Tolerability of Narrow-band Ultraviolet-B Phototherapy for Different Dermatological Diseases in Relation to Co-medications.

Phototherapy is an efficient therapy for a variety of skin diseases. Various drugs can cause photosensitivity and impact tolerability of phototherapy. The tolerability was investigated of narrowband ultraviolet-B 311 nm therapy in dependence on the underlying disease and long-term co-medication. A total of 534 narrowband ultraviolet-B therapy courses were examined. Compared with psoriasis, adverse events were observed more frequently in eczematous diseases and, in some cases, other indications. About two-thirds of all courses were carried out in patients taking at least one photosensitising drug, according to the summaries of product characteristics. Phototherapy was more frequently associated with adverse events when medication was taken concomitantly. When considering the tolerability of phototherapy in dependence on individual substances or drug classes, no statistically significant result was shown after adjustment.

Eradication of skin microbiota restores cytokine production and release in polymorphic light eruption.

Polymorphic light eruption (PLE) has been mechanistically linked to cytokine abnormalities. Emerging preclinical evidence posits the skin microbiome as a critical modulator of ultraviolet (UV)-induced cytokine expression, thereby influencing subsequent immune responses. This intricate relationship remains underexplored in the context of PLE. Hence, we investigated the differential responses between disinfected and non-disinfected skin following both single and repetitive exposures to solar-simulated UV radiation in patients with PLE. An experimental, half-body pilot study was conducted involving six PLE patients and 15 healthy controls. Participants' skin was exposed to single and multiple doses of solar-simulated UV radiation, both in disinfected and in non-disinfected skin areas. The co-primary outcomes were PLE score and cytokine expression in blister fluid analysed through OLINK proteomic profiling. Secondary outcomes were erythema, pigmentation, induction of apoptotic cells in vacuum-generated suction blisters, and density of infiltrate in skin biopsies of PLE patients. Among the 71 cytokines analysed, baseline expression levels of 20 specific cytokines-integral to processes such as apoptosis, inflammation, immune cell recruitment, cellular growth, and differentiation-were significantly impaired in PLE patients compared with healthy controls. Notably, skin disinfection reversed the observed cytokine imbalances following a single UV exposure at the minimal erythema dose (MED) level and exhibited even more pronounced effects after multiple UV exposures. However, no significant differences were evident in PLE score, erythema, pigmentation, or rates of apoptotic cell induction upon UV radiation. These findings provide evidence for UV-driven cytokine regulation by the skin microbiota and imply microbiome involvement in the PLE immune response.

A chronic pro-inflammatory environment contributes to the physiopathology of actinic lentigines.

Actinic lentigines (AL) or age spots, are skin hyperpigmented lesions associated with age and chronic sun exposure. To better understand the physiopathology of AL, we have characterized the inflammation response in AL of European and Japanese volunteers. Gene expression profile showed that in both populations, 10% of the modulated genes in AL versus adjacent non lesional skin (NL), i.e. 31 genes, are associated with inflammation/immune process. A pro-inflammatory environment in AL is strongly suggested by the activation of the arachidonic acid cascade and the plasmin pathway leading to prostaglandin production, along with the decrease of anti-inflammatory cytokines and the identification of inflammatory upstream regulators. Furthermore, in line with the over-expression of genes associated with the recruitment and activation of immune cells, immunostaining on skin sections revealed a significant infiltration of CD68+ macrophages and CD4+ T-cells in the dermis of AL. Strikingly, investigation of infiltrated macrophage subsets evidenced a significant increase of pro-inflammatory CD80+/CD68+ M1 macrophages in AL compared to NL. In conclusion, a chronic inflammation, sustained by pro-inflammatory mediators and infiltration of immune cells, particularly pro-inflammatory M1 macrophages, takes place in AL. This pro-inflammatory loop should be thus broken to normalize skin and improve the efficacy of age spot treatment.

Actinic conjunctivitis and its relationship with prurigo in an indigenous population from the Highlands of Chiapas, Mexico.

