Pigment International

: 2015  |  Volume : 2  |  Issue : 1  |  Page : 67--71

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

Correspondence Address:
Muthu Sendhil Kumaran
Department of Dermatology, Venereology and Leprology, Postgraduate Institute of Medical Education and Research, Sector 12, Chandigarh - 160 012

How to cite this article:
Garima, Kumaran MS. Current best evidence from pigmentary dermatology.Pigment Int 2015;2:67-71

How to cite this URL:
Garima, Kumaran MS. Current best evidence from pigmentary dermatology. Pigment Int [serial online] 2015 [cited 2023 Jan 30 ];2:67-71
Available from: https://www.pigmentinternational.com/text.asp?2015/2/1/67/159406

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Tienthavorn T, Tresukosol P, Sudtikoonaseth P. Patch testing and histopathology in Thai patients with hyperpigmentation due to erythema dyschromicum perstans, lichen planus pigmentosus, and pigmented contact dermatitis. Asian Pac J Allergy Immunol 2014;32:185-92.

Many skin diseases for instance, lichen planus pigmentosus (LPP), ashy dermatosis (AD) or erythema dyschromicum perstans (EDP), fixed drug eruption, postinflammatory pigmentation (PIH), pigmented contact dermatitis (PCD) etc., often have similar clinical presentations. This study was conducted with the objective to search for differences in clinical appearances, histopathology, including direct immunofluorescence (DIF) studies, and patch testing in the patients who were diagnosed as either of these diseases.

Forty-three patients (7 males and 36 females) were enrolled in the study. Patient's demographic details, histological findings, DIF staining, provisional, and histological diagnosis were recorded. Closed patch tests with standard fragrance and cosmetic series allergens were performed in all patients. The face was the most common site of presentation (46.51%), followed by the upper extremities (21.43%). Twenty patients (46.51%) were clinically diagnosed as AD, 11 as LPP (25.58%), 10 as PCD (23.26%), and other 2 as PIH. Histological diagnoses were reported as AD in 14 cases (35.26%), LPP in 11 cases (25.58%), and PIH in 14 cases (35.36%). A lichenoid picture was observed in 8 cases of AD (57.14 %), 10 cases of LPP (90.9%), and 4 cases of PIH (28.5%). Necrotic keratinocytes were observed in 5 patients of LPP, 2 of AD, 2 of PIH, and one of lichenoid drug eruption. Epidermal spongiosis was observed in 2 patients with LPP, 2 patients with AD, and four with PIH. Lymphocytic infiltrate in the dermis was seen in all patients. DIF showed positive results in 6 out of 21 cases (28.57%), all having a colloid IgM deposit. Closed patch testing was positive in 21 of 43 cases (48.83%). The most common allergen was nickel sulfate hexahydrate (8 cases), followed by mixed fragrances II in the standard series set (3 cases). The positive patch test was observed in 8 patients (40%) of AD, 4 cases of LPP (36.36%), 8 of PCD (80%), and one of PIH (50%). Two patients with metal allergy had a positive reaction to manganese chloride.

Comments: Differentiation between AD, LPP, and PCD is still elusive. Many studies carried out for the same have failed to give concrete evidence, which is possibly secondary to overlapping clinical and histological features in between them. Furthermore, few authors consider EDP as a part of LPP as a definitive erythematous border may not be seen in many patients, and they have similar histological findings. Clinical characteristics, histopathology, and DIF results may have been claimed as specific finding in EDP and LPP, but they do not rule out cases with PCD. Similarly, positive patch test may be seen not only in patients with PCD but also of AD, LPP, and PIH. In this study, authors have tried to differentiate the three along with additional investigations like DIF, patch testing, however, the most common allergen found among patients in this study was nickel followed by mixed fragrance as against other studies which have found more cosmetic and fragrance allergen positivity. Patients with a provisional diagnosis of AD and LPP also demonstrated patch test positivity, but the study fails to point whether these allergens are the cause for hyperpigmentation in them. Furthermore, it does not list which allergens were positive in different diseases and if was there any significant difference in between them. However, since majority of lesions were present in photo-exposed sites, it would have been ideal to a photo-patch test which would have been more beneficial than only a closed patch test as it would help in finding cause for the pigmentation. Besides standard, cosmetic and fragrance series patients, personal cosmetic products should also have been used for patch testing. The current study suggests considering patch testing and histopathology in facial hyperpigmentary disorders including LPP, EDP, and PCD. Although the study aims at a sincere effort to help in identification and diagnosis of three easily confused hyperpigmentary disorders, the absence of a photo-patch test result, small study population and shorter duration of follow-up period exemplifies the need for larger studies.

