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| CURRENT BEST EVIDENCE |
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| Year : 2018 | Volume
: 5
| Issue : 2 | Page : 125-129 |
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Current Best Evidence in Pigmentary Dermatology
Divya Kamat, Vinay Keshavamurthy
Department of Dermatology, Venereology and Leprology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| Date of Web Publication | 14-Dec-2018 |
Correspondence Address:
Dr. Vinay Keshavamurthy
Department of Dermatology, Venereology and Leprology, Postgraduate Institute of Medical Education and Research, Chandigarh
India
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/Pigmentinternational.Pigmentinternational_
Keywords: melasma, dermal macular hyperpigmentation, vitiligo, nevus of ota
How to cite this article:
Kamat D, Keshavamurthy V. Current Best Evidence in Pigmentary Dermatology. Pigment Int 2018;5:125-9 |
[TAG:2]Rosario ED, Florez-Pollack S, Zapata L, Hernandez K, Tovar-Garza A, Rodrigues M, et al. Randomized, placebo-controlled, double-blind study of oral tranexamic acid in the treatment of moderate-to-severe melasma. J Am Acad Dermatol 2018;78:363-9. http://dx.doi.org/10.1016/j.jaad.2017.09.053.[/TAG:2]
Tranexamic acid (TA), an antifibrinolytic agent, has emerged as a promising treatment for melasma. TA was originally developed for the treatment of menorrhagia and bleeding diathesis. TA causes decreased production of fibroblast growth factor (FGF) and prostaglandins by blocking the conversion of plasminogen to plasmin. Both FGF and prostaglandins are potent stimulants of melanocyte activity. The objective was to determine the efficacy of oral TA in patients with moderate to severe melasma.
Female patients, age 18 or older with moderate or severe melasma were recruited if they did not have any contraindications to the use of TA (as prescribed by food and drug administration (FDA)). Moderate melasma was defined as those with a modified Melasma Area and Severity Index (mMASI) score of 5.8 to 7.9 and severe melasma were those with a mMASI > 8. Patients were then randomized into TA or placebo groups stratified by severity (moderate or severe melasma). They received 250 mg of TA or placebo twice daily for 3 months and all received sunscreen (Neutrogena Ultra Sheer, sun protection factor (SPF) 30) with instructions to apply every morning, with reapplication every 2 h during daylight hours. Both patients and raters were blinded to treatment arms. mMASI measurement and determination of pigmentation of involved and uninvolved skin with a narrow band reflectance spectrophotometer was performed in all follow up visits. All patients filled out a melasma quality of life questionnaire. Patients were then instructed to use sunscreen alone for further 3 months. A total of 44 patients satisfied the inclusion/exclusion criteria and were randomized into the two treatment groups. Twenty-one (95%) in the TA group and 18 (82%) in the placebo group were Hispanic Caucasian women. Of the 39 patients who completed the study, 18 (46%) reported no previous treatment for melasma. For both melasma groups, mMASI decreased over time, with those on TA decreasing more than the placebo group at 12 weeks. However, mMASI increased in both groups from 12 to 24 weeks but were found to have lower mMASI scores than at baseline. After 3 months of treatment with TA, there was a 49% reduction in mMASI in all patients in the TA arm vs. an 18% reduction in the placebo arm (mean decrease in mMASI of 4.2 vs. 1.4). For both melasma groups, the melanin index decreased from baseline to 12 weeks, with those on TA decreasing more than the placebo group. Melanin index increased in both groups from 12 to 24 weeks except the moderate placebo group; however, both groups had lower melanin index scores at 24 weeks compared to baseline. Side effects occurred in 63.6% of patients on TA vs. 36.3% on placebo. Side effects were predominantly mild and resolved within 1 month despite continued treatment. Only one patient discontinued the medication due to moderate myalgias. No thromboembolic events or other serious adverse events were observed in either group.
Limitations of this study were lack of male patients and enrollment of predominantly Hispanic patients. In addition, the follow-up period after treatment was only 3 months.
