Abstract Sunscreen production, demand and use are increasing. Marketing claims often refer to sun protection factor (SPF), spectrum coverage and allergenicity, but there may be a mismatch between claims and ingredient composition. We aimed to evaluate the characteristics of top-selling sunscreens and concordance between allergenicity claims and ingredient profiles of sunscreens sold in the UK. A cross-sectional analysis was conducted of the 10 top-selling sunscreens from 9 retail platforms where this information was available, including physical and online retailers. Products listed as facial moisturizers with SPF were excluded. Allergens and photoallergens were defined according to national and local general series, the facial series and the European photopatch series. After excluding duplicates, 54 sunscreens were identified: 33 organic filter based, 15 mixed and 6 mineral sunscreens. Of these, 59% were targeted for general use, 39% for facial use and 2% for scalp application. The cost ranged from £0.98 to £190 per 100 mL. The most commonly used sunscreen filters were butyl methoxydibenzoylmethane, ethylhexyl salicylate and bis-ethylhexyloxyphenol methoxyphenyl triazine, present in 39, 37 and 36 sunscreens, respectively. SPF ranged from 15 to 50+, with most (76%) being labelled at least SPF 50. A recognized ultraviolet (UV)A rating (PA, star or UVA circle) was lacking in 11 sunscreens, despite UVA protection claims in 5 of these. Eight sunscreens claimed suitability for sensitive or hypoallergenic skin, but none were free from allergens. Four sunscreens claimed to be fragrance free: one of these included fragrance ingredients; 54% overall included fragrance ingredients. Five sunscreens claimed protection against high-energy visible light and/or infrared radiation; three of these contained iron oxides. The most commonly used additional potentially photoprotective ingredients were tocopherol acetate, alpha tocopherol, nicotinamide and Camellia sinensis extract. Top-selling sunscreens in the UK contain a range of potentially sensitizing ingredients. Physicians should be aware of possible discrepancies between sunscreen marketing and formulation.

Solar urticaria (SU) is a rare, poorly understood photodermatosis characterized by inappropriate mast cell degranulation following cutaneous exposure to sunlight. Based on a lack of Mendelian inheritance in families and its onset in adulthood with limited impact on reproductive fitness, SU is likely a complex trait whose development is determined by genetic and environmental factors. Its rarity and unusual phenotype, which constitutes an extreme aberration of physiological responses to sunlight, imply that its genetic architecture may be underpinned by rare, highly penetrant and deleterious variants. To investigate this, we performed a case–control whole-exome sequencing gene association study in SU. Forty-six patients of European ancestry with phototest-confirmed SU underwent whole-exome sequencing. Healthy control whole exomes (n = 971) were derived from the 1958 British Birth Cohort. Following quality control, joint variant calling and variant filtering to retain rare, high-impact variants, burden testing was performed. Sanger sequencing and bioinformatic resources were used to validate and explore identified genes/variants. Burden testing revealed exome-wide significant enrichment of rare, high-impact variants in ACACA among SU cases (P = 4.7 × 10−7). This gene encodes acetyl-coenzyme A carboxylase alpha, an enzyme that catalyses the rate-limiting step in de novo lipogenesis. Six of 46 SU cases carried rare, heterozygous missense variants in ACACA compared with 3 of 971 controls. Sanger sequencing validated the presence of these variants in ACACA. Structural analyses demonstrated that ACACA variants were predicted to decrease protein stability. Reanalysis of single-cell RNA sequencing data from skin confirmed ACACA expression in all cell types, including mast cells. Enrichment of rare, deleterious ACACA variants among patients with SU suggests a role for altered lipid metabolism, potentially affecting mast cell function, in SU pathogenesis. Characterization of lipid-mediated disease mechanisms in SU should form the basis of future investigations.

