The humanistic burden of vitiligo: a systematic literature review of quality-of-life outcomes.

Despite historical mischaracterization as a cosmetic condition, patients with the autoimmune disorder vitiligo experience substantial quality-of-life (QoL) burden. This systematic literature review of peer-reviewed observational and interventional studies describes comprehensive evidence for humanistic burden in patients with vitiligo. PubMed, EMBASE, Scopus and the Cochrane databases were searched through February 10, 2021, to qualitatively assess QoL in vitiligo. Two independent reviewers assessed articles for inclusion and extracted data for qualitative synthesis. A total of 130 included studies were published between 1996 and 2021. Geographical regions with the most studies were Europe (32.3%) and the Middle East (26.9%). Dermatology-specific instruments, including the Dermatology Life Quality Index (DLQI; 80 studies) and its variants for children (CDLQI; 10 studies) and families (FDLQI; 4 studies), as well as Skindex instruments (Skindex-29, 15 studies; Skindex-16, 4 studies), were most commonly used to measure humanistic burden. Vitiligo-specific instruments, including the Vitiligo-specific QoL (VitiQoL; 11 studies) instrument and 22-item Vitiligo Impact Scale (VIS-22; 4 studies), were administered in fewer studies. Among studies that reported total scores for the overall population, a majority revealed moderate or worse effects of vitiligo on patient QoL (DLQI, 35/54 studies; Skindex, 8/8 studies; VitiQoL, 6/6 studies; VIS-22, 3/3 studies). Vitiligo also had a significant impact on the QoL of families and caregivers; 4/4 studies reporting FDLQI scores indicated moderate or worse effects on QoL. In general, treatment significantly (P < 0.05) improved QoL, but there were no trends for types or duration of treatment. Among studies that reported factors significantly (P ≤ 0.05) associated with reduced QoL, female sex and visible lesions and/or lesions in sensitive areas were most common. In summary, vitiligo has clinically meaningful effects on the QoL of patients, highlighting that greater attention should be dedicated to QoL decrement awareness and improvement in patients with vitiligo.

Sebocyte differentiation as a new target for acne therapy: an in vivo experience.

BACKGROUND: Acne, a disease of the sebaceous gland with multifactorial pathogenesis, affects more than 85% of adolescents. A better deepening of the mechanisms underlying the disease is needed to define effective and mechanism-targeted treatments. OBJECTIVE: To understand whether the sebocyte differentiation process could be involved in the pathogenesis of the disease. METHODS: Protein expressions were evaluated by Western blot analysis and ELISA; mRNA levels by real-time RT-PCR, lipid analysis and lipid peroxidation were performed by gas chromatography, mass spectrometry and spectrophotometric assay. RESULTS: In vitro, low differentiated SZ95 sebocyte expressed an up-modulation of genes involved in sebogenesis and a higher level of insulin receptor respect to differentiated cells, resulting in an increased response to insulin and in the production of acne-like sebum. The induction of SZ95 sebocyte differentiation by the peroxisome proliferator-activated receptor γ (PPARγ) modulator NAC-GED0507 reduced the response to insulin normalizing the sebum production and decreasing the release of proinflammatory mediators. In vivo treatment of acne patients with NAC-GED0507 1% gel ameliorated clinical manifestations and induced in sebum the expression of PPARγ, associated with the decrease in mammalian target of rapamycin activation and levels of inflammatory molecules, confirming the results obtained in vitro. CONCLUSIONS: The study provides relevant insight into acne pathogenesis, identifying an alteration of sebocyte differentiation as pathogenetic basis of the disease and the induction of the differentiation process as a therapeutic target in acne therapy interfering with all pathogenic mechanisms.

Smad7 positively regulates keratinocyte proliferation in psoriasis.

