JAK inhibitors in dermatology: The promise of a new drug class.
Ontology highlight
ABSTRACT:
SUBMITTER: Damsky W
PROVIDER: S-EPMC6035868 | biostudies-literature | 2017 Apr
REPOSITORIES: biostudies-literature
Publications
JAK inhibitors in dermatology: The promise of a new drug class.
Damsky William W King Brett A BA
Journal of the American Academy of Dermatology 20170128 4
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 sugg ...[more]
Similar Datasets
Project description:Accumulating data on cellular and molecular pathways help to develop novel therapeutic strategies in skin inflammation and autoimmunity. Examples are psoriasis and atopic dermatitis, two clinically and immunologically well-defined disorders. Here, the elucidation of key pathogenic factors such as IL-17A/IL-23 on the one hand and IL-4/IL-13 on the other hand profoundly changed our therapeutic practice. The knowledge on intracellular pathways and governing factors is shifting our attention to new druggable molecules. Multiple cytokine receptors signal through Janus kinases (JAKs) and associated signal transducer and activators of transcription (STATs). Inhibition of JAKs can simultaneously block the function of multiple cytokines. Therefore, JAK inhibitors (JAKi) are emerging as a new class of drugs, which in dermatology can either be used systemically as oral drugs or locally in topical formulations. Inhibition of JAKs has been shown to be effective in various skin disorders. The first oral JAKi have been recently approved for the treatment of rheumatoid arthritis and psoriatic arthritis. Currently, multiple inhibitors of the JAK/STAT pathway are being investigated for skin diseases like alopecia areata, atopic dermatitis, dermatomyositis, graft-versus-host-disease, hidradenitis suppurativa, lichen planus, lupus erythematosus, psoriasis, and vitiligo. Here, we aim to discuss the immunological basis and current stage of development of JAKi in dermatology.
| S-EPMC6901833 | biostudies-literature
Project description:Janus kinase (JAK) inhibitors are disease-modifying agents with efficacy in treating a spectrum of burdensome dermatologic conditions. The US Food and Drug Administration (FDA) recently placed a black box warning on this class of medications due to safety concerns based on data from studies investigating tofacitinib in patients with rheumatoid arthritis. Here we provide an overview of the timeline of FDA approval of JAK inhibitors in dermatology. We also discuss the available safety profiles of approved oral JAK1 inhibitors, namely abrocitinib and upadacitinib, oral baricitinib, a JAK1/2 inhibitor, deucravacitinib, a Tyk2 inhibitor, and the topical JAK1/2 inhibitor ruxolitinib in dermatology patients. Additionally, we offer suggestions for initial screening and laboratory monitoring for patients receiving JAK inhibitors. We found that the rates of venous thromboembolism reported in trials ranged from no events to 0.1-0.5% in dermatology-specific phase 3 clinical trials compared with no events in the placebo. The rates of cardiovascular events ranged from no events to 0.4-1.2% compared with no events to 0.5-1.2% in the placebo. The rates of serious infections were 0.4-4.8% compared with no events to 0.5-1.3% in the placebo. The rates of nonmelanoma skin cancer (NMSC) ranged from no event to 0.6-0.9% compared with no events in the placebo. The rates of non-NMSC ranged from no event to 0.2-0.7% compared with no event to 0.6% in the placebo. Most patients who developed these adverse events had risk factors for the specific event. The most common adverse events of oral JAK inhibitors included upper respiratory infections, nasopharyngitis, nausea, headache, and acne. Dermatologists should consider patients' baseline risk factors for developing serious complications when prescribing oral JAK inhibitors.
| S-EPMC9930707 | biostudies-literature
Project description:Current JAK2 inhibitors used for myeloproliferative neoplasms (MPN) treatment are not specific enough to selectively suppress aberrant JAK2 signalling and preserve physiological JAK2 signalling. We tested whether combining a JAK2 inhibitor with a series of serine threonine kinase inhibitors, targeting nine signalling pathways and already used in clinical trials, synergized in inhibiting growth of haematopoietic cells expressing mutant and wild-type forms of JAK2 (V617F) or thrombopoietin receptor (W515L). Out of 15 kinase inhibitors, the ZSTK474 phosphatydylinositol-3'-kinase (PI3K) inhibitor molecule showed strong synergic inhibition by Chou and Talalay analysis with JAK2 and JAK2/JAK1 inhibitors. Other pan-class I, but not gamma or delta specific PI3K inhibitors, also synergized with JAK2 inhibitors. Synergy was not observed in Bcr-Abl transformed cells. The best JAK2/JAK1 and PI3K inhibitor combination pair (ruxolitinib and GDC0941) reduces spleen weight in nude mice inoculated with Ba/F3 cells expressing TpoR and JAK2 V617F. It also exerted strong inhibitory effects on erythropoietin-independent erythroid colonies from MPN patients and JAK2 V617F knock-in mice, where at certain doses, a preferential inhibition of JAK2 V617F mutated progenitors was detected. Our data support the use of a combination of JAK2 and pan-class I PI3K inhibitors in the treatment of MPNs.