Abstract Ultraviolet radiation (UVR) is a major environmental factor affecting human skin, yet the early molecular effects of everyday low-dose exposure remain poorly understood. The objective of this study was to examine the acute molecular and cellular responses to low-dose single and repeated UVR exposure in healthy human skin. Six volunteers (five female, one male; age 28–65 years; skin types II–III) received 10 J cm−2 of solar simulated UVR (290–400 nm), equivalent to around 30 min of UK midday summer sunlight, on an area of upper buttock skin on three consecutive days. Skin biopsies were collected at 30 min, 3 h and 24 h after the first exposure, at 24 h following the third exposure, and from unexposed skin. Biopsies were analysed using immunohistochemistry and RNA sequencing, with predictive analysis from Ingenuity Pathway Analysis software. A single UVR exposure induced only modest transcriptional changes, with 27, 87 and 137 differentially expressed genes (> 1 log2 fold change, q < 0.05) detected at 30 min, 3 h and 24 h, respectively. In contrast, repeated daily exposure induced a pronounced response, with 1498 differentially expressed genes, including 333 long noncoding RNAs. Enriched pathways included cell cycle regulation, melanogenesis, interferon signalling and proinflammatory responses, with predicted activation of upstream regulators ELDR, MITF, VEGF genes, TNF and interferons. Immunohistochemistry after three exposures showed increased epidermal proliferation (Ki-67) and mild immune infiltration (CD4+ and CD8+ T cells, dendritic cells and neutrophils). CIBERSORT also suggested shifts in immune cell proportions after repeated UVR, although these changes were not statistically significant. These findings provide insights into the wide range of transcriptional changes occurring in healthy human skin following low-dose UVR exposure, and indicate that the skin does not return to baseline within 24 h, resulting in cumulative effects with subsequent exposures. Brief UVR exposures as experienced in daily life may profoundly influence skin physiology and health.

Abstract Skin solar ultraviolet radiation (UVR) exposure is a major source of vitamin D synthesis, but UVR concurrently causes skin DNA damage, which may contribute to skin cancer risk. The relationship between these beneficial and hazardous effects may vary by skin phototype. This study aimed to examine the relationship between the vitamin D (UVR-benefit) and skin DNA damage (UVR-harm) concurrently produced following UVR exposure, and to evaluate how this relationship differs across skin phototypes. A systematic review was performed in accordance with the PRISMA guidelines to identify human intervention studies reporting both changes in serum 25-hydroxyvitamin D levels and markers of skin DNA damage following UVR exposure. Literature searches were performed on 26 January 2025 across four databases (PubMed, MEDLINE OVID, MEDLINE Embase and Scopus). Studies were appraised using the National Heart, Lung and Blood Institute quality assessment tools. The findings were synthesized narratively and summarized in tables to inform evidence-based sun-exposure recommendations. The PROSPERO registration number for this study is CRD42025625834. Four studies, comprising data from 158 participants, were included. All studies were assessed as having fair-to-good quality. Two studies on solar-simulated radiation explored the effects of low-level exposure, while two sunlight studies explored the effects of high-level exposures, on 25-hydro­xy­vitamin D gain and cyclobutane pyrimidine dimer (CPD) formation. UVR exposure benefited vitamin D status and generated CPDs across all phototypes. Individuals with darker skin required higher exposure to achieve vitamin D sufficiency, with CPD formation not detected in basal (dividing) epidermal cells where epidermal localization was assessed. In contrast, individuals with the lightest skin phenotypes did not achieve vitamin D gains without concurrent basal cell CPD formation. These findings demonstrate phototype-specific differences in the balance between vitamin D benefit and UVR-induced DNA damage, which have implications for personalized sun-exposure guidance and the role of vitamin D supplementation.

Background Solar urticaria is a rare photodermatosis characterised by rapid onset sunlight-induced urticaria, but its pathophysiology is not well understood. Objective To define the cutaneous cellular and molecular events in the evolution of solar urticaria following its initiation by solar simulated ultraviolet radiation (SSR), and compare with healthy controls (HC). Methods Cutaneous biopsies were taken from unexposed skin and skin exposed to a single low (physiological) dose of SSR, at 30 minutes, 3 and 24 hours post-exposure, in n=6 solar urticaria patients and n=6 HC. Biopsies were assessed by immunohistochemistry and bulk RNA-sequencing analysis. Results In solar urticaria, there was enrichment of several innate immune pathways, with striking early involvement of neutrophils, which was not observed in HC. Multiple pro-inflammatory cytokine and chemokine genes were upregulated (including IL20, IL6, CXCL8) or identified as upstream regulators (including TNF, IL1β, IFNγ). IgE and FcεR1 were identified as upstream regulators, and phosphorylated STAT3 expression in mast cells was increased in solar urticaria at 30 minutes and 3 hours post-SSR exposure, suggesting a mechanism of mast cell activation. Clinical resolution of solar urticaria by 24 hours mirrored resolution of inflammatory gene signature profiles. Comparison with available datasets of chronic spontaneous urticaria showed transcriptomic similarities relating to immune activation but several transcripts were identified solely in solar urticaria including CXCL8 and CSF2/3. Conclusions Solar urticaria is characterised by rapid STAT3 activation in mast cells and involvement of multiple chemotactic and innate inflammatory pathways, with FcεR1 engagement indicated as an early event.

