doi: 10.1111/1346-8138.13186
Journal of Dermatology 2016; 43: 4–8
EDITORIAL REVIEW
Psoriasis: Behind the scenes Masutaka FURUE,1 Takafumi KADONO2 1
Department of Dermatology, Kyushu University, Fukuoka, 2Department of Dermatology, St Marianna University School of Medicine, Kawasaki, Japan
ABSTRACT Psoriasis is a chronic inflammatory skin disease characterized by a significant deterioration in the quality of life of affected individuals. Notably, psoriasis is significantly associated with cardiovascular and metabolic syndrome and other autoimmune disorders. Recent progress in biologic therapies has revealed the fundamental role of tumor necrosis factor-a, interleukin (IL)-23 and the IL-17A axis together with aberrant overproduction of epidermal IL-36c in the pathogenesis of psoriasis. This review provides an update on the clinical, pathological and therapeutic advancements involving psoriasis.
Key words:
interleukin-17, interleukin-23, interleukin-36c, psoriasis, tumor necrosis factor-a.
Psoriasis is a chronic inflammatory skin disorder with a significant physical and psychological burden that affects approximately 2% of the general population in Europe and North America.1 Psoriasis patients comprise 4.43% of all Japanese dermatological patients.2 Men are likely to experience a higher severity of the disease than women.3 The clinical manifestation of psoriasis is divided into five types with some overlap: plaque psoriasis (also known as psoriasis vulgaris), guttate psoriasis, inverse psoriasis (also called intertriginous psoriasis), pustular psoriasis (palmoplantar pustulosis or generalized pustular psoriasis) and erythrodermic psoriasis.1,4 Recent genome-wide association studies have identified numerous risk-associated variants within 44 susceptibility loci for psoriasis, including HLAC*06:02, LCE3D, IL23R and CARD14.1,5–8 HLA-C*12:02 may be a susceptibility locus for late-onset psoriasis in the Japanese population.9 These susceptibility genes are predominantly related to the innate and adaptive immune system and skin barrier function.1,5–7 In generalized pustular psoriasis, IL36RN and CARD14 are recognized as susceptibility genes.10–12 Interestingly, HLA-C*06:02 is not associated with generalized pustular psoriasis, while IL36RN is unrelated to psoriasis.11 Psoriasis often coexists with other systemic diseases such as arthritis, diabetes mellitus, arterial hypertension, obesity, dyslipidemia, non-alcoholic fatty liver diseases and cardiovascular diseases (psoriatic march).1,13–16 An increased risk of cardiovascular mortality and stroke has been identified in psoriasis patients; however, this relationship requires further epidemiological analysis.1,13–15 The gene CDKAL1 is associated with psoriasis and comorbid diseases such as diabetes mellitus and Crohn’s disease.17 Psoriasis is also comorbid with other autoimmune diseases, including Vogt–Koyanagi–Harada disease,18,19 monoclonal gammopathy,20 immunoglobulin G4-related disease,21 myasthenia gravis22 and, most importantly, bullous pemphigoid
(especially anti-laminin-c1 pemphigoid).23–25 Hepatitis C virus infection may be associated with late-onset psoriasis.26,27 A positive association between alcohol consumption and psoriasis remains controversial.28–31 Chronic inflammation has been implicated in the comorbidity of psoriasis with cardiometabolic disorders with particular reference to elevated pro-inflammatory cytokines such as tumor necrosis factor-a (TNF-a).32 Chronic inflammation in adipose tissue accelerates obesityrelated insulin resistance, leading to the development of metabolic syndrome.32,33 Adiponectin is an anti-inflammatory adipose tissue-derived adipokine that attenuates the production of TNF-a, interleukin (IL)-6 and IL-17 in imiquimod-induced psoriasis models.33 Serum adiponectin levels are significantly decreased in psoriasis patients compared with healthy controls; furthermore, normalized levels and an improvement in dermatitis are observed after successful treatments involving anti-TNF-a agents, suggesting that adiponectin negatively regulates psoriasis progression.34,35 However, further clinical studies are necessary to conclude that there is a significant decrease in adiponectin during psoriasis pathogenesis.36 Recent therapeutic advancements in biologics appear to reveal the pivotal role of the TNF-a/IL-23/IL-17 axis in the pathogenesis of psoriasis, stressing the autoimmune nature of psoriasis (Fig. 1).37,38 An initial trigger of psoriasis is thought to be the activation of plasmacytoid dendritic cells (DC) by complexes of host DNA and the antimicrobial peptide LL-37 (cathelicidin) produced by keratinocytes.39–42 Activated plasmacytoid DC and keratinocytes produce interferon (IFN)-a and TNF-a.40,41 Plasmacytoid and inflammatory DC produce TNF-a, IL-23 and IL-12 (Fig. 1).39–42 IL-23 is composed of the IL-23p19 and IL-12p40 subunits and transmits its signal via IL-23R and IL-12Rb1. IL-12 is composed of IL-12p35 and IL-12p40 and transmits its signal via IL-12Rb1 and IL-12Rb2 (Fig. 1).37,38 IL12 promotes the differentiation of naive CD4+ T cells into
Correspondence: Masutaka Furue, M.D., Ph.D., Department of Dermatology, Kyushu University, 3-1-1 Maidashi, Higashiku, Fukuoka 812-8582, Japan. Email: [email protected] Received 12 September 2015; accepted 16 September 2015.
