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.

Protection against visible light by dihydroxyacetone in erythropoietic protoporphyria.

BACKGROUND: Patients with erythropoietic protoporphyria (EPP) are hypersensitive to long wave ultraviolet (UVA) radiation and visible light and they experience severe skin pain by light exposure. The patients have very limited treatment options. Sunless skin tanning with dihydroxyacetone (DHA) is now being investigated as a possible treatment modality of skin photosensitivity in EPP. METHODS: We simulated the theoretical light protection factor provided by DHA application. In addition, we present 19 cases with EPP who were treated at our department with DHA weekly during spring and summer from 2018 to 2021 inclusive. RESULTS: The protection factor against UVA and visible light was estimated to approximately two. Out of the 19 patients with EPP who were treated with DHA in 2018, 11 patients experienced a sustained good effect and continued to use the treatment on a weekly basis in the spring and summer of 2019, 2020, and 2021. CONCLUSION AND PERSPECTIVES: Both the theoretical estimates and the uncontrolled study suggest that sunless tanning with DHA reduces photosensitivity in patients with EPP. Our hypothesis is that skin treated with DHA can tolerate twice the daylight dose compared to untreated skin before onset of skin symptoms. To validate this conclusion, we plan a randomized clinical trial to determine the effect of DHA application to reduce photosensitivity in patients with EPP under controlled clinical conditions. The study protocol for this trial is presented in the paper.

Efficacy Of Methotrexate Versus Azathioprine In The Treatment Of Chronic Actinic Dermatitis: A Randomized Control Trial.

Background: Azathioprine is first line immunosuppressive agent in treatment of chronic actinic dermatitis. The role of methotrexate has been effective in different dermatosis and it seems reasonable to use it in the treatment of chronic actinic dermatitis. Aims: We sought to compare the efficacy of methotrexate versus azathioprine in treatment of chronic actinic dermatitis. Methods: Patients with chronic actinic dermatitis were randomized to receive methotrexate in group A and azathioprine in group B. The response to treatment in terms of percentage PASI reduction and side effects of medications were assessed 12 weeks follow-up. Results: In group A, the percentage PASI reduction was <25% in 2 (1.19%) patients, 25-49% in 47 (27.9%) patients, 50-74% was achieved by 35 (20.8%) patients while in group B, the percentage PASI reduction of 25% was achieved by 2 (1.19%) patients, 25-49% in 45 (26.7%) patients, 50-74% in 37 (22.0%) patients. More than or equal to 75 percentage PASI reduction was not achieved by any patient in the study. Both drugs were found efficacious in treatment of CAD. A total of 23 (27.38%) patients in group A and 22 (26.19%) patients in group B showed derangement in laboratory investigations during 12 weeks treatment. The limitation of study was inability to do photo-patch test, so patients were diagnosed clinically and biopsy was done in clinically challenging cases. Conclusion: : This study shows that methotrexate is equally effective as azathioprine in the treatment of chronic actinic dermatitis with its added benefits of being cost effective and better safety profile.

NRF2 in dermatological disorders: Pharmacological activation for protection against cutaneous photodamage and photodermatosis.

The skin barrier and its endogenous protective mechanisms cope daily with exogenous stressors, of which ultraviolet radiation (UVR) poses an imminent danger. Although the skin is able to reduce the potential damage, there is a need for comprehensive strategies for protection. This is particularly important when developing pharmacological approaches to protect against photocarcinogenesis. Activation of NRF2 has the potential to provide comprehensive and long-lasting protection due to the upregulation of numerous cytoprotective downstream effector proteins that can counteract the damaging effects of UVR. This is also applicable to photodermatosis conditions that exacerbate the damage caused by UVR. This review describes the alterations caused by UVR in normal skin and photosensitive disorders, and provides evidence to support the development of NRF2 activators as pharmacological treatments. Key natural and synthetic activators with photoprotective properties are summarized. Lastly, the gap in knowledge in research associated with photodermatosis conditions is highlighted.

Immunopathogenesis and management of polymorphic light eruption.

