Janus-kinase inhibitors in dermatology: A review of their use in psoriasis, vitiligo, systemic lupus erythematosus, hidradenitis suppurativa, dermatomyositis, lichen planus, lichen planopilaris, sarcoidosis and graft-versus-host disease.

Recent studies on molecular pathways have elucidated novel therapeutic approaches in inflammatory and autoimmune skin disorders. Specifically, the dysregulation of the Janus kinase signal transducer and activator of transcription (JAK-STAT) cascade plays a central role in the pathogenesis of many skin conditions. JAK inhibitors, with their ability to selectively target immune responses, are potential treatment options. Using the National Library of Medicine, we provide a comprehensive review of the use of United States Food and Drug Administration (FDA)-approved and emerging JAK or tyrosine kinase 2 (TYK2) inhibitors in a wide range of dermatologic conditions, including psoriasis, vitiligo, systemic lupus erythematosus, hidradenitis suppurativa, dermatomyositis, lichen planus, lichen planopilaris, sarcoidosis and graft-versus-host disease. In patients with psoriasis, oral deucravacitinib (TYK2 inhibitor) has been approved as a once-daily therapy with demonstrated superiority and efficacy over apremilast and placebo and tolerable safety profiles. In patients with vitiligo, topical ruxolitinib (JAK1 inhibitor) is approved as a twice-daily treatment for repigmentation. The efficacy of several other JAK inhibitors has also been demonstrated in several clinical trials and case studies for systemic lupus erythematosus, hidradenitis suppurativa, dermatomyositis, lichen planus, lichen planopilaris, sarcoidosis and graft-versus-host disease. Further investigations with long-term clinical trials are necessary to confirm their utility in treatment and safety for these diseases.

Protective effects of glutamine on human melanocyte oxidative stress model.

BACKGROUND: Vitiligo is a disorder caused by the loss of the melanocyte activity on melanin pigment generation. Studies show that oxidative-stress induced apoptosis in melanocytes is closely related to the pathogenesis of vitiligo. Glutamine is a well known antioxidant with anti-apoptotic effects, and is used in a variety of diseases. However, it is unclear whether glutamine has an antioxidant or anti-apoptotic effect on melanocytes. AIMS: The aim of this study was to investigate the protective effects of glutamine on a human melanocyte oxidative stress model. METHODS: The oxidative stress model was established on human melanocytes using hydrogen peroxide. The morphology and viability of melanocytes, levels of oxidants [reactive oxygen species and malondialdehyde], levels of antioxidants [superoxide dismutase and glutathione-S-transferase], and apoptosis-related indicators (caspase-3, bax and bcl-2) were examined after glutamine exposure at various concentrations. Expressions of nuclear factor-E2-related factor 2, heme oxygenase-1, and heat shock protein 70 were detected using western blot technique after glutamine exposure at various concentrations. RESULTS: Our results demonstrate that pre-treatment and post-treatment with glutamine promoted melanocyte viability, increased levels of superoxide dismutase, glutathione-S-transferase and bcl-2, decreased levels of reactive oxygen species, malondialdehyde, bax and caspase-3, and enhanced nuclear factor-E2-related factor 2, heme oxygenase-1, and heat shock protein 70 expression in a dose dependent manner. The effect of pre-treatment was more significant than post-treatment, at the same concentration. LIMITATIONS: The mechanisms of glutamine activated nuclear factor-E2-related factor 2 antioxidant responsive element signaling pathway need further investigation. CONCLUSIONS: Glutamine enhances the antioxidant and anti-apoptotic capabilities of melanocytes and protects them against oxidative stress.

A study of the free radical scavenging effects of Piper betle leaf extract in patients with vitiligo.

BACKGROUND: Vitiligo is an idiopathic skin disease manifested by depigmented macules. It is characterised by melanocyte destruction, and redox imbalance is proposed to play a contributory role. AIM: The aim of this study was to analyze the effects of an ethanolic extract of Piper betle leaves on the generation of reactive oxygen species in erythrocytes sourced from vitiligo patients. METHODS: The effect of Piper betle on the generation of reactive oxygen species in erythrocytes was measured by flow cytometry in patients with active and stable vitiligo versus healthy controls, using 5-(and-6)-chloromethyl-2'-7'-dichlorodihydrofluorescein diacetate. RESULTS: The generation of reactive oxygen species in erythrocytes was higher in patients with vitiligo (n = 23) compared to healthy controls (n = 18). The geometrical mean fluorescence channel was 23.05 ± 2.11 in patients versus 17.77 ± 1.79 in controls, P = 0.039. The levels of reactive oxygen species were higher in patients with active vitiligo. Treatment of erythrocytes with Piper betle in concentrations of 0.5 and 1.0 µg/ml significantly decreased the baseline levels of reactive oxygen species by 31.7% in healthy controls, and 47.6% and 44.3% in patients with active vitiligo, respectively. Piper betle effectively scavenged hydrogen peroxide, which was evident by a decrease in the geometrical mean fluorescence channel by 52.4% and 62.9% in healthy controls, and 45.0% and 57.0% in patients with active vitiligo. LIMITATIONS: The study had a small sample size. Future studies should focus on evaluation of the antioxidant role of Piper betle at the lesional site. CONCLUSION: This pilot study indicates that patients with active vitiligo demonstrate enhanced generation of reactive oxygen species in erythrocytes, which was significantly reduced following ex vivo treatment with Piper betle.