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© 2016 Japanese Dermatological Association
Psoriasis: Behind the scenes
Injury
Psoriasis
Clinical effects of biologics
IL-36-γ↑↑
Epidermis
Neutrophil 1 2 3 4 5
TNF-α 1 2 3
iDC
IFN-α
4 8
9 10 4 8
TNF-α 1 2 3
Th1 cells
IFN-γ
IL-12Rβ1
pDC
IL-23 p19 p40
IL-12Rβ2
1 2 3
IL-12 p35 p40
IL-23R
TNF-α
IL-12Rβ1
DNA∞LL-37
IL-22
IL-17A+F
6 5 7
6
7
IL-17A
IL-17RA
IL-17F
IL-17RC
γδ T cells ILC3 Th17 cells CD146+ cell
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PASI 75 PASI 90 19.3% Etanercept, 50 mg, 12W 43.5% 36.5% Adalimumab, 16W 63.0% 49.5% Infliximab, 10W 75.7% 47.2% Ustekinumab, 45 mg, 12W 70.1% 54.2% Secukinumab, 300 mg, 12W 77.1% 75.0% Brodalumab, 210 mg, 12W 82.5% 87.3% 68.1% Ixekizumab, 80 mg, 12W 80.6% 55.4% Briakinumab, 12W Tildrakizumab, 200 mg, 16W 74.4% 52.4% 57.1% Guselkumab, 200 mg, 16W 81.0%
Keratinocytes
Proliferation of KCs ↑↑ Differentiation of KCs ↓↓ Recruitment of neutrophils ↑↑ CXCL1,CXCL8 ↑↑
Figure 1. Simplified presentation of the tumor necrosis factor (TNF)-a/interleukin (IL)-23/IL-17 axis with IL-36c in the pathogenesis of psoriasis. After certain injuries, complexes of DNA fragments and LL-37 are released with TNF-a from the epidermis. A complex of DNA fragments and LL-37 activate plasmacytoid dendritic cells (pDC) to produce interferon (IFN)-a and TNF-a with subsequent activation of inflammatory DC (iDC) and further TNF-a production. The activated DC produce IL-12 and IL-23. The IL-12-p35-p40 binds to IL-12Rb1 and IL-12Rb2 on T-helper (Th)1 cells and induces the production of INF-c. IL-23-p19-p40 binds to IL-12Rb1 and IL-23R on cdT cells, innate lymphoid cells type 3 (ILC3), Th17 cells and CD146+ cells. These innate and adaptive immunity effector cells produce IL-17A, IL17F and IL-22, which further accelerate the production of TNF-a from keratinocytes (KC). The ligation of IL-17RA and IL-17RC by IL-17A induces the proliferation and downregulates the differentiation of KC and also accelerates the recruitment of neutrophils by releasing the CXCL1 and CXCL8 chemokines. In addition, IL-36c is specifically overexpressed in the psoriatic epidermis, which may contribute to the TNF-a production by KC. The clinical effects of various biologics are compared with the percent improvement in the 75% or 90% improvement in the Psoriasis Area and Severity Index scores (PASI75 or PASI90). The biologics that are commercially available or in phase 3 trials are listed with their respective target sites and clinical effectiveness. 62–68 IFN-c-producing T-helper (Th)1 cells. IL-23 does not directly promote Th-cell differentiation because human and murine naive T cells do not express IL-23R.37,38 However, IL-23 is likely to be critically involved in the generation and activation of IL-17-producing effector cells (Fig. 1).37,38,43–45 In human and experimental psoriasis, cdT cells (Vc9Vd2 T cells in human), innate lymphoid cells type 3 (ILC3) and Th17 cells are detected in the lesional skin and blood, and these cells readily produce IL-17A, IL-17F and IL-22.46–51 A recent study by Mehta et al. demonstrated that the primary producers of IL-17 in lesional psoriatic skin express CD146 (the melanoma cell adhesion molecule), which is a cell surface adhesion molecule of endothelial cells.52 IL-17A binds to the IL-17 receptor (IL-17R), which is composed of IL-17RA and IL-17RC (Fig. 1).53 IL-17A upregulates the proliferation and downregulates the differentiation of keratinocytes by inhibiting the expression of filaggrin and loricrin.54 IL-17A also enhances the recruitment of neutrophils and aids in the cross-talk between neutrophils and keratinocytes by upregulating the neutrophil-attractive chemokines CXCL8 and CXCL1.55 Another intriguing observation is that the epidermis of psoriasis patients expresses significantly higher levels of IL-36c (IL-1F9) compared with that of patients with atopic dermatitis, lichen planus, contact dermatitis, pityriasis lichenoides, subacute cutaneous lupus erythematosus, tinea or mycosis fungoides.56 IL-36c and IL-17A promote the expression of TNF-a by keratinocytes.53,57 Moreover, the generation
© 2016 Japanese Dermatological Association
of IL-17-producing cdT cells is abrogated in IL-36 receptordeficient mice,58 indicating that the above-mentioned TNF-a/ IL-23/IL-17 axis likely forms a vicious loop with IL-36c to fully develop the psoriasis lesion (Fig. 1).37,58 In contrast, the decisive pathogenic roles of IL-12, IFN-c and IL-22 in psoriasis remain elusive because clinical trials of the anti-IL-12 p35-p40 antibody (SMART), anti-IFN-c antibody (HuZAF) and anti-IL-22 antibody (fezakinumab) have been discontinued.37,59–61 The clinical effects of biologic therapies that target the TNF-a/IL-23/IL-17 axis are summarized in Figure 1.62–69 Conventional topical, systemic and ultraviolet therapies are effective.70–73 However, the clinical efficacy of biologics is far superior. In accordance with their striking effectiveness, biologics have been determined to provide at least a 75% or 90% improvement in the Psoriasis Area and Severity Index scores (PASI75 or PASI90) (Fig. 1).62–68 Biologics are also a reasonable treatment option for elderly patients and for those undergoing hemodialysis.74–76 Although biologic therapies have revolutionized the treatment of severe psoriasis, drug survival fell to 53% in the third year.77,78 The generation of an antidrug antibody is one of the explanations for this failure.79–82 The major drawback of biologics is the increased risk of infections. In humans, loss-of-function mutations in IL17F, IL17RA and IL17RC manifest with persistent or recurrent mucocutaneous candidiasis.37,38 Lossof-function mutations in IL12RB1 (IL-12Rb1) or IL12B (IL-12/23
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M. Furue and T. Kadono
p40) enhance susceptibility to Mycobacterium tuberculosis and rin vaccines, an effect that is also bacillus Calmette–Gue detected in patients with mutations in the IFNGR1 (IFN-c receptor).37,38 Mucocutaneous candidiasis and invasive salmonellosis may occur in patients with IL12RB1 or IL12B deficiencies, probably due to impaired IL-23-dependent IL-17A immunity.37,38 Therefore, careful monitoring is mandatory to prevent severe infection, especially with Mycobacterium, Candida or Salmonella, during the course of biologic therapy targeting the TNF-a/IL-23/IL-17 axis.37,38,83,84 The risk of herpes zoster is also increased in psoriatic patients undergoing biologic treatment.85 Various paradoxical reactions caused by biologics are also problematic and mysterious, but aberrant activation of the TNF-a/IL-23/IL-17 axis with IL-36c may indicate its pathomechanism.57,86,87 An elevated serum level of KL-6 was recently noted during treatment with a TNF-a inhibitor, irrespective of the presence of interstitial lung disease, which is probably caused by reciprocal activation of the TNFa-converting enzyme.88 Long-term follow up is warranted to elucidate the oncogenic properties of biologics.