Polymorphic light eruption (PLE) is the most common immunologically mediated photodermatosis, demonstrating many abnormalities caused by critical failure of ultraviolet (UV)-induced immunosuppression. The unique expression of antimicrobial peptides in PLE, which is most likely determined by alteration of microbiome components upon UV exposure, implicates their possible triggering role and pathogenic significance in the eruption. The review aims to clarify current knowledge regarding the immunological disturbances correlated with PLE that serve a base for better understanding of molecular pathogenesis of the disease and the development of new therapeutic strategies. Preventive treatment with broad-spectrum suncreens and sunscreens containing DNA repair enzymes, as well as natural photohardening with graduate exposure to sunlight in early spring could be sufficient in milder cases. Antioxidants and topical calcipotriol are promising approach for adjuvant prevention. Phototherapy, mainly with narrow band UVB rays, is more appropriate method in severe cases of the disease. The established treatment options for PLE include local and systemic glucocorticoids, systemic nonsedative antihistamines for itch relief, and rarely, immunosuppressive drugs in the refractory cases. Like medical photohardening, afamelanotide has the potential of photoprotection by inducing a melanization of the skin. Afamelanotide is believed to be a possible new treatment option for very severe and refractory cases of PLE. Targeting the main pruritogenic cytokine, IL-31, opens a new road for the development of novel therapeutic approaches to combat moderate and severe itching in cases of PLE with intense pruritus.

Development of hMC1R Selective Small Agonists for Sunless Tanning and Prevention of Genotoxicity of UV in Melanocytes.

Activation of the human melanocortin 1 receptor (hMC1R) expressed on melanocytes by α-melanocortin plays a central role in regulating human pigmentation and reducing the genotoxicity of UV by activating DNA repair and antioxidant defenses. For the development of a hMC1R-targeted photoprotection strategy, we designed tetra- and tripeptide agonists with modifications that provide the necessary lipophilicity and hMC1R selectivity to be effective drugs. These peptides proved to be superior to most of the existing analogs of the physiological tridecapeptide α-melanocortin because of their small size and high hMC1R selectivity. Testing on primary cultures of human melanocytes showed that these peptides are highly potent with prolonged stimulation of melanogenesis, enhanced repair of UV-induced DNA photoproducts, and reduced apoptosis. One of the tripeptides, designated as LK-514 (5), with a molecular weight of 660 Da, has unprecedented (>100,000) hMC1R selectivity when compared with the other melanocortin receptors hMC3R, hMC4R, and hMC5R, and increases pigmentation (sunless tanning) in a cultured, three-dimensional skin model. These new analogs should be efficacious in preventing skin cancer, including melanoma, and treatment of skin disorders, such as vitiligo and polymorphic light eruptions.

Iron chelation rescues hemolytic anemia and skin photosensitivity in congenital erythropoietic porphyria.

Congenital erythropoietic porphyria (CEP) is an inborn error of heme synthesis resulting from uroporphyrinogen III synthase (UROS) deficiency and the accumulation of nonphysiological porphyrin isomer I metabolites. Clinical features are heterogeneous among patients with CEP but usually combine skin photosensitivity and chronic hemolytic anemia, the severity of which is related to porphyrin overload. Therapeutic options include symptomatic strategies only and are unsatisfactory. One promising approach to treating CEP is to reduce the erythroid production of porphyrins through substrate reduction therapy by inhibiting 5-aminolevulinate synthase 2 (ALAS2), the first and rate-limiting enzyme in the heme biosynthetic pathway. We efficiently reduced porphyrin accumulation after RNA interference-mediated downregulation of ALAS2 in human erythroid cellular models of CEP disease. Taking advantage of the physiological iron-dependent posttranscriptional regulation of ALAS2, we evaluated whether iron chelation with deferiprone could decrease ALAS2 expression and subsequent porphyrin production in vitro and in vivo in a CEP murine model. Treatment with deferiprone of UROS-deficient erythroid cell lines and peripheral blood CD34+-derived erythroid cultures from a patient with CEP inhibited iron-dependent protein ALAS2 and iron-responsive element-binding protein 2 expression and reduced porphyrin production. Furthermore, porphyrin accumulation progressively decreased in red blood cells and urine, and skin photosensitivity in CEP mice treated with deferiprone (1 or 3 mg/mL in drinking water) for 26 weeks was reversed. Hemolysis and iron overload improved upon iron chelation with full correction of anemia in CEP mice treated at the highest dose of deferiprone. Our findings highlight, in both mouse and human models, the therapeutic potential of iron restriction to modulate the phenotype in CEP.

Anti-inflammatory effect of Arnica montana in a UVB radiation-induced skin-burn model in mice.

