The Role of Serum Th1, Th2, and Th17 Cytokines in Patients with Alopecia Areata: Clinical Implications.

Alopecia areata is a type of non-scarring hair loss. The dysregulation of numerous systemic Th1 (IL-2, IFN-γ, TNF, IL-12, and IL-18), Th2 (IL-4, IL-5, IL-6, IL-9, IL-10, IL-13, IL-17E, IL-31 and IL-33) and Th17 (IL-17, IL-17F, IL-21, IL-22, IL-23 and TGF-ß) cytokines was observed in patients with alopecia areata. Positive correlations between the severity of alopecia areata and an increased serum level of various cytokines including IL-2, TNF, IL-12, IL-17, and IL-17E were reported in the literature. An increased serum level of numerous cytokines, such as IL-2, IL-6, TNF, IL-12, IL-17E, and IL-22, was described as positively correlated with the duration of the disease. Moreover, it was shown that increased pre-treatment serum level of IL-12 was a positive, while increased serum levels of IL-4 and IL-13 were negative prognostic markers for the efficacy of diphenylcyclopropenone. In conclusion, alopecia areata is associated with the dysregulation of systemic Th1, Th2 and Th17 cytokines with their role in the pathogenesis, clinical manifestations and prognosis of the disease. Available data indicate the most significant role of serum IL-2, TNF, IL-12, IL-17, and IL-17E as markers of disease activity. The serum levels IL-4, IL-12 and IL-13 may be useful as potential predictors of diphenylcyclopropenone efficacy.

Altered T cell subpopulations and serum anti-TYRP2 and tyrosinase antibodies in the acute and chronic phase of alopecia areata in the C3H/HeJ mouse model.

BACKGROUND: C3H/HeJ mouse models progress gradually in hair loss from acute to chronic phase and reflect the symptoms of patients with alopecia areata (AA). However, the underlying pathological characteristics alteration associated with disease progression and autoantigens remain unclear. OBJECTIVE: We aimed at elucidating the pathological differences between acute and chronic-AA in the C3H/HeJ mouse model. METHODS: We analyzed populations of PBMCs, skin-draining lymph node (SDLN) cells, and cutaneous cells of AA mice using flow cytometry. The cytokine and chemokine expressions in the serum and skin were determined using multiplex assay and qPCR. The antibody serum levels were determined using ELISA and the antigen-specific T cells were detected using the MHC class I tetramer. RESULTS: The CD8+NKG2D+ T and CD8+ TEM cell percentage in the chronic-AA SDLNs or among the unaffected and acute-AA mice PBMCs increased. The Th1 and CD4+ TEM cell percentage in the SDLNs and among PBMCs increased in the unaffected and AA mice. The percentage of CD8+ TEM/TRM cells and MHC class I expression increased in the lesions of acute-AA or the non-lesions and lesions of chronic-AA. The Th1 cells, dendritic cell-related cytokines, CD11c+ cells and MHC class II expression increased in the skin of AA mice. The antibody levels and TYRP2 and tyrosinase-specific CD8+ T cell percentages were upregulated in AA mice. CONCLUSION: These results suggest that the CD8+ and CD4+ T cell subpopulations, cytokine and chemokine expressions differ between the disease phases. Moreover, TYRP2 and tyrosinase are potential autoreactive targets in the AA mouse model.

Adiponectin as a novel biomarker of disease severity in alopecia areata.