COMMENT
Oral TA at a dose of 250 mg twice daily for 3 months significantly improved moderate-to-severe melasma; however, those with severe melasma did not sustain their improvement compared to those with moderate melasma after TA was discontinued. The use of sunscreen alone improves melasma, but its effects are modest. Previous RCT’s also showed similar results with minimal side effects at low doses. The effect was also not sustained after discontinuation of treatment. Studies with longer treatment durations and follow-up periods as well as combining TA with depigmenting creams should be performed.
[TAG:2]Liu Y, Zeng W, Li D, Wang W, Liu F. A retrospective analysis of the clinical efficacies and recurrence of Q-switched Nd:YAG laser treatment of nevus of Ota in 224 Chinese patients. J Cosmet Laser Ther 2018:1-5. http://dx.doi.org/10.1080/14764172.2018.1444772.[/TAG:2]
Nevus of Ota is a benign dermal melanocytic nevus that typically affects Asian children and women. The nevus typically occurs as a persistent, blue-black, or light-brown hyperpigmented macules and patches located along the first and second divisions of the trigeminal nerve. The authors performed a retrospective study on 224 Chinese patients who were treated with QS Nd:YAG laser, to analyze the clinical efficacy and recurrence.
Treatment with 1064-nm QSNd:YAG laser was performed from 2005 to 2012, and all patients were followed up by telephone or an in-person appointment each year after treatment for 2 to 10 years. Patients were treated with a 1064-nm QSNd:YAG laser, using a 2 to 4-mm spot-size and fluences of 4 to 8.0 J/cm2. Clinical response was defined as immediate whitening without purpura. Ice compress was applied for 1 h immediately after the treatment. Patients were advised to use sunscreen for at least 3 months after the treatment. The interval between two consecutive sessions was 4 to 6 months. The degree of efficacy of the QSNd:YAG laser was established based on visual inspection of the percentage of pigmentary clearing on photographs, which was divided into five grades as follows: (1) minimal improvement (<25%), (2) moderate improvement (26%–50%), (3) marked improvement (51%–75%), (4) significant improvement (76%–99%), (5) complete clearing (100%). The patients included in the study were predominantly females (224 patients: 163 females, 61 males). The average visiting age was 21.69 ± 10.14 years. A total of 37.5% of patients had nevi present at birth, and 94.20% were affected before 20 years of age. According to the Tanino classification, the majority of patients were Type I (53.13%) and Type II (37.95%). The predominant lesion color was light-brown (42.41%), followed by brown (29.46%), and blue-black (27.68%). Two hundred and twenty-two patients (99.11%) obtained more than 75% improvement with an average of 3.7 sessions. There was a significant difference between the different types of skin lesions, and the curing rate of Type I was the highest, reaching 72.3%. Other factors, including gender, visiting age, treatment sessions, and lesion colors, were not associated with response to treatment. Eight patients (3.57%) who had complete clearance later developed recurrence at the same site as before. The time of recurrence was 1 to 3 years after the last treatment session. The predominant color of the reappeared lesions was blue-black (5/8). All subtypes as per Tanino classification had recurrence [Type I (2), Type II (3), Type III (3)]. Many patients had temporary postinflammatory hyperpigmentation or hypopigmentation. No other adverse effect such as persistent erythema, scarring, or sensitivity was observed.
COMMENT
In this study, all 224 patients responded to treatment, most within three to four treatment sessions. Recurrence in nevus of Ota is as rare as 0.8% to 2.1% as per retrospective studies. Eight patients had recurrence with blue-black type of skin lesions predominantly. Reasons for recurrence remain unclear. It is postulated that the dermal stem cells that are left behind after laser treatment are triggered to differentiate into melanocytes.