Background: ultraviolet radiation types A and B (UV) (400-315nm and 315-280nm respectively) are the main components present in sunlight known to cause skin injuries. Arnica montana is a plant that has been widely studied for containing anti-inflammatory, healing and analgesic properties capable of preventing or ameliorating lesions. Here, we investigated the therapeutic effect of topical application of Arnica montana after UVB-induced cutaneous injuries in mice.Methods: mice were exposed to UVB radiation (Philips TL40W/12 RS lamp) in a period of 3 hours. After one hour of radiation exposure, the animals were treated with topical application of Arnica montana ointment (250 mg/g) in the ear. At the time of 16 hours after treatment, the parameters of edema, oxidative stress and inflammatory reaction were measured in the ear of mice.Results: our results demonstrated that topical treatment with Arnica montana reduced the UVB-induced inflammatory response as demonstrated by the reduction of ear edema, inhibition of myeloperoxidase activation, decrease of nuclear factor kappa B levels and reduction of proinflammatory cytokines levels, such as interleukin-1beta, interleukin-6, tumour necrosis factor-alpha and interferon-gamma. In addition, Arnica montana ameliorated oxidative damage mediated by UVB radiation, as demonstrated by the reduction of lipid peroxidation, protein oxidation and increase of tissue antioxidant capacity and glutathione levels in the ear.Conclusion: we concluded that Arnica montana ointment is effective in alleviating the auricular inflammatory process and oxidative damage induced by acute UVB radiation, sustaining the traditional use of Arnica montana for the treatment of skin disorders.

Wheat Extract Oil (WEO) Attenuates UVB-Induced Photoaging via Collagen Synthesis in Human Keratinocytes and Hairless Mice.

The efficacy of wheat extract oil (WEO), standardized to glucosylceramides, for protecting against ultraviolet B (UVB)-induced damage of skin barrier function was assessed using the SHK-1 hairless mouse model and two human skin cell lines, namely, CCD-986sk and HeCaT. The ability of repeated oral administration of 30, 60, and 120 mg of WEO/kg/day for 12 weeks to prevent skin damage of SKH-1 hairless mice induced by UVB irradiation was evaluated. The results demonstrated that UVB-induced water evaporation (transepidermal water loss, TEWL) was significantly decreased by WEO. Similarly, UVB-induced losses in moisture and skin elasticity were improved by WEO supplementation. WEO attenuated the tissue procollagen type I, hyaluronic acid (HA), and ceramide reductions induced by UVB treatment as well. Collagen concentrations in skin tissue were increased in the WEO-treated mice, while UVB-induced epidermal thickening was reduced. In vitro studies using HeCaT human keratinocytes confirmed increased HA and collagen synthesis in response to WEO treatment. This may occur via WEO suppression of matrix metallopeptidase-1 (MMP-1), since its induction by UVB treatment was diminished in treated CCD-986sk cells. Oral administration of WEO improves skin barrier function in UVB-irradiated mice by attenuating damage typically observed in photoaging. This research further clarifies the clinical benefits previously observed by dietary WEO consumption.

Acquired erythropoietic protoporphyria: A systematic review of the literature.

BACKGROUND: Erythropoietic protoporphyria (EPP) is a semi-dominantly inherited porphyria presenting with photosensitivity during early childhood. Acquired EPP has been reported; however, data regarding this rare disorder are scarce. PURPOSE: To evaluate the characteristics of acquired EPP. METHODS: A comprehensive search of PubMed, Google Scholar, ScienceDirect, and clinicaltrials.gov databases was performed by three reviewers. Studies describing patients with acquired EPP were included. Additionally, we present an index case of a 26-year-old patient who acquired clinically and biochemically typical EPP in association with myelodysplastic syndrome (MDS). RESULTS: We included 20 case reports describing 20 patients. Most (80%) patients were male of mean age 58 ± 13 years. In all patients, acquired EPP was associated with hematological disease, most commonly MDS (85%) followed by myeloproliferative disease (10%). In 86% of cases, hematological disease led to abnormality or somatic mutation in chromosome 18q (the locus of the ferrochelatase gene). The mean erythrocyte protoporphyrin IX concentration was very high (4286 µg/dL). Most (90%) patients presented with photosensitivity, 20% experienced blistering, and 25% presented with hepatic insufficiency, both uncommon in EPP. In 55% of patients, hematological disease was diagnosed after occurrence of cutaneous symptoms. Beta-carotene led to partial control of symptoms in 5 patients and resolution in another patient. Azacitidine treatment of MDS led to resolution of cutaneous symptoms in three patients. CONCLUSION: We present the distinct features of acquired EPP and highlight that any patient presenting with new-onset photosensitivity, irrespective of age should be evaluated for porphyria.