Ibrahim ZA, Gheida SF, El Maghraby GM, Farag ZE. Evaluation of the efficacy and safety of combinations of hydroquinone, glycolic acid, and hyaluronic acid in the treatment of melasma. J Cosmet Dermatol 2015;14:113-23.

Melasma is a common hyperpigmentary disorder seen following the onset of the second decade of life. It is a therapeutically challenging disease as none of the currently available treatment options provides a long lasting satisfactory outcome. This study was conducted to assess the efficacy and safety of combinations of topical hydroquinone, glycolic acid, and hyaluronic acid in the treatment of melasma and to evaluate the role of dermoscopy in diagnosis and follow-up of melasma treatment. This was a single-blinded, placebo-controlled trial where 100 female patients with melasma were enrolled and then classified into five groups of 20 patients each. Group I patients were treated with topical 4% hydroquinone cream, Group II with topical 4% hydroquinone and 10% glycolic acid cream, Group III with topical cream containing 4% hydroquinone and 0.01% hyaluronic acid, Group IV patients with topical cream containing 4% hydroquinone, 10% glycolic acid, and 0.01% hyaluronic acid; and finally, Group V patients were treated with placebo cream. All the patients in each group were instructed to apply the topical formulation to the affected area of the face once daily for 12 weeks and to apply sunscreen (SPF 30 or more) when going outdoors. Dermoscopic examination, digital photographs and modified melasma area and severity index (mMASI) was evaluated before and after treatment in all patients. All patients were followed up for a period of 6 months. Posttreatment Group I, III, and IV showed a highly significant change in the mMASI, Group II showed a significant change in the mMASI score whereas Group V showed no statistical difference. Group II showed the highest rate of side effects as all (100%) patients reported side effects, followed by Group IV (70%), Group I (60%), Group III (20%), while in Group V no side effects were reported. Recurrence was reported in 6 patients (30%) of Group I and 4 patients (20%) of Group III. There was the highly significant difference between the dermoscopic color findings before and after treatment. In this study pretreatment, epidermal type melasma was seen in 64% patients, dermal type in 2%, and mixed type in 34% using dermoscope. Posttreatment, no pigmentations were detected in 26% patients, 42% had an epidermal type, 14% had mixed type, and 18% of patients had dermal type melasma. Furthermore, vascularization was another important dermoscopic finding in this study.

Comments: Melasma is a common hypermelanotic disorder affecting the face which is associated with considerable psychological impact. The management of melasma is challenging despite a plethora of options as none of the treatment options provides a long lasting satisfactory outcome. In addition to avoidance of aggravating factors such as oral pills and ultraviolet exposure topical depigmenting agents, sun protection, chemical peels, and dermabrasion, are some of the treatment modalities. Hydroquinone used in 2-5% concentration alone or incorporated in modified Kligman's formula is the most effective depigmenting agent. Glycolic acid is an alpha-hydroxy acid that is, usually combined with other agents in a concentration of 5-10% for its skin-lightening property. On combination with hydroquinone theoretically it increases the penetration and efficacy of hydroquinone. However, it often causes irritation and itching, which may cause noncompliance. In this study also, only 8 out of 20 patients in Group II continued the treatment after decreasing the frequency of application (twice weekly) while the rest could not tolerate it. Hyaluronic acid is a glycosaminoglycan, which plays an important role in tissue hydration, lubrication, cellular function, and tissue repair. This study predicted that the water-retaining qualities of hyaluronic acid would improve the tolerability of the formula containing hydroquinone and glycolic acid may seem almost same as addition of moisturizer to hydroquinone and glycolic acid combination. No recurrence was reported in Group II and Group IV possibly owing to use of combination therapy. However, as observed by various studies, recurrence is the rule in melasma. The major limitations of the study were small sample size and short duration of follow-up. Dermoscopy could be used an effective tool in evaluating treatment response in melasma as it is more accurate and less invasive as compared to histopathology and woods lamp.

