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.

Cimetidine for erythropoietic protoporphyria.

BACKGROUND: Erythropoietic protoporphyria (EPP) is caused by deficiency of the enzyme converting protoporphyrin IX (PpIX) into heme resulting in accumulation of PpIX; leading to photosensitivity and liver toxicity. Cimetidine might inhibit δ-aminolevulinic acid synthase influencing the heme biosynthesis. We present cases with EPP treated with cimetidine at our department, and a literature review. METHODS: Systematic searches were performed to identify literature describing EPP patients treated with cimetidine. On that ground we treated EPP patients with cimetidine through spring and summer in 2020 and 2021 at our department. Their erythrocyte PpIX level and standard blood and liver parameters were collected before and during 4 months of treatment. Using a questionnaire, patients were asked about change in photosensitivity, side effects, and whether they would like to resume treatment in the spring of 2022. RESULTS: Literature searches identified 9 patients treated with cimetidine. Four were outpatients reporting decreased photosensitivity. At our department 18 outpatients started treatment. Fifteen used oral cimetidine daily for 4 months or more providing a significant decrease in erythrocyte PpIX with a median of 20% (range: -18% to 53%) after 4 months. Eleven of the 15 patients reported a decrease in photosensitivity during treatment, 3 patients were unsure, and 1 patient experienced unchanged photosensitivity. Only mild side effects were reported. Fourteen patients requested to resume treatment in the spring of 2022. CONCLUSIONS: These cases suggest that cimetidine can lower erythrocyte PpIX in patients with EPP.

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.

Dupilumab for the Treatment of Actinic Prurigo.

A 42-year-old Latino man with a medical history of vitiligo presented to our outpatient clinic with a 25-year history of a recurrent, itchy eruption on his face and hands. Physical examination revealed pink, scaly, erythematous, lichenified papules and plaques with overlying crusts, photodistributed on the nose, chin, cheeks, hands, and ears (Figures 1a and 2a). The lips were edematous with hemorrhagic crusting, and conjunctival injection and partial corneal opacities were noted (Figures 1b-1c). Histologic evaluation demonstrated psoriasiform hyperplasia with hyper-granulosis and a superficial perivascular infiltrate composed of lymphocytes, histiocytes, and eosinophils. Human leukocyte antigen (HLA) class II typing was positive for HLA-DRB1*0407, thus confirming the diagnosis of actinic prurigo (AP).

Clearance of pediatric actinic prurigo with dupilumab.

Actinic prurigo is a rare, idiopathic chronic photodermatosis of childhood characterized by excoriated papules, nodules, and plaques in sun-exposed areas. It is notoriously difficult to treat. The disorder involves a type IV hypersensitivity reaction driven by both Th1 and Th2 inflammatory pathways, the latter of which leads to secretion of IL-4, IL-5, IL-13, and production of B cells, IgE, and IgG4. Dupilumab, an IL-4 receptor antagonist, disrupts the Th2 pathway. We present a pediatric patient with severe, recalcitrant actinic prurigo who achieved rapid and sustained clearance with dupilumab.

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.