tofacitinib and Skin-Diseases

The Janus kinase and Signal Transducer and Activator of Transcription protein (JAK/STAT) pathway is known to be involved in inflammatory and neoplastic skin diseases, like psoriasis, atopic dermatitis, alopecia areata, vitiligo and melanoma. Improved knowledge of the components of this pathway has allowed the development of drugs, which act by inhibiting the pathway, blocking specific components. This offers new therapeutic opportunities. Although evidence on the use of JAK/STAT blockades in dermatological diseases is growing, none have been approved for use in treating skin diseases. The aim of this study is to develop an a priori protocol to broadly review the available evidence on the use of drugs targeting the JAK/STAT pathway in the treatment of dermatological diseases.. For the conduction of the scoping review protocol, we will employ an established scoping review methodology described in the Joanna Briggs Institute manual. This methodology outlines a five-stage approach: (1) identify the research question; (2) identify relevant studies; (3) select studies; (4) chart the data and (5) collate, summarise and report the results, with an optional consultation exercise. Finally, we will use the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews to present the results.. Since this is a review of the literature, ethics approval is not indicated. We will disseminate the findings from this study in publications in peer-reviewed journals as well as presentations at relevant national and international conferences.

Topics: Humans; Janus Kinase Inhibitors; Janus Kinases; Nitriles; Piperidines; Pyrazoles; Pyrimidines; Pyrroles; Skin Diseases; STAT Transcription Factors

Janus kinase family (JAKs) has recently attracted the attention of many researchers, and several JAK inhibitor drugs have been developed targeting different members of the JAK family. Tofacitinib and ruxolitinib are US FDA approved drugs in this family for rheumatoid arthritis and myeloproliferative diseases, respectively. Dysregulation of JAK/STAT pathway is also involved in many skin diseases, specifically inflammatory disorders. The JAK/STAT signaling pathway and its involvement in skin diseases are overviewed in this study. We also review clinical studies of JAK inhibitors in field of dermatology, including psoriasis, atopic dermatitis, alopecia areata and vitiligo. Although the available evidence shows promising results, it is still too early to draw a firm conclusion about the place of these drugs in dermatological treatment.

Topics: Alopecia Areata; Azetidines; Dermatitis, Atopic; Humans; Janus Kinase Inhibitors; Janus Kinases; Nitriles; Piperidines; Psoriasis; Purines; Pyrazoles; Pyrimidines; Pyrroles; Skin Diseases; Sulfonamides; Vitiligo

Tofacitinib (formerly known as CP-690,550, CP690550, tasocitinib), a novel selective immunosuppressant, is a small molecule classified as Janus kinase inhibitor. The aim of this review article is to present updated data summary on the tofacitinib in the field of dermatology.. We undertook a structured search of bibliographic databases for peer-reviewed scientific articles, including review articles, original research articles as well as case report articles based on inclusion/exclusion criteria. Technical reports on tofacitinib from U.S. Food and Drug Administration and European Medical Agency were also included.. Forty-three papers were included in this review. We report current data on tofacitinib chemical properties, pharmacology, non-clinical toxicity, as well as efficacy and safety in potential new indications in dermatology: psoriasis, alopecia areata, vitiligo, atopic dermatitis and nail dystrophy associated with alopecia areata.. JAK/STAT pathway has an important role in the pathogenesis of psoriasis, alopecia areata, atopic dermatitis, and vitiligo. Despite encouraging efficacy, due to concerns about the overall safety profile of tofacitinib, additional studies will have to determine the adequate risk-to-benefit ratio.

Topics: Administration, Oral; Alopecia Areata; Dermatitis, Atopic; Humans; Janus Kinases; Piperidines; Protein Kinase Inhibitors; Psoriasis; Pyrimidines; Pyrroles; Signal Transduction; Skin Diseases; Vitiligo

New molecularly targeted therapeutics are changing dermatologic therapy. Janus kinase-signal transducer and activator of transcription (JAK-STAT) is an intracellular signaling pathway upon which many different proinflammatory signaling pathways converge. Numerous inflammatory dermatoses are driven by soluble inflammatory mediators, which rely on JAK-STAT signaling, and inhibition of this pathway using JAK inhibitors might be a useful therapeutic strategy for these diseases. Growing evidence suggests that JAK inhibitors are efficacious in atopic dermatitis, alopecia areata, psoriasis, and vitiligo. Additional evidence suggests that JAK inhibition might be broadly useful in dermatology, with early reports of efficacy in several other conditions. JAK inhibitors can be administered orally or used topically and represent a promising new class of medications. The use of JAK inhibitors in dermatology is reviewed here.