PURPOSE: Actinic conjunctivitis (AC), along with cheilitis (AChe), is part of the clinical spectrum of actinic prurigo (AP), a rare photo dermatosis that affects high-risk populations. We analyzed the clinical manifestations and onset of actinic conjunctivitis (AC), and its relationship with prurigo (AP) in a susceptible population. METHODS: This prospective observational cohort study was performed on Indigenous populations from the highlands of Chiapas, Mexico. Thorough dermatological and ophthalmological examinations were performed in patients attending a primary health care center. The clinical features, labor and environmental factors, onset timing, and clinical staging of AC and AP were analyzed. RESULTS: Of the 2913 patients studied, 54 patients (108 eyes) (1.8%) had AC, and 14 patients (25.9%) had AP. The mean age at diagnosis was 36.18 ± 18.52 years (6-70 years). The mean residential altitude was 1884 ± 434.2 m above sea level. Mean self-reported sun exposure was 5.14 ± 3.1 h a day (0.5-12 h). A total of 90.7% reported exposure to biomass fuels during cooking, and 50% to farm animals. AC was the sole manifestation in 70% of the cases. All patients had nasal and temporal photo-exposed conjunctiva. Among the eyes, 12.9% were classified as stage-1, 64.8% as stage-2, and 22.2% stage-3. A total of 83.3% of the patients had hyperpigmented lesions, and 35.1% had evaporative dry eye disease. CONCLUSIONS: AC may be the initial or sole manifestation of AP. Most AC cases (87%) were initially observed at the advanced stages of the disease. Although solar exposure was not associated with late AC stages, a positive association was found with farm animal exposure. Evaporative dry eye associated with meibomian gland dysfunction has not been previously reported in patients with AC.

DNA repair-related heritable photosensitivity syndromes: Mutation landscape in a multiethnic cohort of 17 multigenerational families with high degree of consanguinity.

Inherited photosensitivity syndromes are a heterogeneous group of genetic skin disorders with tremendous phenotypic variability, characterized by photosensitivity and defective DNA repair, especially nucleotide excision repair. A cohort of 17 Iranian families with heritable photosensitivity syndromes was evaluated to identify their genetic defect. The patients' DNA was analyzed with either whole-exome sequencing or RNA sequencing (RNA-Seq). The interpretations of the genomic results were guided by genome-wide homozygosity mapping. Haplotype analysis was performed for cases with recurrent mutations. RNA-Seq, in addition to mutation detection, was also utilized to confirm the pathogenicity. Thirteen sequence variants, including six previously unreported pathogenic variants, were disclosed in 17 Iranian families, with XPC as the most common mutated gene in 10 families (59%). In one patient, RNA-Seq, as a first-tier diagnostic approach, revealed a non-canonical homozygous germline variant: XPC:c.413-9 T > A. The Sashimi plot showed skipping of exon 4 with dramatic XPC down-expression. Haplotype analysis of XPC:c.2251-1 G>C and XPC:1243 C>T in four families showed common haplotypes of 1.7 Mb and 2.6 Mb, respectively, denoting a founder effect. Lastly, two extremely rare cases were presented in this report: a homozygous UVSSA:c .1990 C>T was disclosed, and ERCC2-related cerebro-oculo-facio-skeletal (COFS) syndrome with an early childhood death. A direct comparison of our data with the results of previously reported cohorts demonstrates the international mutation landscape of DNA repair-related photosensitivity disorders, although population-specific differences were observed.

Sun pain and solar dysesthesia: A new challenge in clinical practice.