The reservoir effect of topical steroids in vitiliginous skin: A cross-sectional study.

BACKGROUND: Prolonged and frequent use of topical steroids may lead to decrease in efficacy as well as many local adverse effects. Stratum corneum has a unique property of reservoir effect. AIMS: To study the reservoir effect of topical steroids in a steroid-responsive condition which may enable a decrease in the dosing frequency of topical steroids. METHODS: A cross-sectional study design was used. Patients with at least three vitiliginous patches of more than 2 cm 2 present over the trunk or limbs were included. Exclusion criteria were topical or systemic corticosteroid use within the previous 4 weeks, antihistamine use within the previous 7 days, history of any allergy in the past and immunosuppression. Clobetasol propionate cream was applied on the first vitiliginous area (site A) and fluticasone propionate ointment was applied on the second vitiliginous area (site B). The third vitiliginous area, site C (control site) was left without applying any medication. Histamine-induced wheal suppression test was performed on each site, at the same time of the day, on every consecutive day following steroid application, until the values obtained at sites A and B approached those obtained at site C. SPSS software for Windows, version 16.0 was used for statistical analysis. The mean and standard deviation of the various studied parameters were calculated for various treatment groups and compared using analysis of variance (ANOVA) test. RESULTS: Forty patients were included in the study. The average wheal volumes and average erythema sizes at sites A and B were significantly smaller than the corresponding values at site C for up to 5 days after applying medication (P < 0.001). LIMITATIONS: The presence of a cutaneous reservoir of topical steroid was confirmed based on its suppressive effect on the wheal and flare response to histamine. It is not certain that the concentration that suppresses histamine-induced wheal and flare is sufficient for therapeutic efficacy in vitiligo. CONCLUSION: The reservoir effect of topical clobetasol propionate and fluticasone propionate persisted for 5 days in vitiliginous skin. Hence, it may be possible to reduce the frequency of topical steroid application in vitiligo.

Photochemotherapy (PUVA) in psoriasis and vitiligo.

Phototherapy with photochemotherapy (PUVA) is a well-known and well-studied modality for the treatment of psoriasis, which involves systemic or topical administration of chemicals known as psoralens and administration of ultraviolet light in increasing dosages after requisite time gap. PUVA is also used in the treatment of widespread vitiligo with moderately good results, though it is being surpassed by ultraviolet B (UVB), which is equally or slightly more efficacious with fewer side effects. PUVA induces repigmentation by varying mechanisms such as stimulation of melanogenesis, immunomodulation and activation of growth factors, though the exact mechanism is still speculative. There are various studies evaluating the efficacy of PUVA in psoriasis as well as in vitiligo, either alone or in combination with other immunosuppressants like azathioprine and calcipotriene.

Randomized controlled study to evaluate the effectiveness of dexamethasone oral minipulse therapy versus oral minocycline in patients with active vitiligo vulgaris.

BACKGROUND: Oral minocycline has been recently shown to halt disease progression in active vitiligo. AIMS: The present study was planned to compare the efficacy and tolerability of oral minocycline with oral mini pulse (OMP) corticosteroids in active vitiligo. METHODS: A total of 50 patients with actively spreading vitiligo were randomized to receive either minocycline 100 mg/day (Group I-25 patients) or OMP 2.5 mg dexamethasone on 2 consecutive days in a week (Group II-25 patients) for 6 months. These were followed-up at every 2 weeks interval. Mean vitiligo disease activity score (VIDA) and mean Vitiligo Area Scoring Index (VASI) were assessed in all patients in addition to the photographic comparison before and after treatment. RESULTS: Both groups showed a significant decrease in VIDA from 4.0 to 1.64±0.86 (P<0.001) in Group I and from 4.0 to 1.68±0.69 (P<0.001) in Group II. However, the difference between the mean VIDA scores in the two groups was not statistically significant (P=0.60) at the end of treatment period. The mean VASI declined from 1.71±1.45 to 1.52±1.43 Group I (P=0.06) and from 1.39±1.31 to 1.17±1.34 in Group II (P=0.05). The difference between VASI in Group I and II was not significant at the end of 24 weeks of treatment (P=0.11). CONCLUSION: Both dexamethasone OMP and oral minocycline are effective drugs for managing the arrest of disease activity in vitiligo.

Topical treatment in vitiligo and the potential uses of new drug delivery systems.