Abstract Photoaggravated atopic dermatitis (PAD) is a subtype of atopic dermatitis (AD) that is exacerbated or provoked by exposure to ultraviolet radiation. However, its early pathomechanisms are poorly understood. Our aims were (i) to investigate cutaneous clinical, barrier, cellular and molecular changes in the evolution of PAD following low-dose solar simulated ultraviolet radiation (SSR) exposure, and (ii) to compare the findings in healthy controls exposed to the same SSR challenge. Three consecutive daily low-dose (10 J cm−2) SSR exposures were delivered to upper buttock skin of six patients with PAD and six healthy controls. Biopsies were taken from unexposed skin and from SSR-exposed skin at 30 min, 3 h and 24 h after the first exposure, and at 24 h after the third exposure (4 days from baseline). Biopsies were analysed by RNA sequencing using immunohistochemistry and Ingenuity Pathway Analysis. Baseline (unexposed) comparison of PAD vs. healthy control skin revealed 838 differentially expressed genes including significant upregulation of molecules associated with AD, such as inflammatory cytokines and chemokines (CCL1, CCL13, CCL18; all P < 0.01) and epidermal differentiation and proliferation markers (LCE3A, SPRR2B, S100A7; all P < 0.01), along with functional enrichment of immune cell trafficking, T helper (Th)2 pathway response, and cell signalling. Following SSR, clinically and histologically eczematous responses were provoked in patients with PAD, with histological abnormalities becoming progressively more abnormal from baseline to 4 days. Erythema scores were higher in PAD skin than in healthy controls at 24 h and 4 days (24-h erythema score 11.3 vs. 6.8, P < 0.01). In PAD 3 h post-SSR, transcriptomic analysis indicated activation or recruitment of lymphocytes, neutrophils and antigen-presenting cells (all P < 0.001 vs. unexposed skin). Upregulated cytokine genes included IL22, IL20 and IL6 (all P < 0.01 vs. unexposed skin). Interleukin (IL)-1α, tumour necrosis factor and several Toll-like receptors were identified as activated upstream regulators. These findings were not seen in healthy controls, and indicated that innate, Th1 and Th22 activation was provoked by SSR at an early stage. By 24 h post-SSR, additional upregulation of IL13 and CCL17 was consistent with augmented Th2 responses alongside more histologically eczematous features, including lymphocytic infiltration, acanthosis and spongiosis. The evolving dermal inflammatory infiltrate included dual positive CD4+ GATA3+, as well as CD69+ and CD11c+ cells, suggesting involvement of resident memory cells, myeloid dendritic cells and Th2 lymphocytes. In conclusion, PAD was characterized by a predominant Th2 signature, with the additional early involvement of pattern recognition responses, and innate and adaptive immune cells. These findings may inform treatment strategies for flares of both PAD and AD.

Abstract Solar urticaria (SU) is a rare immunologically mediated photodermatosis caused by abnormal cutaneous mast cell degranulation following exposure to solar radiation. It manifests as the rapid development of erythemal flares, weals and/or angio-oedema following sunlight exposure and is associated with anaphylaxis-like symptoms in severe cases. Unsurprisingly, it has a significant impact on patients’ quality of life. As part of a genetic investigation of SU pathobiology, we have undertaken a descriptive cross-sectional study of the demographic, clinical and photobiological features of patients with SU recruited from six UK tertiary photobiology units. Clinical and genetic material were collected from participants following informed consent (19/EM/0312 and 07/H0802/104). Eligibility criteria were a diagnosis of SU made by a consultant dermatologist and confirmed by phototesting. Patients with comorbid porphyrin disorders were excluded. A standardized case report form was used to collect demographic, clinical and photobiological features. A descriptive and exploratory statistical ana­lysis was performed using the R statistical programme (R Foundation, Vienna, Austria). When data were missing for a participant, they were excluded from the relevant analysis. Of 178 included individuals, 66.9% were female and the mean age of disease onset was 36 years (range 1–82). Reported ethnicity was European in 90.2%, South Asian in 5.7%, East Asian in 1.1%, and African, Afro-Caribbean or mixed in 2.9%. Skin phototype was reported as phototype I (16.6%), phototype II (57.3%), phototype III (14.6%), phototype IV (4.5%), phototype V (5.1%) and phototype VI (1.9%). Photoprovocation was achieved using monochromator phototesting in 94.2%, while 5.8% could only be provoked using a solar simulator. Based on monochromator phototesting, the most common pathogenic waveband was ultraviolet A alone (28.1%). Among individuals with skin phototypes I–III, the most common pathogenic wavebands were ultraviolet A and visible light (29.9%), and among skin phototypes IV–VI, it was ultraviolet A and ultraviolet B (25.0%). Over half of the patients (57.3%) had coexisting atopic disorders (eczema, hay fever or asthma), while 15.2% had another photodermatosis, and 27.0% reported another type of urticaria. Sunscreen was used by 92.1% of patients, as were H1-receptor antagonists (92.1%), while 37.1% used H2-receptor antagonists, 44.4% used montelukast, and 20.2% used omalizumab. Of those treated with H1-receptor antagonists (n = 164), 75.0% reported that they were partially or completely effective. Omalizumab was reported to be completely or partially effective in 29 of 36 (81%) treated patients. In conclusion, this study summarizes the demographic and clinicophotobiological features of SU in the UK, while also highlighting the effectiveness of H1-receptor antagonist and omalizumab treatment in many cases.

