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.

Comparative study of the efficacy and safety of two grafting procedures (an automated epidermal harvesting system and non-cultured epidermal cell suspension) in the treatment of stable vitiligo.

Background The non-cultured epidermal cell suspension method is a well-established but tedious grafting modality in the management of stable vitiligo. Recently a more user-friendly automated epidermal harvesting system has been introduced. Aim This was a pilot study to compare the efficacy and safety outcomes of the above two grafting procedures. Study design The study was a single-blinded split-body randomised controlled trial. After scientific and ethical clearance, the trial was registered with CTRI (CTRI/2018/05/014225). Thirty consenting patients of stable vitiligo with 60 near-symmetrical patches were recruited. Block randomisation was done using computer-generated randomisation software and each patch was allocated either of the two grafting modalities. Efficacy was assessed by the Physician Global Assessment Scale on serial images and pain by the Numerical Rating Pain Scale. Results and conclusion The non-cultured epidermal cell suspension was found to be an overall statistically superior technique to the automated epidermal harvesting system in terms of efficacy (re-pigmentation). Both donor and recipient site complications were significantly less with the automated epidermal harvesting system grafting and this method had the distinct advantage of being a painless and easy technique with minimal recovery time. A novel observation was that a good colour match and near-complete re-pigmentation occurred in patients with a darker skin colour with both techniques. Limitations The main limitation of our study was the small sample size. Also, the size of the treated patches was limited such that they could be covered by the 5 × 5 cm size of the automated epidermal harvesting system blade. However, a larger area can be covered with multiple sessions.

Association between exonic polymorphisms of human leukocyte antigen-G gene and non-segmental vitiligo in the Korean population.

Background Vitiligo is a pigmentary skin disorder characterised by a chronic and progressive loss of melanocytes. Although several theories have been suggested to the pathogenesis of vitiligo, an autoimmune process leading to melanocyte destruction appears most likely. Human leukocyte antigen-G is a non-classic, major histocompatibility complex Class I molecule that plays an important role in the suppression of the immune response. Several recent studies have provided evidences that polymorphisms in the human leukocyte antigen-G gene might be related with autoimmune diseases. Objectives The aim of this study was to decide whether exonic single nucleotide polymorphisms in human leukocyte antigen-G contribute to the risk of developing non-segmental vitiligo in the Korean population. Methods To evaluate the associations between exonic single nucleotide polymorphisms (rs1630223 [Ala5Ala] and rs12722477 [Leu134Ile]) of human leukocyte antigen-G and vitiligo, 244 patients with vitiligo and 398 healthy controls were recruited. Genotyping was performed using Fluidigm 192.24 Dynamic Array with EP1 (Fluidigm Corp., CA). The SNP type assay (Fluidigm Corp., CA), which employs allele-specifically designed fluorescences (FAM or VIC) primers and a common reverse primer was applied and the data were analysed using the EP1 single nucleotide polymorphisms genotyping analysis software to obtain genotype calls. Results Two exonic single nucleotide polymorphisms (rs1630223 and rs12722477) exhibited significant associations with susceptibility and remained a statistically significant association following Bonferroni correction. These two single nucleotide polymorphisms were located within a block of linkage disequilibrium. Haplotypes G-C and A-A comprising rs1630223 and rs12722477 demonstrated a significant association with non-segmental vitiligo. Limitations The protein expression level of patients with vitiligo and controls was not studied and a replication study of the genetic association in an independent group was not managed. Conclusion Our results suggest that exonic human leukocyte antigen-G polymorphisms (rs1630223 and rs12722477) are associated with the development of non-segmental vitiligo.

Thymocyte selection-associated high-mobility group box as a potential diagnostic marker differentiating hypopigmented mycosis fungoides from early vitiligo: A pilot study.