BACKGROUND: Transforming growth factor (TGF)-ß1 exerts inhibitory effects on keratinocyte proliferation. OBJECTIVES: To examine whether Smad7, a known inhibitor of TGF-ß1 signalling, is involved in psoriasis-associated keratinocyte hyperproliferation. METHODS: Smad7 was evaluated in skin sections of patients with psoriasis and healthy controls and in mice with Aldara-induced skin pathology by real-time polymerase chain reaction and immunohistochemistry. To assess whether Smad7 positively regulates in vivo keratinocyte growth, mice treated with Aldara received daily cutaneous administration of Smad7 antisense oligonucleotide (AS). Keratin (K)6 and K16, cell-cycle-associated factors, cell-cycle and cell proliferation were evaluated in HaCaT cells either treated with Smad7 AS or transfected with Smad7 plasmid and in mice given Smad7 AS. RESULTS: Smad7 was highly expressed in keratinocytes of patients with psoriasis and of mice treated with Aldara. In HaCaT cells, Smad7 knockdown inhibited cell growth, reduced K6 and K16 expression and promoted accumulation of cells in the S-phase of the cell cycle. Smad7-deficient keratinocytes exhibited reduced levels of CDC25A protein, a phosphatase that facilitates progression of cells through the S-phase, and hyperphosphorylation of eukaryotic initiation factor 2 (eIF2)α, a negative regulator of CDC25 protein translation. Consistently, Smad7 overexpression in HaCaT cells was followed by induction of K6 and K16 and increased cell proliferation. Topical application of Smad7 AS to Aldara-treated mice reduced epidermal thickness. CONCLUSIONS: Our data show that Smad7 is overexpressed in human and murine psoriasis and suggest a key role of this molecule in the control of keratinocyte proliferation.

Latent tuberculosis infection in patients with chronic plaque psoriasis: evidence from the Italian Psocare Registry.

BACKGROUND: The nationwide prevalence of latent tuberculosis infection (LTBI) in Italian patients with psoriasis has never been investigated. OBJECTIVES: To estimate the nationwide prevalence of LTBI in Italian patients with psoriasis who are candidates for systemic treatment. METHODS: Data were obtained from the Psocare Registry on those patients (n = 4946) with age > 18 years, systemic treatment at entry specified and tuberculin skin test (TST) performed according to the Mantoux method. LTBI diagnosis was based on a positive TST result in the absence of any clinical, radiological or microbiological evidence of active tuberculosis. RESULTS: Latent tuberculosis infection was diagnosed in 8·3% of patients with psoriasis (409 of 4946). The prevalence of LTBI was lower in patients on biologics than in those on conventional systemic treatments, ranging from 4·3% (19 of 444) of patients on adalimumab to 31% (eight of 26) of those on psoralen-ultraviolet A (P < 0·05). Independent factors associated with LTBI were male sex [odds ratio (OR) 1·30, 95% confidence interval (CI) 1·04-1·62; P = 0·02], age over 55 years (OR 2·93, 95% CI 2·18-3·93; P < 0·001) and being entered into a conventional treatment (OR 3·83, 95% CI 3·10-4·74; P < 0·001). Positive history of tuberculosis was seen in 1% of patients (n = 49). CONCLUSIONS: The nationwide prevalence of LTBI in Italian patients with psoriasis candidate to systemic treatment is high, and screening is recommended prior to biological treatment.

Vitiligo: characterization of melanocytes in repigmented skin after punch grafting.

BACKGROUND: Punch grafting is a surgical technique mainly applied in therapy-resistant, stable and circumscribed vitiligo. OBJECTIVE: (i) To characterize in detail the features of the repigmented skin among punch grafts; and (ii) to correlate the ex vivo results with clinical data and punch grafting outcome. METHODS: We evaluated by immunohistochemistry and image analysis the expression of a panel of specific melanocyte markers including HMB45, MITF, c-kit, MART-1 and TRP1, the proliferation marker Ki67 and the cell-cell adhesion molecule E-cadherin in tissue samples collected from nine patients after punch grafting. RESULTS: Cells positive for MITF, c-kit, MART-1 and TRP1 were detected in the repigmented skin of all biopsies, whereas no reactivity was observed for HMB45. Melanocytes were identified along the entire length of the sections, and their mature state was assessed by the immuno-reactivity for the differentiation marker MART-1, the absence of cells positively stained for Ki67 and by the co-expression of c-kit and TRP1, a marker of a differentiated and pigmented state. Clinically, smaller punch grafts aimed at repigmenting lesional areas on the face gave the faster clinical results with no side-effects. Patients subjected to bigger punch grafts on the knee exhibited a longer repigmentation time and presented cobble stoning. CONCLUSION: Our results suggest that the repigmentation observed in the areas between the grafts is due to the activation of the melanocytes located in the donor sites. These cells start to horizontally migrate towards the lesional skin thanks to successively the enlargement of intercellular spaces in relation to a decrease of E-cadherin reactivity and the up-modulation of pro-melanogenic mediators. Production and transfer of melanin in the surrounding keratinocytes and their persistence were assessed by the reactivity for MITF, c-kit, MART-1 and TRP1 but not for the pre-melanosome marker (HMB45).

