PHAR 827: Th1/Th17 mediated diseases [Psoriasis] (Leo R. Fitzpatrick Ph.D.) Key Learning Objectives: 1) Understand the overall pathogenesis for the development of plaque psoriasis. 2) Recognize the roles of Th17 and Th1 cells in the development of psoriasis. 3) Learn about established and novel drug approaches for psoriasis. 4) Understand the role of IL-22 in the pathogenesis of psoriasis. Overview Psoriasis is an immune-regulated skin disease with various clinical subtypes and disease activities. This TBL class will focus on the immunological basis for Plaque Psoriasis (Psoriasis vulgaris). The exact initial trigger(s) for the onset of psoriasis remains unidentified. However, environmental factors such as trauma could play a role in disease initiation. At the onset of new lesions in previously unaffected skin, plaque-type psoriasis frequently demonstrates highly inflammatory papules sometimes with an inflammatory border (see the left panel below). The pathology of initial psoriasis differs from stable plaque-type psoriasis (see the right panel below). Early lesions demonstrate the involvement of innate immune cells, such as neutrophils and macrophages. This activation of the innate immune system is followed by the appearance of the T cell-dominated immunopathology for stable plaque-type psoriasis. Therefore, it is possible that both highly inflammatory neutrophil predominant lesions and stable T cell predominant plaques can exist in the same patient. [Christophers et al., Br. J. Dermatol., 2014]. The source of controversy in the pathogenesis of psoriasis involved the relative importance of Th1 or Th17 cells in the process. Clinical data with specific monoclonal antibodies directed against IFN-γ (Fontolizumab) and IL-17A (Secukinumab) suggests that Th17 cells (and related cytokines) are important in the pathogenesis of chronic plaque psoriasis. Th22 cells are also involved in the etiology of this disease. 1 Th1 Cells and Psoriasis Pertinent clinical data showed that mRNA expression of IFN-γ (the key Th1 cytokine) is increased in the skin of patients with psoriasis (Ps) compared to normal (NL) subjects [Lowes et al., Journal of Investigative Dermatology, 2008]. Interestingly, the levels of IFN-γ mRNA were significantly reduced after Cyclosporine treatment for 14 to 56 days. Based on such data, an interesting hypothesis was put forth to explain the pathogenesis of psoriasis [Christophers et al., 2014]. Their etiology theory is shown within this figure. During the initiation phase of psoriasis, innate inflammatory cells would predominate, together with the presence of IL-1 produced by keratinocytes. Particularly, there would be the recruitment of neutrophils (PMN’s) into the epidermis. This first phase of psoriasis pathogenesis would be followed by the appearance of CD4+ cells (IL-17 and IL-22-producing Th17 cells). Next, IFN-γ- producing Th1 cells would become increasingly important in the developing plaque-type psoriasis. Thus, clinical development of single psoriasis lesions could follow periodic waves, where auto-inflammatory bursts of neutrophils and Th17 cells initiate the disease pathogenesis, 2 which would then turn into a Th1-associated inflammation. Th1 cells would then predominate in chronic psoriasis plaques [Christophers et al., 2014]. As a whole, this type of etiology would suggest that patients with plaque psoriasis should respond to treatment with an antibody directed against IFN-γ. However, recently published clinical data does not support this hypothesis. Specifically, 20 patients with moderate-severe stable plaque psoriasis were treated with Fontolizumab (HuZAF) at doses up to 10 mg/kg (by iv infusion) [Harden et al., J Allergy Clin Immunol, 2015]. Some of this clinical data is shown here. These data suggest that fontolizumab (HuZAF) treatment did not consistently reduce disease activity (PASI scores), or provide long-lasting efficacy in most patients with plaque psoriasis. The investigators concluded that anti-IFN-γ therapy had minimal efficacy in the treatment of psoriasis. They suggested that IFN-γ is not a major pathogenic cytokine in chronic psoriasis lesions, and also proposed changing the pathogenic model of the disease [Harden et al., 2015]. Th17 Cells and Psoriasis: Both the innate and adaptive immune systems are involved in psoriasis. Psoriatic plaque shows infiltration of activated T-cells, including Th17 and Th22 cells [Lonnberg et al. Clinical, Cosmetic and Investigational Dermatology, 2014 and Ports et al., British Journal of Dermatology, 2013]. The proposed central role of Th17 cells in the pathogenesis of psoriasis is shown within the figure on page 4 [S Handa, Indian Journal of Dermatology, Venereology and Leprology, 2013]. 