BACKGROUND: Hypopigmented mycosis fungoides is a rare variant of mycosis fungoides that may mimic many benign inflammatory hypopigmented dermatoses, and as yet there is no identified marker to differentiate between them. AIM: The aim of this study was to study the expression of thymocyte selection-associated high-mobility group box (TOX) in hypopigmented mycosis fungoides and one of its inflammatory mimickers (early active vitiligo) to assess its potential as a differentiating diagnostic marker. METHODS: A case-control study was done using immunohistochemical analysis of TOX expression in 15 patients with hypopigmented mycosis fungoides and 15 patients with early active vitiligo. Immunohistochemical analysis was done via a semi-quantitative method and an image analysis method. RESULTS: Hypopigmented mycosis fungoides showed a statistically significant higher expression of TOX than early active vitiligo. The expression of TOX was positive in a majority of hypopigmented mycosis fungoides cases (14 cases, 93.3%), while only one case (6.7%) of vitiligo was weakly positive. TOX also displayed 93.3% sensitivity and specificity, with a cut-off value of 1.5. LIMITATIONS: This was a pilot study testing hypopigmented mycosis fungoides against only a single benign inflammatory mimicker (early vitiligo). Other benign mimickers were not included. CONCLUSION: Our findings showed that TOX expression can differentiate hypopigmented mycosis fungoides from early active vitiligo which is one of its benign inflammatory mimickers, with a high degree of sensitivity and specificity.

Validation of the diagnostic criteria for segmental vitiligo.

BACKGROUND: Segmental vitiligo has a different clinical course and prognosis as compared to nonsegmental vitiligo, which necessitates its correct diagnosis. It may be difficult to distinguish segmental vitiligo from the limited or focal types of nonsegmental vitiligo. OBJECTIVE: To validate the previously proposed diagnostic criteria for segmental vitiligo. METHODS: This was a cross-sectional validation study involving patients with limited vitiligo. The diagnostic criteria were used to classify vitiligo lesions as segmental or nonsegmental, and was compared with the experts' diagnosis, which was considered as the "gold standard". RESULTS: The study included 200 patients with 225 vitiligo lesions. As per the diagnostic criteria, 146 vitiligo lesions were classified as segmental and 79 as nonsegmental. The experts classified 147 vitiligo lesions as segmental and 39 as nonsegmental, while the diagnosis either was labeled "unsure" or could not be agreed upon for 39 lesions. As compared with the experts' opinions ("for sure" cases, n = 186), the sensitivity and specificity of the diagnostic criteria was 91.8% (95% confidence interval [CI]: 86.2%-95.7%) and 100% (95% CI: 91%-100%), respectively. The positive predictive value was 100% (95% CI: 97.3-100%), while the negative predictive value was 76.5% (95% CI: 62.5%-87.2%). There was a 93.5% agreement between the clinical criteria and experts' opinions (k = 0.83, P < 0.001). LIMITATION: The diagnostic criteria were compared with the experts' opinion in the absence of an established diagnostic "gold standard". CONCLUSIONS: The proposed diagnostic criteria for segmental vitiligo performed well, and can be used in clinical practice, as well as in research settings.

Experimental study and clinical observations of autologous hair follicle cell transplants to treat stable vitiligo.

BACKGROUND: Vitiligo is characterized by the loss and/or dysfunction of melanocytes in the skin and has a profound impact on the social interactions of patients. Although there are many treatment options for vitiligo, the outcome is frequently unsatisfactory, especially for patients with stable vitiligo. OBJECTIVES: To study the biological properties of melanocytes derived from human hair follicles and to observe the efficacy of using transplants of autologous hair follicle cells to treat patients with stable vitiligo. METHODS: From February 2014 to March 2017, 26 patients with stable vitiligo, who were refractory to all current routine therapy, underwent treatment with transplanted autologous hair follicle cells. The skin graft from each patient's occipital region was trimmed to remove excess adipose tissue and some of the upper part of the dermis. The remaining tissue, including hair follicles and dermal papillae, was cut into pieces and incubated in collagenase type IV and then in trypsin-ethylenediaminetetraacetic acid solutions. The cells were recovered, resuspended in the patient's own serum and then applied to the recipient area. Clinical observations continued for 6 months to 1 year. Laboratory experiments were also performed during this time on scalp specimens obtained from normal human volunteers. Cells migrating from the outer root sheath and the dermal papillae at various times of culture were observed using a microscope. RESULTS: Most of the repigmentation in the vitiligo areas appeared within 8 weeks of transplantation of autologous hair follicle cells. Early skin repigmentation was not uniform and appeared more repigmented than the surrounding normal skin. As time went by, the repigmentation became more obvious and matched the color of the skin around the lesion. Most of the pigmentation presented as a diffuse pattern and was not localized around the hair follicles. Among the 26 patients, 9 (34.6%) achieved excellent repigmentation, while 13 (50.0%) had good, 3 (11.5%) fair and 1 (3.9%) poor repigmentation. During the follow-up visit at 1 year, no excess hair growth was observed in the recipient areas and there was no scarring or ulcer formation in the donor or recipient areas. In the experimental part of the study, many keratinocytes, melanocytes and fibroblasts migrated from the adherent outer root sheath. In later subcultures using a specialized medium, pure melanocytes were obtained that had a strong proliferative capacity and had bipolar or poly-dendritic shapes. On the other hand, cells from the dermal papillae grew radially in primary culture and were almost fibroblast-like. However, a few bipolar melanocytes appeared in the later stage of culture. CONCLUSIONS: The results of our study show that transplantation of autologous hair follicle cells is a simple and effective method to treat patients with stable vitiligo. Hair follicles (especially the outer root sheath) harbor many melanocytes with potential proliferative ability. LIMITATIONS: There are a few limitations of the present study: a small sample size, a short follow-up period, no cell counting or viability testing.