Cosmetics for acne: indications and recommendations for an evidence-based approach.

AIM: The aim of this review was to evaluate, by a thorough revision of the literature, the true efficacy of currently available topic and systemic cosmetic acne agents. METHODS: The efficacy of currently available cosmetic acne agents has been retrospectively evaluated via thorough revision of the literature on matched electronic databases (PubMed). All retrieved studies, either randomized clinical trials or clinical trials, controlled or uncontrolled were considered. RESULTS: Scientific evidence suggests that most cosmetic products for acne may enhance the clinical outcome. Cleansers should be indicated to all acne patients; those containing benzoyl peroxide or azelaic/salicylic acid/triclosan show the best efficacy profile. Sebum-controlling agents containing nicotinamide or zinc acetate may minimize excessive sebum production. Cosmetics with antimicrobial and anti-inflammatory substances such as, respectively, ethyl lactate or phytosphingosine and nicotinamide or resveratrol, may speed acne recovery. Topical corneolytics, including retinaldehyde/glycolic acid or lactic acid, induce a comedolytic effect and may also facilitate skin absorption of topical drugs. Finally, the use of specific moisturizers should be strongly recommended in all acne patients. CONCLUSION: Cosmetics, if correctly prescribed, may improve the performance of the therapy, whereas wrong procedures and/or inadequate cosmetics may worsen acne. Cosmetological recommendations may allow clinicians to make informed decisions about the role of various cosmetics and to indentify the appropriate indications and precautions. The choice of the most effective product should take into consideration the ongoing pharmacological therapy and acne type/severity as well.

Inflammasome activation and vitiligo/nonsegmental vitiligo progression.

BACKGROUND: Polymorphisms of NLR (nucleotide-binding domain and leucine rich repeat containing) family, pyrin domain containing protein 1 (NLRP1) have been found in patients with vitiligo/nonsegmental vitiligo (NSV), and increased NLRP1 expression has been detected in the leading edge of lesional skin biopsies. OBJECTIVES: To evaluate the presence and intensity of NLRP1 immunostaining in lesional and perilesional skin of patients with vitiligo/NSV and to search for possible correlations between NLRP1 and interleukin (IL)-1ß expression, lymphocytic infiltrates and disease activity. METHODS: Of 14 consecutive vitiligo/NSV patients, eight had active disease [Vitiligo European Task Force (VETF) spreading score +1 to +5], one patient had stable disease and five patients had regressive disease (VETF spreading score -1 to -3). We performed immunostaining for NLRP1, B and T lymphocytes, IL-1ß and kallikrein 7 on lesional and perilesional vitiligo skin. RESULTS: NLRP1 and IL-1ß immunostaining in perilesional vitiligo/NSV skin was significantly associated with progressive disease (P = 0·009 and 0·04, respectively) and performed better than the simple detection of lymphocytic infiltrates. CONCLUSIONS: Our findings suggest that markers of the NLRP1 inflammasome could be a useful test for assessing disease activity in addition to the detection of inflammatory infiltrates in the progressing margins of vitiligo/NSV lesions.

Leptin promotes a proinflammatory lipid profile and induces inflammatory pathways in human SZ95 sebocytes.