Yazdanpanah MJ, Banihashemi M, Pezeshkpoor F, Moradifar M, Feli S, Esmaeili H. Evaluation between Association of Psoriasis and Vitiligo. J Cutan Med Surg 2015;19:140-3.

Psoriasis and vitiligo both affect 1-3% of the population each, therefore, it not unusual to see the coexistence of the two diseases. There have been numerous reports about the coexistence of psoriasis and vitiligo in patients; however, a definitive interaction between the two is yet to be established. Recognition of this association can lead to better understanding of the etiologies, pathogenesis, and treatment of the two diseases. This study was conducted to identify the frequency of the coincidence of these two diseases. It was cross-sectional study wherein 6200 consequent dermatology outpatients were enrolled. Patients affected by psoriasis, and/or vitiligo were included, and variables such as age, gender, extent of disease, family background, duration of disease, and coincident disease were studied. Among 6200 consecutive dermatology patients, 361 cases were enrolled in the study, which consisted of 207 (57.3%) cases of psoriasis, 142 (39.4%) cases of vitiligo, and 12 (3.3%) cases of coexisting psoriasis and vitiligo. The prevalence of each of these was psoriasis 3.34%; vitiligo 2.29%; and coexisting psoriasis; and vitiligo 0.19%. The coincidence in the psoriasis group was 5.48% and in the vitiligo group was 7.79%; hence, the coincidence of both diseases was greater than the incidence of each alone. Positive family history was present in 69 (33.3%) cases of psoriasis, 38 (26.7%) cases of vitiligo, and 8 (66.7%) cases with the coexistence of both diseases.

Comments: The current study tries to identify the prevalence of coexistence between two common dermatological conditions, psoriasis, and vitiligo. Although many case reports have been published in this regard, there have not been enough studies to document an interaction between these two. Several theories have been put forth to explain concomitant vitiligo and psoriasis in patients. The role of cytokines and neuropeptides has been proposed. Tumor necrosis factor alpha (TNF-α) is a major cytokine involved in the pathogenesis of both diseases. Besides TNF-α, interleukin-2, interferon-γ have an important role in the pathogenesis of both psoriasis and vitiligo. They may also have a common genetic link as they share common human leukocyte antigen (HLA) haplotypes (HLA-CW6, HLA-B27, DR-7). In this study also, out of 12 patients with vitiligo, 8 had a family history of both vitiligo and psoriasis, further stressing the role of the common genetic link between the two. The present study suggests that the existence of psoriasis or vitiligo in a patient may be a predictor of the potential tendency for the other disease (vitiligo or psoriasis) in the same patient or his/her family. Other hypotheses used to explain the association between them include koebnerization, similarity in structures of anti-stratum corneum antibodies and anti-melanocyte antibodies. The present study highlights the association between the two, may be more than chance occurrence and may have a genetic predisposition. However, further studies involving a larger cohort are needed to study the common HLA types and role of difference cytokines between the two.

Cavalié M, Ezzedine K, Fontas E, Montaudié H, Castela E, Bahadoran P, et al. Maintenance therapy of adult vitiligo with 0.1% tacrolimus ointment : a0 randomized, double-blind, placebo-controlled study. J Invest Dermatol 2015;135:970-4.