The frequent coexistence of obesity and metabolic syndrome in patients with alopecia areata may indicate the common pathogenetic pathway in these conditions with an important role of adipokines. The aim of the study was to evaluate the serum level of adiponectin, resistin and leptin in patients with alopecia areata in comparison to healthy controls. The study included 65 patients with alopecia areata and 71 healthy controls. The concentration of adipokines was determined with the enzyme-linked immunosorbent assay. The mean concentrations of adiponectin and resistin were significantly lower in the sera of patients with alopecia areata when compared to healthy controls (7966 [Formula: see text] 4087 vs 9947 [Formula: see text] 5692 ng/ml; p = 0.0312 and 11.04 [Formula: see text] 3.88 vs 14.11 [Formula: see text] 8.69 ng/ml; p = 0.0176, respectively). A negative correlation between the serum level of adiponectin and severity of alopecia tool (SALT) score was observed (r = - 0.26; p < 0.05). The concentration of adiponectin was significantly lower in patients with alopecia universalis than in patients with patchy alopecia areata (4951 [Formula: see text] 2499 vs 8525 [Formula: see text] 4085 ng/ml; p = 0.0135). No significant difference in the serum concentration of leptin was observed between patients with alopecia areata and healthy controls. The negative correlation between the serum level of adiponectin and hair loss severity indicates that adiponectin may be considered a marker of hair loss severity in alopecia areata. Further studies are needed to evaluate the role of resistin in patients with alopecia areata and its decreased level irregardless of severity or activity of the disease.

Coagulation status in patients with alopecia areata: a cross-sectional study.

BACKGROUND: Alopecia areata (AA) is an autoimmune skin disease that causes non-scarring hair loss with lymphatic infiltration around and within follicles. There are interactions between inflammation and coagulation. The present study investigated the changes in coagulation status in patients with AA. METHODS: In this study, the plasma level of three coagulation markers including fibrinogen, C-reactive protein (CRP), and D-dimer were measured in 30 patients (21 females 9 male) and 30 controls (21 females 9 male) matched by age and sex, and the results were compared between groups. RESULTS: Plasma D-dimer levels were significantly higher in patients with AA (398.45±300 ng/mL vs. 244.4±129.92 ng/mL, P=0.014). Plasma fibrinogen and CRP levels were not significantly different between the two groups. There was no correlation between the plasma levels of the studied coagulation markers and the severity/duration of the disease, sex, and age. CONCLUSIONS: As the present study was the first investigation on the coagulation status in patients with AA, elevated D-dimer levels in alopecia areata may suggest a deficient coagulation in these patients that may contribute to an increase in the risk of thrombosis. Further studies are needed to evaluate this hypothesis using a larger sample size.

Cross-sectional study of blood biomarkers of patients with moderate to severe alopecia areata reveals systemic immune and cardiovascular biomarker dysregulation.

BACKGROUND: Although there is increased understanding of the alopecia areata (AA) pathogenesis based on studies in scalp tissues, little is known about its systemic profile. OBJECTIVE: To evaluate the blood proteomic signature of AA and determine biomarkers associated with increased disease severity. METHODS: In a cross-sectional study, we assessed 350 inflammatory and cardiovascular proteins using OLINK high-throughput proteomics in patients with moderate to severe AA (n = 35), as compared with healthy individuals (n = 36), patients with moderate to severe psoriasis (n = 19), and those with atopic dermatitis (n = 49). RESULTS: Seventy-four proteins were significantly differentially expressed between AA and control individuals (false discovery rate, <.05) including innate immunity (interleukin [IL] 6/IL-8), T helper (Th) type 1 (interferon [IFN] γ/CXCL9/CXCL10/CXCL11), Th2 (CCL13/CCL17/CCL7), Th17 (CCL20/PI3/S100A12), and cardiovascular-risk proteins (OLR1/OSM/MPO/PRTN3). Eighty-six biomarkers correlated with AA clinical severity (P < .05), including Th1/Th2, and cardiovascular/atherosclerosis-related proteins, including SELP/PGLYRP1/MPO/IL-18/OSM (P < .05). Patients with AA totalis/universalis showed the highest systemic inflammatory tone, including cardiovascular risk biomarkers, compared to control individuals and even to patients with atopic dermatitis and those with psoriasis. The AA profile showed some Th1/Th2 differences in the setting of concomitant atopy. LIMITATIONS: Our analysis was limited to 350 proteins. CONCLUSION: This study defined the abnormalities of moderate to severe AA and associated circulatory biomarkers. It shows that AA has systemic immune, cardiovascular, and atherosclerosis biomarker dysregulation, suggesting the need for systemic treatment approaches.