Topics: Alopecia Areata; Anti-Inflammatory Agents; Azetidines; Clinical Trials as Topic; Dermatitis, Atopic; Dermatologic Agents; Humans; Janus Kinases; Molecular Targeted Therapy; Nitriles; Piperidines; Protein Kinase Inhibitors; Psoriasis; Purines; Pyrazoles; Pyrimidines; Pyrroles; Signal Transduction; Skin Diseases; Sulfonamides; Vitiligo

Janus kinase (JAK) inhibitors are emerging as a promising new treatment modality for many inflammatory conditions.. Our aim was to systematically review the available data on the use of JAK inhibitors in cutaneous diseases.. This is a systematic review of PubMed and ClinicalTrials.gov.. One hundred thirty-four articles matched our search terms, of which 78 were original articles and 12 reports on adverse events. Eighteen clinical trials were found. JAK inhibitors have been extensively studied for psoriasis, showing beneficial results that were comparable to the effects achieved by etanercept. Favorable results were also observed for alopecia areata. Promising preliminary results were reported for vitiligo, dermatitis, graft versus host disease, cutaneous T cell lymphoma, and lupus erythematosus. The most common adverse events reported were infections, mostly nasopharyngitis and upper respiratory tract infections.. It was not possible to perform a meta-analysis of the results.. This systematic review shows that while JAK inhibitors hold promise for many skin disorders, there are still gaps regarding the correct dosing and safety profile of these medications for dermatologic indications. Additional trials are necessary to address these gaps.

Topics: Alopecia Areata; Anti-Inflammatory Agents; Antineoplastic Agents; Azetidines; Dermatologic Agents; Drug Eruptions; Humans; Janus Kinases; Molecular Targeted Therapy; Nitriles; Piperidines; Protein Kinase Inhibitors; Psoriasis; Purines; Pyrazoles; Pyrimidines; Pyrroles; Randomized Controlled Trials as Topic; Signal Transduction; Skin Diseases; Sulfonamides

Over the last year there has been major publications related to therapeutic trials in infectious dermatology, not only with regard to Herpes zoster subunit vaccine but also for the treatment of uncomplicated abscesses or scabies. In addition, biological treatments continue to be on the forefront, not only in the treatment of psoriasis but also in other chronic inflammatory dermatologic diseases such as atopic dermatitis and hidradenitis suppurativa, two diseases that significantly impact quality of life and for which there are to date, few therapeutic alternatives in moderate to severe forms. In addition, the treatment of cyclin-resistant papulopustular rosacea was also the subject of a large French controlled randomized controlled trial that could modify our therapeutic approach by the use of isotretinoin. Finally, the prevention of rashes induced by erlotinib with oral doxycyline is also part of this 2016 "what's new in dermatological therapeutics".

Topics: Adalimumab; Anti-Bacterial Agents; Anti-Inflammatory Agents; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Dermatologic Agents; Dermatology; Erlotinib Hydrochloride; Herpes Zoster Vaccine; Humans; Interleukin 1 Receptor Antagonist Protein; Isotretinoin; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Skin Diseases; Trimethoprim, Sulfamethoxazole Drug Combination

Topics: Amyloidosis; Humans; Piperidines; Pyrimidines; Skin Diseases

We here report a case of a middle-aged man with an unusual case of bullous lichen sclerosus complicated with generalized morphea. He showed initial recurrent flaccid bullae, followed by ivory-white sclerotic plaques and extensive skin sclerosis, with additional walking disorder caused by knee-joint contracture, and ulcers on the lower extremities and back. The patient had no visceral involvement. After oral hydroxychloroquine and oral corticosteroids failed, the patient was given tofacitinib, which resolved his ulcers after 4 weeks and ameliorated his knee-joint contracture and skin sclerosis within 4 months. Owing to the occurrence of diffuse large B-cell lymphoma, he stopped using tofacitinib, and the ulcer and walking disorder reappeared. This is rare case of bullous lichen sclerosus-generalized morphea overlap syndrome. The patient recovered well after treatment with tofacitinib. His symptoms recurred after discontinuation of tofacitinib.