Vitiligo is a chronic pigmentary disorder with a worldwide distribution. Although a continuous research is still ongoing concerning its pathogenesis and treatment, a definitive solution is still awaited. Posttreatment, one of the major concerns in patients who achieve repigmentation of vitiligo lesions is the risk of relapse. This risk is estimated to be ~40% within the 1 st year after stopping treatment. This study was conducted with the objective to evaluate role 0.1% tacrolimus ointment twice-weekly in maintaining repigmentation in therapeutically repigmented lesions of vitiligo patients. The study is a prospective randomized, double-blind placebo-controlled trial wherein patients with vitiligo in whom lesions had been successfully treated (at least 75% of repigmentation) were included and randomly assigned, to either tacrolimus group or placebo. After repigmentation, patients were immediately (or within a maximum of 2 weeks) transitioned to the maintenance protocol. Patients were advised to apply the ointment twice weekly, in nonconsecutive days, on all the repigmented areas for 24 weeks. The efficacy of the treatment was evaluated using standardized pictures with direct light and Wood's lamp by two blinded physicians. Main criteria for evaluating the efficacy were the level of depigmentation. Physician global assessment (PGA) was used to assess the evolution of vitiligo between initial and final pictures in three categories: Stable; repigmentation, and depigmentation. Depigmentation was observed in 48.4% of lesions in the placebo group and 26.8% in the tacrolimus group. More than 50% depigmentation was noted in 12% of the lesions in placebo group whereas it was 0% in the tacrolimus group. This study shows the benefits of a twice weekly tacrolimus maintenance therapy, especially in face/neck areas but also on the rest of the body. The PGA score in the placebo and tacrolimus groups respectively, showed repigmentation in 11.1% versus 31% of the lesions, depigmentation in 48.2% versus 10.4%, and no change in 40.7% versus 58.6%. Side-effects in tacrolimus group were with mild and transient erythema, stinging, and burning sensations mostly which did not require any specific intervention.

Comments: Multiple treatment options are currently available for the treatment of vitiligo, and many more are currently under development process. However, not much work has been to prevent relapse risk in vitiligo patients after repigmentation. In atopic dermatitis, both topical steroids and tacrolimus ointment have shown to be effective for preventing relapses. A meta-analysis concluded that topical steroids might be the more effective than tacrolimus in this regard. In vitiligo, topical steroids, and tacrolimus ointment are both effective in repigmenting the lesions, but side-effects were fewer with tacrolimus. Similarly, twice-weekly applications of topical steroids could also be effective for the maintenance therapy in vitiligo. Twice weekly tacrolimus is thought to inhibit the low-grade immune reaction against melanocytes. In this study, it was observed that the success rate of tacrolimus maintenance therapy is independent of the modality of the initial treatment used by physician and appeared to be more effective to maintain pigmentation on face and neck as compared with the rest of the body (96% and 78% of the lesions treated, respectively). The study, however, did not include very resistant areas such as hands and feet in either group. The study reported that twice weekly application of topical tacrolimus 0.1% can help to prevent depigmentation and achieve repigmentation. Major advantages of this regimen were the low frequency of application and the absence of need for concomitant ultraviolet or light therapy, therefore, good compliance. However, the sample size was small, and follow-up duration was short. Further studies are required to determine optimal topical therapy, the schedule of application and total duration of such maintenance therapy to decrease the risk of relapse in vitiligo patients.

Komen L, van der Kraaij GE, van der Veen JP, de Rie MA, Wolkerstorfer A. The validity, reliability, and acceptability of the SAVASI; a new self-assessment score in vitiligo. J Eur Acad Dermatol Venereol 2015;e-publication ahead of print.

