Project description:BACKGROUND:Alopecia areata (AA) is an autoimmune disease characterized by hair loss mediated by CD8+ T cells. There are no reliably effective therapies for AA. Based on recent developments in the understanding of the pathomechanism of AA, JAK inhibitors appear to be a therapeutic option; however, their efficacy for the treatment of AA has not been systematically examined. METHODS:This was a 2-center, open-label, single-arm trial using the pan-JAK inhibitor, tofacitinib citrate, for AA with >50% scalp hair loss, alopecia totalis (AT), and alopecia universalis (AU). Tofacitinib (5 mg) was given twice daily for 3 months. Endpoints included regrowth of scalp hair, as assessed by the severity of alopecia tool (SALT), duration of hair growth after completion of therapy, and disease transcriptome. RESULTS:Of 66 subjects treated, 32% experienced 50% or greater improvement in SALT score. AA and ophiasis subtypes were more responsive than AT and AU subtypes. Shorter duration of disease and histological peribulbar inflammation on pretreatment scalp biopsies were associated with improvement in SALT score. Drug cessation resulted in disease relapse in 8.5 weeks. Adverse events were limited to grade I and II infections. An AA responsiveness to JAK/STAT inhibitors score was developed to segregate responders and nonresponders, and the previously developed AA disease activity index score tracked response to treatment. CONCLUSIONS:At the dose and duration studied, tofacitinib is a safe and effective treatment for severe AA, though it does not result in a durable response. Transcriptome changes reveal unexpected molecular complexity within the disease. TRIAL REGISTRATION:ClinicalTrials.gov NCT02197455 and NCT02312882. FUNDING:This work was supported by the US Department of Veterans Affairs Office of Research and Development, National Institute of Arthritis and Musculoskeletal and Skin Diseases National Institutes of Health grant R01 AR47223 and U01 AR67173, the National Psoriasis Foundation, the Swedish Society of Medicine, the Fernström Foundation, the Locks of Love Foundation, the National Alopecia Areata Foundation, and the Ranjini and Ajay Poddar Resource Fund for Dermatologic Diseases Research.
Project description:Alopecia areata (AA) is a common autoimmune disease with a lifetime risk of ?2%. In AA, the immune system targets the hair follicle, resulting in clinical hair loss. The prognosis of AA is unpredictable, and currently there is no definitive treatment. Our previous whole genome expression studies identified active immune circuits in AA lesions, including common ?-chain cytokine and IFN pathways. Because these pathways are mediated through JAK kinases, we prioritized clinical exploration of small molecule JAK inhibitors. In preclinical trials in mice, tofacitinib successfully prevented AA development and reversed established disease. In our tofacitinib trial in 12 patients with moderate to severe AA, 11 patients completed a full course of treatment with minimal adverse events. Following limited response to the initial dose (5 mg b.i.d.), the dose was escalated (10 mg b.i.d.) for nonresponding subjects. Eight of 12 patients demonstrated ?50% hair regrowth, while three patients demonstrated <50% hair regrowth, as measured by Severity in Alopecia Tool scoring. One patient demonstrated no regrowth. Gene expression profiles and Alopecia Areata Disease Activity Index scores correlated with clinical response. Our open-label studies of ruxolitinib and tofacitinib have shown dramatic clinical responses in moderate to severe AA, providing strong rationale for larger clinical trials using JAK inhibitors in AA. ClinicalTrials.gov ID NCT02299297.
Project description:The samples include RNA from scalp biopsies before treatment and at 8 weeks of treatment with Tofacitinib Citrate 5 mg BID in patients with Alopecia Areata. 32% had a SALT score of 50% or higher and 47% had clinically significant response. Overall design: Open label trial of patients with Alopecia Areata of more than 6 months in duration refractory to standard therapy. Each patient took tofacitinib citrate 5mg BID for 3 months and then stopped. Biopsies were taken pretreatment and then at 8 weeks from the scalp and submitted for RNA sequencing.
