|CURRENT BEST EVIDENCE
|Year : 2015 | Volume
| Issue : 2 | Page : 108-112
Current best evidence from pigmentary dermatology
Garima, Muthu Sendhil Kumaran
Department of Dermatology, Venereology and Leprology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
|Date of Web Publication||29-Dec-2015|
Muthu Sendhil Kumaran
Department of Dermatology, Venereology and Leprology, Postgraduate Institute of Medical Education and Research, Sector 12, Chandigarh - 160 012
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
Garima, Kumaran MS. Current best evidence from pigmentary dermatology. Pigment Int 2015;2:108-12
Singh H, Kumaran MS, Bains A, Parsad D. A randomized comparative study of oral corticosteroid minipulse and low-dose oral methotrexate in the treatment of unstable vitiligo. Dermatology 2015;231:286-90.
Vitiligo is a common acquired pigmentary disorder characterized by depigmented lesions over the body due to selective loss of melanocytes. Till now, various modalities of treatment have been used for vitiligo, some of which help to arrest the disease progression whereas others help in achieving repigmentation. This study was conducted with the aim to compare the efficacy of methotrexate with that of oral mini-pulse (OMP) in patients with unstable vitiligo. This was a prospective, randomized open label study in which 52 unstable vitiligo patients were divided into two groups. In Group 1, patients received 10 mg methotrexate weekly and in Group 2 patients, they received OMP, which comprised 5 tablets of dexamethasone of 0.5 mg (2.5mg) taken on 2 consecutive days in a week, i.e., total dose was 5mg/week. Evaluation was done using Vitiligo Area Scoring Index and Vitiligo Disease Activity Score (VIDA) at every visit. In addition, repigmentation was assessed in each area using digital photography and reported as no improvement, minimal (<25%), mild (26–50%), moderate (51–75%), and marked to complete (>75%). All patients were followed fortnightly for first 2 months and later monthly for during the subsequent 4 months. In addition, appropriate hematological and radiological investigations were done for each visit. Fifty patients (25 in both groups) completed the study. During the 24 weeks of treatment, 6/25 patients in Group 1 and 7/25 patients in Group 2, developed new vitiliginous lesions, patients in both groups had a similar reduction in VIDA with score of +4 at the start of treatment in both to 1.72 in Group 1 and 1.76 in Group 2, at completion of treatment. Totally 26 patients, 11 and 15 patients in Groups 1 and 2, respectively, achieved repigmentation. There was no statistical difference between the groups. Side effects reported in the study in both groups were mild and did not warrant medication withdrawal apart for 1 patient who discontinued methotrexate because of severe nausea.
Comments: Vitiligo is a chronic pigmentary disorder with a worldwide distribution causing severe psychological distress among the patients. Among various theories put forth to explain the pathogenesis of vitiligo, autoimmune theory is recognized as one of the most likely mechanisms. Recently, it was reported that a significantly higher expression of tumor necrosis factor alpha (TNF-α) was observed in vitiligo affected skin as compared with nonlesional area. In addition, an increase in proinflammatory cytokines such as interleukin 6 (IL-6) and IL-2 is seen in vitiligo skin which may play an important role in melanocyte cytotoxicity. As most of the patients present in active stage of the disease, it is of paramount importance to control the progression. This study compares two modalities, one time-tested (OMP) and the other one novel (methotrexate) to arrest the disease progression. In addition, it has been shown to induce simultaneous repigmentation. Methotrexate suppresses TNFα-production by inhibiting nuclear factor-κB activation. Prior to this study, one case report and a small pilot study demonstrated the efficacy of methotrexate in vitiligo. A patient receiving methotrexate (7.5 mg/week) for psoriatic arthritis showed improvement in vitiligo lesions. Al Ghamdi and Khurrum studied six vitiligo patients with >6% of the body surface area, treated them with methotrexate (25 mg/week) for 6 months and did not report any change in lesions or any side effects. This is the first study comparing traditional OMP with novel methotrexate in controlling the vitiligo disease activity and reported that both drugs are equally effective. Hence, methotrexate can be used in active vitiligo patients, wherever corticosteroids are contraindicated. As uniform dose of methotrexate was used for all patients irrespective of their body weight or age, it implies the effect may be due to its anti-inflammatory effects. The major drawbacks of the study are small sample size and short follow-up period. Further studies involving a larger cohort with longer follow-up time are required to validate the result of this study.
