Michael D Howell1, Carolyn Fitzsimons2, Paul A Smith2. 1. Incyte Corporation, Wilmington, Delaware. Electronic address: mhowell@incyte.com. 2. Incyte Corporation, Wilmington, Delaware.
Abstract
OBJECTIVE: To provide an overview of janus kinase (JAK), chemoattractant receptor homologous molecule expressed on TH2 cells (CRTH2), and phosphodiesterase 4 (PDE4) inhibitors in allergic disorders. DATA SOURCES: PubMed literature review. STUDY SELECTIONS: Articles included in this review discuss the emerging mechanism of action of small molecule inhibitors and their use in the treatment of atopic dermatitis (AD), asthma, and allergic rhinitis (AR). RESULTS: Allergic diseases represent a spectrum of diseases, including AD, asthma, and AR. For decades, these diseases have been primarily characterized by increased TH2 signaling and downstream inflammation. In recent years, additional research has identified disease phenotypes and subsets of patients with non-Th2 mediated inflammation. The increasing heterogeneity of disease has prompted investigators to move away from wide-ranging treatment approaches with immunosuppressive agents, such as corticosteroids, to consider more targeted immunomodulatory approaches focused on specific pathways. In the past decade, inhibitors that target JAK signaling, PDE4, and CRTH2 have been explored for their potential activity in models of allergic disease and therapeutic benefit in clinical trials. Interestingly, although JAK inhibitors provide an opportunity to interfere with cytokine signaling and could be beneficial in a broad range of allergic diseases, current clinical trials are focused on the treatment of AD. Conversely, both PDE4 and CRTH2 inhibitors have been evaluated in a spectrum of allergic diseases. This review summarizes the varying degrees of success that these small molecules have demonstrated across allergic diseases. CONCLUSION: Emerging therapies currently in development may provide more consistent benefit to patients with allergic diseases by specifically targeting inflammatory pathways important for disease pathogenesis.
OBJECTIVE: To provide an overview of janus kinase (JAK), chemoattractant receptor homologous molecule expressed on TH2 cells (CRTH2), and phosphodiesterase 4 (PDE4) inhibitors in allergic disorders. DATA SOURCES: PubMed literature review. STUDY SELECTIONS: Articles included in this review discuss the emerging mechanism of action of small molecule inhibitors and their use in the treatment of atopic dermatitis (AD), asthma, and allergic rhinitis (AR). RESULTS:Allergic diseases represent a spectrum of diseases, including AD, asthma, and AR. For decades, these diseases have been primarily characterized by increased TH2 signaling and downstream inflammation. In recent years, additional research has identified disease phenotypes and subsets of patients with non-Th2 mediated inflammation. The increasing heterogeneity of disease has prompted investigators to move away from wide-ranging treatment approaches with immunosuppressive agents, such as corticosteroids, to consider more targeted immunomodulatory approaches focused on specific pathways. In the past decade, inhibitors that target JAK signaling, PDE4, and CRTH2 have been explored for their potential activity in models of allergic disease and therapeutic benefit in clinical trials. Interestingly, although JAK inhibitors provide an opportunity to interfere with cytokine signaling and could be beneficial in a broad range of allergic diseases, current clinical trials are focused on the treatment of AD. Conversely, both PDE4 and CRTH2 inhibitors have been evaluated in a spectrum of allergic diseases. This review summarizes the varying degrees of success that these small molecules have demonstrated across allergic diseases. CONCLUSION: Emerging therapies currently in development may provide more consistent benefit to patients with allergic diseases by specifically targeting inflammatory pathways important for disease pathogenesis.