BACKGROUND: Leptin, the adipocyte-secreted hormone that regulates weight, is known to link lipid metabolism with inflammation in various cell types. However, its role in human sebocytes has not yet been investigated. OBJECTIVES: The purpose of this study was to investigate the effects of leptin in human sebaceous gland biology. METHODS: Expression of the long form of the leptin receptor (Ob-Rb) was detected by real-time quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) and immunochemistry. Lipid analysis was by high-performance thin-layer chromatography, gas chromatography-mass spectrometry and time-of-flight mass spectrometer mass detection. Lipid bodies were visualized by BODIPY staining using fluorescent microscopy and measured by flow cytometry. Interleukin (IL)-6 and IL-8 mRNA levels were assessed by real-time qRT-PCR and their release was evaluated by enzyme-linked immunosorbent assay. Cyclooxygenase (COX)-2 and 5-lipooxygenase (LOX) protein expression and phosphorylation of p65 and signal transducer and activator of transcription (STAT)-3 were determined by Western blot analysis. RESULTS: Expression of Ob-Rb was detected in human sebaceous glands and in cultured human SZ95 sebocytes. The treatment of SZ95 sebocytes with leptin led to enlarged intracellular lipid bodies, increased ratios of unsaturated/saturated fatty acids and decreased vitamin E levels. Further supporting a proinflammatory role, leptin induced COX-2 and 5-LOX expression in SZ95 sebocytes and augmented the production of IL-6 and IL-8 cytokines. On leptin treatment, the STAT-3 and nuclear factor-κB pathways were activated, indicating that these known leptin signalling pathways are active in human sebocytes. CONCLUSIONS: Our findings suggest that leptin signalling may be involved in the proinflammatory regulation of sebaceous lipid metabolism and the induction of inflammatory enzymes and cytokines.

Acne is an inflammatory disease and alterations of sebum composition initiate acne lesions.

Hyperseborrhoea has been considered as a major aetiopathogenetic factor of acne. However, changes in sebaceous gland activity not only correlate with seborrhoea but also with alterations in sebum fatty acid composition. Current findings indicate that sebum lipid fractions with proinflammatory properties and inflammatory tissue cascades are associated in the process of the development of acne lesions. The oxidant/antioxidant ratio of the skin surface lipids and alterations of lipid composition are the main players in the induction of acne inflammation. Nutrition may influence the development of seborrhoea, the fractions of sebum lipids and acne. Acne is an inflammatory disease probably triggered, among others, by proinflammatory sebum lipid fractions.

Guidelines for the management of vitiligo: the European Dermatology Forum consensus.

The aetiopathogenic mechanisms of vitiligo are still poorly understood, and this has held back progress in diagnosis and treatment. Up until now, treatment guidelines have existed at national levels, but no common European viewpoint has emerged. This guideline for the treatment of segmental and nonsegmental vitiligo has been developed by the members of the Vitiligo European Task Force and other colleagues. It summarizes evidence-based and expert-based recommendations (S1 level).

Metabolic abnormalities associated with initiation of systemic treatment for psoriasis: evidence from the Italian Psocare Registry.

OBJECTIVE: To evaluate variations in laboratory parameters and diagnoses of selected clinical conditions up to 16 weeks after starting a new systemic psoriasis treatment for Psocare Registry enrollees. DESIGN: Prospective cohort study. SETTING: Italian public referral centres for psoriasis treatment. PATIENTS: First-time recipients (n = 10,539) of continuous systemic psoriasis treatment for at least 16 weeks. MAIN OUTCOME MEASURE: Mean variations in (weeks 8 and 16) and proportions of patients reaching a clinically meaningful increase in serum levels (week 16) of total and low-density lipoprotein cholesterol, triglycerides, aspartate amino transferase, alanine amino transferase and creatinine, as well as week-16 cumulative incidences of new diagnoses of diabetes mellitus and arterial hypertension. RESULTS: Mean cholesterol and triglyceride levels significantly increased in patients treated with acitretin or cyclosporine. Mean triglyceride levels also increased in efalizumab- and etanercept-treated patients. Mean transaminase values increased in methotrexate-treated patients, and mean aspartate amino transferase levels increased in infliximab-treated patients. The average serum creatinine value increased in cyclosporine-treated patients. Acitretin and cyclosporine were associated with risk of hypercholesterolaemia (odds ratios 1.51 and 1.34) and acitretin with risk of hypertriglyceridaemia (odds ratio 1.43). Methotrexate and infliximab were associated with risk of more than doubling the upper normal aspartate amino transferase (odds ratios 2.06 and 1.87) and alanine amino transferase (odds ratios 2.38 and 1.74) values. The relative risk of developing arterial hypertension and diabetes was increased for patients receiving cyclosporine (odds ratios 3.31 and 2.88). CONCLUSION: Systemic treatments for psoriasis resulted in heterogeneous effects on the parameters analysed.

Anti-oxidant defence mechanism in vitiliginous skin increases with skin type.

