Melanogenesis Inhibitors.

Abnormally high production of melanin or melanogenesis in skin melanocytes results in hyperpigmentation disorders, such as melasma, senile lentigines or freckles. These hyperpigmentary skin disorders can significantly impact an individual's appearance, and may cause emotional and psychological distress and reduced quality of life. A large number of melanogenesis inhibitors have been developed, but most have unwanted side-effects. Further research is needed to better understand the mechanisms of hyperpigmentary skin disorders and to develop potent and safe inhibitors of melanogenesis. This review summarizes the current understanding of melanogenesis regulatory pathways, the potential involvement of the immune system, various drugs in current use, and emerging treatment strategies to suppress melanogenesis.

Linear atrophoderma of Moulin: a disease related to immunity or a kind of connective tissue disease?

We describe a 28-year-old man with linear atrophoderma of Moulin (LAM), whose serum immunological markers were abnormal (including antinuclear antibody, ribonucleoprotein, immunoglobulin M and anti-SM antibody). In addition, however, a histological analysis identified unexpected connective tissue disease changes in this patient. We speculate that the pathogenesis of LAM is associated with immunity or that LAM itself is a kind of connective tissue disease.

Clinical presentation, immunopathology, and treatment of juvenile-onset mycosis fungoides: a case series of 34 patients.

BACKGROUND: Mycosis fungoides (MF), the most common form of cutaneous T-cell lymphoma, typically presents in middle-aged to elderly individuals. OBJECTIVE: We sought to study the demographics, clinicopathologic features, treatment response, and prognosis of patients with biopsy-proven MF diagnosed before 20 years of age. METHODS: Patients were identified from a prospectively collected database for retrospective analysis. RESULTS: Of 1902 patients with MF, 34 had juvenile-onset MF: 41% were stage IA, 56% were stage IB, and 3% were stage IIB at diagnosis. The male to female ratio was 1.1:1. The median age of symptom onset was 9 years (range 3-19 years), with a delay in diagnosis between 1 month and 14 years. Patients primarily presented with hypopigmented (53%), hyperpigmented (29%), and pink-violaceous (41%) patches/plaques. Immunohistochemistry revealed 39% with CD8(+) immunophenotype, 67% of which had hypopigmented lesions. The phototherapy response rate in 21 patients was 81%. All patients who completely responded to narrowband ultraviolet B phototherapy had hypopigmented MF. LIMITATIONS: This is a single cancer center study. CONCLUSION: Juvenile-onset MF presents with early-stage disease with an overrepresentation of hypopigmented MF and CD8(+) immunophenotype. Narrowband ultraviolet B is an effective treatment option for juveniles, especially for those with the hypopigmented variant.

Macular lymphocytic arteritis: three cases questioning its classification as primary lymphocytic vasculitis.

BACKGROUND: Macular arteritis, macular lymphocytic arteritis (MLA) or lymphocytic thrombophilic arteritis all correspond to an identical new clinicopathological entity. Its individualization as a primary cutaneous lymphocytic arteritis is still controversial for certain authors as it could represent a latent form of cutaneous polyarteritis nodosa. MATERIALS AND METHODS: We report here 3 additional cases of MLA, present a review of the literature and discuss the disease's nosology. RESULTS: MLA is characterized clinically by a benign skin eruption consisting in bilateral asymptomatic erythematous/hyperpigmented macules mainly located on the lower legs and histologically by a medium-sized cutaneous lymphocytic prominent arteritis present in early cutaneous lesions. CONCLUSION: These findings support that MLA may be considered as a chronic and indolent primary lymphocytic cutaneous arteritis. Nevertheless, in some cases the objective obliteration of cutaneous vessels underlines the need for continuous monitoring in MLA patients.

Major histocompatibility complex (MHC) gene frequency in acquired dermal macular hyperpigmentation: a case control study.