Evaluation of serum cardiac troponin I and N-terminal pro-B-type natriuretic peptide levels in patients with alopecia areata.

Alopecia areata (AA) is a recurrent, immune-mediated, hair-loss disorder. It is associated with other autoimmune disorders that carry a high risk of cardiovascular disease (CVD). However, there is a lack of reports on the association of cardiovascular comorbidities and AA. Cardiac troponin I is a biomarker of myocardial ischaemia and inflammation, while N-terminal pro-B-type natriuretic peptide is used in the diagnosis of congestive heart failure. This study was conducted to assess the serum level of both markers by ELISA in 44 patients with AA compared with 44 healthy controls (HCs). None of the participants had CVD, CVD risk factors or other diseases associated with elevation of either marker. The study revealed that serum levels of both markers were significantly higher in patients with AA compared with HCs (P < 0.001). The inflammatory milieu encountered in AA may be associated with subtle myocardial inflammation that causes elevation of levels of both of these cardiac markers.

Diphenylcyclopropenone plays an effective therapeutic role by up-regulating the TSLP/OX40L/IL-13 pathway in severe alopecia areata.

Topical immunotherapy with diphenylcyclopropenone (DPCP) is considered to be the most effective treatment of severe AA. However, the mechanism is unclear and an early predictor for the efficacy needs to be explored. The TSLP/OX40L/IL-13 pathway is an important pathway to initiate and maintain Th2 immune responses. Our previous work suggests this pathway may play a role in severe AA treated with DPCP. Thus, to further investigate the mechanism of TSLP/OX40L/IL-13 pathway in severe AA treated with DPCP and explore the predictor for the efficacy of DPCP therapy, we conducted a prospective study to compare expression levels of TSLP, OX40L, Th2 cytokines IL-4, IL-5 and IL13, and Th1 cytokine IFN-γ in severe AA patients before and after the treatment. Results showed that 21 AA patients were responsive (responders) to the DPCP therapy and 12 were not responsive (non-responders). Responders had lower levels of TSLP, OX40L and IL-13 than non-responders before the treatment. After the DPCP treatment, TSLP, IL-5 and IL-13 increased and IFN-γ decreased in responders while there were no changes of TSLP, IL-4, IL-13 and IFN-γ in non-responders. Our data suggest that the TSLP/OX40L/IL-13 pathway is down-regulated in some severe AA patients and DPCP might play a therapeutic role by up-regulating the pathway in these severe AA patients. The TSLP/OX40L/IL-13 pathway could be a predictor of response to the DPCP therapy for severe AA patients.

Ginger (Zingiber officinale (L.) Rosc) improves oxidative stress and trace elements status in patients with alopecia areata.

BACKGROUND: Alopecia areata (AA) involves oxidative reactions in the hair follicle. Its treatment is difficult due to both the unknown etiology and the adverse drug effects. Aims: This study aimed to evaluate the effects of orally administered ginger powder on the oxidative stress markers of the plasma and blood cells in Iraqi patients with AA. SUBJECTS AND METHODS: Twenty patients (9 females and 11 males), with a mean age of 26.0 ± 8.0 years, with different lesions of stable alopecia areata localized on the scalp, were enrolled in this pilot study. Exclusion criteria include the use of any medication that may influence the course of the disease. All patients were treated with 500 mg of ginger powder once daily for 60zz days. Blood samples were obtained at zero time, day-30 and day-60 and utilized for the evaluation of the erythrocytes and lymphocytes contents of reduced glutathione (GSH), malondialdehyde (MDA) and total antioxidant status (TAS), in addition to the assessment of serum zinc (Zn) and copper (Cu) levels. The results are compared with those of 20 healthy subjects served as a control group. RESULTS: Treatment of the AA patients with ginger significantly improves the antioxidant/oxidant balance of the erythrocytes and lymphocytes, which is known to be impaired in the patient group as compared with healthy subjects. The ginger powder also elevates the serum concentration of zinc up to that reported in controls and associated with normalizing serum copper levels at the end of the treatment period. CONCLUSION: Consumption of ginger as a supplement by the patients with AA could improve the oxidant/antioxidant balance of the erythrocytes and lymphocytes and restoring the normal level of serum zinc.