Adalatkhah H, Sadeghi-Bazargani H. The first clinical experience on the efficacy of topical flutamide on melasma compared with topical hydroquinone: A randomized clinical trial. Drug Des Devel Ther 2015;9:4219-25.
Melasma is a common hyperpigmentary disorder seen in second to third decade of life. Various modalities of treatment have been used without a satisfactory outcome. Hormones have been shown to have a role in pathogenesis of the melasma. Theoretically, flutamide as an anti-androgenic agent may be used in treating melasma. This was a randomized clinical trial conducted to compare the efficacy of 1% flutamide cream versus 4% hydroquinone cream in melasma. After baseline assessments, 74 patients were allocated into two groups, one group was treated with topical flutamide and other with 4% hydroquinone once daily at night for 4 months. Patients in both groups were advised about regular use of sunscreen in the morning. Pigmentation reduction was the primary outcome which was assessed through Melasma Area and Severity Index (MASI), mexameter melanin assay and patient satisfaction was assessed through five Likert-type scale, one for improvement in melasma patches, two for satisfaction with potential side effects, three for improvement in skin succulence, four for improvement in skin darkness, and five for overall satisfaction with treatment. The mean age of the participants was 33.8 years, and mean length of time suffering from melasma was 96.3 months. Mean standardized total patient satisfaction score was 28.8 in flutamide group patients versus 18 in hydroquinone group. Total dissatisfaction was observed in 35% of hydroquinone group patients versus 22% in flutamide. The MASI score showed decreasing trend over the treatment course for both the groups, the difference was seen in only skin darkness and homogeneity. The total percentage of the area involving melasma did not also change significantly with treatment.
Comments: This is the first study indicating the use of flutamide in melasma. Melasma is an acquired pigmentary disorder characterized by symmetrical hyperpigmented macules on the face. Its pathogenesis is complex and involves the interplay of various factors such as genetic predisposition, ultraviolet radiation, hormonal factors, and drugs. An insight into the pathogenesis is important to devise treatment modalities that accurately target the disease process and prevent relapses. Hydroquinone used in 2–5% concentration alone or incorporated in modified Kligman's formula is the most effective depigmenting agent. It acts by inhibiting tyrosine and direct melanocyte damage. Topical flutamide has been used earlier for the treatment of hair-loss and has not been used in the treatment of melasma till now. In melasma, it is believed to act by modifications in alpha-melanocyte-stimulating hormone or cyclic adenosine monophosphate-elevating agents which affect the melanin synthesis. However, the exact mechanism of flutamide in melasma is not known. No histopathological evaluation was done to indicate whether there was a reduction in melanocyte density or not. The present study indicates topical flutamide is relatively safe and effective treatment when compared with hydroquinone without any side effects. Major drawbacks of the study include the absence of clear pathogenesis or an explanation as to why flutamide causes improvement, no follow-up of treated patients after treatment, no decrease in the area affected by melasma despite 4 months of treatment. Darkness and homogeneity are both very subjective parameters. These initial results require further studies for confirmation.
Banihashemi M, Zabolinejad N, Jaafari MR, Salehi M, Jabari A. Comparison of therapeutic effects of liposomal Tranexamic Acid and conventional Hydroquinone on melasma. J Cosmet Dermatol 2015;14:174-7.