[TAG:2]Park KY, Kwon HJ, Wie JH, Lee HH, Cho SB, Kim BJ, et al. Pregnancy outcomes in patients with vitiligo: A nationwide population-based cohort study from Korea. J Am Acad Dermatol 2018;79:836-42. http://dx.doi.org/10.1016/j.jaad.2018.02.036.[/TAG:2]
Recently, the autoimmune nature of vitiligo has been emphasized, with CD8+ T cells being shown to play a major role in vitiligo dissemination. Evidence suggests that systemic autoimmunity can affect the progress of pregnancy, triggering maternal complications and adverse fetal outcomes. Several poor outcomes, including recurrent abortion, fetal death, preeclampsia, intrauterine growth restriction (IUGR), and preterm birth have been observed in women with a variety of autoimmune diseases. The objective was to investigate adverse pregnancy outcomes in patients with vitiligo.
The authors performed a nationwide, population-based, retrospective cohort study using an National health insurance (NHI) claims database that contained all claims information from the NHI and the Korean Medical Aid program from 2007 to 2016. A total of 4738 confirmed first-pregnancy women with vitiligo identified between January 1, 2007, and December 31, 2016 in Korea were included. The control group included women who had no history of vitiligo during the same period. They were randomly selected (10 controls for each vitiligo patient) after frequency matching in terms of age with the vitiligo group. Patients with diabetes, hypertension, and/or hyperlipidemia were defined as those with at least 10 documented physician contacts attributable to these when the first diagnosis of any of these diseases was made before the diagnosis of pregnancy. Pregnancy outcomes were divided into four categories: (1) live births, (2) spontaneous abortion, (3) cesarean delivery, and (4) perinatal events. Perinatal events included the following five subclassifications: (4-a) preterm delivery, (4-b) preeclampsia, (4-c) gestational diabetes mellitus, (4-d) stillbirths, and (4-e) IUGR. Cases included 4738 pregnant women with vitiligo, and 47,380 pregnancies in age-matched women without vitiligo were identified as controls. Of the vitiligo patients, 4038 (85.2%) had limited lesions, and 700 (14.8%) showed extensive involvement. In this nationwide cohort study, it was found that pregnant women with vitiligo (n = 4738) had a significantly lower rate of live births (Odds ratio (OR) 0.870, 95% confidence interval (CI) 0.816–0.927) and a higher incidence of spontaneous abortion (OR 1.250, 95% CI 1.148–1.362) than women without vitiligo (n = 47,380). The higher incidence of spontaneous abortion and the lower live birth rate of vitiligo patients may reflect the autoimmune nature of vitiligo.
Limitations: First, the NHI Claims database may contain incorrect diagnoses. Second, the database lacked detailed clinical information on individual patients, such as age at disease onset, disease duration, and the vitiligo subtype, including segmental vitiligo. Thus, some possible covariants affecting pregnancy outcomes could not be explored. Third, information on lifestyle factors such as smoking status and the extent of physical activity were missing: both might have influenced pregnancy outcomes. Other autoimmune rheumatic disorders were not evaluated in detail, as these could affect pregnancy outcomes.
COMMENT
This was the first large-scale cohort study to identify adverse pregnancy outcomes in vitiligo patients. Further studies are needed to determine whether systemic autoimmunity underlies these finding. Physician consultations with patients addressing the increased risks of both spontaneous abortion and non attainment of a live birth would be prudent both before and during pregnancy.
[TAG:2]Kim SR, Heaton H, Liu LY, King BA. Rapid repigmentation of vitiligo using tofacitinib plus low-dose, narrowband UV-B phototherapy. JAMA Dermatol 2018;154:370. http://dx.doi.org/10.1001/jamadermatol.2017.5778.[/TAG:2]
Janus kinase (JAK) inhibitors are a promising class of targeted therapy, and concomitant low-dose light treatment may be necessary to stimulate melanocytes to achieve repigmentation. The authors describe two patients with vitiligo with significant facial involvement treated successfully with tofacitinib, a JAK 1/3 inhibitor, plus low-dose, narrowband Ultraviolet B (UV-B).