BACKGROUND: Vitiligo skin shows different burning capacity in people with different phototype. In normal skin antioxidant status is correlated to skin phototype, but unexpectedly it appears that there is a gradual decrease in burning susceptibility of depigmented skin of individuals with increasing phototype (II→VI). OBJECTIVE: To assess if the antioxidant response in the lesional vitiligo skin is involved in those protection mechanisms. Moreover, a possible correlation between cutaneous and systemic endogenous antioxidants in vitiligo patients has been investigated. METHODS: We enrolled in the study 29 patients with active vitiligo, divided into five groups according to skin type (II to VI). We analysed reduced and oxidized glutathione (GSH and GSSG, respectively), ubiquinone (CoQ10), catalase (Cat), superoxide dismutases (Cu/Zn-SOD and Mn-SOD), GSH peroxidase (GSH-Px), as indexes of chemical and enzymatic antioxidants, in suction blister roofs as well as in peripheral blood mononuclear cells (PBMNCs). RESULTS: The vitiligo patients showed an imbalance of antioxidant network, both in depigmented skin and PBMNCs. Interestingly, in vitiligo skin a phototype-related increase of antioxidant enzyme activities (Cat, Mn-SOD and GPx) and GSH amount have been observed. Similarly in PMBNCs Cat and total SOD activities, as well as GSH content progressively increased from skin type II to skin type VI. Endogenous antioxidants in vitiligo skin are correlated to those in PBMNCs, suggesting that systemic and epidermal antioxidant network functionalities are connected. CONCLUSIONS: The correlation between antioxidant levels and clinical phototype confirmed the hypothesis that other factors than melanin determine largely the minimal erythema dose values in vitiligo lesional skin.

[Mechanisms underlying post-inflammatory hyperpigmentation: lessons from solar lentigo]. / Mécanismes de l'hyperpigmentation post-inflammatoire: ce que le lentigo actinique nous a appris.

Hyperpigmentation of the skin is a common dermatologic condition in all skin types but most prominent in brown-skinned population. In skin of color any inflammation or injury can be accompanied by alterations in pigmentation (hyper/hypo-pigmentation). Postinflammatory hyperpigmentation (PIH) can be observed in many skin conditions including acne, eczema, and contact dermatitis. In the control of skin pigmentation, parallel to the cross-talk between keratinocytes and melanocytes, increasing evidence has underlined the crucial role exerted by the interactions between mesenchymal and epithelial cells through the release of fibroblast-derived growth factors. Among these factors, the keratinocyte growth factor (KGF), alone or in combination with interleukin-1α, induces melanin deposition in vitro and hyperpigmented lesions in vivo. Furthermore, a moderate increase of KGF and a high induction of its receptor have been shown in solar lentigo lesions, suggesting the involvement of this growth factor in the onset of the hyperpigmented spots. Several studies highlight the possible contribution of the fibroblast-derived melanogenic growth factors to the hyperpigmentated lesions, in the context of the mesenchymal - epithelial interactions modulating melanocyte functions.

Mechanisms underlying post-inflammatory hyperpigmentation: lessons from solar lentigo.

Hyperpigmentation of the skin is a common dermatologic condition in all skin types but most prominent in brown-skinned population. In skin of color any inflammation or injury can be accompanied by alterations in pigmentation (hyper/hypo-pigmentation). Postinflammatory hyperpigmentation (PIH) can be observed in many skin conditions including acne, eczema, and contact dermatitis. In the control of skin pigmentation, parallel to the cross-talk between keratinocytes and melanocytes, increasing evidence has underlined the crucial role exerted by the interactions between mesenchymal and epithelial cells through the release of fibroblast-derived growth factors. Among these factors, the keratinocyte growth factor (KGF), alone or in combination with interleukin-1α, induces melanin deposition in vitro and hyperpigmented lesions in vivo. Furthermore, a moderate increase of KGF and a high induction of its receptor have been shown in solar lentigo lesions, suggesting the involvement of this growth factor in the onset of the hyperpigmented spots. Several studies highlight the possible contribution of the fibroblast-derived melanogenic growth factors to the hyperpigmentated lesions, in the context of the mesenchymal - epithelial interactions modulating melanocyte functions.

Rosacea - global diversity and optimized outcome: proposed international consensus from the Rosacea International Expert Group.