BACKGROUND: A few patients report intense pain and other unpleasant sensations, such as burning, dysesthesia and hyperalgesia, after even brief exposure to the sun and in the absence of any skin lesion. Sometimes they also develop systemic symptoms, such as mild fever, fatigue, faintness and fainting. As a result, these patients carefully avoid even short-term sun exposure with a consequent severe negative impact on their lives. METHODS: We have reviewed the clinical findings and the results of photobiological investigations of 10 patients who presented this clinical picture. Six of these patients were previously described by our group with the diagnosis of sun pain. We have reviewed the similarities with other previously described disorders such as solar dysesthesia and PUVA pain and have evaluated possible pathogenetic mechanisms. RESULTS: During phototesting our patients experienced intense pain in the exposed area and in the surrounding skin, without any visible lesion, even with very low sub-erythemal doses. At follow-up, five patients were diagnosed with fibromyalgia, three with a major depressive disorder, one with bipolar syndrome and one with a conversion disorder. The pathogenesis remains unclear, but the use of a psychopharmacological treatment with antidepressants improved both the neuropsychiatric symptoms and sensitivity to the sun in most subjects. CONCLUSION: For patients with pain and other severe symptoms in the absence of skin lesions and clinical and laboratory manifestations of known photodermatoses, a neuropsychiatric evaluation should be suggested.

Characteristics of dermal vascularity in melasma and solar lentigo.

BACKGROUND /PURPOSE: Melasma and solar lentigo (SL) are major benign hyperpigmented lesions, and both have been shown to involve the dermal vasculature. This review discusses current knowledge regarding the clinical characteristics of dermal vascularity in melasma and SL, as well as the results of relevant molecular biological investigations. METHODS: PubMed and Google Scholar were searched in December 2023 to identify articles related to melasma, SL, and the dermal vasculature in these lesions. RESULTS: Vascular morphologies in melasma and SL have been detected by histological and non-invasive methods, including modalities such as optical coherence tomography. Biological studies have indicated that factors secreted from vascular endothelial cells, such as stem cell factor and endothelin-1, can promote melanogenesis. With respect to phototherapy, blood vessel-targeting laser treatments are expected to provide long-term suppression of pigmentation, but this regimen is only effective when dilated capillaries are visible. CONCLUSION: In both melasma and SL, clinical and experimental investigations are revealing the contributions of dermal vascularity to hyperpigmentation. More effective treatment may require identification of hyperpigmentation subtypes. In the future, knowledge of treatment (including phototherapy) is expected to accumulate through reliable and validated non-invasive measurements.

Epidermal turnover and iron metabolism in senile lentigo.

Senile lentigo (SL) is a pigmentary disorder associated with disrupted epidermal turnover. Trace minerals in the skin are known to regulate keratinocyte proliferation and differentiation. To clarify the role of iron in SL, we compared the expression of molecules related to iron metabolism between SL lesion (lesion) and the surrounding normal skin (nonlesion). Our results revealed that proteins involved in iron uptake and utilization such as transferrin receptor 1, iron regulatory protein 1, mitoferrin 1, and divalent metal transporter 1 were expressed in the lower epidermis in the nonlesion, while expression of them was also observed in the upper epidermis in the lesion. Ferroportin (FPN), involved in iron export, was expressed in the upper epidermis in the nonlesion, but was only scarcely expressed in the upper epidermis in the lesion. Hepcidin, which promotes FPN degradation, was expressed in the lower epidermis in the nonlesion; however, its expression was also observed in the upper epidermis in the lesion. These changes in the expression of molecules involved in iron uptake/export/utilization might reflect the altered iron utilization state in SL, resulting in disruption of keratinocyte differentiation and disturbing epidermal turnover. Our results suggest that the metabolism of iron in keratinocytes in SL differs from that in the normal epidermis, and these changes could be associated with the abnormal epidermal turnover and decreased melanin excretion in SL.

Evaluation of Skin Damage Under UV Exposure.

Photosensitivity disorder caused by sunlight, including ultraviolet (UV) rays, often occurs in connective tissue diseases such as lupus erythematosus. In addition, UVA (320-400 nM) and UVB (280-320 nM) trigger the progression of skin inflammation in the patients. Therefore, it is crucial to evaluate skin damage under UV exposure using experimental animals to clarify the relationship between connective tissue disease and photosensitivity disorder. In this chapter, our original protocol for evaluating UVA-dependent skin damage, which is known as photoaging via oxidative stress, is described.