| S-EPMC4117552 | biostudies-literature
Project description:Certain inflammatory disorders are characterized by macrophage activation and accumulation in tissue; sometimes leading to the formation of granulomas, as in sarcoidosis. These disorders are often difficult to treat and more effective, molecularly targeted therapies are needed. Recent work has shown that overproduction of inflammatory cytokines, such as interferon gamma (IFN-?) leading to constitutive activation of the JAK-STAT pathway may be a conserved feature of these disorders. Use of JAK inhibitors, which can block these signals, has resulted in dramatic improvement in several patients with sarcoidosis. JAK inhibitors also appear to have activity in other inflammatory disorders with macrophage activation including hemophagocytic lymphohistiocystosis, Crohn's disease, granuloma annulare, and necrobiosis lipoidica. Here, we review the role of JAK dependent cytokines in macrophage activation and granuloma formation and the clinical evidence supporting the use of JAK inhibition in these disorders. Ongoing efforts to evaluate role of JAK inhibitors in these disorders is also discussed.
| S-EPMC7087061 | biostudies-literature
Project description:The concepts of developing RNAs as new molecular entities for therapies have arisen again and again since the discoveries of antisense RNAs, direct RNA-protein interactions, functional noncoding RNAs, and RNA-directed gene editing. The feasibility was demonstrated with the development and utilization of synthetic RNA agents to selectively control target gene expression, modulate protein functions or alter the genome to manage diseases. Rather, RNAs are labile to degradation and cannot cross cell membrane barriers, making it hard to develop RNA medications. With the development of viable RNA technologies, such as chemistry and pharmaceutics, eight antisense oligonucleotides (ASOs) (fomivirsen, mipomersen, eteplirsen, nusinersen, inotersen, golodirsen, viltolarsen and casimersen), one aptamer (pegaptanib), and three small interfering RNAs (siRNAs) (patisiran, givosiran and lumasiran) have been approved by the United States Food and Drug Administration (FDA) for therapies, and two mRNA vaccines (BNT162b2 and mRNA-1273) under Emergency Use Authorization for the prevention of COVID-19. Therefore, RNAs have become a great addition to small molecules, proteins/antibodies, and cell-based modalities to improve the public health. In this article, we first summarize the general characteristics of therapeutic RNA agents, including chemistry, common delivery strategies, mechanisms of actions, and safety. By overviewing individual RNA medications and vaccines approved by the FDA and some agents under development, we illustrate the unique compositions and pharmacological actions of RNA products. A new era of RNA research and development will likely lead to commercialization of more RNA agents for medical use, expanding the range of therapeutic targets and increasing the diversity of molecular modalities.
| S-EPMC9477512 | biostudies-literature
Project description:The past decade has witnessed an explosion in trial data on JAK inhibitors (JAKi). These small molecules target the Janus kinase - signal transducer and activator of transcription (JAK-STAT) pathway, blocking crucial cytokines across a septum of rheumatic diseases. As a class, JAKi are beginning to demonstrate efficacy on par, if not superior to biologics. Two first generation JAKi are licensed for use in inflammatory arthritis; tofacitinib and baricitinib. Next-generation JAKi have been designed with selective affinity for one JAK enzymes, the aim to reduce unwanted adverse effects without declining clinical efficacy. Emerging data with selective JAK1 inhibitors upadacitinib and filgotinib looks very promising. Despite differences in selectivity between JAKi, an overlap exists in their safety profiles. Across the class, a characteristic safety signal is emerging with viral opportunistic infections, particularly herpes zoster. Post marketing drug surveillance will be essential in evaluating the long-term risk with these agents.
| S-EPMC6876279 | biostudies-literature
Project description:Inflammatory bowel disease (IBD) is a chronic immune-mediated condition of the gastrointestinal tract that requires chronic treatment and strict surveillance. Development of new monoclonal antibodies targeting one or a few single cytokines, including anti-tumor necrosis factor agents, anti-IL 12/23 inhibitors, and anti-α4β7 integrin inhibitors, have dominated the pharmacological armamentarium in IBD in the last 20 years. Still, many patients experience incomplete or loss of response or develop serious adverse events and drug discontinuation. Janus kinase (JAK) is key to modulating the signal transduction pathway of several proinflammatory cytokines directly involved in gastrointestinal inflammation and, thus, probably IBD pathogenesis. Targeting the JAK-STAT pathway offers excellent potential for the treatment of IBD. The European Medical Agency has approved three JAK inhibitors for treating adults with moderate to severe Ulcerative Colitis when other treatments, including biological agents, have failed or no longer work or if the patient cannot take them. Although there are currently no approved JAK inhibitors for Crohn's disease, upadacitinib and filgotinib have shown increased remission rates in these patients. Other JAK inhibitors, including gut-selective molecules, are currently being studied IBD. This review will discuss the JAK-STAT pathway, its implication in the pathogenesis of IBD, and the most recent evidence from clinical trials regarding the use of JAK inhibitors and their safety in IBD patients.
