Reversal of alopecia areata, osteoporosis follow treatment with activation of Tgr5 in mice.

BACKGROUND: Alopecia areata is an autoimmune hair loss disease with infiltration of pro-inflammatory cells into hair follicles. The role of Tgr5 in dermatitis has attracted considerable attention. The present study aimed to investigate the effect of Tgr5 in the development of Alopecia areata. METHODS: The study utilized a comparison control group design with four groups of wild-type group, wild-type+INT777 group, Tgr5-/- group, and Tgr5-/-+INT777 group. The mice were treated with INT777 (30 mg/kg/day) or the carrier solution (DMSO) intraperitoneally for 7 weeks, and the back skin was collected and analyzed by histology and immunohistochemistry staining. The lumbar vertebrae 4 has also been analyzed by DXA and Micro-CT. RESULTS: Tgr5-/- mice displayed the decreasingly significant in hair area and length, skin thickness, and the ratio of anagen and telogen, collagen, and mast cell number and loss the bone mass than WT group. After treating with INT777, the appearance of alopecia areata and bone microstructure has improved. Immunohistochemistry and qPCR analysis showed that activation of Tgr5 can down-regulate the express of JAK1, STAT3, IL-6, TNF-α, and VEGF. CONCLUSION: These findings indicate that activation of Tgr5 mediated amelioration of alopecia areata and osteoporosis by down-regulated JAK1-STAT3 signaling pathway.

Unexpected Hair Regrowth in a Patient with Longstanding Alopecia Universalis During Treatment of Recalcitrant Dermatomyositis with the Janus Kinase Inhibitor Ruxolitinib.

is missing (Short communication).

Immune cell regulation of the hair cycle.

The ability to manipulate the mammalian hair cycle will lead to novel therapies and strategies to combat all forms of alopecia. Thus, in addition to the epithelial-mesenchymal interactions in the hair follicle, niche and microenvironmental signals that accompany the phases of growth, regression and rest need to be scrutinized. Immune cells are well described in skin homeostasis and wound healing and have recently been shown to play an important role in the mammalian hair cycle. In this review, we will summarize our current knowledge of the role of immune cells in hair cycle control and discuss their relevance to human hair cycling disorders. Increased attention to this aspect of the hair cycle will provide new avenues to manipulate hair regeneration in humans and provide better insight into developing better ex vivo models of hair growth.

JAK inhibition in the treatment of alopecia areata - a promising new dawn?

Introduction: Alopecia areata (AA) is a T-cell-mediated disease which produces circular patches of non-scarring hair loss and nail dystrophy. Current treatment options for AA are limited and often yield unsatisfactory results. Pharmacologic inhibition of the Janus kinase (JAK) enzyme family is regrowing hair and reversing nail dystrophy in a number of patients with hitherto refractory AA. The six JAK inhibitors which have been successful in treating AA are tofacitinib, ruxolitinib, baricitinib, CTP-543, PF-06651600 and PF-06700841.Areas covered: This review reports randomized-controlled trials, open-label trials, case series and case reports published in the literature to date and describes the epidemiology and pathophysiology of AA, the mechanism of action of JAK inhibitors and the adverse effects identified. Electronic searches were performed using Medline Ovid, PubMed, Embase, Cochrane Library and Evidence-Based Medicine Reviews.Expert opinion: The discovery of JAK inhibition represents a major breakthrough in the treatment of AA. Positive results in early phase 1 and phase 2 clinical trials have enabled the commencement of phase 3 clinical trials and there is now a growing sense of optimism among patients with long-standing, treatment-refractory AA. Further work is required to determine the optimal dose and treatment duration and whether maintenance therapy is universally required.

Pathogenesis and clinical features of alopecia in epidermolysis bullosa: A systematic review.

BACKGROUND: Epidermolysis bullosa (EB) is a group of rare genetic skin diseases characterized by the gene mutations encoding adhesion proteins within the skin. These adhesion proteins are also present in normal hair follicles. Anecdotally, there have been reports of scalp alopecia as a complication of EB and there are scattered cases in the literature, but alopecia has generally been overlooked in severe blistering diseases because it is regarded as a cosmetic issue. Therefore, there is no consensus about the natural history and clinical manifestations of alopecia in EB to allow potential intervention. OBJECTIVES: To review the current literature detailing the pathogenesis and clinical presentations of alopecia in EB patients. METHODS: Relevant human studies were searched in Medline, PubMed, and EMBASE electronic databases up to October 2018. RESULTS: Only 15 reports detailed 29 EB patients with demographic and clinical manifestations of alopecia. Vertical biopsy sections were the most common method of alopecia diagnosis, and the most common pattern was patchy scalp alopecia (45%) followed by diffuse alopecia (41%). The most robust finding was nonspecific scarring alopecia in all dystrophic EB (DEB) patients and nonspecific nonscarring alopecia in most patients with EB simplex (EBS). CONCLUSIONS: Hair abnormalities observed in EB are of variable severity despite there being no universal validated alopecia scoring system, with alopecia occurring secondary to blistering, or in areas prone to trauma.