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CONFLICT OF INTEREST:
None declared. 22
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Psoriasis: Behind the scenes
36 Zhu KJ, Shi G, Zhang C et al. Adiponectin levels in patients with psoriasis: a meta-analysis. J Dermatol 2013; 40: 438–442. 37 Teng MW, Bowman EP, McElwee JJ et al. IL-12 and IL-23 cytokines: from discovery to targeted therapies for immune-mediated inflammatory diseases. Nat Med 2015; 21: 719–729. 38 Blauvelt A, Lebwohl MG, Bissonnette R. IL-23/IL-17A dysfunction phenotypes inform possible clinical effects from anti-IL-17A therapies. J Invest Dermatol 2015; 135: 1946–1953. 39 Lande R, Gregorio J, Facchinetti V et al. Plasmacytoid dendritic cells sense self-DNA coupled with antimicrobial peptide. Nature 2007; 449: 564–569. 40 Nestle FO, Conrad C, Tun-Kyi A et al. Plasmacytoid predendritic cells initiate psoriasis through interferon-alpha production. J Exp Med 2005; 202: 135–143. €hleisen B et al. Cathelicidin antimicro41 Morizane S, Yamasaki K, Mu bial peptide LL-37 in psoriasis enables keratinocyte reactivity against TLR9 ligands. J Invest Dermatol 2012; 132: 135–143. rez-Farin ~as M, Krueger JG. Immunology of psoriasis. 42 Lowes MA, Sua Annu Rev Immunol 2014; 32: 227–255. 43 Aggarwal S, Ghilardi N, Xie MH, de Sauvage FJ, Gurney AL. Interleukin-23 promotes a distinct CD4 T cell activation state characterized by the production of interleukin-17. J Biol Chem 2003; 278: 1910–1914. 44 LeibundGut-Landmann S, Gross O, Robinson MJ et al. Syk- and CARD9-dependent coupling of innate immunity to the induction of T helper cells that produce interleukin 17. Nat Immunol 2007; 8: 630– 638. 45 McGeachy MJ, McSorley SJ. Microbial-induced Th17: superhero or supervillain? J Immunol 2012; 189: 3285–3291. 46 Laggner U, Di Meglio P, Perera GK et al. Identification of a novel proinflammatory human skin-homing Vc9Vd2 T cell subset with a potential role in psoriasis. J Immunol 2011; 187: 2783–2793. 47 Ramırez-Valle F, Gray EE, Cyster JG. Inflammation induces dermal Vc4+ cdT17 memory-like cells that travel to distant skin and accelerate secondary IL-17-driven responses. Proc Natl Acad Sci USA 2015; 112: 8046–8051. 48 O’Brien RL, Born WK. Dermal cd T cells - What have we learned? Cell Immunol 2015; 296: 62–69. 49 Ward NL, Umetsu DT. A new player on the psoriasis block: IL-17Aand IL-22-producing innate lymphoid cells. J Invest Dermatol 2014; 134: 2305–2307. 50 Teunissen MB, Yeremenko NG, Baeten DL et al. The IL-17A-producing CD8+ T-cell population in psoriatic lesional skin comprises mucosa-associated invariant T cells and conventional T cells. J Invest Dermatol 2014; 134: 2898–2907. 51 Kagami S, Rizzo HL, Lee JJ, Koguchi Y, Blauvelt A. Circulating Th17, Th22, and Th1 cells are increased in psoriasis. J Invest Dermatol 2010; 130: 1373–1383. 52 Mehta NN, Dagur PK, Rose SM et al. IL-17A production in human psoriatic blood and lesions by CD146+ T cells. J Invest Dermatol 2015; 135: 311–314. 53 Iwakura Y, Ishigame H, Saijo S, Nakae S. Functional specialization of interleukin-17 family members. Immunity 2011; 34: 149–162. 54 Ha HL, Wang H, Pisitkun P et al. IL-17 drives psoriatic inflammation via distinct, target cell-specific mechanisms. Proc Natl Acad Sci USA 2014; 111: E3422–E3431. 55 Reich K, Papp KA, Matheson RT et al. Evidence that a neutrophilkeratinocyte crosstalk is an early target of IL-17A inhibition in psoriasis. Exp Dermatol 2015; 24: 529–535. 56 D’Erme AM, Wilsmann-Theis D, Wagenpfeil J et al. IL-36c (IL-1F9) is a biomarker for psoriasis skin lesions. J Invest Dermatol 2015; 135: 1025–1032. 57 Friedrich M, Tillack C, Wollenberg A, Schauber J, Brand S. IL-36c sustains a proinflammatory self-amplifying loop with IL-17C in antiTNF-induced psoriasiform skin lesions of patients with Crohn’s disease. Inflamm Bowel Dis 2014; 20: 1891–1901. 58 Tortola L, Rosenwald E, Abel B et al. Psoriasiform dermatitis is driven by IL-36-mediated DC-keratinocyte crosstalk. J Clin Invest 2012; 122: 3965–3976.
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59 Harden JL, Johnson-Huang LM, Chamian MF et al. Humanized antiIFN-c (HuZAF) in the treatment of psoriasis. J Allergy Clin Immunol 2015; 135: 553–536. 60 Noda S, Krueger JG, Guttman-Yassky E. The translational revolution and use of biologics in patients with inflammatory skin diseases. J Allergy Clin Immunol 2015; 135: 324–336. 61 Shimauchi T, Hirakawa S, Suzuki T et al. Serum interleukin-22 and vascular endothelial growth factor serve as sensitive biomarkers but not as predictors of therapeutic response to biologics in patients with psoriasis. J Dermatol 2013; 40: 805–812. pez A, Vilarrasa E, Garcıa I. Efficacy of biologics in the 62 Puig L, Lo treatment of moderate-to-severe plaque psoriasis: a systematic review and meta-analysis of randomized controlled trials with different time points. J Eur Acad Dermatol Venereol 2014; 28: 1633– 1653. 63 Langley RG, Elewski BE, Lebwohl M et al. Secukinumab in plaque psoriasis–results of two phase 3 trials. N Engl J Med 2014; 371: 326–338. 64 Papp KA, Leonardi C, Menter A et al. Brodalumab, an anti-interleukin-17-receptor antibody for psoriasis. N Engl J Med 2012; 366: 1181–1189. 65 Griffiths CE, Reich K, Lebwohl M et al. Comparison of ixekizumab with etanercept or placebo in moderate-to-severe psoriasis (UNCOVER-2 and UNCOVER-3): results from two phase 3 randomised trials. Lancet 2015;pii: S0140-6736(15)60125-8. 66 Strober BE, Crowley JJ, Yamauchi PS, Olds M, Williams DA. Efficacy and safety results from a phase III, randomized controlled trial comparing the safety and efficacy of briakinumab with etanercept and placebo in patients with moderate to severe chronic plaque psoriasis. Br J Dermatol 2011; 165: 661–668. 67 Papp K, Thacß i D, Reich K et al. Tildrakizumab (MK-3222), an AntiIL-23p19 Monoclonal Antibody, Improves Psoriasis in a Phase 2b Randomized Placebo- Controlled Trial. Br J Dermatol 2015; doi:10.1111/bjd.13932. 68 Gordon KB, Duffin KC, Bissonnette R et al. A Phase 2 Trial of Guselkumab versus Adalimumab for Plaque Psoriasis. N Engl J Med 2015; 373(2): 136–144. 69 Ohtsuki M, Morita A, Abe M et al. Secukinumab efficacy and safety in Japanese patients with moderate-to-severe plaque psoriasis: subanalysis from ERASURE, a randomized, placebo-controlled, phase 3 study. J Dermatol 2014; 41: 1039–1046. 70 Akasaka E, Mabuchi T, Manabe Y et al. Long-term efficacy of psoriasis vulgaris treatments: analysis of treatment with topical corticosteroid and/or vitamin D3 analog, oral cyclosporin, etretinate and phototherapy over a 35-year period, 1975–2010. J Dermatol 2013; 40: 238–243. 71 Ryu HH, Choe YS, Jo S, Youn JI, Jo SJ. Remission period in psoriasis after multiple cycles of narrowband ultraviolet B phototherapy. J Dermatol 2014; 41: 622–627. 72 Ito T, Furukawa F, Iwatsuki K et al. Efficacious treatment of psoriasis with low-dose and intermittent cyclosporin microemulsion therapy. J Dermatol 2014; 41: 377–381. 73 Takahashi H, Tsuji H, Ishida-Yamamoto A, Iizuka H. Comparison of clinical effects of psoriasis treatment regimens among calcipotriol alone, narrowband ultraviolet B phototherapy alone, combination of calcipotriol and narrowband ultraviolet B phototherapy once a week, and combination of calcipotriol and narrowband ultraviolet B phototherapy more than twice a week. J Dermatol 2013; 40: 424–427. 74 Hayashi M, Umezawa Y, Fukuchi O et al. Efficacy and safety of ustekinumab treatment in elderly patients with psoriasis. J Dermatol 2014; 41: 974–980. 75 Umezawa Y, Hayashi M, Kikuchi S et al. Ustekinumab treatment in patients with psoriasis undergoing hemodialysis. J Dermatol 2015; 42: 731–744. 76 Kusakari Y, Yamasaki K, Takahashi T et al. Successful adalimumab treatment of a psoriasis vulgaris patient with hemodialysis for renal failure: A case report and a review of the previous reports on biologic treatments for psoriasis patients with hemodialysis for renal failure. J Dermatol 2015; 42: 727–730.
