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Targeting the Plasticity of Psoriasis

      Psoriasis is a common inflammatory condition found in 1–2% of the population. The greatest advances in psoriasis treatment have occurred in patients with severe psoriasis, moving from systemic small molecules including methotrexate, cyclosporine, and retinoids to targeted agents against psoriasis-associated cytokines, such as TNF-α, IL-12, IL-23, and IL-17. Although the new biologics do not have the same adverse effects as the systemic drugs, they do predispose to systemic infections (and perhaps cancer), and they are extremely expensive. The focus on biologic therapies has been accompanied by a relative neglect of small molecules, which can be used either topically or systemically. No small molecule has been able to compete significantly with topical glucocorticoids, the mainstay of treatment for mild to moderate psoriasis for more than half a century.
      • Multiple signaling pathways are involved in the pathogenesis of psoriasis. Targeting these pathways may lead to long-term remission.
      • Specificity of a drug is not necessarily an asset in treatment of a disease. Partial lack of specificity may lead to greater efficacy.
      • Partial benefit of a drug is important from a biological and treatment response perspective, because it can inform what additional signaling pathways must be targeted for long-term remission. This can help determine biomarkers for when one can discontinue biologic therapies for psoriasis.
      Genetic, epidemiologic, and clinical studies have provided a vast amount of new knowledge about psoriasis in the 21st century. We now know that psoriasis is not one disease, but many that share common phenotypes (
      • Liang Y.
      • Sarkar M.K.
      • Tsoi L.C.
      • Gudjonsson J.E.
      Psoriasis: a mixed autoimmune and autoinflammatory disease.
      ). We also know the major cytokine drivers of psoriasis, including TNF-α, IL-17, and IL-23 (
      • Guttman-Yassky E.
      • Lowes M.A.
      • Fuentes-Duculan J.
      • Zaba L.C.
      • Cardinale I.
      • Nograles K.E.
      • et al.
      Low expression of the IL-23/Th17 pathway in atopic dermatitis compared to psoriasis.
      ,
      • Nakajima K.
      • Kanda T.
      • Takaishi M.
      • Shiga T.
      • Miyoshi K.
      • Nakajima H.
      • et al.
      Distinct roles of IL-23 and IL-17 in the development of psoriasis-like lesions in a mouse model.
      ,
      • Xing X.
      • Liang Y.
      • Sarkar M.K.
      • Wolterink L.
      • Swindell W.R.
      • Voorhees J.J.
      • et al.
      IL-17 responses are the dominant inflammatory signal linking inverse, erythrodermic, and chronic plaque psoriasis.
      ). We know that both keratinocyte and lymphocyte intrinsic factors can mediate psoriasis (
      • Wrone-Smith T.
      • Nickoloff B.J.
      Dermal injection of immunocytes induces psoriasis.
      ), and that the effects of this interaction are not limited to the skin but are associated with generalized vascular inflammation, leading to an increased incidence of cardiovascular disease (
      • Langan S.M.
      • Seminara N.M.
      • Shin D.B.
      • Troxel A.B.
      • Kimmel S.E.
      • Mehta N.N.
      • et al.
      Prevalence of metabolic syndrome in patients with psoriasis: a population-based study in the United Kingdom.
      ). We know that transcriptional factors in both lymphocytes and keratinocytes mediate psoriasis (loss of AP-1, Psors4) (
      • Park C.C.
      • Kim K.J.
      • Woo S.Y.
      • Chun J.H.
      • Lee K.H.
      Comparison of the expression profile of JunB, c-Jun, and S100A8 (calgranulin A) in psoriasis vulgaris and guttate psoriasis.
      ,
      • Zenz R.
      • Eferl R.
      • Kenner L.
      • Florin L.
      • Hummerich L.
      • Mehic D.
      • et al.
      Psoriasis-like skin disease and arthritis caused by inducible epidermal deletion of Jun proteins.
      ), gain of function of NF-κB (lymphocytes and keratinocytes) (
      • Stuart P.E.
      • Nair R.P.
      • Tsoi L.C.
      • Tejasvi T.
      • Das S.
      • Kang H.M.
      • et al.
      Genome-wide Association Analysis of Psoriatic Arthritis and Cutaneous Psoriasis Reveals Differences in Their Genetic Architecture.
      ), gain of function of STAT3 and STAT5 (keratinocytes, lymphocytes) (
      • Sano S.
      • Chan K.S.
      • Carbajal S.
      • Clifford J.
      • Peavey M.
      • Kiguchi K.
      • et al.
      Stat3 links activated keratinocytes and immunocytes required for development of psoriasis in a novel transgenic mouse model.
      ), RORγT (lymphocytes) (
      • Massot B.