Evaluation of Glutathione Reductase and Glutathione Peroxidase in the Serum of Iranian Patients with Alopecia Areata: A Case-control Study.

No Abstract.

Serum level of IL-4 predicts response to topical immunotherapy with diphenylcyclopropenone in alopecia areata.

BACKGROUND: This study investigated predictors of response to topical diphenylyclopropenone (DPCP) immunotherapy in patients with alopecia areata (AA). OBJECTIVE: To identify predictors of response, or resistance, to treatment for AA through clinical observations and serum tests. METHODS: Eighty four AA patients were treated with DPCP. Serum cytokine levels were measured in 33 AA patients pre- and post-treatment, and in 18 healthy controls, using ELISA assays. RESULTS: Of patients, 56.1% responded to DPCP with satisfactory hair regrowth; the response rate was negatively correlated with hair loss extent. Before DPCP treatment, higher serum IFN-γ and IL-12 cytokine levels were observed in AA patients compared to healthy controls. Non-responders to DPCP had significantly elevated serum IL-4 pre-treatment (3.07 fold higher) and lower IL-12 levels compared with responders. After DPCP treatment, non-responders had persistently high IL-4, increased IL-12, negligible decrease in IFN-γ and decreased IL-10. Post-treatment DPCP responders exhibited significantly decreased IFN-γ and IL-12, and increased IL-4 and IL-10. Development of adverse side-effects was significantly associated with higher pre-treatment serum IgE levels. LIMITATIONS: A small number of subjects were evaluated. CONCLUSIONS: Potentially, elevated pre-treatment serum levels of IL-4 and IL-12 can be used as unfavorable and favorable predictors of DPCP therapeutic effect, respectively. In addition, pre-treatment elevated serum total IgE may predict increased risk for severe adverse side-effects to DPCP application. Whether serum cytokine expression levels can be used as predictors of response to other forms of treatment is unknown, but it may warrant investigation in the development of personalized treatments for AA.

Elevated serum tumour necrosis factor-like weak inducer of apoptosis in alopecia areata: a possible marker of disease severity.

BACKGROUND: Alopecia areata (AA) is, an organ-specific autoimmune disease, characterized by an aberrant expression of cytokines of the T helper 1 type. Tumour necrosis factor-like weak inducer of apoptosis (TWEAK) is a multifactorial cytokine that exerts a role in the pathogenesis of inflammatory and autoimmune diseases, especially in cutaneous diseases. AIM: To estimate the serum level of TWEAK in AA and to correlate it with different parameters. METHODS: This case-control study enrolled 40 patients with AA and 50 clinically healthy volunteers matched for age and sex. A blood sample (5 mL) was extracted from each participant for analysis of serum TWEAK levels by ELISA. RESULTS: Levels of TWEAK were significantly higher in patients with AA (mean ± SD 213.7 ± 59.2 pg/mL, range 109.1-341.6 pg/mL) than in controls (95.97 ± 13.28 pg/mL, range 80.1-152.3 pg/mL) (P < 0.001). A significant positive correlation was found between serum TWEAK level and the Severity of Alopecia Tool (SALT) score (r = 0.56, P < 0.001). CONCLUSION: To our knowledge, this study highlights for the first time a possible link between higher serum TWEAK level and AA. Serum TWEAK level appears to reflect AA disease severity.

Evaluation of complete blood cell and inflammatory parameters in patients with alopecia areata: Their association with disease severity.