Melasma is a common hypermelanotic disorder affecting the face. The management of melasma is challenging despite a plethora of options as none of the treatment options provides long lasting satisfactory outcome. Tranexamic acid (TA), a plasmin inhibitor has been used in melasma in topical, oral, and injectable form. The objective of this study was to compare therapeutic effects of 5% topical liposomal TA and 4% topical hydroquinone cream on melasma. It was a split face double-blind clinical trial including 30 women with bilateral melasma. Patients were instructed to apply 5% topical liposomal TA and 4% hydroquinone cream, to the designated sides of the face twice daily for 12 weeks. They also used standard sunscreen in the morning. Evaluation was done using Melasma Area and Severity Index (MASI) at each visit separately for each side at the baseline and every month for 4 months. Liposomes containing 5% TA were prepared by the fusion method. The lipid components consisted of soybean phosphatidylcholine (10%), cholesterol (1%), propylene glycol (6%), Vitamin E (0.1%), methylparaben (0.1%), and propyl paraben (0.02%) and all these components were melted at about 65°C and added to heated TA injections (250 mg/5 ml). The mixture was vigorously vortexed and allowed to cool to room temperature. The particle diameter of 5% liposomal TA as measured by the use of dynamic light was 126 nm. A total of 23 of 30 patients completed the study. Clinical improvement was noted in both groups with a reduction in mean MASI score in the liposomal TA group from 14.72 at baseline to 7.69 at the end of treatment and 6.78 at 1 month follow-up. In the hydroquinone group, MASI score reduced from 14.6 at baseline to 7.86 at the end of treatment and 7.6 at 1st follow-up. The difference was not statistically significant.
Comments: Melasma is a common pigmentary disorder manifesting as symmetric hyperpigmented macules and patches on the face. It typically affects men and women of reproductive age with Fitzpatrick skin type III–VI. Multiple treatment options are currently available for the treatment of melasma, and many more are currently under development process. Hydroquinone is considered gold standard in the treatment of melasma. TA has been used in many forms such as oral, topical, and injectable with micro-needling and iontophoresis since past few years. The exact mechanism of action is yet elusive, Manosroi A et al. developed lipososmal TA in 2002 and reported it was more effective as it potentially reduces the skin irritation, improves the moisturizing effect, and has prolonged action with better tissue distribution of the drug. This study also observed that topical liposomal TA can be considered as a safe and effective therapeutic option for the treatment of melasma with no much side effect. Another group, Kanechorn Na AyuthayaP et al. conducted a split-face trial of 5% topical TA as compared to vehicle and observed no extra benefit of topical TA, which could be due to decreased tissue delivery of TA as compared to liposomal TA. Major drawbacks of this study are small sample size, the very short follow-up period of 1 month, and absence of histological confirmation for improvement. Therefore, it is imperative to study a larger sample size and longer follow-up to demonstrate the efficacy of TA on melasma.
Bae JM, Yoo HJ, Kim H, Lee JH, Kim GM. Combination therapy with a 308-nm excimer laser, topical tacrolimus, and short-term systemic corticosteroids for segmental vitiligo: A retrospective study of 159 patients. J Am Acad Dermatol 2015;73:76-82.