A cross-sectional study of spontaneous repigmentation in vitiligo.

BACKGROUND: Spontaneous regression is well documented in several chronic skin diseases such as psoriasis, alopecia areata, and atopic dermatitis. However, information on vitiligo is scarce. AIMS: We studied the frequency, extent, and factors affecting spontaneous repigmentation in vitiligo. METHODS: A cross-sectional descriptive study was undertaken in 167 patients with vitiligo with an emphasis on history of spontaneous repigmentation. Where available, photographs documenting spontaneous repigmentation were also obtained. Repigmentation was defined as spontaneous if it occurred when the patient was off treatment for at least 3 consecutive months. RESULTS: Spontaneous repigmentation occurred in 36 (21.5%) patients with complete repigmentation in 6 (3.6%) patients. The extent varied from 0.5% to 100% (mean, 35.4 ± 37.9%) of vitiliginous skin. It occurred after 3 months to 47 years (mean, 8.7 ± 9.5 years) of onset of vitiligo and persisted for 2 months to 27 years (mean, 4.4 ± 6.2 years). Diffuse repigmentation was the most common pattern observed in 20 (55.6%) patients and there was a good color match in 26 (72.2%) patients. Likelihood of spontaneous repigmentation was 3.5 times greater in patients with more than 3 years of stable disease (P = 0.001). LIMITATIONS: The chief limitation was the dependence on patient recall for the data, except when documented by images. CONCLUSION: Spontaneous repigmentation occurs in one-fifth of patients with vitiligo. In some patients, the repigmentation is clinically significant and long-lasting. Considering its frequency and extent, spontaneous repigmentation should be taken into account both when evaluating novel interventions and counselling patients about the course of the disease.

Clinimetric analysis of recently applied quantitative tools in evaluation of vitiligo treatment.

BACKGROUND: Vitiligo affects about 1% of the world's population, however, there is currently no universally used standardized measure to assess its response to treatment. OBJECTIVE: To find the most effective technique for the quantitative assessment of therapeutic results in vitiligo patients. MATERIALS AND METHODS: The study was performed in three stages: (1) Conducting an adapted Delphi survey to check current dermatologists' attitudes regarding the topic of study. (2) Conducting a pilot study that involves testing the selected digital image analysis software in the laboratory to validate future tasks. (3) The chief clinimetric study that implicates selecting actual vitiligo lesion models and evaluating them. RESULTS: Regarding the surface area measuring techniques, the most accurate results were gained through the digital image analysis for surface area, followed by point-counting technique. The digital image analysis for color measurement was accurate and reliable in getting a percentage representation of color improvement within the vitiligo lesions, in response to therapy. LIMITATIONS: Many dermatologists lack understanding of basic concepts about imaging techniques. The study does not include a traditional assessment method such as vitiligo area scoring index. CONCLUSION: Our designated digital image analysis technique was able to efficiently assess the changes that occur both on surface area and the color of vitiligo lesions in response to therapy.