      • Michel M.L.
      • Diem S.
      • Ohnmacht C.
      • Latour S.
      • Dy M.
      • et al.
      TLR-induced cytokines promote effective proinflammatory natural Th17 cell responses.
      ) (Figure 1). Finally, we also know that clinical and histologic phenotypes of psoriasis are mediated by specific transcription factors and cytokines (hyperkeratosis, loss of specific AP-1 subunits, NF-κB activation), redness (nicotinamide adenine dinucleotide phosphate-oxidase driving angiopoietin-2) (
      • Hara-Chikuma M.
      • Satooka H.
      • Watanabe S.
      • Honda T.
      • Miyachi Y.
      • Watanabe T.
      • et al.
      Aquaporin-3-mediated hydrogen peroxide transport is required for NF-kappaB signalling in keratinocytes and development of psoriasis.
      ,
      • Perry B.N.
      • Govindarajan B.
      • Bhandarkar S.S.
      • Knaus U.G.
      • Valo M.
      • Sturk C.
      • et al.
      Pharmacologic blockade of angiopoietin-2 is efficacious against model hemangiomas in mice.
      ), and loss of barrier function due to impaired ceramide generation and metabolism to sphingosine 1-phosphate (
      • Arbiser J.L.
      • Nowak R.
      • Michaels K.
      • Skabytska Y.
      • Biedermann T.
      • Lewis M.J.
      • et al.
      Evidence for biochemical barrier restoration: topical solenopsin analogs improve inflammation and acanthosis in the KC-Tie2 mouse model of psoriasis.
      ).
      Figure 1
      Figure 1Known signaling abnormalities in psoriasis. Every layer of the skin is affected, with loss of AP-1 and activation of NF-κB giving rise to hyperkeratosis in the stratum corneum. NF-κB activates the calprotectin complex S100A8/A9, which can chelate zinc, which has both anti-infective and proinflammatory activity. The lower layers of the epidermis have decreased ceramide levels, due to either insufficient production of ceramides or rapid metabolism to sphingosine-1 phosphate, which promotes proliferation and inflammation. These effects of ceramide deficiency may be mediated in part by IL-22. In the basal layer of the skin, Rac activation promotes keratinocyte production of cytokines, such as IL-21, vascular endothelial growth factor, angiopoietin-2, IL-17, and TNF-α, which attract and maintain lymphocytes in the upper dermis. Th, T helper.
      Psoriasis is a moving target. Patients may have initial good responses and then have flares. Loss of response can be due to tachyphylaxis (topical steroids), poor delivery (all topical agents), antibodies against biologics, and up-regulation of compensatory signaling pathways as a response to therapy. Thus, novel treatments for psoriasis are needed.
      • Fuhriman J.M.
      • Winge M.C.G.
      • Haberstock-Debic H.
      • Funk J.O.
      • Bradshaw J.M.
      • Marinkovich M.P.
      ITK and RLK inhibitor PRN694 improves skin disease in two mouse models of psoriasis.
      tested the efficacy of systemic PRN694, a potent inhibitor of ITK and RLK tyrosine kinases, in two murine models of psoriasis, the CBA/CaJ K14 RAC1 and the topical imiquimod model. They found this small molecule to have preferential inhibitory effects on T helper type (Th) 17 lymphocytes compared with Th1 or Th2 subsets. This inhibitory effect was translated in vivo, showing efficacy, but not complete resolution, of psoriatic phenotypes. Of particular interest, they showed decreased Stat3 phosphorylation in both epidermis and dermal components. The decreased phosphorylation in the dermis likely represents inhibition of signaling in Th17 lymphocytes due to inhibition of ITK and RLK. The decreased phosphorylation in the epidermis likely represents decreased levels of cytokines expressed by Th17 cells, possibly IL-21. Finally, although the numbers of CD68-positive macrophages are not significantly affected, the number of F4/80 macrophages is significantly increased, and this subset of macrophage has been linked to increased tolerance.
      These findings have implications for the treatment of psoriasis. PRN694 most potently inhibits ITK and RLK but also has inhibitory activity against another T-cell kinase, TEC. This might make it an even better drug, because inhibiting multiple kinases makes it less likely that the disease will become more resistant by amplifying a closely related kinase. As is observed in the oncology community, resistance evolves rapidly to targeted therapies. Second, Fuhriman et al. (2017) showed efficacy of this compound in two models of psoriasis, underlining the importance of this signaling pathway in psoriasis caused by two different genotypes. Of great interest is to know what sustains the psoriatic phenotype in the presence of PRN694. This can be subdivided into the question of whether higher doses of PRN694 would cause prolonged remission or if the current dose is optimal.