BACKGROUND: The absence of specific histological or serological markers, the gaps in understanding the aetiology and pathophysiology of rosacea, and the broad diversity in its clinical manifestations has made it difficult to reach international consensus on therapy guidelines. OBJECTIVES: The main objective was to highlight the global diversity in current thinking about rosacea pathophysiology, classification and medical features, under particular consideration of the relevance of the findings to optimization of therapy. METHODS: The article presents findings, proposals and conclusions reached by the ROSacea International Expert group (ROSIE), comprising European and US rosacea experts. RESULTS: New findings on pathogenesis provide a rationale for the development of novel therapies. Thus, recent findings suggest a central role of the antimicrobial peptide cathelicidin and its activator kallikrein-5 by eliciting an exacerbated response of the innate immune system. Cathelicidin/kallikrein-5 also provide a rationale for the effect of tetracyclines and azelaic acid against rosacea. Clinically, the ROSIE group emphasized the need for a comprehensive therapy strategy - the triad of rosacea care - that integrates patient education including psychological and social aspects, skin care with dermo-cosmetics as well as drug- and physical therapies. Classification of rosacea into stages or subgroups, with or without progression, remained controversial. However, the ROSIE group proposed that therapy decision making should be in accordance with a treatment algorithm based on the signs and symptoms of rosacea rather than on a prior classification. CONCLUSION: The ROSIE group reviewed rosacea pathophysiology and medical features and the impact on patients and treatment options. The group suggested a rational, evidence-based approach to treatment for the various symptoms of the condition. In daily practice this approach might be more easily handled than prior subtype classification, in particular since patients often may show clinical features of more than one subtype at the same time.

A data independent acquisition all ion fragmentation mode tool for the suspect screening of natural toxins in surface water.

Among natural freshwater pollutants, cyanotoxins, mycotoxins, and phytotoxins are the most important and less studied. Their identification in surface water is challenging especially cause of the lack of standards and established analytical parameters. Most target methods focus one or a single group of compounds with similar characteristics. Here we present an AIF fast method for the tentative identification of natural toxins in water. Respect to the previous method [1], it offers higher performances for the acquisition of unknown compounds at low levels for higher number of analytes. The key aspects of the method are: • The qualitative screening DIA-AIF workflow using Q Exactive Orbitrap. Both targeted and suspect screening bases have been combined with online databases and suspect list to retrieve candidates as suspect natural toxins and their metabolites or degradation products. • The in-silico analysis of mass spectrums allowed a fast structural characterization. • The workflow has been finally applied to real samples coming from the Czech Republic, Italy, and Spain allowing the determination of 17 suspect natural toxins, 4 of them confirmed. None toxin passed the limit of 1 µg/L taken from the legislation applied for microcystin LR and arbitrarily extended to all toxins.

Role of fibroblast-derived growth factors in regulating hyperpigmentation of solar lentigo.

BACKGROUND: Cutaneous pigmentation is regulated by a complex melanogenic network in which both keratinocytes and fibroblasts synthesize growth factors and cytokines. Solar lentigo (SL) is characterized by hyperpigmented lesions occurring on photodamaged skin areas. Despite the association of SL to ultraviolet (UV) exposure, the mechanisms underlying the development of these spots are not completely defined. OBJECTIVES: To analyse the involvement of the fibroblast-derived growth factors, hepatocyte growth factor (HGF), keratinocyte growth factor (KGF) and stem cell factor (SCF) in SL hyperpigmentation; to evaluate whether the photoageing process occurring in fibroblasts could be responsible for the altered expression of these cytokines; and to investigate a new possible role of KGF in regulating pigmentation through the specific induction of melanogenic cytokines by keratinocytes. METHODS: We performed immunohistochemical analysis of HGF, KGF and SCF on SL biopsies. We analysed the mRNA expression of these cytokines using an in vitro model of photoageing induced on fibroblasts. Finally, we evaluated the effects of KGF on the expression of melanogenic cytokines at the mRNA and protein levels on keratinocytes. RESULTS: We found positive staining for HGF, KGF and SCF in the upper dermis of SL lesions and a significant induction of the three cytokines in photoaged fibroblasts. We also demonstrated the contribution of KGF to pigmentation, showing its ability specifically to modulate the expression of SCF in keratinocytes. CONCLUSIONS: Fibroblasts may be persistently activated by UV exposure to release melanogenic growth factors; this inducible cytokine network acts both directly and indirectly through keratinocytes and may contribute to the hyperpigmentation of SL.