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doi: 10.1111/1346-8138.13186
Journal of Dermatology 2016; 43: 4–8
EDITORIAL REVIEW
Psoriasis: Behind the scenes Masutaka FURUE,1 Takafumi KADONO2 1
Department of Dermatology, Kyushu University, Fukuoka, 2Department of Dermatology, St Marianna University School of Medicine, Kawasaki, Japan
ABSTRACT Psoriasis is a chronic inflammatory skin disease characterized by a significant deterioration in the quality of life of affected individuals. Notably, psoriasis is significantly associated with cardiovascular and metabolic syndrome and other autoimmune disorders. Recent progress in biologic therapies has revealed the fundamental role of tumor necrosis factor-a, interleukin (IL)-23 and the IL-17A axis together with aberrant overproduction of epidermal IL-36c in the pathogenesis of psoriasis. This review provides an update on the clinical, pathological and therapeutic advancements involving psoriasis.
Key words:
interleukin-17, interleukin-23, interleukin-36c, psoriasis, tumor necrosis factor-a.
Psoriasis is a chronic inflammatory skin disorder with a significant physical and psychological burden that affects approximately 2% of the general population in Europe and North America.1 Psoriasis patients comprise 4.43% of all Japanese dermatological patients.2 Men are likely to experience a higher severity of the disease than women.3 The clinical manifestation of psoriasis is divided into five types with some overlap: plaque psoriasis (also known as psoriasis vulgaris), guttate psoriasis, inverse psoriasis (also called intertriginous psoriasis), pustular psoriasis (palmoplantar pustulosis or generalized pustular psoriasis) and erythrodermic psoriasis.1,4 Recent genome-wide association studies have identified numerous risk-associated variants within 44 susceptibility loci for psoriasis, including HLAC*06:02, LCE3D, IL23R and CARD14.1,5–8 HLA-C*12:02 may be a susceptibility locus for late-onset psoriasis in the Japanese population.9 These susceptibility genes are predominantly related to the innate and adaptive immune system and skin barrier function.1,5–7 In generalized pustular psoriasis, IL36RN and CARD14 are recognized as susceptibility genes.10–12 Interestingly, HLA-C*06:02 is not associated with generalized pustular psoriasis, while IL36RN is unrelated to psoriasis.11 Psoriasis often coexists with other systemic diseases such as arthritis, diabetes mellitus, arterial hypertension, obesity, dyslipidemia, non-alcoholic fatty liver diseases and cardiovascular diseases (psoriatic march).1,13–16 An increased risk of cardiovascular mortality and stroke has been identified in psoriasis patients; however, this relationship requires further epidemiological analysis.1,13–15 The gene CDKAL1 is associated with psoriasis and comorbid diseases such as diabetes mellitus and Crohn’s disease.17 Psoriasis is also comorbid with other autoimmune diseases, including Vogt–Koyanagi–Harada disease,18,19 monoclonal gammopathy,20 immunoglobulin G4-related disease,21 myasthenia gravis22 and, most importantly, bullous pemphigoid
(especially anti-laminin-c1 pemphigoid).23–25 Hepatitis C virus infection may be associated with late-onset psoriasis.26,27 A positive association between alcohol consumption and psoriasis remains controversial.28–31 Chronic inflammation has been implicated in the comorbidity of psoriasis with cardiometabolic disorders with particular reference to elevated pro-inflammatory cytokines such as tumor necrosis factor-a (TNF-a).32 Chronic inflammation in adipose tissue accelerates obesityrelated insulin resistance, leading to the development of metabolic syndrome.32,33 Adiponectin is an anti-inflammatory adipose tissue-derived adipokine that attenuates the production of TNF-a, interleukin (IL)-6 and IL-17 in imiquimod-induced psoriasis models.33 Serum adiponectin levels are significantly decreased in psoriasis patients compared with healthy controls; furthermore, normalized levels and an improvement in dermatitis are observed after successful treatments involving anti-TNF-a agents, suggesting that adiponectin negatively regulates psoriasis progression.34,35 However, further clinical studies are necessary to conclude that there is a significant decrease in adiponectin during psoriasis pathogenesis.36 Recent therapeutic advancements in biologics appear to reveal the pivotal role of the TNF-a/IL-23/IL-17 axis in the pathogenesis of psoriasis, stressing the autoimmune nature of psoriasis (Fig. 1).37,38 An initial trigger of psoriasis is thought to be the activation of plasmacytoid dendritic cells (DC) by complexes of host DNA and the antimicrobial peptide LL-37 (cathelicidin) produced by keratinocytes.39–42 Activated plasmacytoid DC and keratinocytes produce interferon (IFN)-a and TNF-a.40,41 Plasmacytoid and inflammatory DC produce TNF-a, IL-23 and IL-12 (Fig. 1).39–42 IL-23 is composed of the IL-23p19 and IL-12p40 subunits and transmits its signal via IL-23R and IL-12Rb1. IL-12 is composed of IL-12p35 and IL-12p40 and transmits its signal via IL-12Rb1 and IL-12Rb2 (Fig. 1).37,38 IL12 promotes the differentiation of naive CD4+ T cells into
Correspondence: Masutaka Furue, M.D., Ph.D., Department of Dermatology, Kyushu University, 3-1-1 Maidashi, Higashiku, Fukuoka 812-8582, Japan. Email: [email protected] Received 12 September 2015; accepted 16 September 2015.