[Translated article] Fixed Sunlight Eruption: A Series of 13 Cases in Bogotá, Colombia.

Few reports describing an association between UV radiation and fixed skin eruptions have been published since 1975. These reactions have received various names, including fixed sunlight eruption, fixed exanthema due to UV radiation, and broad-spectrum abnormal localized photosensitivity syndrome. We present a series of 13 patients (4 men [30.8%] and 9 women [69.2%]) aged between 28 and 56 years who were evaluated for fixed eruptions induced by UV radiation at a dermatology referral hospital in Bogotá, Colombia. The lesions were located on the inner thighs, buttocks, popliteal region, anterior and posterior axilla, and dorsum of the feet. Photoprovocation reproduced lesions in all the affected areas, and histopathology showed changes similar to those seen in fixed drug eruptions. While these UV-provoked reactions may be a type of fixed skin eruption, we cannot rule out that they may also be a distinct condition that simply shares a pathogenic mechanism with fixed eruptions.

Awareness of sun exposure risks and photoprotection for preventing pigmentary disorders in Asian populations: Survey results from three Asian countries and expert panel recommendations.

BACKGROUND: In this article, we review and discuss the photoprotection behavior of Asians based on the literature, along with a subanalysis of an original online survey, and make recommendations to optimize photoprotection for Asian populations to prevent photoaging and pigmentary disorders. METHODS: An international panel of eight dermatologists from Asia (China, Korea, Japan, Singapore, Indonesia, and Vietnam) met to discuss sunscreen photoprotection for Asian patients. Additionally, a subanalysis of an online survey by 3000 respondents from three Asian countries (China, Indonesia, and Japan) investigated general public awareness and attitudes to sun exposure. RESULTS: A pre-meeting survey of the eight experts from Asia showed key concerns of Asian patients consulting dermatologists are pigmentary disorders, especially actinic/senile lentigo, post-inflammatory hyperpigmentation, melasma, vitiligo, and Hori's nevus. The survey subanalysis of participants from China, Indonesia, and Japan with predominantly Fitzpatrick skin types (FST) II to IV revealed that they are particularly concerned about sun exposure causing photoaging and pigmentary disorders. Most of the respondents indicated they have limited knowledge on sunlight radiation and appropriate sunscreen protection factors. Only 22%, 13%, and 3% for China, Indonesia, and Japan, respectively, systematically use multiple protective measures (using sunscreen, avoiding midday sun, staying in the shade, wearing a hat, protective clothing, and sunglasses) when exposed to the sun. CONCLUSIONS: Further education is needed for Asian populations on the importance of comprehensive daily photoprotection, including broad-spectrum sunscreen, with high UVA and visible light protection, to reduce and prevent photoaging and pigmentary disorders.

Deficiency of N6-Methyladenosine Demethylase ALKBH5 Alleviates Ultraviolet B Radiation-Induced Chronic Actinic Dermatitis via Regulating Pyroptosis.

Pyroptosis is an inflammatory programmed cell death (PCD) and is reported to be associated with N6-methyladenosine (m6A) modification. This study aimed to investigate the mechanism of m6A demethylase AlkB homolog 5 (ALKBH5) in pyroptosis in the process of chronic actinic dermatitis (CAD). Changes of m6A-related genes were evaluated between CAD and normal samples using quantitative reverse-transcription polymerase chain reaction (qRT-PCR). Human keratinocytes (HaCaT cells) exposed to ultraviolet B (UVB; 10, 20, and 30 mJ/cm2), followed by evaluation of cell proliferation, cell apoptosis, inflammatory cytokines (interleukin (IL)-1ß, IL-18, and tumor necrosis factor (TNF-α)), and pyroptosis-related proteins (gasdermin D (GSDMD), Caspase-1, and Caspase-4). Small interfering RNA (siRNA) targeting ALKBH5 was transfected into HaCaT cells to assess the effect of si-ALKBH5 on CAD. A CAD mice model was induced after exposure to UVB (250 mJ/cm2 per day) to confirm the role of ALKBH5 in CAD. AKKBH5 was highly expressed in CAD patients. UVB also promoted ALKBH5 expression, increased cell apoptosis, and induced the release of inflammatory cytokines (IL-1ß, IL-18, and TNF-α) as well as pyroptosis-related proteins (GSDMD, Caspase-1, and Caspase-4). Silencing ALKBH5 repressed cell apoptosis and suppressed UVB-induced pyroptosis and inflammatory response. Meanwhile, silencing ALKBH5 attenuated UVB-induced skin damage of CAD mice, accompanied with the reduction in expression of inflammatory cytokines and pyroptosis-related proteins. This study helps to further understand the mechanism of ALKBH5 in CAD-induced pyroptosis and provides novel ideas for the research and management of CAD.