Vitiligo is a common chronic depigmenting skin disorder that can affect a patient's quality of life. Self-assessment scores can be effective tools to improve communication between patients and physicians and act as a valuable supplement in therapeutic education programs. Unlike psoriasis and atopic dermatitis, a self-assessment tool to assess the degree of depigmentation in vitiligo is not available. The aim of our study was to assess the measurement properties of this self-assessment tool - self-assessed vitiligo area and severity index (SAVASI). The SAVASI uses the same basic principles as the VASI, adapted for patients. In SAVASI, first the patient indicates in a drawing the body parts affected by vitiligo. Thereafter, the patient assesses per body part the number of hand units affected (a patient's own handset at 1% of the body surface area per unit) and the extent of depigmentation within these affected hand units (possible values of 0%, 10%, 25%, 50%, 75%, 90%, or 100%, which are illustrated with patient photographs). To assess the validity, SAVASI scores assessed by the patient was compared with VASI assessed by the physician. To assess the intra-rater reliability, the correlation between the baseline SAVASI and the SAVASI after 2 weeks was calculated. To assess the acceptability, patients indicated the time needed to complete the SAVASI, and the patient assessed the difficulty of the questionnaire on a five-point scale. The acceptability of the SAVASI was assessed by the patient with an additional questionnaire. Skindex-29 was used to determine the quality of life. The overestimation of the SAVASI compared to the VASI was calculated by subtracting the VASI scores off from the SAVASI scores. A total of 60 patients completed SAVASI 1 however, only 31 patients (52%) completed SAVASI 2. A high correlation between the VASI and the SAVASI was seen in all 60 patients. The intra-rater reliability of the SAVASI was adequate in 31 patients. Fifty (83%) of the patients completed the questionnaire within 10 min, and 5 (8%) patients considered the SAVASI hard. There was no correlation between overestimation of the SAVASI score and the Skindex-29 score. The correlation between the vitiligo disease activity (VIDA) assessed by the patient and the VIDA assessed by the physician was good, the weighted kappa was 0.70. Twenty-eight patients (47%) assessed the questionnaire as very easy or easy, from which 8 patients assessed the questionnaire as very easy. Twenty-seven patients (45%) assessed the questionnaire not easy not hard, and 5 patients (8%) assessed the questionnaire as hard.

Comments: This is the first study reporting a validated self-assessment instrument to measure the degree of depigmentation in vitiligo. Similar studies on patient orientated measurement instruments in atopic dermatitis and psoriasis concluded that self-assessment tools are valuable for everyday practice and epidemiological studies. It is expected that an impaired health-related quality of life (HRQL) could influence the ability of the patients to assess their own degree of depigmentation. The study shows, in contrast, that there is no correlation between overestimation of the degree of depigmentation by the patient and the HRQL. The major drawback of the study is only 31 patients (52%) returned their SAVASI 2 questionnaire, which could indirectly indicate it was too difficult, time consuming or lack of motivation to fill it at home. Furthermore, there was no effort to simplify the questionnaire and to make it more patients friendly, VASI was taken as it is and made into a self-assessment format. The measurement conditions for the first and second intra-rater reliability measure were different. The first SAVASI score was assessed in the hospital directly after watching an instruction video; the second score was assessed at home. In this study, the SAVASI is an acceptable, reliable, and valid self-assessment instrument for vitiligo patients to assess their degree of depigmentation. In addition, the VIDA could be added to the SAVASI to measure the activity of vitiligo. These measurement instruments may pave way for other simpler and less time consuming self-assessment scores in vitiligo.

Matsui MS, Petris MJ, Niki Y, Karaman-Jurukovska N, Muizzuddin N, Ichihashi M, et al. Omeprazole, a gastric proton pump inhibitor, inhibits melanogenesis by blocking ATP7A trafficking. J Invest Dermatol 2015;135:834-41.