The association between rs2476601 polymorphism in PTPN22 gene and risk of alopecia areata: A meta-analysis of case-control studies.

BACKGROUND: The single nucleotide polymorphism (SNP) rs2476601 of the protein tyrosine phosphatase, nonreceptor type 22 (PTPN22) gene has been presented to implicate in the pathogenesis of alopecia areata (AA) in a few association investigations with limited sample size and inconsistent conclusions. METHODS: The aim of the current meta-analysis was to assess and synthesize the presently available data on the connection between rs2476601 and AA vulnerability. Six electronic databases, including EMBASE, PubMed, Web of Science, the Cochrane Library, Wanfang data, and the China National Knowledge Infrastructure database (CNKI), were systematically retrieved for relevant observational studies published previous to November 2018. Total odds ratios (ORs) and corresponding 95% confidence intervals (95% CIs) were analyzed to evaluate the correlation between PTPN22 polymorphism and AA. Risk of bias was estimated according to the Newcastle-Ottawa Scale (NOS). Sensitivity analyses were carried out using the RevMan 5.3 software. RESULTS: In general, 5 case-control studies including 1129 AA patients and 1702 healthy control individuals were obtained for this meta-analysis. The pooled results suggested that rs2476601 SNP was significantly associated with AA susceptibility under allelic model (C vs T, OR = 0.77, 95% CI, 0.64-0.92, P = .003) and recessive model (CC vs CT + TT, OR = 0.73, 95% CI, 0.60-0.88, P = .001). CONCLUSION: On the basis of the results of the current research, the rs2476601 polymorphism of PTPN22 gene is significantly correlated with AA susceptibility. The C-allele and CC-genotype carriers at this locus have a lower risk of AA.

Alopecia areata: a long-term follow-up study of 104 patients.

BACKGROUND: Alopecia areata (AA) is a common autoimmune disease that considerably affects the quality of life. Although several studies have investigated the epidemiology, clinical characteristics and treatment of AA, limited recent data are available regarding its long-term course. OBJECTIVES: To evaluate the long-term course of AA in different age groups. METHODS: A retrospective evaluation of patients who were newly diagnosed with AA from 2008 to 2011 and had at least 7 years of follow-up. Data regarding the initial episode, treatment given, disease-free interval and relapses were analysed. RESULTS: A total of 104 cases were analysed: 31 childhood-onset, 63 adult-onset and 10 late-onset. At first episode, 88.5% of patients had mild, 3.8% moderate and 7.7% severe AA. Full or significant re-growth was observed in 74%, 94% and 100% of childhood-onset, adult-onset and late-onset AA patients, respectively. There was no re-growth in 13%, 3% and 0% of childhood-onset, adult-onset and late-onset patients, respectively. The duration of the initial episode and the disease-free interval negatively correlated with age. Systemic steroids were the most effective treatment for the primary episode. The frequency of relapses was high overall (52%, 44% and 30% in childhood-onset, adult-onset and late-onset, respectively), but significantly declined over time with a majority (79%) occurring within the first 4 years. The disease-free interval and relapse rate were not correlated with gender, disease severity at onset or treatment given. CONCLUSIONS: The prevalence of severe disease, duration of an initial episode and the rate of relapses decreased with an older age at onset. In addition, the outcome and the disease-free interval improved with age at onset. The frequency of relapses declined over time and most appear early on. The current treatment modalities do not seem to influence the long-term outcome.

Differential expression patterns of specific long noncoding RNAs and competing endogenous RNA network in alopecia areata.