Segmental vitiligo (SV) is a subtype of vitiligo presenting with unilateral distribution, earlier age of onset, rapidly progressive but the limited course. The 308-nm xenon chloride excimer laser has been used to treat vitiligo since past decade. This study was conducted to evaluate the effectiveness of combination therapy with 308-nm excimer laser, topical tacrolimus, and short-term systemic corticosteroids for treatment of SV and to determine independent prognostic factors associated with good treatment response. This was a retrospective interventional case-series study wherein medical records and photographs of 159 patients with SV-treated with 308-nm excimer laser, topical tacrolimus, and short-term systemic corticosteroids were included in the study. All the patients aged ≥19 years received 20 mg of prednisolone daily for the first 3 weeks, and patients <19 years received 0.3 mg/kg prednisolone (maximum daily dose: 20 mg). In addition, all of them were advised to apply 0.1% topical tacrolimus ointment concurrently to all vitiliginous lesions throughout the treatment period. Patients were also treated with the 308-nm xenon chloride excimer laser on 2 nonconsecutive days a week. The dosing schedule was as per the standard protocol followed in most centers. Evaluation was done by two blinded dermatologists independently weekly, and improvement reported as - Grade 0 - no repigmentation, Grade 1 - 1–24%, Grade 2 - 25–49%, Grade 3 - 50–74%, Grade 4 - 75–99%, and finally Grade 5 - complete resolution. Treatment success was defined as ≥75% repigmentation in the entire lesion. It was observed that the median age of onset and median disease duration were 24 years (range: 1–62) and 12 months (range: 1–260), respectively. The majority of patients belonged to Fitzpatrick skin type III (31.4%) and type IV (68.6%). Face and neck (77.3%) was the most commonly involved site followed by upper extremities (10.7%), trunk (10.1%), and lower extremities (1.9%). Median number of treatment sessions was 71 (range: 16–387) and median duration of treatment was 12.1 months (range: 1.1–52.5). Treatment success rate was 50.3% with Grade 4 improvement in 36.5% patients and Grade 5 in 13.8% of the patients. Disease duration longer than 12 months (odds ratio [OR] = 0.37), poliosis (OR = 0.49), and plurisegmental subtype (OR = 0.17) were shown to be independent prognostic factors with poor response in multivariable analysis.
Comments: SV has typical course, depigmentation usually spreads within the segment over a period of 6–24 months and then stops and further extension is rare. SV is often associated with a poor response to medical treatments including conventional phototherapy and excimer laser therapy and good response to surgery. In addition, in contrast to non-SV, SV has early involvement of melanocytes of hair follicles, with up to 50% of SV patients exhibiting poliosis in affected areas. Tacrolimus has been reported to increase melanocyte migration and improve pigmentation in vitiligo. Corticosteroid helps in the stabilization of disease by reducing complement-mediated cytotoxicity. The excimer laser has become the treatment of choice for localized vitiligo as it is superior to phototherapy in inducing T-cell apoptosis and achieving repigmentation. Various studies have been done in SV, and their response to phototherapy with or without tacrolimus and most of the researchers have found the response was suboptimal. In another study done by Do JE et al., 23.8% of patients with SV showed ≥75% with excimer laser treatment but none of them achieved complete repigmentation after a median treatment of 20.6 months. They concluded that excimer laser when used in earlier stages of the disease and long-term use and high cumulative UV energy of the excimer laser elicit better responses. In another study done by Park JH et al., in 2013, it was observed that 50% of SV patients treated with oral corticosteroids, topical tacrolimus, and phototherapy showed >50% improvement when treated within first 5 months when the disease is spreading. In another recent study by Jang YH et al., 4 out 5 SV patients treated with oral corticosteroids for 4–8 weeks, topical tacrolimus, and excimer laser showed an excellent response or complete repigmentation, but most of these patients presented with in few weeks of onset of disease. In the current study, all patients irrespective of disease duration were treated with same protocol. The rationale for using systemic steroids in the later stage of SV when lesions have stabilized has not been explained properly. In addition, in this study most patients had involvement of face and small sized lesions show good response to various treatment modalities. Very few cases of SV lesions over acral areas and bony prominences have been included; these areas are often resistant to all forms of treatment and may lead to some bias in the result. Since it was retrospective study, patients who were lost to follow-up due to nonimprovement have been excluded which may have led to selection bias. Another major drawback was that there was no report of any relapse or recurrence of vitiligo after treatment completion. There is a need for better, well-controlled prospective trials to validate the results of this study and to find if treatment with systemic corticosteroids is beneficial once the disease has stabilized.
Tay EY, Gan EY, Tan VW, Lin Z, Liang Y, Lin F, et al. Pilot study of an automated method to determine Melasma Area and severity index. Br J Dermatol 2015;172:1535-40.