BACKGROUND: Alopecia areata (AA) is a chronic inflammatory disease characterized by non-cicatricial hair loss. The cause of the disease is still unknown. It can appear at any age and occurs in 0.2% of the general population. Red cell distribution width (RDW), mean platelet volume (MPV), plateletcrit (PCT), the ratio of neutrophils to lymphocytes (NLR), and the ratio of platelets to lymphocytes (PLR) have all been reported as inflammatory markers in recent studies. However, these parameters have not been investigated in AA patients. AIM: We investigated the haematological and inflammatory parameters of AA and considered their association with disease severity. PATIENTS/METHODS: One hundred and five patients with AA and 108 healthy controls were enrolled in the study. RDW, MPV, PCT, NLR, PLR, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) were studied retrospectively. Disease severity was evaluated by using the Severity of Alopecia Tool (SALT) score. RESULTS: There were no statistically significant differences between RDW, MPV, PCT, NLR, and PLR levels in AA patients and in healthy controls. Only the CRP values were significantly higher in the AA group. CONCLUSION: Complete blood count (CBC) parameters are low-cost tests that can be used to define inflammation levels in inflammatory diseases. Our study shows that CRP can be used as a marker in diagnosing AA.

Oxidative stress in alopecia areata: a systematic review and meta-analysis.

BACKGROUND: Several studies have investigated the oxidative stress parameters in alopecia areata (AA) patients with variable results. This study aims to analyze the association between oxidative stress and AA based on current literature. METHODS: A systematic review of the existing literature was performed in PubMed, Scopus, and Cochrane databases by two authors independently. Mean and standard deviation values of oxidative stress parameters of AA patients and healthy controls were extracted for quantitative analysis. RESULTS: A total of 18 studies were included in the analysis. Patients with AA had impaired oxidative balance with elevated levels of serum malondialdehyde, nitric oxide, and total oxidant capacity and lower levels of serum superoxide dismutase, paraoxonase, glutathione peroxidase, and total antioxidant capacity. Levels of oxidative parameters were significantly higher in severe AA compared to mild/moderate AA. Heterogeneity in the baseline characteristics of the included studies and limited available data for most parameters were the limitations of this study. CONCLUSIONS: Current evidence suggests that AA is associated with oxidative stress. More studies are needed to strengthen this association. Moreover, studies evaluating the role of antioxidant use in AA may be rewarding.

The profile of cytokines (IL-2, IFN-γ, IL-4, IL-10, IL-17A, and IL-23) in active alopecia areata.

BACKGROUND: Alopecia areata (AA) is an autoimmune disease due to aberrant T-cell response against hair follicle self-antigens. Previous studies support the role of Th1 cytokines in pathogenesis of AA, but the role of Th2, Th17, and Treg cytokines remains to be fully elucidated. OBJECTIVES: To assess the serum levels of cytokines secreted by Th1 (IL-2, IFN-γ), Th2 (IL-4), Th17 (IL-23, IL-17A), and Treg (IL-10) pathways in patients of active AA and to correlate their levels with the severity of the disease. MATERIAL AND METHODS: Forty patients with untreated active AA of the scalp and forty age- and sex-matched healthy controls were included. Serum levels of cytokines IL-2, IFN-γ, IL-17A, IL-23, IL-4, and IL-10 were measured using enzyme-linked immunosorbent assay. RESULTS: Serum levels of cytokines IL-2, IFN-γ, IL-17A, and IL-10 were significantly raised while serum levels of IL-23 were nonsignificantly raised in AA patients as compared to controls. The levels of IL-4 were significantly lower in AA patients as compared to controls. (P < 0.05). Also, significant positive correlation was found between increase in SALT Score and serum levels of IL-2, IL-17A, and IL-23. (P < 0.05). CONCLUSION: Th1 and Th17 pathways play a central role in the initiation and progression of AA, while Th2 pathway is suppressed in active AA. Treg pathway may be opposing Th1 and Th17 pathway and causes disease localization. The instant study lays the groundwork for understanding the pathogenesis of AA and suggests the role of implicated cytokines as potential therapeutic targets and as biomarkers of disease activity.