BACKGROUND: Long noncoding RNAs (lncRNAs) regulate gene expression by acting with microRNAs (miRNAs) and indirectly interact with messenger RNA (mRNAs). However, the roles of specific lncRNA and its related competing endogenous RNAs (ceRNA) network in alopecia areata (AA) are not fully understood. METHODS: The blood lncRNA profiles were obtained by microarray from 10 samples, including five alopecia areata samples and five normal samples. Based on bioinformatics generated from miRcode, starBase, and miRTarBase, we constructed an lncRNA-miRNA-mRNA network (ceRNA network) in alopecia areata. RESULTS: We found 154 differentially expressed lncRNAs and 46 differentially expressed genes (DEGs). The functional enrichment indicated that the DEGs mainly regulated the pathways of focal adhesion, Mucin type O-glycan biosynthesis, and so on. The differentially expressed lncRNA (DElncRNA) involved in the pathway of thyronamine and iodothyronamine metabolism and so on. Through integrated lncRNA-mRNA and miRNA-mRNA pairs, the ceRNA network was constructed, thereafter, six ceRNA subnetworks were identified and subnetwork 1 were found to be significantly associated with the occurrence of alopecia areata. CONCLUSION: Our results showed blood lncRNA expression patterns and a complex ceRNA network in alopecia areata. However, futher studies on blood and tissue verification of these lncRNAs and relative pathways are needed.

New drugs under investigation for the treatment of alopecias.

INTRODUCTION: Alopecia is a very common complaint in medical practice, which usually has a large psychological impact in patients. Treatment of alopecia is often difficult and frustrating for patients and clinicians owing to the slow growth rate of the hair, long treatment terms, limited efficacy, and possible adverse side effects. AREAS COVERED: This paper reviews the new and emerging treatments for two of the most common forms of alopecia, known as androgenetic alopecia and alopecia areata. A literature search of PubMed/MEDLINE and ClinicalTrial.gov was performed to gather information about active research on new treatments for alopecias. Websites of companies sponsoring clinical trials were also searched for interim result data. EXPERT OPINION: Many new therapies in two of the most common forms of hair loss have been developed and are currently being studied with encouraging results. In alopecia areata, JAK inhibitors are promising. The discovery of JAK inhibitors has prompted the research and identification of new molecules. In androgenetic alopecia, we are still looking for a topical treatment that is superior to topical minoxidil. However, stem-cell research is advancing and the goal to create new follicles or refresh dormant follicles may be realized in the near future.

The Use of Janus Kinase Inhibitors in Alopecia Areata: A Review of the Literature.

Alopecia areata (AA) is a chronic, immune-mediated disorder that targets hair follicle epithelium, thereby restricting hair growth in localized patches. Although several therapies for AA have been tested, responses with traditional therapies have been limited. In recent years, numerous reports have been published of patients with AA responding to Janus kinase (JAK) inhibitors. This literature review aims to describe AA pathophysiology, explore how and why JAK inhibitors can be used for AA treatment, and review published case reports, case series, and open-label studies published to date. Pathogenesis of AA includes interactions between genetic, environmental, and immune factors and is mediated by the cytokines interferon-γ and interleukin (IL)-15. JAK inhibition resulting in hair regrowth in some cases supports that AA is associated with the Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling pathway. The emergence of JAK inhibitors for AA therapy is changing the way health care providers think about and treat AA. A mixture of animal model studies and human case studies have reported the use of baricitinib (JAK 1/2), ruxolitinib (JAK 1/2), and tofacitinib (JAK 1/3) for the management of AA. JAK inhibition has shown potential as an effective AA therapy when used in case studies, case series, and open-label trials. Formal clinical trials are ongoing and will yield more definitive conclusions about the safety and efficacy of JAK inhibitors.

Efficacy and safety of secukinumab treatment in adults with extensive alopecia areata.

Alopecia areata (AA) is a common form of non-scarring hair loss. The pathogenesis of AA is believed to involve multiple inflammatory cytokines, including possibly IL-17A. To assess the efficacy and safety of the IL-17A antagonist secukinumab in AA, we conducted a double-blinded, randomized prospective pilot study in which 11 subjects were treated with either secukinumab (n = 7) or placebo (n = 4) subcutaneously at weeks 0, 1, 2, 3, 4 and every 4 weeks thereafter until (inclusive of) week 20. The primary endpoint for the study was the percentage of patients achieving SALT50 at 24 weeks. A total of three subjects out of 11 completed the study through the primary endpoint, and therefore, we used the last observation carried forward method to analyze the missing data. At the primary endpoint or last completed observation, 0% (0/7) of the secukinumab-treated subjects achieved a 50% reduction in SALT score (SALT50), and likewise, 0% (0/4) of the placebo-treated subjects achieved SALT50. In the secukinumab group, one (14.3%) subject had some hair regrowth, one (14.3%) subject had worsening hair loss, and five (71.4%) subjects had no change in response to treatment. No adverse events attributable to the study drug were observed. The lack of a treatment response to most of our treated patients suggests that the TH17/IL-17 axis likely has no pathogenic role in AA and an alternative therapeutic approach should be considered for this disease. However, due to the low statistical power of this study, future studies may be required to corroborate these findings.