Project description:INTRODUCTION:The JAK/STAT signaling pathway is involved in the immune-mediated inflammatory skin diseases atopic dermatitis (AD), vitiligo, and alopecia areata (AA), and represents a potential target when developing treatments. So far, no drugs targeting this pathway have been approved for the treatment of dermatological diseases. We reviewed the use of drugs blocking the JAK/STAT pathway in the aforementioned diseases. METHODS:An a priori protocol was published. We used Joanna Briggs Institute Reviewer's Manual methodology to conduct the review and PRISMA Extension for Scoping Review (PRISMA-ScR) to report results. MEDLINE, EMBASE, CINAHL, Scopus, and Web of Science databases were searched in a three-step approach on April 2019 by two researchers. RESULTS:Ninety-six mainly multicenter observational studies were included (66, 10, and 20 studies on AA, vitiligo, and AD, respectively). Tofacitinib and ruxolitinib were mainly used for the three diseases, and also upadacitinib, abrocitinib, baricitinib, cerdulatinib, delgocitinib, gusacitinib for AD, and baricitinib, PF-06700841, and PF-06651600 for AA. All patients with AD improved, whereas patients with vitiligo and patients with AA showed varied responses, including unresponsive cases. The safety profiles were similar for all drugs and diseases, mainly comprising mild or no adverse events. CONCLUSIONS:Evidence on the efficacy and safety of drugs targeting the JAK/STAT pathway for the treatment of patients with AD, vitiligo, or AA is increasing but is still of low quality.
Project description:Alopecia areata (AA) is an autoimmune disease in which cytotoxic T cells specifically target growing hair follicles. We used high-throughput TCR sequencing in the C3H/HeJ mouse model of AA and in human AA patients to gain insight into pathogenic T cell populations and their dynamics, which revealed clonal CD8+ T cell expansions in lesional skin. In the C3H/HeJ model, we observed interindividual sharing of TCR? chain protein sequences, which strongly supports a model of antigenic drive in AA. The overlap between the lesional TCR repertoire and a population of CD8+NKG2D+ T cells in skin-draining lymph nodes identified this subset as pathogenic effectors. In AA patients, treatment with the oral JAK inhibitor tofacitinib resulted in a decrease in clonally expanded CD8+ T cells in the scalp but also revealed that many expanded lesional T cell clones do not completely disappear from either skin or blood during treatment with tofacitinib, which may explain in part the relapse of disease after stopping treatment.
Project description:Background:There are many treatments available for alopecia areata; however, none are approved by the US Food and Drug Administration. Thus, there is clinician benefit in efficacy comparison. Methods:A network meta-analysis was used to create direct and indirect comparisons of alopecia areata studies in addition to an inconsistency analysis, risk of bias, and quality of evidence assessment. Results:For mild disease, intralesional corticosteroids were ranked the most likely to produce a response at 78.9% according to SUCRA (surface under the cumulative ranking curve) followed by topical corticosteroids (67.9%), prostaglandin analogs (67.1%), diphenylcyclopropenone (DPCP, 63.4%), topical minoxidil (61.2%), and squaric acid dibutylester (SADBE, 35.0%). In contrast, for moderate to severe disease (>50% scalp hair loss), DPCP was the top-ranked treatment (87.9%), followed by laser (77.9%), topical minoxidil (55.5%), topical corticosteroids (50.1%), SADBE (49.7%), and topical tofacitinib (47.6%). There were insufficient eligible trials to include oral tofacitinib in the network. Conclusion:Statistically significant evidence is presented for the use of intralesional and topical corticosteroids for treatment of mild disease and DPCP, laser, SADBE, topical minoxidil and topical corticosteroids for moderate to severe disease. Further controlled trials are required to analyze the relative efficacy of oral tofacitinib.
Project description:The recent interest and elucidation of the JAK/STAT signaling pathway created new targets for the treatment of inflammatory skin diseases (ISDs). JAK inhibitors in oral and topical formulations have shown beneficial results in psoriasis and alopecia areata. Patients suffering from other ISDs might also benefit from JAK inhibition. Given the development of specific JAK inhibitors, the expression patterns of JAKs in different ISDs needs to be clarified. We aimed to analyze the expression of JAK/STAT family members in a set of prevalent ISDs: psoriasis, lichen planus (LP), cutaneous lupus erythematosus (CLE), atopic dermatitis (AD), pyoderma gangrenosum (PG) and alopecia areata (AA) versus healthy controls for (p)JAK1, (p)JAK2, (p)JAK3, (p)TYK2, pSTAT1, pSTAT2 and pSTAT3. The epidermis carried in all ISDs, except for CLE, a strong JAK3 signature. The dermal infiltrate showed a more diverse expression pattern. JAK1, JAK2 and JAK3 were significantly overexpressed in PG and AD suggesting the need for pan-JAK inhibitors. In contrast, psoriasis and LP showed only JAK1 and JAK3 upregulation, while AA and CLE were characterized by a single dermal JAK signal (pJAK3 and pJAK1, respectively). This indicates that the latter diseases may benefit from more targeted JAK inhibitors. Our in vitro keratinocyte psoriasis model displayed reversal of the psoriatic JAK profile following tofacitinib treatment. This direct interaction with keratinocytes may decrease the need for deep skin penetration of topical JAK inhibitors in order to exert its effects on dermal immune cells. In conclusion, these results point to the important contribution of the JAK/STAT pathway in several ISDs. Considering the epidermal JAK3 expression levels, great interest should go to the investigation of topical JAK3 inhibitors as therapeutic option of ISDs.