Melasma is a common acquired hyperpigmenting skin disorder that can affect patient's quality of life. Various treatment modalities have been used in melasma and Melasma Area and Severity Index (MASI) and modified MASI score (mMASI) are frequently used validated tools to measure disease severity and treatment response in clinical trials. This study was conducted with the aim to develop and validate novel image analysis software designed to automatically calculate the area and degree of hyperpigmentation in melasma from computer image analysis of whole-face digital photographs and help in the derivation of an automated mMASI score (aMASI) thereby reducing interobserver variability. Three photographs were taken of each patient, one full frontal picture, one for each side (right and left) to help in the calculation of area involved. Total darkness score is obtained by comparing the value of one pixel against that of normal reference skin. An area which is darker than the reference value would be considered as an area affected by melasma. The area involved is calculated as a percentage of the total surface area of the part of the patient's face, the areas selected as per MASI. Thereafter, the darkness of an area is calculated by taking average darkness of the pixels in areas affected by melasma. These scores are then fed into the mMASI formula to generate aMASI. After the development of aMASI score, 29 patients with melasma who received treatment with standard depigmenting agents were included in the prospective study for validation of the score. Three dermatologists scored mMASI at baseline and posttreatment, and these scores were compared with aMASI scores derived from computer analysis. It was observed that aMASI scores correlated well with clinical mMASI pretreatment (r = 0.73, P < 0.001) and posttreatment (r = 0.60, P < 0.001). Hence, aMASI was reliable in detecting changes with treatment. The changes in aMASI scores correlated well with changes in clinician-assessed mMASI (r = 0.62, P < 0.001).
Comments: This is the first study done to develop and evaluate automated score. The use of automated score may help decrease interobserver variability in the scoring system. In melasma, the presence of multiple hyperpigmented macules and irregular borders which often merge with surrounding skin make the assessment of exact area involved difficult. MASI and mMASI score are most valid and widely used tool to asses' treatment response in melasma. The aMASI is simple, semi-automatic and needs only minimal training for the assessors. A major setback of this algorithm is that as it detects subtle changes in pigmentation, it may not be able to differentiate between melasma and other causes of hyperpigmentation such as lentigenes and melanocytic nevi and therefore give falsely elevated scores. Even though scalp hair, eyebrows, and eyelashes have been excluded from the algorithm, facial hair has not been which may also lead to wrongly increased scores especially in patients with brown or blond hair. Both of these problems can be solved if a provision to mark the area involved with melasma can be provided before calculation of darkness and then the darkness of only the marked area can be calculated, and rest can be excluded. Another option is to remove the area not intended for evaluation from the photographs, but both of these would increase the time taken to generate aMASI. This aMASI score has only been validated for patients with Fitzpatrick skin types III–VI with only minor melasma. Nonuniform illumination, wrong selection of normal skin and obscuring of chin area in photographs can also lead to wrong results. It is a sincere effort toward decreasing interobserver variation in scoring systems; however, it need to be validated by multiple centers, across different skin types and in patients with mild to severe melasma after modifying it for patients with concomitant pigmentary disorders. It would be ideal if this automated assessment scoring system can be used in other facial pigmentary disorders such as pigmented contact dermatitis, erythema dischromicum perstans, and lichen planus pigmentosus.
Kim MS, Bang SH, Kim JH, Shin HJ, Choi JH, Chang SE. Tranexamic acid diminishes Laser-induced melanogenesis. Ann Dermatol 2015;27:250-6.