Vitiligo is a psychologically devastating condition. Topical therapy is employed as first-line treatment in localized vitiligo. Currently, several topical agents are available in many forms viz. methoxsalen (solution and cream), trioxsalen (solution), corticosteroids (gel, cream, ointment and solution) and calcineurin inhibitors (ointment and cream). Although topical therapy has an important position in vitiligo treatment, side-effects or poor efficacy affect their utility and patient compliance. Novel drug delivery strategies can play a pivotal role in improving the topical delivery of various drugs by enhancing their epidermal localization with a concomitant reduction in their side-effects and improving their effectiveness. The current review emphasizes the potential of various phospholipid based carriers viz. liposomes, transferosomes, ethosomes, lipid emulsions, solid lipid nanoparticles and organogels in optimizing and enhancing the topical delivery of anti-vitiligo agents, whilst reducing the side effects of drugs commonly used in its topical treatment.

Topical placental extract: does it increase the efficacy of narrowband UVB therapy in vitiligo?

BACKGROUND: Narrowband UVB therapy is presently one of the most effective therapies for generalized vitiligo. Many topical agents have been used in combination with narrowband UVB therapy to increase its efficacy in causing repigmentation in vitiligo. Placental extract is used topically usually in combination with sun exposure to cause repigmentation of vitiligo lesions. AIMS: The present study aims to study whether the efficacy of narrowband UVB therapy would be enhanced by addition of topical placental extract to the treatment regimen. METHODS: Ninety patients with vitiligo having more or less bilaterally symmetrical lesions on the face, trunk or limbs and receiving narrowband UVB therapy were enrolled for the study and instructed to apply topical placental extract (placentrex) lotion on their vitiligo lesions on the right side of the body. The other side of the body received narrowband UVB therapy alone and served as the control side. The extent of repigmentation achieved was assessed by VASI scoring and compared between the symmetrical lesions present on the two sides at monthly intervals and at the end of study period. RESULTS: Seventy-eight patients with 218 symmetrically distributed lesions, excluding those present on the hands or feet, were evaluated for study results at the end of treatment period. The time to onset of repigmentation as well as the mean NB-UVB dosage required was the same on the two sides. The mean repigmentation achieved was 63% (VASI score of 3.69) on the right (placental extract) sided lesions in comparison with 62% (VASI score of 3.60) on the left (control) sided lesions. Greater than 90% repigmentation was achieved in 70 symmetrical lesions in 24 patients. Of these 70 lesions, 39 were located on the right side of the body while 31 belonged to the left side of the body. CONCLUSIONS: Addition of the topical placental extract was seen to have a modest but a statistically insignificant effect on the efficacy of NB-UVB therapy in causing repigmentation in vitiligo.

Keratinocyte-melanocyte graft technique followed by PUVA therapy for stable vitiligo.

BACKGROUND: Various surgical procedures for correcting stable vitiligo exist but these have their own limitations. Autologous, non-cultured, non-trypsinized, melanocyte plus keratinocyte grafting is a new and simple method of vitiligo surgery. OBJECTIVE: The study aimed to evaluate efficacy of a new grafting technique in vitiligo patches. METHODS: Eighteen vitiligo patches underwent this procedure. The upper layer of epidermis was removed by superficial dermabrasion using a dermabrader micromotor until the epidermis appeared wet and shiny. Then, antibiotic ointment was applied and dermabrasion was continued up to the whitish area of the upper dermis. The paste-like material (ointment with entangled epidermal particles) was collected and spread over the dermabraded recipient site. RESULTS: Pigmentation usually started at 4-6 weeks. Complete uniform pigmentation took 16-20 weeks. CONCLUSION: For smaller vitiligo patches this method gives cosmetically acceptable results. It is easy to perform and does not require specific laboratory setup.

Topical immunotherapy with diphenylcyclopropenone in vitiligo: a preliminary experience.

BACKGROUND: Despite recent significant therapeutic advances, vitiligo remains a clinical conundrum. Topical immunotherapy has been extensively tested in the treatment of various dermatologic disorders, especially those believed to have an immunologic basis. AIM: To evaluate the role of topical diphenylcyclopropenone (DPCP) in the treatment of vitiligo. METHODS: Nineteen patients with limited vitiligo lesions were enrolled in this study. After sensitization with 2% lotion of DPCP in acetone, progressively higher concentrations beginning at 0.001% up to 2% were applied weekly for 6 months to the depigmented skin lesions. RESULTS: Thirteen of the 19 patients were evaluated at the end of 6 months. Four patients with focal vitiligo, one patient with vitiligo vulgaris, and three patients with segmental vitiligo showed marked (grade 3) repigmentation. CONCLUSION: Marginal and central repigmentation with hyperpigmented borders was seen in the majority of lesions. Further controlled trials should be undertaken to evaluate the use of topical DPCP in vitiligo.