Project description:Molecular targeting therapies represent a new exciting era in dermatology. A promising novel drug class, subject of intense research, is Janus kinase (JAK) inhibitors. Multiple cytokine receptors signal through the Janus kinase and signal transducer and activator of transcription (STAT) pathway. The pathway plays a central role in innate and adaptive immunity, and haematopoiesis. The understanding of the contribution of JAKs to the immunologic processes of inflammatory diseases led to the development of JAK inhibitors, initially for rheumatologic and hematologic diseases. Soon, their efficacy in some dermatologic conditions was also demonstrated, and today their role as therapeutic agents is thoroughly researched, mainly in atopic dermatitis, psoriasis, vitiligo, and alopecia areata. JAK inhibitors can be administered orally or used topically. As they are relatively new treatment modalities in dermatology, many questions concerning their efficacy and safety remain unanswered. Data from ongoing trials are eagerly awaited. Here, we summarize under development JAK inhibitors for dermatologic diseases.
Project description:This study was an open-label, clinical trial to investigate tofacitinib 5 mg to 10 mg PO twice daily in the treatment of moderate/severe alopeica areata and to identify if gene expression of the scalp correlates with clinical response. Gene expression profiling was performed on scalp biopsies of alopecia areata patients taken at baseline and up to 24 weeks of treatment of tofacitinib. We applied both naïve and supervised clustering to this dataset in order to assess two features: the overall molecular effect of tofacitinib treatment on patient samples, and the concordant molecular response of the disease. The former was assessed by an unbiased, unsupervised differential expression analysis and the latter was measured by response to previously published gene expression signatures defining AA pathology. To ensure parity of the data, for this analysis we only included patient samples that had matched pre-treatment, Tx-00, and 24 weeks of treatment, Tx-24, samples. Gene expression profiles and Alopecia Areata Disease Activity Index (ALADIN) scores correlated with clinical response. Overall design: Gene expression analysis of 12 (6 T0 and 6 T24) scalp biopsies of alopecia areata patients and 6 control samples.
Project description:Background:Anti-cytokine therapies such as adalimumab, tocilizumab, and the small molecule JAK inhibitor tofacitinib have proven that cytokines and their subsequent downstream signaling processes are important in the pathogenesis of rheumatoid arthritis. Tofacitinib, a pan-JAK inhibitor, is the first approved JAK inhibitor for the treatment of RA and has been shown to be effective in managing disease. However, in phase 2 dose-ranging studies tofacitinib was associated with dose-limiting tolerability and safety issues such as anemia. Upadacitinib (ABT-494) is a selective JAK1 inhibitor that was engineered to address the hypothesis that greater JAK1 selectivity over other JAK family members will translate into a more favorable benefit:risk profile. Upadacitinib selectively targets JAK1 dependent disease drivers such as IL-6 and IFN?, while reducing effects on reticulocytes and natural killer (NK) cells, which potentially contributed to the tolerability issues of tofacitinib. Methods:Structure-based hypotheses were used to design the JAK1 selective inhibitor upadacitinib. JAK family selectivity was defined with in vitro assays including biochemical assessments, engineered cell lines, and cytokine stimulation. In vivo selectivity was defined by the efficacy of upadacitinib and tofacitinib in a rat adjuvant induced arthritis model, activity on reticulocyte deployment, and effect on circulating NK cells. The translation of the preclinical JAK1 selectivity was assessed in healthy volunteers using ex vivo stimulation with JAK-dependent cytokines. Results:Here, we show the structural basis for the JAK1 selectivity of upadacitinib, along with the in vitro JAK family selectivity profile and subsequent in vivo physiological consequences. Upadacitinib is ~?60 fold selective for JAK1 over JAK2, and?>?100 fold selective over JAK3 in cellular assays. While both upadacitinib and tofacitinib demonstrated efficacy in a rat model of arthritis, the increased selectivity of upadacitinib for JAK1 resulted in a reduced effect on reticulocyte deployment and NK cell depletion relative to efficacy. Ex vivo pharmacodynamic data obtained from Phase I healthy volunteers confirmed the JAK1 selectivity of upadactinib in a clinical setting. Conclusions:The data presented here highlight the JAK1 selectivity of upadacinitinib and supports its use as an effective therapy for the treatment of RA with the potential for an improved benefit:risk profile.