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© 2016 Japanese Dermatological Association
Journal of Dermatology 2016; 43: 4–8
EDITORIAL REVIEW
Psoriasis: Behind the scenes Masutaka FURUE,1 Takafumi KADONO2 1
Department of Dermatology, Kyushu University, Fukuoka, 2Department of Dermatology, St Marianna University School of Medicine, Kawasaki, Japan
ABSTRACT Psoriasis is a chronic inflammatory skin disease characterized by a significant deterioration in the quality of life of affected individuals. Notably, psoriasis is significantly associated with cardiovascular and metabolic syndrome and other autoimmune disorders. Recent progress in biologic therapies has revealed the fundamental role of tumor necrosis factor-a, interleukin (IL)-23 and the IL-17A axis together with aberrant overproduction of epidermal IL-36c in the pathogenesis of psoriasis. This review provides an update on the clinical, pathological and therapeutic advancements involving psoriasis.
Key words:
interleukin-17, interleukin-23, interleukin-36c, psoriasis, tumor necrosis factor-a.
Psoriasis is a chronic inflammatory skin disorder with a significant physical and psychological burden that affects approximately 2% of the general population in Europe and North America.1 Psoriasis patients comprise 4.43% of all Japanese dermatological patients.2 Men are likely to experience a higher severity of the disease than women.3 The clinical manifestation of psoriasis is divided into five types with some overlap: plaque psoriasis (also known as psoriasis vulgaris), guttate psoriasis, inverse psoriasis (also called intertriginous psoriasis), pustular psoriasis (palmoplantar pustulosis or generalized pustular psoriasis) and erythrodermic psoriasis.1,4 Recent genome-wide association studies have identified numerous risk-associated variants within 44 susceptibility loci for psoriasis, including HLAC*06:02, LCE3D, IL23R and CARD14.1,5–8 HLA-C*12:02 may be a susceptibility locus for late-onset psoriasis in the Japanese population.9 These susceptibility genes are predominantly related to the innate and adaptive immune system and skin barrier function.1,5–7 In generalized pustular psoriasis, IL36RN and CARD14 are recognized as susceptibility genes.10–12 Interestingly, HLA-C*06:02 is not associated with generalized pustular psoriasis, while IL36RN is unrelated to psoriasis.11 Psoriasis often coexists with other systemic diseases such as arthritis, diabetes mellitus, arterial hypertension, obesity, dyslipidemia, non-alcoholic fatty liver diseases and cardiovascular diseases (psoriatic march).1,13–16 An increased risk of cardiovascular mortality and stroke has been identified in psoriasis patients; however, this relationship requires further epidemiological analysis.1,13–15 The gene CDKAL1 is associated with psoriasis and comorbid diseases such as diabetes mellitus and Crohn’s disease.17 Psoriasis is also comorbid with other autoimmune diseases, including Vogt–Koyanagi–Harada disease,18,19 monoclonal gammopathy,20 immunoglobulin G4-related disease,21 myasthenia gravis22 and, most importantly, bullous pemphigoid
(especially anti-laminin-c1 pemphigoid).23–25 Hepatitis C virus infection may be associated with late-onset psoriasis.26,27 A positive association between alcohol consumption and psoriasis remains controversial.28–31 Chronic inflammation has been implicated in the comorbidity of psoriasis with cardiometabolic disorders with particular reference to elevated pro-inflammatory cytokines such as tumor necrosis factor-a (TNF-a).32 Chronic inflammation in adipose tissue accelerates obesityrelated insulin resistance, leading to the development of metabolic syndrome.32,33 Adiponectin is an anti-inflammatory adipose tissue-derived adipokine that attenuates the production of TNF-a, interleukin (IL)-6 and IL-17 in imiquimod-induced psoriasis models.33 Serum adiponectin levels are significantly decreased in psoriasis patients compared with healthy controls; furthermore, normalized levels and an improvement in dermatitis are observed after successful treatments involving anti-TNF-a agents, suggesting that adiponectin negatively regulates psoriasis progression.34,35 However, further clinical studies are necessary to conclude that there is a significant decrease in adiponectin during psoriasis pathogenesis.36 Recent therapeutic advancements in biologics appear to reveal the pivotal role of the TNF-a/IL-23/IL-17 axis in the pathogenesis of psoriasis, stressing the autoimmune nature of psoriasis (Fig. 1).37,38 An initial trigger of psoriasis is thought to be the activation of plasmacytoid dendritic cells (DC) by complexes of host DNA and the antimicrobial peptide LL-37 (cathelicidin) produced by keratinocytes.39–42 Activated plasmacytoid DC and keratinocytes produce interferon (IFN)-a and TNF-a.40,41 Plasmacytoid and inflammatory DC produce TNF-a, IL-23 and IL-12 (Fig. 1).39–42 IL-23 is composed of the IL-23p19 and IL-12p40 subunits and transmits its signal via IL-23R and IL-12Rb1. IL-12 is composed of IL-12p35 and IL-12p40 and transmits its signal via IL-12Rb1 and IL-12Rb2 (Fig. 1).37,38 IL12 promotes the differentiation of naive CD4+ T cells into
Correspondence: Masutaka Furue, M.D., Ph.D., Department of Dermatology, Kyushu University, 3-1-1 Maidashi, Higashiku, Fukuoka 812-8582, Japan. Email: [email protected] Received 12 September 2015; accepted 16 September 2015.
