Worldwide expert recommendations for the diagnosis and management of vitiligo: Position statement from the international Vitiligo Task Force-Part 2: Specific treatment recommendations.

BACKGROUND: The treatment of vitiligo can be challenging. Up-to-date agreed consensus recommendations on the use of topical and systemic therapies to facilitate the clinical management of vitiligo are currently lacking. OBJECTIVES: To develop internationally agreed-upon expert-based recommendations for the treatment of vitiligo. METHODS: In this consensus statement, a consortium of 42 international vitiligo experts and four patient representatives participated in different online and live meetings to develop a consensus management strategy for vitiligo. At least two vitiligo experts summarized the evidence for different topics included in the algorithms. A survey was then given to a core group of eight experts to resolve the remaining issues. Subsequently, the recommendations were finalized and validated based on further input from the entire group during two live meetings. RESULTS: The recommendations provided summarize the latest evidence regarding the use of topical therapies (steroids, calcineurin inhibitors and Jak-inhibitors) and systemic therapies, including steroids and other systemic immunomodulating or antioxidant agents. The different modalities of phototherapies (NB-UVB, photochemotherapy, excimer devices and home phototherapy), which are often combined with other therapies, are also summarized. Interventional approaches as well as depigmentation strategies are presented for specific indications. Finally, the status of innovative and targeted therapies under development is discussed. CONCLUSIONS: This international consensus statement culminated in expert-based clinical practice recommendations for the treatment of vitiligo. The development of new therapies is ongoing in vitiligo, and this will likely improve the future management of vitiligo, a disease that still has many unmet needs.

Clinical Factors Affecting the Serum Retention of a Teratogenic Etretinate after the Acitretin Administration.

Etretinate, an acitretin metabolite, has a long retention duration in adipose tissues with a teratogenic potential. FDA advises a contraceptive period of at least three years after discontinuing acitretin. However, the effect of accumulated etretinate in adipose tissues on fetus is unknown. Although the teratogenic threshold for serum concentration of etretinate has been presented as higher than 2 ng/mL, that of acitretin is unknown. To examine factors affecting body retention of acitretin and etretinate, effects of acitretin dosage, acitretin-taking duration, elapsed time after stopping acitretin, age, sex, concomitant alcohol consumption, and foods and supplements rich in vitamin A intake on serum concentrations of acitretin and etretinate were analyzed in 14 acitretin-taken patients and 58 controls without taking acitretin or etretinate. Serum concentrations of acitretin, but not etretinate, tended to be inversely related to the discontinuation duration. They were also related to old age. Different from a published result that alcohol consumption could promote the metabolism of acitretin into etretinate, alcohol intake did not affect serum concentrations of etretinate. Unexpectedly, more frequent intake of vitamin A or provitamin A-rich food and supplements was associated with higher serum acitretin, whereas less frequent intake of vitamin A or provitamin A-rich food and supplements was associated with higher serum levels of etretinate in acitretin-taken patients. Despite preliminary data, inter-individual variations in serum retention of etretinate suggest the necessity of further research before applying the same guidelines to everyone to minimize unnecessary contraception.

The long-term risk of lymphoma and skin cancer did not increase after topical calcineurin inhibitor use and phototherapy in a cohort of 25,694 patients with vitiligo.

BACKGROUND: Topical calcineurin inhibitors have been used to treat vitiligo, either alone or in combination with phototherapy; however, the long-term safety of these agents remains controversial. OBJECTIVE: To investigate the risk of lymphoma and skin cancer in vitiligo patients who received topical calcineurin inhibitors or phototherapy. METHODS: A multicenter retrospective cohort study of 25,694 vitiligo patients who received topical calcineurin inhibitors or phototherapy for 6 weeks or more between 2001 and 2019 was performed. Cumulative doses of topical calcineurin inhibitors and total phototherapy sessions were determined. Outcomes were the development of lymphoma or skin cancer after enrollment, confirmed through chart review and pathology reports. RESULTS: During 95,203 person-years, 13 cases of lymphoma, 22 of actinic keratosis, 15 of nonmelanoma skin cancer, and 5 of melanoma were observed. The risk of lymphoma and skin cancer was not significantly increased by topical calcineurin inhibitor dose or phototherapy sessions. The interaction between the topical calcineurin inhibitors and phototherapy was not associated with an increased risk of skin cancer. LIMITATIONS: Retrospective study, individual follow-up duration less than 4 years, and no adjustment for comorbidities and medication history. Not generalizable to other races. CONCLUSION: The long-term risk of skin cancer or lymphoma was not associated with the use of topical calcineurin inhibitors, phototherapy, and both treatments in combination in patients with vitiligo.

Development of evidence-based consensus on critical issues in the management of patients with vitiligo: A modified Delphi study.