Algorithmic approach toward diagnosis of patients with congenital photosensitivity disorders and review of literature.

The congenital photosensitivity disorders present as cutaneous signs and symptoms secondary to photosensitivity, extracutaneous manifestations, and a predisposition to malignancy. Diagnosis of these conditions mainly depend on clinical findings as the molecular analysis is not always feasible. A review of all the related articles collected after a thorough literature search using keywords, "congenital AND photosensitivity NOT acquired" and the individual diseases was done. A total of 264 articles were included in the review. An algorithm for diagnosis of the different congenital photosensitivity disorders based on the various clinical presentations has been proposed. An early suspicion and diagnosis of the different congenital photosensitivity disorders is the cornerstone behind prompt institution of prevention and treatment, and decreasing the associated morbidity.

Equipment developed for simplifying routine phototesting in dermatology.

Some people react abnormally when exposed to sunlight by getting easily burned or develop a rash. When testing a patient's level of photosensitivity in the clinic, the UVR dose to provoke erythema is determined by the minimal erythema dose (MED) test. Subsequently, a photoprovocation test is performed to detect abnormal skin reactions by daily exposing the skin to UVR for several consecutive days. Associated problems in MED testing include choice of an even skin area for testing, patients keeping still during the test, testing with different UVR doses simultaneously, and securing clear borders of erythema. To address these issues, a MED Test Patch was developed which adheres closely to the skin to ensure sharp erythema borders and provides six irradiation fields with decremental doses of 20%. For MED testing, we constructed a solar simulator and LED lamps with peak emissions at 309 and 370 nm, small enough to be mounted directly on to the MED Test Patch and accommodate patient movements. These lamps and a 415 nm LED can also be used for provocation testing which is best performed on the back where the skin is assumed to have identical UVR sensitivity, and the area is large enough for adjacent MED and provocation test fields. Reading of erythema is still performed by visual and tactile evaluation. The UVA and UVB MED test can be performed in 1 h. The advantage of these developments is an easy-to-use, standardized test method with improved accuracy of the results.

Erythropoietic protoporphyria: case reports for clinical and therapeutic hints.

BACKGROUND: Erythropoietic protoporphyria is a rare disorder which represents an important health problem in children, causing painful photosensitivity. Little is known on the correlation between genetic profile and clinical manifestations. The standard of care for Erythropoietic protoporphyria is based on avoiding sun and using sun protections, but recent literature has suggested that cimetidine may have a role in improving sun sensitivity. Herein we report our case series describing the successful use of cimetidine and analyzing potential phenotype-genotype correlations. CASE PRESENTATION: This case series describes five patients presented to our Rheumatology Service complaining sun sensitivity. Blood exams and genetic analysis were consistent with the diagnosis of erythropoietic protoporphyria. Four of 5 patients received cimetidine in addition to standard therapies and the effect of treatment was evaluated by Erythropoietic Protoporphyria - Quality of Life questionnaire. CONCLUSIONS: Erythropoietic protoporphyria usually manifests in early childhood after a short sun exposure. Skin manifestations are the main reason for investigations, although sometimes they can be more subtle, leading to a significant diagnostic delay. Skin diseases in children can have profound effects on their family and social relationships. A treatment with cimetidine appears to be an excellent therapeutic option in children with Erythropoietic protoporphyria.