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© 2016 Japanese Dermatological Association
Psoriasis: Behind the scenes
Injury
Psoriasis
Clinical effects of biologics
IL-36-γ↑↑
Epidermis
Neutrophil 1 2 3 4 5
TNF-α 1 2 3
iDC
IFN-α
4 8
9 10 4 8
TNF-α 1 2 3
Th1 cells
IFN-γ
IL-12Rβ1
pDC
IL-23 p19 p40
IL-12Rβ2
1 2 3
IL-12 p35 p40
IL-23R
TNF-α
IL-12Rβ1
DNA∞LL-37
IL-22
IL-17A+F
6 5 7
6
7
IL-17A
IL-17RA
IL-17F
IL-17RC
γδ T cells ILC3 Th17 cells CD146+ cell
8 9 10
PASI 75 PASI 90 19.3% Etanercept, 50 mg, 12W 43.5% 36.5% Adalimumab, 16W 63.0% 49.5% Infliximab, 10W 75.7% 47.2% Ustekinumab, 45 mg, 12W 70.1% 54.2% Secukinumab, 300 mg, 12W 77.1% 75.0% Brodalumab, 210 mg, 12W 82.5% 87.3% 68.1% Ixekizumab, 80 mg, 12W 80.6% 55.4% Briakinumab, 12W Tildrakizumab, 200 mg, 16W 74.4% 52.4% 57.1% Guselkumab, 200 mg, 16W 81.0%
Keratinocytes
Proliferation of KCs ↑↑ Differentiation of KCs ↓↓ Recruitment of neutrophils ↑↑ CXCL1,CXCL8 ↑↑
Figure 1. Simplified presentation of the tumor necrosis factor (TNF)-a/interleukin (IL)-23/IL-17 axis with IL-36c in the pathogenesis of psoriasis. After certain injuries, complexes of DNA fragments and LL-37 are released with TNF-a from the epidermis. A complex of DNA fragments and LL-37 activate plasmacytoid dendritic cells (pDC) to produce interferon (IFN)-a and TNF-a with subsequent activation of inflammatory DC (iDC) and further TNF-a production. The activated DC produce IL-12 and IL-23. The IL-12-p35-p40 binds to IL-12Rb1 and IL-12Rb2 on T-helper (Th)1 cells and induces the production of INF-c. IL-23-p19-p40 binds to IL-12Rb1 and IL-23R on cdT cells, innate lymphoid cells type 3 (ILC3), Th17 cells and CD146+ cells. These innate and adaptive immunity effector cells produce IL-17A, IL17F and IL-22, which further accelerate the production of TNF-a from keratinocytes (KC). The ligation of IL-17RA and IL-17RC by IL-17A induces the proliferation and downregulates the differentiation of KC and also accelerates the recruitment of neutrophils by releasing the CXCL1 and CXCL8 chemokines. In addition, IL-36c is specifically overexpressed in the psoriatic epidermis, which may contribute to the TNF-a production by KC. The clinical effects of various biologics are compared with the percent improvement in the 75% or 90% improvement in the Psoriasis Area and Severity Index scores (PASI75 or PASI90). The biologics that are commercially available or in phase 3 trials are listed with their respective target sites and clinical effectiveness. 62–68 IFN-c-producing T-helper (Th)1 cells. IL-23 does not directly promote Th-cell differentiation because human and murine naive T cells do not express IL-23R.37,38 However, IL-23 is likely to be critically involved in the generation and activation of IL-17-producing effector cells (Fig. 1).37,38,43–45 In human and experimental psoriasis, cdT cells (Vc9Vd2 T cells in human), innate lymphoid cells type 3 (ILC3) and Th17 cells are detected in the lesional skin and blood, and these cells readily produce IL-17A, IL-17F and IL-22.46–51 A recent study by Mehta et al. demonstrated that the primary producers of IL-17 in lesional psoriatic skin express CD146 (the melanoma cell adhesion molecule), which is a cell surface adhesion molecule of endothelial cells.52 IL-17A binds to the IL-17 receptor (IL-17R), which is composed of IL-17RA and IL-17RC (Fig. 1).53 IL-17A upregulates the proliferation and downregulates the differentiation of keratinocytes by inhibiting the expression of filaggrin and loricrin.54 IL-17A also enhances the recruitment of neutrophils and aids in the cross-talk between neutrophils and keratinocytes by upregulating the neutrophil-attractive chemokines CXCL8 and CXCL1.55 Another intriguing observation is that the epidermis of psoriasis patients expresses significantly higher levels of IL-36c (IL-1F9) compared with that of patients with atopic dermatitis, lichen planus, contact dermatitis, pityriasis lichenoides, subacute cutaneous lupus erythematosus, tinea or mycosis fungoides.56 IL-36c and IL-17A promote the expression of TNF-a by keratinocytes.53,57 Moreover, the generation
© 2016 Japanese Dermatological Association
of IL-17-producing cdT cells is abrogated in IL-36 receptordeficient mice,58 indicating that the above-mentioned TNF-a/ IL-23/IL-17 axis likely forms a vicious loop with IL-36c to fully develop the psoriasis lesion (Fig. 1).37,58 In contrast, the decisive pathogenic roles of IL-12, IFN-c and IL-22 in psoriasis remain elusive because clinical trials of the anti-IL-12 p35-p40 antibody (SMART), anti-IFN-c antibody (HuZAF) and anti-IL-22 antibody (fezakinumab) have been discontinued.37,59–61 The clinical effects of biologic therapies that target the TNF-a/IL-23/IL-17 axis are summarized in Figure 1.62–69 Conventional topical, systemic and ultraviolet therapies are effective.70–73 However, the clinical efficacy of biologics is far superior. In accordance with their striking effectiveness, biologics have been determined to provide at least a 75% or 90% improvement in the Psoriasis Area and Severity Index scores (PASI75 or PASI90) (Fig. 1).62–68 Biologics are also a reasonable treatment option for elderly patients and for those undergoing hemodialysis.74–76 Although biologic therapies have revolutionized the treatment of severe psoriasis, drug survival fell to 53% in the third year.77,78 The generation of an antidrug antibody is one of the explanations for this failure.79–82 The major drawback of biologics is the increased risk of infections. In humans, loss-of-function mutations in IL17F, IL17RA and IL17RC manifest with persistent or recurrent mucocutaneous candidiasis.37,38 Lossof-function mutations in IL12RB1 (IL-12Rb1) or IL12B (IL-12/23
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M. Furue and T. Kadono
p40) enhance susceptibility to Mycobacterium tuberculosis and rin vaccines, an effect that is also bacillus Calmette–Gue detected in patients with mutations in the IFNGR1 (IFN-c receptor).37,38 Mucocutaneous candidiasis and invasive salmonellosis may occur in patients with IL12RB1 or IL12B deficiencies, probably due to impaired IL-23-dependent IL-17A immunity.37,38 Therefore, careful monitoring is mandatory to prevent severe infection, especially with Mycobacterium, Candida or Salmonella, during the course of biologic therapy targeting the TNF-a/IL-23/IL-17 axis.37,38,83,84 The risk of herpes zoster is also increased in psoriatic patients undergoing biologic treatment.85 Various paradoxical reactions caused by biologics are also problematic and mysterious, but aberrant activation of the TNF-a/IL-23/IL-17 axis with IL-36c may indicate its pathomechanism.57,86,87 An elevated serum level of KL-6 was recently noted during treatment with a TNF-a inhibitor, irrespective of the presence of interstitial lung disease, which is probably caused by reciprocal activation of the TNFa-converting enzyme.88 Long-term follow up is warranted to elucidate the oncogenic properties of biologics.