Background: Solar urticaria is a rare photodermatosis characterized by rapid-onset sunlight-induced urticaria, but its pathophysiology is not well understood. Objective: We sought to define cutaneous cellular and molecular events in the evolution of solar urticaria following its initiation by solar-simulated UV radiation (SSR) and compare with healthy controls (HC). Methods: Cutaneous biopsy specimens were taken from unexposed skin and skin exposed to a single low (physiologic) dose of SSR at 30 minutes, 3 hours, and 24 hours after exposure in 6 patients with solar urticaria and 6 HC. Biopsy specimens were assessed by immunohistochemistry and bulk RNAsequencing analysis. Results: In solar urticaria specimens, there was enrichment of several innate immune pathways, with striking early involvement of neutrophils, which was not observed in HC. Multiple proinflammatory cytokine and chemokine genes were upregulated (including IL20 , IL6 , and CXCL8 ) or identified as upstream regulators (including TNF, IL-1 b , and IFN- g ). IgE and Fc epsilon RI were identified as upstream regulators, and phosphorylated signal transducer and activator of transcription 3 expression in mast cells was increased in solar urticaria at 30 minutes and 3 hours after SSR exposure, suggesting a mechanism of mast cell activation. Clinical resolution of solar urticaria by 24 hours mirrored resolution of inflammatory gene signature profiles. Comparison with available datasets of chronic spontaneous urticaria showed transcriptomic similarities relating to immune activation, but several transcripts were identified solely in solar urticaria, including CXCL8 and CSF2/3 . Conclusions: Solar urticaria is characterized by rapid signal transducer and activator of transcription 3 activation in mast cells and involvement of multiple chemotactic and innate inflammatory pathways, with Fc epsilon RI engagement indicated as an early event. (J Allergy Clin Immunol 2024;153:1369-80.)

This patient perspective on solar urticaria demonstrates some of the key clinical characteristics and impact of solar urticaria, as well as a first-hand account of the transformative potential of omalizumab therapy. The clinicians’ comment reviews clinical features and aspects of diagnosis and management.

Abstract Afamelanotide, a potent analogue of α-melanocyte-stimulating hormone, is known to stimulate melanogenesis by binding to the melanocortin 1 receptor. Additionally, in experimental models it has anti-inflammatory and antioxidative effects. Consequently, afamelanotide is employed and under development as a therapeutic agent for patients with photodermatoses, who can experience debilitating effects from exposure to sunlight’s ultraviolet radiation (UVR) and visible light. However, limited knowledge exists regarding the scope of the effects of afamelanotide in humans in vivo. This study evaluated the short-term impact of afamelanotide on UVR-induced acute inflammatory and DNA damage repair skin responses in healthy volunteers. Skin biopsies from seven healthy volunteers (skin type II–III, age range 27–43 years) were taken firstly prior to afamelanotide treatment, and procedures were then repeated 6 days following administration of a single 16-mg subcutaneous implant of afamelanotide. Volunteers received 2 × minimal erythema doses of UVR (broadband UVB, Philips TL12 lamp; Philips, Amsterdam, the Netherlands) to buttock skin. Biopsies were collected 24 h post-UVR exposure and from unirradiated skin, before and after afamelanotide administration. Samples underwent gene expression analysis using bulk RNA-Seq and Ingenuity Pathway Analysis. Transcriptomic analysis demonstrated that without afamelanotide, UVR irradiation resulted in 625 significantly differentially expressed genes (DEGs) compared with nonirradiated skin (> 1 log2 fold change, q < 0.05). In contrast, with afamelanotide, the DEGs between irradiated and nonirradiated skin reduced to 183, a factor of 3.4 less DEGs. These included genes associated with inflammatory and immune responses, including tumour necrosis factor (TNF) receptors and interleukins, and with DNA repair. Top predicted upstream regulators (with the highest z-score) in UVR-irradiated vs. nonirradiated skin were the same regardless of afamelanotide treatment. These included proinflammatory mediators such as TNF, interleukin-1 signalling, interferon-γ, and Toll-like receptor 3. However, the number of DEGs associated in the predicted activation of such upstream regulators and overall z-scores were reduced in skin following afamelanotide administration. Additionally, in untreated skin, UVR-induced proinflammatory pathways were enriched, but conversely this was not observed in skin following afamelanotide intervention. Oxidative stress and DNA damage repair pathways also appeared reduced after afamelanotide intervention, including oxidative-stress-induced senescence, DNA methylation and the DNA double strand break response. Transcriptomic analysis also demonstrated that, through comparison of skin under the same irradiation conditions, intervention with afamelanotide significantly upregulated premelanosome protein (PMEL gene), which plays a role in the synthesis of melanosomes. In conclusion, in addition to promoting melanogenesis, in this study afamelanotide reduced the magnitude of UVR-induced proinflammatory and DNA damage repair and oxidative stress responses in human skin, indicating its potential broad, innovative scope in treatment of UVR-induced skin disorders. This research was sponsored by CLINUVEL (UK) Ltd.

