazine (n=4); butylmethoxydibenzoylmethane (Avobenzone/Parsol 1789) (n=4), benzophenone-3 (oxybenzone) (n=3) and etofenamate (n=3). Contact allergies were less frequent (14 reactions). When a 24h occlusion was used prior to irradiation, 53% of sunscreen photoallergic reactions and 36% of NSAID reactions were missed compared with the 48h occlusion. Most participants had a history of photo-exposed site dermatitis or sunscreen/NSAID reaction or had a photosensitivity disease, and 49% of participants had a history of dermatological conditions. All indications for photopatch testing were represented in those with positive photopatch tests, with no specific indicator of those most at risk. CONCLUSIONS: Photopatch testing remains an essential investigation for people with suspected photocontact allergies. Based on these study findings, the nature of topical photoallergens appears stable, but vigilance and ongoing review are required. To optimise the pick-up rate of photoallergy, we recommend, if practicable, a 48h occlusion period prior to irradiation.(Clinicaltrials.gov - NCT03812887).
BACKGROUND: Keratinocyte carcinoma (KC) rates continue to increase, despite current prevention strategies. Effective treatment of actinic keratoses (AKs) can reduce the risk of subsequent KC; however, the prevalence of A...BACKGROUND: Keratinocyte carcinoma (KC) rates continue to increase, despite current prevention strategies. Effective treatment of actinic keratoses (AKs) can reduce the risk of subsequent KC; however, the prevalence of AKs precludes treating all individuals. Recently, we identified a subset of human papillomavirus 8 (HPV8)-associated AKs. Hence, further stratification is needed to better identify patients at high risk of KC. OBJECTIVES: To determine the association of HPV8 with subsequent KC and identify specific treatment. METHODS: Patients with a prior history of pathologist-proven AK were recruited. Histology samples were analysed for HPV8, and medical records were reviewed for KC. HPV8-associated human AK, cell lines and mouse models were interrogated for expression of Src family kinases. The in vitro and in vivo biologic effects of Src inhibition were determined using small interfering RNA and tirbanibulin. RESULTS: Sixty-one patients with AK without a history of antecedent KC were divided into those with (n = 31) and without HPV8 (n = 30) infection. Using multivariable Cox regression with data adjusted for sex, age and body site, patients with HPV8-associated AKs had a greater risk of subsequent KC (hazard ratio 5.5, 95% confidence interval 2.3-12.9; P < 0.001). Independently, HPV8-associated AKs were associated with invasive squamous cell [odds ratio (OR) 32.0; P < 0.001] and basal cell carcinoma (OR 4.5; P < 0.01), and included all nine patients with multiple KCs. HPV8-associated AKs showed elevated expression of phosphorylated Src kinase. Inhibition of Src reduced cell proliferation and blocked colony-forming efficiency. In vivo, Src inhibition restored epidermal thickness and hindered the development of skin tumours. CONCLUSIONS: The presence of koilocytes in AK histology is indicative of a subset of patients at risk of multiple KCs. Inhibiting Src kinase blocked this HPV8-associated keratinocyte proliferation and prevented skin tumours in a mouse model.