An investigation of vitamin D status in alopecia areata.

Alopecia areata (AA) is a type of non-scarring, recurrent patchy loss of hair in hair-bearing areas and is mostly of autoimmune origin. Previous studies have suggested that some autoimmune diseases were found to be associated with vitamin D deficiency. The current study was designed to assess the levels of serum 25-hydroxy vitamin D and C-reactive protein in AA, as compared with controls and to further identify the association between vitamin D levels and disease severity in patients with AA. This cross-sectional study included 45 patients with AA and 45 healthy volunteers. Clinical and anthropometric parameters were recorded, according to a pre-designed proforma. Serum 25-hydroxy vitamin D and high-sensitivity C-reactive protein were estimated using ELISA kits. The severity of AA was determined using Severity of Alopecia Tool (SALT) score. We observed a significant rise in systemic inflammation as seen by elevated high-sensitive C-reactive protein levels and lowered 25-hydroxy vitamin D levels in patients with alopecia areata, compared to controls (p = 0.001). The levels of 25-hydroxy vitamin D showed a significant negative correlation with disease severity, while hs-CRP levels showed a significant positive correlation with disease severity (ρ = - 0.714, p = 0.001 and ρ = 0.818, p = 0.001). Our results suggest significant systemic inflammation and vitamin D deficiency in alopecia areata, more so with increasing disease severity. This gains particular importance in the treatment of alopecia areata in future, as supplementing vitamin D to AA patients would result in reducing the disease severity and inducing remission.

Emerging drugs for alopecia areata: JAK inhibitors.

INTRODUCTION: Alopecia Areata is a common form of non-scarring hair loss that usually starts abruptly with a very high psychological impact. Due to the still not completely understood etiopathogenesis, at present there is no treatment that can induce a permanent remission and there is no drug approved for the treatment of this disorder. Areas covered: Leading existing treatment are briefly overviewed and then ongoing research on Janus Kinases Inhibitors is discussed, reviewing trials with oral and topical formulations so as new opportunities for other forms of alopecia, such as cicatricial alopecia. Expert opinion: JAK inhibitors represent a promise among alopecia treatments, but further studies are needed on long term safety. There is still no validated dosage for alopecia areata and the vehicles used for topical formulations seem not yet ideal in terms of skin penetration and reduced systemic absorption. Hopefully several studies are ongoing and we hope, in the near future, that JAK inhibitors will become part of the armamentarium to treat alopecia areata patients in terms of safety and costs.

An Overview of the Biology of Platelet-Rich Plasma and Microneedling as Potential Treatments for Alopecia Areata.

Platelet-rich plasma and microneedling have been investigated recently as potential therapeutic options for the treatment of hair disorders. Evidence from laboratory studies indicates that these treatments enhance growth factor production that in turn facilitates hair follicle development and cycling. Several small studies and case reports have presented encouraging findings regarding the use of these treatments for alopecia areata. Future investigations will be needed to validate these therapeutic techniques for patients with alopecia areata and further refine which subtypes of the disease these methods are best indicated for.

The Utility and Validity of the Alopecia Areata Symptom Impact Scale in Measuring Disease-Related Symptoms and their Effect on Functioning.

Alopecia areata (AA) is an autoimmune disease that causes hair loss. Although persons with the disease can be physically described as having varying degrees of hair loss, the condition has significant ramifications on an individual's well-being. We previously reported the preliminary psychometric properties of the Alopecia Areata Symptom Impact Scale (AASIS), a disease-specific measure that asks participants about their AA symptoms and how these symptoms interfere with their daily functioning. The goals of this article are to provide a detailed description of the development of the AASIS items and to offer a psychometric update for the measure. Preliminary items for the AASIS were developed on the basis of responses from 1,649 participants to 125 health-related quality-of-life questions/items from the National Alopecia Areata Registry. Clinicians affiliated with the registry were asked to rate the relevance of these items for content validity. Cluster analysis and clinician ratings were used to reduce the number of items. The resulting 13-item AASIS was administered to 452 participants, who were also cognitively debriefed. Results showed that the AASIS is a valid and reliable measure of AA symptoms and their impact on functioning.