      The holy grail of psoriasis treatment is long-term remission. Of all therapies for psoriasis, the most well-documented therapy causing long-term remission is the Goeckerman treatment, using coal tar and UV light (
      • Koo J.
      • Lebwohl M.
      Duration of remission of psoriasis therapies.
      ). Currently, it is unclear when and if therapies can be discontinued. We do not have biomarkers to tell us who can be taken off biologic therapy. Of interest, one of the bioactive components of coal tar is carbazole, a small molecule that inhibits Rac1/Stat3 signaling (
      • Arbiser J.L.
      • Govindarajan B.
      • Battle T.E.
      • Lynch R.
      • Frank D.A.
      • Ushio-Fukai M.
      • Perry B.N.
      • et al.
      Carbazole is a naturally occurring inhibitor of angiogenesis and inflammation isolated from antipsoriatic coal tar.
      ). It may be that inhibition of Rac1/Stat3 signaling in combination with a UV light-induced signal (i.e., induction of AP-1) may be sufficient to induce long-term remissions. In addition, Rac inhibition might account for the lack of increased rate of cutaneous carcinogenesis seen in Goeckerman treatment compared with control populations in a 25-year retrospective study (
      • Pittelkow M.R.
      • Perry H.O.
      • Muller S.A.
      • Maughan W.Z.
      • O’Brien P.C.
      Skin cancer in patients with psoriasis treated with coal tar. A 25-year follow-up study.
      ). UV radiation diminishes proliferation of keratinocytes but induces proinflammatory and carcinogenic TLR4 induction and AP-1 induction, which may be anti-inflammatory (
      • Ahmad I.
      • Simanyi E.
      • Guroji P.
      • Tamimi I.A.
      • delaRosa H.J.
      • Nagar A.
      • et al.
      Toll-like receptor-4 deficiency enhances repair of UVR-induced cutaneous DNA damage by nucleotide excision repair mechanism.
      ,
      • Smith R.L.
      • Hebert H.L.
      • Massey J.
      • Bowes J.
      • Marzo-Ortega H.
      • Ho P.
      • et al.
      Association of Toll-like receptor 4 (TLR4) with chronic plaque type psoriasis and psoriatic arthritis.
      ). TLR4 signals in part through Rac activation. Inhibition of Rac1/Stat3 signaling with drugs like PRN694 and/or carbazole may dampen proinflammatory TRL4 signaling and synergize with the anti-inflammatory and anti-neoplastic effect of UV-induced AP-1 induction (
      • Arbiser J.L.
      • Nowak R.
      • Michaels K.
      • Skabytska Y.
      • Biedermann T.
      • Lewis M.J.
      • et al.
      Evidence for biochemical barrier restoration: topical solenopsin analogs improve inflammation and acanthosis in the KC-Tie2 mouse model of psoriasis.
      ).
      In summary, a finite number of signaling pathways give rise to the disease we know as psoriasis. Failure of a particular therapy may be due in part to rapid adaptation of a patient’s psoriasis. Thus, partially effective and even clinically ineffective therapy may still cause profound signaling changes in psoriasis. The future of psoriasis treatment may involve assessing signaling pathways in psoriatic lesions with a partial or no response, showing the additional therapies that require targeting. Sequential or combination therapies may become the norm for psoriasis treatment. As a final goal, we should accept no less than long-term remission.

      Conflict of Interest

      JLA is inventor of technology U.S. Patents 9289414 (carbazole) and 9592226 (ceramide derivatives-solenopsin).

      Acknowledgments

      Supported by National Institute of Arthritis and Musculoskeletal and Skin Diseases grant number RO1AR 47901.

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      Linked Article

      • ITK and RLK Inhibitor PRN694 Improves Skin Disease in Two Mouse Models of Psoriasis
        Journal of Investigative DermatologyVol. 138Issue 4
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          The chronic and highly prevalent skin disorder psoriasis vulgaris is characterized by a hyperproliferative epidermis and aberrant immune activity. Many studies have highlighted the role of differentiated T lymphocytes in psoriasis progression. Several biologics are currently available that target proinflammatory cytokines produced by T lymphocytes, but the need for improved therapies persists. The small molecule PRN694 covalently binds ITK and RLK, two Tec kinases activated downstream of T-lymphocyte activation, both of which are up-regulated in psoriatic skin.
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