Omeprazole is a proton pump inhibitor used in the treatment of peptic ulcer disease, which acts by irreversibly blocking ATP4A, a P-type H + /K + ATPase in gastric parietal cells. However, ATP4A gene is undetectable in melanocytes, suggesting the role of ATP7A, an alternative P-type ATPase in blocking melanogenesis. The objective of this study was to examine the effect of omeprazole on melanogenesis and ATP7A function. It was observed that omeprazole and its congeners inhibit melanogenesis at micromolar concentrations in B16 mouse melanoma cells, human epidermal melanocytes, and in reconstructed human skin model with decreased levels of melanin being evident by 72 hours of treatment. Omeprazole was found to exhibit a more potent hypopigmentation effect compared with kojic acid. Omeprazole on topical application over ultraviolet-irradiated human skin showed a significant reduction in pigment level after 3 weeks as compared to untreated controls. Omeprazole induced a dose-dependent decrease in tyrosinase activity from 48 hours onward with a peak at 72 hours on incubation with B16 mouse melanoma cells. These effects of omeprazole required at least 48 hours of treatment, 6-24 hours incubation failed to reduced tyrosinase activity significantly. Omeprazole had no significant inhibitory effect on the activities of purified human tyrosinase or on the messenger RNA (mRNA) levels of tyrosinase, dopachrome tautomerase, Pmel17, or microphthalmia-associated transcription factor mRNA level as detected by quantitative real- time polymerase chain reaction (PCR), suggesting its role in enhancing tyrosine degradation and possibly inhibiting copper transport to tyrosine via ATP7A. Omeprazole treatment increased the proportion of EndoH sensitive tyrosinase, indicating that tyrosinase maturation was impaired. In addition, omeprazole reduced tyrosinase protein abundance in the presence of cycloheximide, suggestive of increased degradation. This study suggests that omeprazole reduces melanogenesis by inhibiting ATP7A and by enhancing degradation of tyrosinase.

Comments: Hyperpigmentation of skin especially over the 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. Proton pump inhibitors with the pharmacophore 2-pyridylmethylsulfinylbenzimidazole that inhibited melanin synthesis in mouse melanoma B16 cells and exacerbated vitiligo in 2 patients are the latest addition to this group. These proton pump inhibitors acts by irreversibly blocking the H + /K + ATPase of the gastric parietal cell. In the acidic environment of the stomach, omeprazole undergoes molecular rearrangement, exposing a reactive imidazole that covalently binds to a conserved cysteinyl sulfur moiety of the ATPase and inhibiting its activity. However, ATP4A is not found in melanocytes, leading to search for newer targets of omeprazole, which were identified as ATP7A and ATP12A using reverse transcriptase PCR. ATP12A inhibitor ouabain did not inhibit melanogenesis, whereas mutations in the ATP7A gene in Menkes disease is associated with hypopigmentation of skin due to deficiency in ATP7A-dependent copper delivery to tyrosinase suggesting a possible interaction between omeprazole induced hypopigmentation and ATP7A. In this study, a lag time of 48- to 72-hours was required to detect significant inhibition of melanogenesis in cultured melanocytes which indicates that omeprazole does not act by direct inhibition of tyrosinase or as a copper chelation, rather it inhibits newly synthesized tyrosinase with the delay in its effects due to the requirement for the turnover of preexisting tyrosinase. It is also hypothesized that these delayed effects of omeprazole may reflect the time required to reach inhibitory concentrations within specific organelles such as the luminal compartments of the Golgi or the melanosome or it may undergo activation by molecular rearrangement prior to binding to its target. ATP7A is a copper transporting P-type ATPase in the trans-Golgi network that is, required for copper acquisition by tyrosinase. ATP7A relocalization from the trans-Golgi network to the plasma membrane in response to elevated copper concentrations in melanocytes was inhibited by omeprazole. Thus, it prevents melanogenesis in part by blocking ATP7A copper transport or by causing increased degradation possibly due to the destabilization of the protein. This novel study evaluates the role of proton pump inhibitors on melanogenesis, however, this is a single center study and much more work is needed to be done in this regard before a definite role of proton pump inhibitors in inhibiting melanogenesis can be concluded.