BACKGROUND: Human leukocyte antigen (HLA) allele frequencies have a known association with the pathogenesis of various autoimmune diseases. METHODS: We recruited 31 Indian patients of acquired dermal macular hyperpigmentation (ADMH) and 60 unrelated, age-and-gender-matched healthy controls. After history and clinical examination, 5 ml of blood in EDTA vials was collected. These samples were subjected to DNA extraction and the expression of HLA A, B, C, DR, DQ-A, and DQ-B was studied. RESULTS: There was a predominance of females with a gender ratio of 23 : 8 and the most common phototype was Fitzpatrick type IV (83.9%). There was a significant association of HLA A*03:01 (OR: 5.8, CI: 1.7-17.0, P = 0.005), HLA B*07:02 (OR: 5.3, CI: 1.9-14.6, P = 0.003), HLA C*07:02 (OR: 4.3, CI: 1.8-9.6, P = 0.001), HLA DRB1*10:01 (OR: 7.6, CI: 1.7-38.00, P = 0.022), and HLA DRB1*15:02 (OR: 31.0, CI: 4.4-341.8, P < 0.001) with patients compared to controls, whereas HLA DQB*03:01 was less associated with patients compared to controls (OR: 0.2, CI: 0.0-0.6, P = 0.009). CONCLUSION: Patients with ADMH are more likely to have the HLA A*03:01, HLA B 07*02, HLA C*07:02, HLA DRB1*10:01, HLA DRB1*15:02 and less likely to have the HLA DQB*03:01 allele. Larger cohort studies may thus be conducted studying these specific alleles.

Bilaterally symmetrical alopecia with reticulated hyperpigmentation: a manifestation of cutaneous lupus erythematosus in a dog with systemic lupus erythematosus.

An adult castrated male Doberman Pinscher was presented with a 6-month history of well-demarcated alopecic patches with reticulated hyperpigmentation and fine peripheral scaling on the axillae, thorax, abdomen, inguinal region, and thighs. The dog later developed hyperthermia, lethargy, apparent joint pain, peripheral lymphadenomegaly, vomiting, and diarrhea. Relevant laboratory tests results included anemia, thrombocytopenia, proteinuria, and an elevated antinuclear antibodies serum titer. Histologically, skin biopsy specimens had a lymphocyte-rich interface dermatitis and interface mural folliculitis ending in follicular destruction. Altogether, these signs were consistent with a unique alopecic variant of chronic cutaneous lupus erythematosus, eventually associated with the development of systemic lupus erythematosus. This rare form of chronic cutaneous lupus needs to be added to the expanding list of lymphocyte-mediated autoimmune alopecias in dogs.

A case of H syndrome showing immunophenotye similarities to Rosai-Dorfman disease.

H syndrome (OMIM 612391) is a recently described autosomal recessive genodermatosis characterized by indurated, hyperpigmented, and hypertrichotic skin and systemic manifestations including hepatosplenomegaly, cardiac anomalies, hearing loss, hypogonadism, low height, hypertriglyceridemia, hallux valgus, and flexion contractures. H syndrome results from mutations in the SLC29A3 gene, which encodes the human equilibrative nucleoside transporter hENT3. The cutaneous histopathology is characterized by a striking mononuclear cell infiltrate in the dermis consisting of CD68+ monocyte-derived cells and CD34+ and factor XIIIa+ dendrocytes. We describe a case of H syndrome in which the infiltrating mononuclear cells were CD68+, CD163+, S-100+, and CD1a-, thus simulating the immunophenotype observed in Rosai-Dorfman disease (RDD). The immunostaining for CD21, fascin, and CD34 were negative, and there were also many factor XIIIa+ dendrocytes interspersed within the dense mononuclear cell infiltrate. Recent findings of biallelic mutations in SLC29A3 in 2 families reported to have familial RDD and in a kindred with Faisalabad histiocytosis (OMIM 602782), which is an autosomal inherited form of histiocytosis with similarities to RDD, may explain the RDD-like immunophenotype in our H syndrome case.