Topical calcipotriol vs narrowband ultraviolet B in treatment of alopecia areata: a randomized-controlled trial.

Alopecia areata is a chronic relapsing autoimmune inflammatory hair disorder with no novel therapy. The objectives of this study are to compare the efficacy of topical calcipotriol vs narrow band ultraviolet B phototherapy (NB-UVB) in the treatment of alopecia areata and its correlation with serum vitamin D3 levels. A randomized-controlled trial has been conducted on 60 patients with scalp alopecia areata randomized into four groups; topical calcipotriol, NB-UVB, both and placebo. All patients were evaluated by assessment of severity of alopecia areata by severity of alopecia tool (SALT) score at baseline and 3 months after treatment and vitamin D3 levels at baseline and after 3 months. SALT score and vitamin D3 levels were significantly improved in all groups except placebo after treatment with (P = 0.026, P = 0.005, P = 0.004, P = 0.140) and (P = 0.028, P = 0.011, P = 0.003, P = 0.725), respectively. Combined therapy showed non-significant improvement in SALT score (P = 0.530, P = 0.643), respectively, and significant improvement in serum vitamin D3 levels than each line alone with (P = 0.021, P = 0.044), respectively. Both topical calcipotriol and NB-UVB are effective therapies in the treatment of AA and associated with improvement of SALT score and vitamin D3 levels.

Chronological association between alopecia areata and autoimmune thyroid diseases: A systematic review and meta-analysis.

The association between alopecia areata (AA) and autoimmune thyroid diseases (AITD) has been suggested; however, the chronological relationship between AA and AITD remains elusive. A systematic review and meta-analysis were conducted to assess the association between AA and AITD focusing on the prevalence of thyroid antibodies, thyroid diseases and serological thyroid dysfunctions, respectively. Data collection was performed in October 2018 by searching for articles in two electronic databases: Medline and Embase. Case-control, cohort and cross-sectional studies were included. Meta-analysis of studies eligible for quantitative synthesis was performed to estimate pooled odds ratios of thyroid antibodies; thyroid peroxidase antibody (TPO-Ab) and thyroglobulin antibody (TG-Ab), diagnosed thyroid diseases and serological thyroid dysfunctions. Four hundred and eighty nine research papers were identified and 17 studies with 262 581 patients and 1 302 655 control subjects were included for quantitative synthesis. AA was significantly associated with both TPO-Ab and TG-Ab. In comparison, there was no significant association between AA and diagnosed hypothyroidism or hyperthyroidism and serological hypothyroidism or hyperthyroidism. In conclusion, AA is significantly associated with the existence of thyroid antibodies rather than with clinical or laboratory thyroid abnormality. Lack of long-term follow-up data is a limitation of the existing published work. Our findings do not support routine screening of thyroid diseases for asymptomatic AA patients but highlight the potential future risk of AITD particularly in severe and refractory AA.

Study on Serum Vitamin D in Alopecia Areata Patients.

BACKGROUND: Alopecia areata is the commonest cause of non-scarring alopecia. Few previous studies have found correlation between AA and vitamin D deficiency, suggesting that vitamin D deficiency can be a risk factor for Alopecia areata. To compare serum vitamin D level between Alopecia areata patients and healthy controls; and to assess the relation between serum vitamin D levels and AA disease severity. METHODS: This case control study included 30 newly diagnosed Alopecia areata patients. Thorough history was taken, detail examination was done and relevant findings were recorded in the standardized pro-forma. Their serum vitamin D (25-hydroxyvitamin D) levels were determined by competitive chemiluminescence methods; and were compared with that of age and sex matched healthy controls. Chi square test and Spearman's rho correlation test were used for the inferential statistics using SPSS version 11.5. RESULTS: There were 30 AA patients with mean age 28.37+10.07 years. Mean Severity of Alopecia Tool score was 3.56+3.50. Prevalence of 25-hydroxyvitamin D [25(OH)D] deficiency was significantly higher in AA group (83.3%) compared to the control group (53.3%) (P=0.01). Similarly, serum 25(OH)D level was reduced more in Alopecia areata group (12.84, IQR=8.87-20.47) than the control group (29.5, IQR=19.85-41.27) (P=0.06). There was inverse co-relation between serum 25(OH)D level and SALT score. CONCLUSIONS: Prevalence of serum 25(OH)D deficiency was significantly higher in Alopecia areata group compared to the control, with inverse co-relation between its level and Alopecia areata disease severity.