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CONFLICT OF INTEREST:
None declared. 22
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36 Zhu KJ, Shi G, Zhang C et al. Adiponectin levels in patients with psoriasis: a meta-analysis. J Dermatol 2013; 40: 438–442. 37 Teng MW, Bowman EP, McElwee JJ et al. IL-12 and IL-23 cytokines: from discovery to targeted therapies for immune-mediated inflammatory diseases. Nat Med 2015; 21: 719–729. 38 Blauvelt A, Lebwohl MG, Bissonnette R. IL-23/IL-17A dysfunction phenotypes inform possible clinical effects from anti-IL-17A therapies. J Invest Dermatol 2015; 135: 1946–1953. 39 Lande R, Gregorio J, Facchinetti V et al. Plasmacytoid dendritic cells sense self-DNA coupled with antimicrobial peptide. Nature 2007; 449: 564–569. 40 Nestle FO, Conrad C, Tun-Kyi A et al. Plasmacytoid predendritic cells initiate psoriasis through interferon-alpha production. J Exp Med 2005; 202: 135–143. €hleisen B et al. Cathelicidin antimicro41 Morizane S, Yamasaki K, Mu bial peptide LL-37 in psoriasis enables keratinocyte reactivity against TLR9 ligands. J Invest Dermatol 2012; 132: 135–143. rez-Farin ~as M, Krueger JG. Immunology of psoriasis. 42 Lowes MA, Sua Annu Rev Immunol 2014; 32: 227–255. 43 Aggarwal S, Ghilardi N, Xie MH, de Sauvage FJ, Gurney AL. Interleukin-23 promotes a distinct CD4 T cell activation state characterized by the production of interleukin-17. J Biol Chem 2003; 278: 1910–1914. 44 LeibundGut-Landmann S, Gross O, Robinson MJ et al. Syk- and CARD9-dependent coupling of innate immunity to the induction of T helper cells that produce interleukin 17. Nat Immunol 2007; 8: 630– 638. 45 McGeachy MJ, McSorley SJ. Microbial-induced Th17: superhero or supervillain? J Immunol 2012; 189: 3285–3291. 46 Laggner U, Di Meglio P, Perera GK et al. Identification of a novel proinflammatory human skin-homing Vc9Vd2 T cell subset with a potential role in psoriasis. J Immunol 2011; 187: 2783–2793. 47 Ramırez-Valle F, Gray EE, Cyster JG. Inflammation induces dermal Vc4+ cdT17 memory-like cells that travel to distant skin and accelerate secondary IL-17-driven responses. Proc Natl Acad Sci USA 2015; 112: 8046–8051. 48 O’Brien RL, Born WK. Dermal cd T cells - What have we learned? Cell Immunol 2015; 296: 62–69. 49 Ward NL, Umetsu DT. A new player on the psoriasis block: IL-17Aand IL-22-producing innate lymphoid cells. J Invest Dermatol 2014; 134: 2305–2307. 50 Teunissen MB, Yeremenko NG, Baeten DL et al. The IL-17A-producing CD8+ T-cell population in psoriatic lesional skin comprises mucosa-associated invariant T cells and conventional T cells. J Invest Dermatol 2014; 134: 2898–2907. 51 Kagami S, Rizzo HL, Lee JJ, Koguchi Y, Blauvelt A. Circulating Th17, Th22, and Th1 cells are increased in psoriasis. J Invest Dermatol 2010; 130: 1373–1383. 52 Mehta NN, Dagur PK, Rose SM et al. IL-17A production in human psoriatic blood and lesions by CD146+ T cells. J Invest Dermatol 2015; 135: 311–314. 53 Iwakura Y, Ishigame H, Saijo S, Nakae S. Functional specialization of interleukin-17 family members. Immunity 2011; 34: 149–162. 54 Ha HL, Wang H, Pisitkun P et al. IL-17 drives psoriatic inflammation via distinct, target cell-specific mechanisms. Proc Natl Acad Sci USA 2014; 111: E3422–E3431. 55 Reich K, Papp KA, Matheson RT et al. Evidence that a neutrophilkeratinocyte crosstalk is an early target of IL-17A inhibition in psoriasis. Exp Dermatol 2015; 24: 529–535. 56 D’Erme AM, Wilsmann-Theis D, Wagenpfeil J et al. IL-36c (IL-1F9) is a biomarker for psoriasis skin lesions. J Invest Dermatol 2015; 135: 1025–1032. 57 Friedrich M, Tillack C, Wollenberg A, Schauber J, Brand S. IL-36c sustains a proinflammatory self-amplifying loop with IL-17C in antiTNF-induced psoriasiform skin lesions of patients with Crohn’s disease. Inflamm Bowel Dis 2014; 20: 1891–1901. 58 Tortola L, Rosenwald E, Abel B et al. Psoriasiform dermatitis is driven by IL-36-mediated DC-keratinocyte crosstalk. J Clin Invest 2012; 122: 3965–3976.
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59 Harden JL, Johnson-Huang LM, Chamian MF et al. Humanized antiIFN-c (HuZAF) in the treatment of psoriasis. J Allergy Clin Immunol 2015; 135: 553–536. 60 Noda S, Krueger JG, Guttman-Yassky E. The translational revolution and use of biologics in patients with inflammatory skin diseases. J Allergy Clin Immunol 2015; 135: 324–336. 61 Shimauchi T, Hirakawa S, Suzuki T et al. Serum interleukin-22 and vascular endothelial growth factor serve as sensitive biomarkers but not as predictors of therapeutic response to biologics in patients with psoriasis. J Dermatol 2013; 40: 805–812. pez A, Vilarrasa E, Garcıa I. Efficacy of biologics in the 62 Puig L, Lo treatment of moderate-to-severe plaque psoriasis: a systematic review and meta-analysis of randomized controlled trials with different time points. J Eur Acad Dermatol Venereol 2014; 28: 1633– 1653. 63 Langley RG, Elewski BE, Lebwohl M et al. Secukinumab in plaque psoriasis–results of two phase 3 trials. N Engl J Med 2014; 371: 326–338. 64 Papp KA, Leonardi C, Menter A et al. Brodalumab, an anti-interleukin-17-receptor antibody for psoriasis. N Engl J Med 2012; 366: 1181–1189. 65 Griffiths CE, Reich K, Lebwohl M et al. Comparison of ixekizumab with etanercept or placebo in moderate-to-severe psoriasis (UNCOVER-2 and UNCOVER-3): results from two phase 3 randomised trials. Lancet 2015;pii: S0140-6736(15)60125-8. 66 Strober BE, Crowley JJ, Yamauchi PS, Olds M, Williams DA. Efficacy and safety results from a phase III, randomized controlled trial comparing the safety and efficacy of briakinumab with etanercept and placebo in patients with moderate to severe chronic plaque psoriasis. Br J Dermatol 2011; 165: 661–668. 67 Papp K, Thacß i D, Reich K et al. Tildrakizumab (MK-3222), an AntiIL-23p19 Monoclonal Antibody, Improves Psoriasis in a Phase 2b Randomized Placebo- Controlled Trial. Br J Dermatol 2015; doi:10.1111/bjd.13932. 68 Gordon KB, Duffin KC, Bissonnette R et al. A Phase 2 Trial of Guselkumab versus Adalimumab for Plaque Psoriasis. N Engl J Med 2015; 373(2): 136–144. 69 Ohtsuki M, Morita A, Abe M et al. Secukinumab efficacy and safety in Japanese patients with moderate-to-severe plaque psoriasis: subanalysis from ERASURE, a randomized, placebo-controlled, phase 3 study. J Dermatol 2014; 41: 1039–1046. 70 Akasaka E, Mabuchi T, Manabe Y et al. Long-term efficacy of psoriasis vulgaris treatments: analysis of treatment with topical corticosteroid and/or vitamin D3 analog, oral cyclosporin, etretinate and phototherapy over a 35-year period, 1975–2010. J Dermatol 2013; 40: 238–243. 71 Ryu HH, Choe YS, Jo S, Youn JI, Jo SJ. Remission period in psoriasis after multiple cycles of narrowband ultraviolet B phototherapy. J Dermatol 2014; 41: 622–627. 72 Ito T, Furukawa F, Iwatsuki K et al. Efficacious treatment of psoriasis with low-dose and intermittent cyclosporin microemulsion therapy. J Dermatol 2014; 41: 377–381. 73 Takahashi H, Tsuji H, Ishida-Yamamoto A, Iizuka H. Comparison of clinical effects of psoriasis treatment regimens among calcipotriol alone, narrowband ultraviolet B phototherapy alone, combination of calcipotriol and narrowband ultraviolet B phototherapy once a week, and combination of calcipotriol and narrowband ultraviolet B phototherapy more than twice a week. J Dermatol 2013; 40: 424–427. 74 Hayashi M, Umezawa Y, Fukuchi O et al. Efficacy and safety of ustekinumab treatment in elderly patients with psoriasis. J Dermatol 2014; 41: 974–980. 75 Umezawa Y, Hayashi M, Kikuchi S et al. Ustekinumab treatment in patients with psoriasis undergoing hemodialysis. J Dermatol 2015; 42: 731–744. 76 Kusakari Y, Yamasaki K, Takahashi T et al. Successful adalimumab treatment of a psoriasis vulgaris patient with hemodialysis for renal failure: A case report and a review of the previous reports on biologic treatments for psoriasis patients with hemodialysis for renal failure. J Dermatol 2015; 42: 727–730.