The Pathogenesis and Management of Acne-Induced Post-inflammatory Hyperpigmentation.

Acne vulgaris is a common inflammatory disease. Among patients with darker skin phototypes (Fitzpatrick III-VI), the inflammatory processes of acne stimulate excess melanogenesis and abnormal melanin deposition, leading to pigmentary sequelae known as post-inflammatory hyperpigmentation and post-inflammatory erythema in all skin tones, although post-inflammatory hyperpigmentation is more common in darker skin and post-inflammatory erythema in lighter skin. These pigmentary alterations can be long lasting and are often more distressing to patients than the active acne lesions. This article discusses what is known about acne-related pigmentation, much of which is extrapolated from general study of nonspecific pigment deposition. Because dyspigmentation poses both a significant clinical concern to patients and a therapeutic challenge to clinicians, we formed a working group consisting of pigmentary experts with the aim of increasing awareness and education of acne-related pigmentary sequelae.

Use of nail and oral pigmentation to determine ART eligibility among HIV-infected Ugandan adults.

OBJECTIVES: To evaluate the use of grey/distal banded nails as an indicator of advanced immunosuppression, and thus eligibility for ART, in resource poor settings. METHODS: We tested whether grey/distal banded nails and/or oral pigmentation could be used to identify patients with low CD4 cell counts at two cut-offs: <200 and <350 cells/microl in ART naive adults. RESULTS: Four hundred and three nail and oral cavities were photographed and assessed. Grey/distal banded nails and/or oral pigmentation were significantly associated with a CD4 cell count <200 cells/microl (P < 0.001), with a sensitivity of 66%, a specificity of 50% and a negative predictive value of 77%. However, there was no association when a CD4 cell count cut-off of <350 cells/microl was used. Inter-observer agreement (k 0.46) was fair/moderate. CONCLUSIONS: While grey/distal banded nails and/or oral pigmentation are associated with low CD4 counts, the sensitivity and kappa score are too low for this method to be recommended as a tool to guide ART initiation; large number of individuals eligible for ART would be missed.

Efficacy of a wound-dressing biomaterial on prevention of postinflammatory hyperpigmentation after suction blister epidermal grafting in stable vitiligo patients: a controlled assessor-blinded clinical study with in vitro bioactivity investigation.

Postinflammatory hyperpigmentation (PIH) is a common disfiguring complication following inflammatory dermatoses and cosmetic procedures in dark-skinned individuals. Anti-inflammatory and repairing agents targeting primary inflammation and injury are becoming promising choices for preventing PIH. The aim of this active-controlled, assessor-blinded, intra-individual monocentric study was to evaluate the preventive effect of a wound-dressing biomaterial, mussel adhesive protein (MAP) in the suction blister-induced PIH model. Twenty Chinese patients underwent suction blister epidermal grafting had defined wound areas to receive a topical MAP spray or a potent corticosteroid cream once daily for seven consecutive days after operation. In situ semi-quantitative evaluations of inflammation and pigmentation were achieved by Mexameter, reflectance confocal microscopy and dermoscopy on week 1, week 4, and week 12. Topical application of MAP exerted remarkably inhibitory effect on PIH comparable to fluticasone propionate, manifested as significantly lower melanin index and papillary contrast measured by Mexameter and confocal microscopy on week 12 compared to untreated sites. Although MAP exhibited moderate anti-inflammatory effect weaker than fluticasone propionate, MAP-treated sites healed faster than steroid-treated and untreated sites. The biological activity of MAP was further studied in UVB-irradiated HaCaT cell model, which revealed MAP decreased the expression of UVB-induced α-melanocyte stimulating hormone (α-MSH) and pro-inflammatory cytokines (IL-1α, IL-6, COX-2). It also protected HaCaT cells from UVB-induced cell death and apoptosis. In conclusion, MAP could be a novel postoperational wound dressing preventing PIH associated with skin inflammation and injury.