Postinflammatory hyperpigmentation is a common complaint in patients with skin type IV–VI and a major complication after cosmetic procedures such as laser treatment or chemical peeling. Tranexamic acid (TA) has been used to reduce pigmentation in melasma, although its exact mechanism of action on melanogenesis are not fully known. This study investigated the effects of TA on murine and human melanocytes under laser-induced melanin production and effects of TA on melanogenesis as well as melanogenesis-related signal transduction pathways. HaCaT keratinocytes (immortalized keratinocyte) were cultured in Dulbecco's modified Eagle medium supplemented with 10% heat-inactivated fetal bovine serum, penicillin, and streptomycin. Murine melanocytes (melan-a) cells were cultured in RPMI 1640 medium. HaCaT keratinocytes were then seeded in wells and treated with fractional CO2 laser (pulse energy 100 mJ, 8 mm microbeam, density 100 spots/cm 2) in serum-free conditions. After 24 h, the supernatant medium was harvested and mixed 1:1 with RPMI 1640 medium to make laser-treated keratinocyte-conditioned medium (LT-KCM). Similar procedure was done for human melanocytes. Thereafter using ELISA, the concentrations of inflammatory mediators such as interleukin (IL)-1α, IL-8, and prostaglandin E2 were measured in LT-KCM. The melanin contents of melan-a cells and human melanocytes grown in KCM and LT-KCM were also determined. Human melanocytes and melan-a cells were seeded on well plates with different concentrations of TA (10, 50, and or 100 mg/l). Arbutin was used as positive control. The tyrosinase activities of melan-a cells and human melanocytes grown in KCM as well as that of melan-a cells grown in LT-KCM were determined. Titer of inflammatory markers was significantly higher in LT-KCM (P< 0.01), indicating laser treatment induced their formation. Melan-a cell and human melanocytes both when grown in LT-KCM showed increased melanin content (adjusted for protein content). The melanin content and tyrosinase activity was significantly higher (P< 0.01) in melan-a cells cultured with LT-KCM without TA than those with TA in a dose-dependent manner indicating TA inhibited melanin synthesis in LT-KCM. Arbutin and 100 mg/L TA markedly reduced melanin content without adjustment as the decreased protein content affected the adjusted melanin content. However, the inhibition was not statistically significant. TRP-1 and TRP-2 protein levels were elevated in melan-a cells cultured with LT-KCM, which reduced after TA treatment in a dose-dependent manner. TA induced sustained activation of extracellular-regulated protein kinase (ERK) and elevation in phosphorylated ERK and a time-dependent decrease in microphthalmia-associated transcription factor (MITF) as observed in B16F10 cells.
Comments: Hyperpigmentation of skin, especially on face and other exposed sites, causes significant distress to the patient; hence there is a continuous ongoing research for newer molecules which can reduce pigmentation without much side effects. Postinflammatory hyperpigmentation after cosmetic procedures significantly decreases treatment satisfaction. TA acts by inhibiting UV-induced plasmin activity in keratinocytes and preventing the binding of plasminogen to the keratinocyte which then decreases free arachidonic acid and various prostaglandins synthesis. In this study, we observe that the inflammatory mediators such as IL-1 and IL-8 were significantly higher in LT-KCM than KCM, suggesting laser treatment leads to induction of more intense inflammatory conditions which may lead to melanogenesis. Furthermore, melanin content and tyrosinase activity were higher in LT-KCM than the control media and TA reduced melanin content and tyrosinase activity in melan-a cells in LT-KCM. However, the effect of TA on cultured human melanocytes was not definitive in this study. Melanin reduction was marked after treatment with arbutin and 100 mg/L TA. In human melanocytes, a decrease in melanin content was not statistically significant even in the arbutin group because human melanocytes are much more vulnerable to laser treatment than melan-a cell. These damaged human melanocytes consequently affect the results of protein assays and adjusted melanin contents. This novel study suggests TA inhibits melanin synthesis, decreasing melanin content, and tyrosinase activity in a dose-dependent manner by decreasing TRP-1 and TRP-2 levels in addition to decreasing tyrosinase levels. ERK activation leads to MITF phosphorylation and subsequent degradation. In this study, it was observed that TA stimulated the ERK signaling pathway and downregulated MITF protein resulting in reduced melanogenesis. This study dwells deeper into exact mechanism of action of TA on human and murine melanocytes and shows its potential role in reducing laser induced postinflammatory hyperpigmentation. However further animal and human studies are required to evaluate in which form TA is most effective in reducing laser induced pigmentation, oral, topical, or injectable.
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