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doi: 10.1111/1346-8138.13186
Journal of Dermatology 2016; 43: 4–8
EDITORIAL REVIEW
Psoriasis: Behind the scenes Masutaka FURUE,1 Takafumi KADONO2 1
Department of Dermatology, Kyushu University, Fukuoka, 2Department of Dermatology, St Marianna University School of Medicine, Kawasaki, Japan
ABSTRACT Psoriasis is a chronic inflammatory skin disease characterized by a significant deterioration in the quality of life of affected individuals. Notably, psoriasis is significantly associated with cardiovascular and metabolic syndrome and other autoimmune disorders. Recent progress in biologic therapies has revealed the fundamental role of tumor necrosis factor-a, interleukin (IL)-23 and the IL-17A axis together with aberrant overproduction of epidermal IL-36c in the pathogenesis of psoriasis. This review provides an update on the clinical, pathological and therapeutic advancements involving psoriasis.
Key words:
interleukin-17, interleukin-23, interleukin-36c, psoriasis, tumor necrosis factor-a.
Psoriasis is a chronic inflammatory skin disorder with a significant physical and psychological burden that affects approximately 2% of the general population in Europe and North America.1 Psoriasis patients comprise 4.43% of all Japanese dermatological patients.2 Men are likely to experience a higher severity of the disease than women.3 The clinical manifestation of psoriasis is divided into five types with some overlap: plaque psoriasis (also known as psoriasis vulgaris), guttate psoriasis, inverse psoriasis (also called intertriginous psoriasis), pustular psoriasis (palmoplantar pustulosis or generalized pustular psoriasis) and erythrodermic psoriasis.1,4 Recent genome-wide association studies have identified numerous risk-associated variants within 44 susceptibility loci for psoriasis, including HLAC*06:02, LCE3D, IL23R and CARD14.1,5–8 HLA-C*12:02 may be a susceptibility locus for late-onset psoriasis in the Japanese population.9 These susceptibility genes are predominantly related to the innate and adaptive immune system and skin barrier function.1,5–7 In generalized pustular psoriasis, IL36RN and CARD14 are recognized as susceptibility genes.10–12 Interestingly, HLA-C*06:02 is not associated with generalized pustular psoriasis, while IL36RN is unrelated to psoriasis.11 Psoriasis often coexists with other systemic diseases such as arthritis, diabetes mellitus, arterial hypertension, obesity, dyslipidemia, non-alcoholic fatty liver diseases and cardiovascular diseases (psoriatic march).1,13–16 An increased risk of cardiovascular mortality and stroke has been identified in psoriasis patients; however, this relationship requires further epidemiological analysis.1,13–15 The gene CDKAL1 is associated with psoriasis and comorbid diseases such as diabetes mellitus and Crohn’s disease.17 Psoriasis is also comorbid with other autoimmune diseases, including Vogt–Koyanagi–Harada disease,18,19 monoclonal gammopathy,20 immunoglobulin G4-related disease,21 myasthenia gravis22 and, most importantly, bullous pemphigoid
(especially anti-laminin-c1 pemphigoid).23–25 Hepatitis C virus infection may be associated with late-onset psoriasis.26,27 A positive association between alcohol consumption and psoriasis remains controversial.28–31 Chronic inflammation has been implicated in the comorbidity of psoriasis with cardiometabolic disorders with particular reference to elevated pro-inflammatory cytokines such as tumor necrosis factor-a (TNF-a).32 Chronic inflammation in adipose tissue accelerates obesityrelated insulin resistance, leading to the development of metabolic syndrome.32,33 Adiponectin is an anti-inflammatory adipose tissue-derived adipokine that attenuates the production of TNF-a, interleukin (IL)-6 and IL-17 in imiquimod-induced psoriasis models.33 Serum adiponectin levels are significantly decreased in psoriasis patients compared with healthy controls; furthermore, normalized levels and an improvement in dermatitis are observed after successful treatments involving anti-TNF-a agents, suggesting that adiponectin negatively regulates psoriasis progression.34,35 However, further clinical studies are necessary to conclude that there is a significant decrease in adiponectin during psoriasis pathogenesis.36 Recent therapeutic advancements in biologics appear to reveal the pivotal role of the TNF-a/IL-23/IL-17 axis in the pathogenesis of psoriasis, stressing the autoimmune nature of psoriasis (Fig. 1).37,38 An initial trigger of psoriasis is thought to be the activation of plasmacytoid dendritic cells (DC) by complexes of host DNA and the antimicrobial peptide LL-37 (cathelicidin) produced by keratinocytes.39–42 Activated plasmacytoid DC and keratinocytes produce interferon (IFN)-a and TNF-a.40,41 Plasmacytoid and inflammatory DC produce TNF-a, IL-23 and IL-12 (Fig. 1).39–42 IL-23 is composed of the IL-23p19 and IL-12p40 subunits and transmits its signal via IL-23R and IL-12Rb1. IL-12 is composed of IL-12p35 and IL-12p40 and transmits its signal via IL-12Rb1 and IL-12Rb2 (Fig. 1).37,38 IL12 promotes the differentiation of naive CD4+ T cells into
Correspondence: Masutaka Furue, M.D., Ph.D., Department of Dermatology, Kyushu University, 3-1-1 Maidashi, Higashiku, Fukuoka 812-8582, Japan. Email: [email protected] Received 12 September 2015; accepted 16 September 2015.
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