| S-EPMC10017532 | biostudies-literature
Project description:Asthma is an inflammatory disease of the airways characterized by intermittent episodes of wheezing, chest tightness, and cough. Many of the inflammatory pathways implicated in asthma involve cytokines and growth factors that activate Janus kinases (JAKs). The discovery of the JAK/signal transducer and activator of transcription (STAT) signaling pathway was a major breakthrough that revolutionized our understanding of cell growth and differentiation. JAK inhibitors are under active investigation for immune and inflammatory diseases, and they have demonstrated clinical efficacy in diseases such as rheumatoid arthritis and atopic dermatitis. Substantial preclinical data support the idea that inhibiting JAKs will ameliorate airway inflammation and hyperreactivity in asthma. Here, we review the rationale for use of JAK inhibitors in different asthma endotypes as well as the preclinical and early clinical evidence supporting such use. We review preclinical data from the use of systemic and inhaled JAK inhibitors in animal models of asthma and safety data based on the use of JAK inhibitors in other diseases. We conclude that JAK inhibitors have the potential to usher in a new era of anti-inflammatory treatment for asthma.
| S-EPMC8771907 | biostudies-literature
Project description:Small-molecule inhibitors of the Janus kinase family (JAKis) are clinically efficacious in multiple autoimmune diseases, albeit with increased risk of certain infections. Their precise mechanism of action is unclear, with JAKs being signaling hubs for several cytokines. We assessed the in vivo impact of pan- and isoform-specific JAKi in mice by immunologic and genomic profiling. Effects were broad across the immunogenomic network, with overlap between inhibitors. Natural killer (NK) cell and macrophage homeostasis were most immediately perturbed, with network-level analysis revealing a rewiring of coregulated modules of NK cell transcripts. The repression of IFN signature genes after repeated JAKi treatment continued even after drug clearance, with persistent changes in chromatin accessibility and phospho-STAT responsiveness to IFN. Thus, clinical use and future development of JAKi might need to balance effects on immunological networks, rather than expect that JAKis affect a particular cytokine response and be cued to long-lasting epigenomic modifications rather than by short-term pharmacokinetics.
| S-EPMC5024632 | biostudies-literature
Project description:During SARS-CoV-2 infection, the innate immune response can be inhibited or delayed, and the subsequent persistent viral replication can induce emergency signals that may culminate in a cytokine storm contributing to the severe evolution of COVID-19. Cytokines are key regulators of the immune response and virus clearance, and, as such, are linked to the-possibly altered-response to the SARS-CoV-2. They act via a family of more than 40 transmembrane receptors that are coupled to one or several of the 4 Janus kinases (JAKs) coded by the human genome, namely JAK1, JAK2, JAK3, and TYK2. Once activated, JAKs act on pathways for either survival, proliferation, differentiation, immune regulation or, in the case of type I interferons, antiviral and antiproliferative effects. Studies of graft-versus-host and systemic rheumatic diseases indicated that JAK inhibitors (JAKi) exert immunosuppressive effects that are non-redundant with those of corticotherapy. Therefore, they hold the potential to cut-off pathological reactions in COVID-19. Significant clinical experience already exists with several JAKi in COVID-19, such as baricitinib, ruxolitinib, tofacitinib, and nezulcitinib, which were suggested by a meta-analysis (Patoulias et al.) to exert a benefit in terms of risk reduction concerning major outcomes when added to standard of care in patients with COVID-19. Yet, only baricitinib is recommended in first line for severe COVID-19 treatment by the WHO, as it is the only JAKi that has proven efficient to reduce mortality in individual randomized clinical trials (RCT), especially the Adaptive COVID-19 Treatment Trial (ACTT-2) and COV-BARRIER phase 3 trials. As for secondary effects of JAKi treatment, the main caution with baricitinib consists in the induced immunosuppression as long-term side effects should not be an issue in patients treated for COVID-19.We discuss whether a class effect of JAKi may be emerging in COVID-19 treatment, although at the moment the convincing data are for baricitinib only. Given the key role of JAK1 in both type I IFN action and signaling by cytokines involved in pathogenic effects, establishing the precise timing of treatment will be very important in future trials, along with the control of viral replication by associating antiviral molecules.
| S-EPMC9035837 | biostudies-literature