Topics: Contracture; Humans; Lichen Sclerosus et Atrophicus; Male; Middle Aged; Neoplasm Recurrence, Local; Scleroderma, Localized; Scleroderma, Systemic; Sclerosis; Skin Diseases; Ulcer

Topics: Administration, Oral; Aged; Biopsy; Female; Humans; Janus Kinases; Lung; Middle Aged; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Retrospective Studies; Sarcoidosis; Sarcoidosis, Pulmonary; Signal Transduction; Skin; Skin Diseases; STAT Transcription Factors; Tomography, X-Ray Computed; Treatment Outcome

Chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE) syndrome is a rare autoinflammatory disorder. Cutaneous manifestations of CANDLE syndrome include characteristic recurring violaceous annular plaques comprised of an immature dermal mononuclear cell infiltrate. In CANDLE syndrome, deleterious genetic mutations inhibit proteasome-immunoproteasome function, resulting in cellular accumulation of ubiquitinated waste proteins that activate type I interferon signaling to drive inflammation. We describe a report of successful treatment of a 12-year-old girl with CANDLE syndrome with tofacitinib.

Topics: Child; Female; Fever; Humans; Immunologic Deficiency Syndromes; Lipodystrophy; Piperidines; Pyrimidines; Skin Diseases; Sweet Syndrome

There is evidence that Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling plays a role in the pathogenesis of sarcoidosis. We treated a patient with cutaneous sarcoidosis with the JAK inhibitor tofacitinib; the patient had not previously had a response to medications and had not received systemic glucocorticoids. This treatment resulted in clinical and histologic remission of her skin disease. Sequencing of RNA and immunohistochemical examination of skin-lesion samples obtained from the patient before and during therapy and immunohistochemical testing of lesion samples obtained from other patients with cutaneous sarcoidosis support a role for JAK-STAT signaling in cutaneous sarcoidosis. (Funded by the Ranjini and Ajay Poddar Resource Fund for Dermatologic Diseases Research and others.).

Topics: Female; Humans; Immunohistochemistry; Janus Kinases; Middle Aged; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Remission Induction; Sarcoidosis; Sarcoidosis, Pulmonary; Sequence Analysis, RNA; Signal Transduction; Skin; Skin Diseases; STAT Transcription Factors

By use of a structure-based computational method for identification of structurally novel Janus kinase (JAK) inhibitors predicted to bind beyond the ATP binding site, a potent series of indazoles was identified as selective pan-JAK inhibitors with a type 1.5 binding mode. Optimization of the series for potency and increased duration of action commensurate with inhaled or topical delivery resulted in potent pan-JAK inhibitor 2 (PF-06263276), which was advanced into clinical studies.

Topics: Administration, Cutaneous; Administration, Inhalation; Animals; Anti-Inflammatory Agents; Binding Sites; Crystallography, X-Ray; Dogs; Drug Design; Hepatocytes; Heterocyclic Compounds, 2-Ring; Humans; Indazoles; Janus Kinase 1; Janus Kinase 2; Janus Kinase 3; Janus Kinases; Lung Diseases; Mice, Inbred BALB C; Microsomes, Liver; Phosphorylation; Protein Kinase Inhibitors; Rats; Skin Diseases; Solubility

Topics: Adult; Aged; Female; Humans; Hypereosinophilic Syndrome; Janus Kinase Inhibitors; Male; Middle Aged; Nitriles; Piperidines; Pyrazoles; Pyrimidines; Pyrroles; Skin Diseases

Topics: Antifungal Agents; Attention Deficit Disorder with Hyperactivity; Boron Compounds; Botulinum Toxins, Type A; Bridged Bicyclo Compounds, Heterocyclic; Brimonidine Tartrate; Depression; Dermatitis, Atopic; Food Hypersensitivity; Humans; Immunologic Factors; Ivermectin; Phosphodiesterase Inhibitors; Phototherapy; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Quinoxalines; Skin Diseases; Societies, Medical; Thalidomide; Triazoles; United States