BACKGROUND/PURPOSE: Vitiligo remains a major challenge in dermatology. However, much of the treatment remains unclear, because little evidence is available. We sought to answer some critical questions pertaining to management of vitiligo patients. METHODS: A modified Delphi process among 31 vitiligo experts was conducted. A total of 12 clinical vitiligo treatment questions without clear answers were collected via a vote. To address each question, two members performed systematic literature reviews and prepared draft statements along with the levels of evidence and strength of recommendation. After reviewing the draft, all expressed their extent of agreement from 1 (strong disagreement) to 9 (strong agreement) for each item. The drafts were revised to reflect suggested comments. Discussion continued until all members agreed with the ultimate decision. RESULTS: The consensus process was completed after five rounds. We identified the best answers to 12 key questions, including issues on long-term phototherapy, systemic and topical corticosteroids, topical calcineurin inhibitors, immunosuppressants, excimer laser treatment, and surgical interventions. CONCLUSION: This consensus would complement current guidelines and aid both physician and patient decision-making in the treatment of vitiligo.

Complementary effect of hydroquinone and retinoic acid on corneocyte desquamation with their combination use.

BACKGROUND: Retinoic acid (RA) enhances skin-lightening capabilities of hydroquinone (HQ), at least in part, by facilitating desquamation which leads to increase penetration of HQ. The desquamation also affects skin irritation levels. The mechanism of RA-induced desquamation, however, has not been completely explored and no such data has been available for HQ uses. OBJECTIVE: To examine the role of HQ, RA, and their combination in the desquamation. METHODS: Primary cultured normal human keratinocytes, which were treated with HQ and/or RA in presence or absence of serine-specific inhibitor Kazal type5 (SPINK5)/lympho-epithelial Kazal-type-related inhibitor (LEKTI) knockdown or recombinant human SPINK5/LEKTI, and biopsied skin samples applied with HQ or RA were examined. Expression levels of corneodesmosin (CDSN), desmocollin1 (DSC1), kallikrein5 (KLK5), KLK7, and SPINK5/LEKTI, and proteolysis activity against extracted human skin epidermal protein were determined using time-course real-time PCR, Western blotting, ELISA, and immunofluorescence staining. RESULTS: HQ increased but RA decreased the synthesis of CDSN and DSC1. HQ reduced corneodesmosome degradation by the upregulation of SPINK5/LEKTI, whereas RA showed opposite results without upregulation of SPINK5/LEKTI. The combination of HQ and RA was close to the sum of the individual components. CONCLUSIONS: HQ reduced corneocyte desquamation. However, RA enhanced desquamation. The combination induced more desquamation than HQ but less than RA.

Effects of low-dose light-emitting-diode therapy in combination with water bath for atopic dermatitis in NC/Nga mice.

BACKGROUND: Light-emitting diode (LED) phototherapy and water bath therapy have beneficial effect on atopic dermatitis (AD)-like skin disease. However, not all current treatments work well and alternative therapies are need. The contribution of combination therapy with low-dose 850 nm LED and water bath was investigated on dermatophagoides farina (Df)-induced dermatitis in NC/Nga mice. METHODS: Low-dose LED (10, 15, and 20 J/cm(2) ) irradiation, water bath (36 ± 1°C) were administered separately and together to the Df-induced NC/Nga mice in acrylic jar once a day for 2 weeks. RESULTS: Combined therapy with low-dose LED therapy and water bath therapy significantly ameliorated the development of AD-like skin lesions. These effects were correlated with the suppression of total IgE, NO, histamine, and Th2-mediated immune responses. Furthermore, combination therapy significantly reduced the infiltration of inflammatory cells and the induction of thymic stromal lymphopoietin (TSLP) in the skin lesions. The beneficial therapeutic effects of this combination therapy might regulate by the inhibition of various immunological responses including Th2-mediated immune responses, inflammatory mediators such as IgE, histamine, and NO, as well as inflammatory cells. CONCLUSIONS: The combination therapy of LED and water bath might be used as an efficacious, safe, and steroid-free alternative therapeutic strategy for the treatment of AD.

Therapeutic and immunomodulatory effects of glucosamine in combination with low-dose cyclosporine a in a murine model of imiquimod-induced psoriasis.