Case 1—A 30-year-old Hispanic woman presented with a 12-year history of vitiligo. Facial lesions appeared during her first pregnancy and spread over the following year to her neck, torso, and extremities. Treatment with liquid nitrogen and topical corticosteroids had been unsuccessful, and a 3-month course of topical monobenzyl ether of hydroquinone (MBEH) failed to induce depigmentation. On physical examination, there were white patches involving about 75% of her face as well as white patches on the neck, chest, forearms, hands, and shins. Treatment was begun with tofacitinib 5 mg twice daily and full-body narrowband UV-B (400–500 mJ) twice weekly. After 3 months of treatment, there was a near-complete repigmentation of her face 75% or greater repigmentation of her neck, chest, forearms, shins and only minimal freckling of the dorsal hands.
Case 2—A male in his 50s presented with long-standing vitiligo. Treatment with topical corticosteroids, topical calcineurin inhibitors, excimer laser, and narrowband UV-B had been unsuccessful. Four years prior to presentation, he had achieved depigmentation of the face using topical MBEH. On physical examination, there were white patches involving about 90% of his face as well as white patches on the torso and arms. Treatment was begun with tofacitinib 5 mg twice daily and narrowband UV-B (360–500 mJ) two to three times weekly to only the face. After 3 months of treatment, there was about 50% repigmentation of the face and after 6 months, about 75% facial repigmentation. No repigmentation occurred at the other body sites.
Improved response to JAK inhibitors in sun-exposed areas has been observed in a recent study by Liu et al. Suction blister fluid was analyzed for chemokine ligand (CXCL9) and CXCL10, before and after treatment with tofacitinib from both treatment responsive and non responsive areas. Levels of these chemokine ligands are known to increase in active vitiligo due to stimulation by interferon (IFN) gamma. It was observed that CXCL9 and CXCL10 levels reduced in both sites post treatment thus demonstrating the suppression of the autoimmune response by tofacitinib in both responding (sun-exposed) and nonresponding (sun-protected) vitiligo lesions. This suggests that in addition to suppression of autoimmune response, light is required for melanocyte regeneration. In the present cases, treatment of two patients with vitiligo with significant facial involvement using a combination of tofacitinib and low-dose, narrowband UV-B led to rapid repigmentation in both. The results support the hypothesis that photo activation is required to stimulate melanocytes to leave their stem-cell niche and seed the epidermis, whereas tofacitinib suppresses the autoimmune response.
COMMENT
It was interesting to note the rapid response in spite of both patients having received MBEH in the past with patient 2 having achieved successful depigmentation. This result suggests that melanocytes of the interfollicular epidermis, but not melanocyte stem cells, are destroyed by MBEH. Combination therapy with JAK inhibitors and low-dose, narrowband UV-B may be an effective targeted treatment for vitiligo. Prospective studies are needed to evaluate the efficacy and durability of response. Even after 6 months of therapy, patient 2 did not have repigmentation over the torso in spite of 75% facial repigmentation which emphasizes on the key role that sun exposure has to play.
[TAG:2]Vinay K, Dabas G, Parsad D, Kumaran M. A novel scale for measurement of acquired dermal macular hyper pigmentation severity. J Eur Acad Dermatol Venereol 2018;32. http://dx.doi.org/10.1111/jdv.14772.[/TAG:2]
Despite affecting a large number of patients, there is no validated quantitative scale for acquired dermal macular hyper pigmentation (ADMH). The authors propose a scoring method that objectively measures ADMH disease activity by a numerical score and combines analysis of extent and severity of disease which ultimately produces a constant, reproducible number. The scores were devised only for face and neck as they are the most important in terms of cosmetic and psychological concerns. Based on rule of nine, the total facial area and neck to be assessed constitutes 4% (face plus both surfaces of ears) and 2% (anterior and posterior neck) of total body surface area (BSA), respectively. This implies out of total 100% area to be assessed; face and neck constitutes 66.66% and 33.33% of total area, respectively. Face was divided into four segments—forehead, right and left cheek which constitute 20% of area each, and nose and perioral area which constituted 10% of area. Neck was divided in two segments constituting 15% area each. The severity of disease was assessed by color coding the intensity of pigment using a photo spectrometer, color-coded strips as per Fitzpatrick skin types or dermoscopy severity grades; Grade 0: No change in color/normal pattern on dermoscopy; Grade 1: Mild disease—light brown color change and/or dotted pattern on dermoscopy; Grade 2: Moderate disease—bluish/violaceous color and/or Chinese letter/semiarcuate pattern on dermoscopy; Grade 3: Severe disease—slate gray/brown color and/or reticulate pattern on dermoscopy; Grade 4: Very severe disease—dark brown to black color and/or diffuse pattern on dermoscopy.