3 IL-22 induces keratinocyte proliferation and epidermal acanthosis (skin thickening). IL-17 amplifies the inflammatory response by inducing production of pro-inflammatory cytokines (IL-6, IL-1β) and chemokines (e.g., IL-8, CCL-20). The important role of IL-17 in the pathogenesis of psoriasis suggested that antibody approaches directed against this cytokine (or its receptor) would be effective in patients with psoriasis. Some of the results obtained with Ixekizumab (an anti-IL-17A antibody) are shown on page 5. Specifically, this antibody improved moderate to severe psoriasis in this clinical trial, as determined by reductions in the Psoriasis Area and PASI scores. Also, the Static Physician’s Global Assessment (sPGA) was improved in the Ixekizumab treatment groups [Leonardi et al., NEJM, 2012]. 4 Of note, in January of 2015, the Food and Drug Administration (FDA) announced that it had approved Secukinumab (Cosentyx®) to treat adults with moderate-to-severe plaque psoriasis. Ixekizumab and Brodalumab were also approved for this indication in 2016. The recent clinical results with these antibodies clearly confirm an important role for IL-17 in the pathogenesis of psoriasis. In this regard, a recent review paper referred to psoriasis as a prototypic Th17 disease [Eberle et al., F1000 Research, 2016]. 5 Th17 Pathway Related Drugs: Summary A summary of drugs that can modulate the Th17 pathway (see the figure on page 4) and are being investigated/used for the treatment of psoriasis is shown in this table [Eberle et al., F100 Research, 2016]. Phase 3 Trials Other Drugs for Psoriasis Some clinicians use methotrexate as a systemic therapy for patients with psoriasis. Other clinicians use cyclosporine, which induces general immunosuppression, by preventing T cell activation and cytokine expression. Both compounds are effective in psoriasis. However, their long term use is complicated by drug related toxicities. Dimethyl fumarate (DMF) and Apremilast (a PDE4 inhibitor) modulate cytokine expression in activated dendritic cells. Biologics (like Infliximab) were developed to neutralize TNF-α, a critical mediator released by inflammatory Th1 and Th17 cells, but also by other cells (e.g., macrophages). Anti-TNF antibodies have greatly aided the therapy of psoriasis, with good response rates in some patients. Tofacitinib (Xeljanz®) is a novel, small-molecule Janus kinase (JAK) inhibitor currently in development for the treatment of several inflammatory diseases including psoriasis. It is also approved in the United States for the treatment of Rheumatoid Arthritis. The proposed mechanism of action for Tofacitinib is shown on page 7 [Tanaka and Yamaoka, Mod Rheumatol, 2013]. 6 Therefore, as shown in the relevant figure, Tofacitinib could inhibit the actions of both IL-17 and IFN-γ, by blocking the production of these cytokines. In patients with moderate-to-severe chronic plaque psoriasis, twelve-week treatment with oral tofacitinib (b.i.d.) improved clinical outcomes, as well as a patient assessment of disease severity and symptoms. Interestingly, there was an early onset of drug action noted in these patients [Mamolo et al., J Eur Acad Dermatol Venereol, 2013]. In October of 2015, the FDA rejected approval of Tofacitinib for psoriasis, and requested additional safety information. While Pfizer works with the FDA to provide the needed information related to possible future approval of the drug, another approach may be the topical use of Tofacitininib in psoriasis patients. 7 A published study found that topical application of Tofacitinib (in a specific ointment formulation) demonstrated efficacy in patients with mild to moderate plaque psoriasis. As shown here, topical application of Tofacitinib reduced the plaque area, as well as a calculated severity score in patients with psoriasis [Ports et al., 2013]. Severity Score = 8 Severity Score = 3 IL-22 and Psoriasis IL-22 is a cytokine that is involved in the modulation of tissue responses during inflammation. It is produced by CD4+ T lymphocyte subsets, while the expression of its receptor is restricted to cells of non-hematopoietic origin, particularly epithelial cells. In the skin, IL-22 induces keratinocyte proliferation and epidermal hyperplasia, inhibits terminal differentiation of keratinocytes, and promotes the production of antimicrobial proteins. IL-22 was initially thought to be produced mainly by Th17 cells. However, IL-22 production can also occur in an apparently unique subset of cells (i.e., Th22 cells), which lack the ability to produce IL-17 and interferon-γ. Importantly, Th22 cells are also enriched in the lesions of psoriasis patients. An important study has reported that epidermal Th22 cells in resolved psoriatic plaques were still functional after several years of disease remission underlining a role for this T cell