Although cyclosporine A (CsA) is a potent immunomodulating agent and is commonly used as a systemic agent for the management of psoriasis patients, current clinical treatments are not always effective due to the clinical inefficacy of low-doses and numerous harmful effects of higher doses. Currently, the combined use of two other systemic drugs often has better therapeutic efficacy and is safer than low or high dose of a single drug. Glucosamine (Glu) also has immunomodulatory properties for autoimmune diseases. The aims of our study were to investigate the therapeutic efficacy of Glu in combination with low-dose CsA on imiquimod (IMQ)-induced psoriasis-like dermatitis in mice and to determine its immunomodulatory mechanism. We found that combined treatment with Glu (300 mg/kg) and low-dose (10 or 20mg/kg) CsA strongly ameliorated the development of psoriasis-like skin lesions and reduced the levels of Th1 cytokine (TNF-α) and Th17 cytokines (IL-17, IL-22, and IL-23) in the serum and dorsal skin. Histological findings also showed that the thickening of epidermis, stratum corneum, and inflammatory cell infiltration. Particularly, these combined treatments increased the number of CD4(+)CD25(+) regulatory T (Treg) cells in splenic. These results suggest that use of a combination of each drug might be used as an efficacious and safe alternative therapeutic strategy, as well as may provide an immunomodulatory approach for T cell-mediated autoimmune diseases, including psoriasis.

850nm light-emitting-diode phototherapy plus low-dose tacrolimus (FK-506) as combination therapy in the treatment of Dermatophagoides farinae-induced atopic dermatitis-like skin lesions in NC/Nga mice.

BACKGROUND: Light emitting diode (LED) phototherapy is an effective alternative for the treatment of inflammatory skin disorders. Tacrolimus (FK-506) is a potent immunomodulating agent, which has been used to treat AD. Combination therapy is often used in the treatment of AD to improve therapeutic efficacy or to reduce the dose of each drug. OBJECTIVE: To investigate the therapeutic efficacy of monotherapy with either 850nm LED phototherapy or low-dose FK-506, and combination therapy in Dermatophagoides farina (Df)-induced AD-like skin lesions in NC/Nga mice. METHODS: The Df-induced NC/Nga mice with a clinical score of 7 were used for treatment with LED (10 and 25J/cm(2)) alone, low-dose FK-506 (1mg/kg) or in combination. The synergistic effects of combined therapy were evaluated by dermatitis scores, skin histology, skin barrier function, and immunological parameters, such as IgE, NO, Th2-mediated cytokines and chemokines. RESULTS: Combination therapy with 850nm (25J/cm(2)) LED and low-dose FK-506 showed a significant reduction in the severity of skin lesions. Combined therapy decreased in the serum level of IgE, NO, and in the splenic level of Th2-mediated cytokines and chemokines. Combination therapy significantly also reduced the inflammatory cellular infiltrate into the skin lesions. Moreover, combination therapy led to recovery of skin barrier function in the skin lesions. CONCLUSIONS: The use of combination of LED phototherapy and low-dose immunosuppressant improved Df-induced AD-like skin lesions in an NC/Nga mouse model by dominantly reducing IgE, NO, suppressing Th2-mediated immune responses, and inhibiting inflammatory cells, as well as improving skin barrier function.

Antiphotoaging effects of light-emitting diode irradiation on narrow-band ultraviolet B-exposed cultured human skin cells.

BACKGROUND: Antiaging effects of light-emitting diodes (LEDs) have been clinically demonstrated using one or two wavelengths. The mechanism is unclear. OBJECTIVE: To examine direct and indirect photobiomodulation effects of LEDs on narrow-band ultraviolet B (NB-UVB)-induced photoaging using seven different wavelengths alone or in combination. MATERIALS AND METHODS: Four LED wavelengths were chosen based on type I collagen and metalloproteinase (MMP)-1 expression. NB-UVB-irradiated fibroblasts or keratinocytes were irradiated using these four wavelengths. The expression of collagen and MMP-1 in fibroblasts with or without conditioned medium from LED-irradiated keratinocytes and the expression of proinflammatory cytokines in the LED-irradiated keratinocytes were examined. RESULTS: Irradiation with four wavelengths (630, 660, 830, and 850 nm) significantly increased the number of viable fibroblasts. These four wavelengths also increased type I collagen expression, particularly four combinations (630/830, 660/850, 630/850, and 660/830 nm). The fibroblasts cultured with the keratinocyte conditioned medium, particularly with a combination of 630/850 or 660/830 nm, increased collagen levels. Low tumor necrosis factor alpha (TNF-α) and high transforming growth factor beta 1 (TGF-ß1) expression was detected in the LED-irradiated keratinocytes. CONCLUSION: The combination of 630/850- or 660/830-nm irradiation led to better direct and indirect antiphotoaging outcomes than single LED wavelengths in NB-UVB-irradiated cultured normal human skin cells.

Greater collagen deposition with the microneedle therapy system than with intense pulsed light.