Final score: ADMH area and severity index (DPASI): 2 × (percentage of forehead × grade) + 2 × (percentage of right cheek involvement × grade) + 2 × (percentage of left cheek involvement × grade) + 1 × (percentage of central face involvement × grade) + 1.5 × (percentage of left neck involvement × grade) + 1.5 × (percentage of right neck involvement × grade). By this method, the maximum possible DPASI is 40.
COMMENT
There is lack of consensus to describe the spectrum of this entity. It includes lichen planus pigmentosus, Riehl’s melanosis (RM), pigmented contact dermatitis, and erythema dyschromicum perstans. There is no standard scoring system for either of these conditions nor is there a standard satisfactory treatment. There is a need for trials to evaluate the efficacy of various treatment options, but there is a lack of uniform scale for the assessment of response. This is the first scoring method that has been proposed to surmount this problem and offer more accurate assessment. The major advantage of a quantitative scale is that they provide direct estimates of the expected quantitative responses that patients might expect to achieve. Quantitative methods provide data that are both sensitive and meaningful to both the patients and physicians. This scoring system markedly reduces interobserver variability as subjective evaluation of the extent or severity by the observer is eliminated.
[TAG:2]Richmond JM, Strassner JP, Zapata L, Garg M, Riding RL, Refat MA, et al. Antibody blockade of IL-15 signaling has the potential to durably reverse vitiligo. Sci Transl Med 2018;10. http://dx.doi.org/10.1126/scitranslmed.aam7710.[/TAG:2]
Vitiligo is an autoimmune disease of the skin mediated by CD8+ T cells. Skin lesions in vitiligo frequently recur after discontinuing conventional treatments, supporting the hypothesis that autoimmune memory is formed at these locations. Previous studies in mice have shown that interleukin-15 (IL-15) is important for the generation of TRM (resident memory) in viral infections and in cutaneous lymphomas. The objectives of this study were to determine whether TRM exist in human vitiligo, how they contribute to disease in a mouse model of vitiligo, and to determine whether these cells could be targeted therapeutically. The authors sought to target IL-15 signaling. The heterodimeric IL-15 receptor is composed of CD122 and CD132 only and is expressed on memory T-cell populations. The authors also tested whether blockade of CD122 signaling with a monoclonal antibody could serve as a durable treatment for vitiligo. Flow cytometry staining of blister fluid in a vitiligo patient showed that melanocyte-specific CD8+ TRM are present in vitiligo patient skin and express the CD122 chain of the IL-15 receptor, whereas keratinocytes express the CD215 chain. This was also confirmed in mouse models. It was found that systemic anti-CD122 antibody treatment durably reverses disease in mice via inhibition of antigen-specific T-cell IFN gamma production. Local intradermal injection of anti-CD122 antibody treatment also durably reverses disease in mice. These data support targeting IL-15 as a strategy to clear auto reactive memory cells from the tissue, resulting in a long-lasting, durable response to treatment.
COMMENT
These data emphasize on the role of TRM cells which are responsible for relapse after discontinuation of treatment. Thus, depleting these TRM forms the basis of further research. Anti-CD 122 antibody treatment showed durable response not just as a systemic therapy but also with intradermal injections. The option of treating intradermally seems clinically attractive. Future human trials in patients will provide important insights into targeting TRM via IL-15 signaling.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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