Trichloroacetic acid model to accurately capture the efficacy of treatments for postinflammatory hyperpigmentation.

Postinflammatory hyperpigmentation (PIH) occurs following cutaneous injury and is common following resolution of acne especially in patients with skin of color. The objective of this study was to further validate a trichloroacetic acid (TCA)-induced PIH model and compare it to acne-induced PIH using topical bakuchiol, a botanical extract that has been shown to have antimicrobial, anti-inflammatory, antioxidant, and antiacne properties. A prospective, non-randomized clinical trial was conducted on subjects with skin phototypes IV-VI with a history of acne-induced PIH. Subjects applied bakuchiol or vehicle cream twice daily to 2 acne-induced and 2 TCA-induced PIH lesions for 28 days with a third lesion serving as a control in each group. Degree of improvement was defined as the change in the Investigator Global Assessment (IGA) score over 28 days of treatment. Twenty subjects (6 males, 14 females) completed the study. For TCA-induced PIH sites, there was a statistically significant (p < 0.05) degree of improvement with bakuchiol treatment (- 0.50 ± 0.18) compared to vehicle (0.05 ± 0.15) and control (- 0.06 ± 0.17). For acne-induced PIH, there was a greater degree of improvement for bakuchiol (- 1.06 ± 0.23) when compared to vehicle (- 0.56 ± 0.16) and control (- 0.69 ± 0.18); however, statistical significance was not reached (p > 0.05). TCA-induced PIH sites were uniform in size and pigment intensity thereby allowing better comparison among sites. This emphasizes the relevance of using this model for PIH which may help reduce the barriers in clinical trials and help improve access to treatments for patients who suffer from PIH. The results suggest that topical bakuchiol may decrease the severity of PIH.

Salidroside can target both P4HB-mediated inflammation and melanogenesis of the skin.

Rationale: Many external factors can induce the melanogenesis and inflammation of the skin. Salidroside (SAL) is the main active ingredient of Rhodiola, which is a perennial grass plant of the Family Crassulaceae. This study evaluated the effect and molecular mechanism of SAL on skin inflammation and melanin production. It then explored the molecular mechanism of melanin production under ultraviolet (UV) and inflammatory stimulation. Methods: VISIA skin analysis imaging system and DermaLab instruments were used to detect the melanin reduction and skin brightness improvement rate of the volunteers. UV-treated Kunming mice were used to detect the effect of SAL on skin inflammation and melanin production. Molecular docking and Biacore were used to verify the target of SAL. Immunofluorescence, luciferase reporter assay, CO-IP, pull-down, Western blot, proximity ligation assay (PLA), and qPCR were used to investigate the molecular mechanism by which SAL regulates skin inflammation and melanin production. Results: SAL can inhibit the inflammation and melanin production of the volunteers. SAL also exerted a protective effect on the UV-treated Kunming mice. SAL can inhibit the tyrosinase (TYR) activity and TYR mRNA expression in A375 cells. SAL can also regulate the ubiquitination degradation of interferon regulatory factor 1 (IRF1) by targeting prolyl 4-hydroxylase beta polypeptide (P4HB) to mediate inflammation and melanin production. This study also revealed that IRF1 and upstream stimulatory factor 1 (USF1) can form a transcription complex to regulate TYR mRNA expression. IRF1 also mediated inflammatory reaction and TYR expression under UV- and lipopolysaccharide-induced conditions. Moreover, SAL derivative SAL-plus (1-(3,5-dihydroxyphenyl) ethyl-ß-d-glucoside) showed better effect on inflammation and melanin production than SAL. Conclusion: SAL can inhibit the inflammation and melanogenesis of the skin by targeting P4HB and regulating the formation of the IRF1/USF1 transcription complex. In addition, SAL-plus may be a new melanin production and inflammatory inhibitor.