BACKGROUND: Intense pulsed light (IPL) and the microneedle therapy system (MTS) are currently available for the treatment of scars. Greater collagen deposition has been proposed as a mechanism for the treatment of scars. OBJECTIVE: To compare the effects of IPL and MTS on collagen deposition. MATERIALS AND METHODS: Fifty-four imprinting control region mice were divided into three groups: untreated controls, treatment with IPL, and treatment with MTS. A single pass of IPL 10.5 J/cm(2) and five passes (total 15 strokes) of MTS were performed three times every 2 weeks. Four weeks after the last treatment, skin thickness measurements using a caliper, microscopic examination, Western blot analysis for type I collagen, and enzyme-linked immunosorbent assay for total collagen content were performed. RESULTS: Measured using calipers, MTS, resulted in greater skin thickness than IPL that paralleled the dermal thickness of the biopsied specimens. MTS also increased expression levels of type I collagen and total collagen content more than IPL. IPL effects were superior to control. CONCLUSION: MTS increased collagen deposition more than IPL, and MTS might be more effective than IPL for scar treatment. The authors have indicated no significant interest with commercial supporters.

Lotus (Nelumbo nuficera) flower essential oil increased melanogenesis in normal human melanocytes.

In this study, the essential oil from lotus flower extract, including petals and stamens, was assessed with regard to its effects on melanogenesis in human melanocytes. The lotus flower essential oil was shown to stimulate melanin synthesis and tyrosinase activity in a dose-dependent manner. The lotus flower essential oil induced the expression of tyrosinase, microphthalmia-associated transcription factor M (MITF-M), and tyrosinase-related proten-2 (TRP-2) proteins, but not tyrosinase mRNA. Moreover, it increased the phosphorylation of ERK and cAMP response element binding protein (CREB). In order to verify the effective components of the lotus flower oil, its lipid composition was assessed. It was found to be comprised of palmitic acid methyl ester (22.66%), linoleic acid methyl ester (11.16%), palmitoleic acid methyl ester (7.55%) and linolenic acid methyl ester (5.16%). Among these components, palmitic acid methyl ester clearly induced melanogenesis as the result of increased tyrosinase expression, thereby indicating that it may play a role in the regulation of melanin content. Thus, our results indicate that lotus flower oil may prove useful in the development of gray hair prevention agents or tanning reagents.

Fragrance contact dermatitis in Korea: a joint study.

The purpose of this study is to determine the frequency of responses to selected fragrances in patients with suspected fragrance allergy and to evaluate the risk factors. 9 dermatology departments of university hospitals have participated in this study for the past 1 year. To determine allergic response to fragrances, 18 additional fragrances in addition to the Korean standard and a commercial fragrance series were patch-tested in patients with suspecting cosmetic contact dermatitis. Over 80% of the patients were women, and the most common site was the face. Cinnamic alcohol and sandalwood oil (Santalum album L.) showed high frequencies of positive responses. Of the specific fragrances, ebanol, alpha-isomethyl-ionone (methyl ionone-gamma) and Lyral (hydroxyisohexyl 3-cyclohexane carboxdaldehyde) showed high positive responses. We compared the results obtained during this study with those of other studies and concluded that including additional fragrance allergens may be useful for the detection of fragrance allergy.

All trans-retinoic acid (ATRA) elevated eukaryotic translation initiation factor 4A1 (eIF4A1) mRNA in ATRA-responsive vitiliginous epidermis.

Chronic skin disorders that require long-term treatment with corticosteroids, such as vitiligo, may use a combination of topical corticosteroids and topical all-trans-retinoic acid (ATRA) to prevent corticosteroid-induced skin atrophy. Besides protecting against the side effects of corticosteroids, ATRA produces a better clinical outcome in some patients. This study examined whether ATRA influences the expression of mRNAs responsible for the clinical correlation. Differential display was performed using kits incorporating an annealing control primer. Epidermis from suction blisters taken from six patients diagnosed with a generalized type of vitiligo, who were included in a placebo-controlled paired-comparison left-right study using ATRA and vehicle for 3-6 months, were used. Ten differentially expressed mRNAs were identified in those six patients. Expression levels were restored to normal particularly in four types of mRNAs, which were matched with sequences encoding eukaryotic translation initiation factor 4A1 (eIF4A1), ribosomal protein L13, mediator of RNA polymerase to transcription (MRT) and ribosomal phosphoprotein PO. Of those mRNAs, the level of eIF4A1 mRNA showed a clinical correlation; The expression of eIF4A1 mRNA, examined by real-time PCR, was elevated in four patients who showed a favorable clinical response to ATRA, whereas no change or a decrease occurred in three patients whose clinical responses did not differ between ATRA and vehicle treatment. The eIF4A1 protein expression from the other two patients, one of them with a favorable response to ATRA, also showed a clinical correlation. Therefore, eIF4A1 mRNA may be an important gene related to ATRA effects, although further studies are required.