Information about the prevalence of photodermatoses is lacking, despite their substantial impact on life quality. Our objective was to systematically review the literature to establish what is known regarding prevalence and incidence of photodermatoses. We searched Medline, CINAHL and Embase from inception to 2021 to identify original population-based studies in English literature reporting the prevalence and/or incidence of photodermatoses. Information was extracted according to geographical location and risk of bias was assessed using a 10-point risk of bias tool for prevalence studies. Primary outcome was the population prevalence of photodermatoses. Prevalence data for polymorphic light eruption (PLE) were used to calculate the global pooled prevalence of PLE. Twenty-six studies were included; 15 reported prevalence of photodermatoses based on samples of the general population and 11 on prevalence and/or incidence from national and international registry data. The general population studies involved PLE (nine studies), unspecified photosensitivity (2), actinic prurigo (2), juvenile spring eruption (1), chronic actinic dermatitis (1) and variegate porphyria (1), while registry studies reported on cutaneous porphyrias and genophotodermatoses (nine and two studies, respectively). Worldwide the prevalence of PLE between countries ranged from 0.65% (China) to 21.4% (Ireland). The pooled estimated prevalence of PLE was 10% (95% CI 6%-15%) among the general population (n = 19,287), and PLE prevalence increased with distance from the equator (r = 0.78, p < 0.001). While several photodermatoses are rare, photosensitivity can be prevalent at wide-ranging world locations, including Egypt where photosensitivity was found in 4% of children and 10% of adults. This study showed that PLE is highly prevalent in many populations and that its prevalence shows a highly significant correlation with increasing northerly or southerly latitude. Available population-based studies for photodermatoses suggest they can be prevalent at a range of world locations; more attention is required to this area.

A subset of patients with chronic plaque psoriasis exhibits severely photosensitive psoriasis (PP) with a pronounced seasonal pattern, but the pathomechanism is not understood. We performed two related studies; first, a detailed clinical characterization of PP, and second, a controlled investigation exploring the underlying pathomechanisms through the assessment of disease onset after photoprovocation. Patients with PP (n - 20) showed striking female predominance (19F:1M), very low mean age of psoriasis onset (11 years, range 2-24), family history of psoriasis (13/20), a strong HLA-Cw*0602 association (16/17), and a rapid abnormal clinical response to broadband UVA, comprising erythema +/- scaling plaques (17/20). Subsequently, patients with PP (n = 10), non-PP (n = 9), and healthy volunteers (n = 11) were challenged with low-dose broadband UVA on 3 consecutive days, and serial biopsies were taken after 6 hours to 7 days and from unchallenged skin. Histological changes consistent with early psoriasis occurred in 4 of 10 PP patients, but in neither of the control groups, with significant dermal infiltration by neutrophils, CD4(+), CD8(+), and CD45RO(+) cells at 24 h, accompanied by acanthosis. Thus, a phenotypically distinct subset of psoriasis has been characterized. In contrast with earlier assumptions, UV can provoke psoriasiform features rapidly de novo; a role for memory effector T cells is supported in the early phase.