Incapacitating solar urticaria: successful treatment with omalizumab

Abstract: Solar urticaria is a rare form of physical urticaria mediated by immunoglobulin E. The lesions appear immediately after the sun exposure, interfering with the patient's normal daily life. Omalizumab, a monoclonal anti-IgE antibody, has been recently approved for the treatment of chronic spontaneous urticaria, and the latest reports support its role also in the treatment of solar urticaria. Hereby, we report a case of solar urticaria refractory to conventional treatment strategies, with an excellent response to treatment with omalizumab and phototesting normalization.

Pirfenidone-induced photosensitivity confirmed by pathological phototest.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is an idiopathic interstitial progressive fibrotic lung disease and the most lethal of all interstitial lung diseases. Pirfenidone is a novel antifibrotic and anti-inflammatory agent which reduces decline in lung function and prolonges progression-free survival. It has a favourable benefit-risk profile and is generally well tolerated. However gastrointestinal events, photosensitivity reactions and rash are the most common adverse events. OBJECTIVE: We report a 71-year-old man with 1 week history of erythematous partially pruritic lesions on both sides of the neck and the back of the hands limited to sun exposed areas. He had been diagnosed with IPF and was being treated with pirfenidone (Esbriet) for 8 months. We suspected a photosensitivity reaction caused by pirfenidone. METHODS: A phototest and a punch biopsy were performed. RESULTS: The phototest had a pathological result. The minimal erythema dose was decreased, presenting with erythema and edema starting from 7 mJ/cm2 of UVB and an aberrant response to UVA starting from 2 J/cm2. Histopathological examination revealed spongiotic acute dermatitis with focal presence of necrotic keratinocytes. The patient was diagnosed with pirfenidone-induced photosensitivity and treated with high potency topical steroid leading to the resolution of the lesions, without the need for discontinuation of the drug. CONCLUSION: To our Knowledge, this is the first pirfenidone-induced photosensitivity reported case confirmed by pathological phototest. Patient education and photoprotection advice are essential for prevention.

Erythropoietic Protoporphyria: Initial Diagnosis With Cholestatic Liver Disease.

The porphyrias are a group of rare metabolic disorders that result from defects in heme biosynthesis. Erythropoietic protoporphyria (EPP) is the most common inherited porphyria in children and is diagnosed in most individuals after the onset of cutaneous manifestations. Hepatobiliary disease affects the minority of individuals with EPP and usually manifests in patients with an established diagnosis of EPP. We report on a classic but rare case of EPP that masqueraded as cholestasis. An 8-year-old boy was referred to the Hepatology Clinic after an abrupt onset of jaundice with a longstanding history of dermatitis. The diagnosis of EPP was established with liver biopsy, which revealed dense, dark-brown pigment in hepatocytes and Kupffer cells that, on polarization, displayed bright-red birefringence and centrally located Maltese crosses. Plasma total porphyrins and erythrocyte protoporphyrin were elevated and confirmed a diagnosis of EPP. We hope to raise awareness of this diagnosis among pediatricians, hepatologists, and pathologists and increase the consideration of EPP in patients with cholestatic liver disease and chronic dermatitis.

Isocitrate dehydrogenase 2 deficiency exacerbates dermis damage by ultraviolet-B via ΔNp63 downregulation.

Isocitrate dehydrogenase 2 (IDH2) is a key enzyme that maintains the balance of mitochondrial redox status by generating NADPH as a reducing factor, which is used to reduce oxidized antioxidant proteins and oxidized glutathione. Therefore, the role of IDH2 is crucial in organs that are easily influenced by reactive oxygen species (ROS) or mechanical damage. Humans are constantly exposed to ultraviolet (UV) radiation throughout their lifetime, which can cause various cutaneous diseases, such skin carcinoma, dermatitis, and sunburn. ROS play an important role in the initial step of these diseases; therefore, IDH2 deficient mice (Idh2-/-) could be a useful model to investigate UV-mediated skin damage. When we exposed the dorsal skin of Idh2-/- mice to UVB, pyrimidine dimers and (6-4) photoproducts (6-4PPs), marker of photoproducts generated by UVB, were found in the dermis of the knockout mice. Increased collagen degradation, apoptosis, inflammation, and ROS levels in the dermis were also observed. These results indicated that UVB could reach the dermis by penetrating the epidermis. We then attempted to determine how the epidermis was breached, and observed a decrease in the expression level of ΔNp63, a major protein required for epidermis generation, in the Idh2-/- mice. The mito-TEMPO supplement significantly ameliorates UVB-induced damage in the skin of Idh2-/- mice. In the present study, we provided a role for IDH2 in protection against UVB-induced skin damage and a new connection between IDH2 and ΔNp63.