Patients with alopecia areata show signs of insulin resistance.

Alopecia areata (AA) is an autoimmune disease associated with high levels of proinflammatory cytokines. Since chronic inflammation plays a major role in the pathogenesis of insulin resistance, AA can theoretically increase the risk of diabetes. We sought to investigate this theory by conducting a case-control study. Sixty patients with alopecia areata and 60 healthy volunteers (matched for age, sex, and body mass index) were evaluated. Fasting blood glucose (FBS), C-peptide, plasma insulin, and homeostasis model assessment for insulin resistance (HOMA-IR) were measured for each individual. Plasma levels of insulin [median (interquartile range IQR): 11.22 (7.28-18.15) µIU/ml vs. 4.80 (3.20-9.00), p < 0.0001)], C-peptide [median (IQR): 2.10 (1.61-3.00) ng/ml vs. 1.40 (1.20-1.88), p < 0.0001)] and HOMA-IR [median (IQR): 2.70 (1.58-3.96) µIU/ml vs. 1.01 (0.64-1.98, p < 0.0001)] were significantly higher in patients with AA compared to controls. The differences remained significant even after controlling for age, gender, and BMI. Patients with a more severe disease (alopecia totalis/universalis) had higher levels of insulin [median (IQR): 15.80 (9.68-21.55) vs. 9.30 (5.33-14.40), p = 0.02)] and HOMA-IR [median (IQR): 3.30 (2.20-4.84) vs. 2.15 (1.29-3.52), p = 0.01] compared to those with patchy hair loss. Our data suggest that individuals with AA are at a higher risk of developing insulin resistance. This may be due to common inflammatory pathogenesis or a shared genetic background.

Identification of blood microRNA alterations in patients with severe active alopecia areata.

BACKGROUND: Alopecia areata (AA) is a common inflammatory disease characterized by cellular infiltration of T cells targeting the anagen-stage hair follicle. Lack of efficacious treatment for AA may be due to little knowledge about its exact cellular mechanism. Studies have demonstrated that microRNAs (miRNAs) play an important role in the regulation of inflammatory skin diseases such as atopic dermatitis and psoriasis. However, little is known about the role of miRNAs in AA. OBJECTIVE: The present study aimed to explore the blood miRNAs alterations in patients with severe active AA. METHODS: We constructed a bipartite miRNA-messenger RNA (mRNA) regulatory network by the validated miRNA-mRNA relationships. Subsequently, the miRNA-miRNA synergistic network was formed in consideration of the Gene Ontology function enrichment of coregulated target genes. Lastly, the functional network was identified by the ingenuity pathway analysis. RESULTS: By using an Agilent microarray that covers 2549 human miRNAs, we identified 36 significantly differentially expressed miRNAs in severe active AA patients. miRNA target gene prediction and functional annotation analysis showed significant enrichment in several pathways including the ribosome, cancer, cell cycle, insulin signaling, transforming growth factor-ßsignaling, and p53 signaling pathways. Analysis of the three kinds of network showed that miR-185-5p, miR-125b-5p, and miR-186-5p might play important and synergistic roles in the active phase of AA. According to the receiver operating characteristic curve analysis, several miRNAs were selected for the quantitative real-time polymerase chain reaction validation. Among the miRNAs, miR-210 and miR-1246 had high prediction with high accuracy. CONCLUSION: Blood dysregulated miRNAs are potentially associated with the severe active AA. These miRNAs could function synergistically and might be promising targets for the development of novel treatments for AA in the future.