Dermoscopy and patch testing in patients with lichen planus pigmentosus on face: A cross-sectional observational study in fifty Indian patients.

BACKGROUND: Lichen planus pigmentosus (LPP) is a common cause of facial melanosis in the dark-skinned population. At present, information on dermoscopy and patch testing in LPP is limited. OBJECTIVES: To describe dermoscopic findings and study the role of patch testing in patients with LPP on the face. METHODS: Facial lesions of 50 patients with LPP were studied dermoscopically, followed by histological evaluation. Patch and photopatch tests with the Indian Standard Series and Scandinavian series, respectively, and patient's own cosmetics were performed on all patients. RESULTS: The most common dermoscopic finding was dots and/or globules (43/50, 86%) in different patterns: hem-like (20.9%), arcuate (18.6%), incomplete reticular (39.5%), complete reticular (7%), and not otherwise specified (14%). Other patterns were exaggerated pseudoreticular pattern, accentuation of pigmentation around follicular openings, targetoid appearance, and obliteration of the pigmentary network. There were 26 relevant patch tests in 17 (34%) patients: para-phenylenediamine (n = 5), nickel (n = 3), colophony, perfume mix and fragrance mix (n = 2 each), thiuram mix and 3,3,4,5-tetrachlorosalicylanilide (n = 1 each), and patients' own products (n = 9). The only positive photopatch test was to fentichlor. No clinical or histological finding differed significantly based on patch test results. The only dermoscopic finding to be statistically associated with a positive patch test was the non-characteristic arrangement of dots/globules (P = 0.042). LIMITATIONS: Dermoscopic features were not correlated with clinical features or disease duration. Implications of patch testing on the management of LPP cannot be commented upon as ours was a cross-sectional study. CONCLUSIONS: The present study describes the dermoscopic findings of facial lesions in LPP. Our patch test results suggest a probable role of allergens in causing LPP on the face.

[Blaschkolinear eruption with biological signs of lupus]. / Eruption blaschko-linéaire avec biologie lupique.

INTRODUCTION: Acquired inflammatory dermatoses of the adult with a blaschkolinear arrangement are rare. Their cause is unknown. CASE REPORT: We report the case of a 35-year-old man who presented an unilateral skin eruption covering the forearm and with secondary blaschkolinear extension to the arm, the axillary region and the chest. In this particular case, the patient was positive for RNP type anti-nuclear antibodies and direct immunofluorescence was positive in both biopsies of the lesions and of healthy skin. The eruption lasted 6 months and regressed spontaneously. DISCUSSION: Such cases are exceptional and the nosology is difficult to establish. A particular form of lupus erythematosus? Fortuitous coexpression of lupus antibodies and blaschkitis in an adult?

Inflammation drives wound hyperpigmentation in zebrafish by recruiting pigment cells to sites of tissue damage.

In humans, skin is the largest organ and serves as a barrier between our body and the outside world. Skin protects our internal organs from external pathogens and other contaminants, and melanocytes within the skin protect the body from damage by ultraviolet light. These same pigment cells also determine our skin colour and complexion. Skin wounding triggers a repair response that includes a robust recruitment of inflammatory cells, which function to kill invading microbes and clear away cell and matrix debris. Once at the wound site, these innate immune cells release a barrage of cytokines that direct the activities of other cells during the repair process. Tissue damage and repair also frequently lead to alterations in skin pigmentation, in particular to wound hyperpigmentation. In this study, we describe a model of wound hyperpigmentation in the translucent zebrafish larva, where we can live-image the recruitment of melanocytes and their precursors, melanoblasts, to the wound site. We show that these pigment cells are drawn in after the initial recruitment of innate immune cells and that the inflammatory response is essential for wound hyperpigmentation. This new model will allow us to uncover the molecular link between immune and pigment cells during tissue repair and to screen for potential therapeutics to dampen wound hyperpigmentation.