Curr Rheumatol Rep (2014) 16:414 DOI 10.1007/s11926-014-0414-y
PSORIATIC ARTHRITIS (O FITZGERALD AND P HELLIWELL, SECTION EDITORS)
The Interleukin-17 Pathway in Psoriasis and Psoriatic Arthritis: Disease Pathogenesis and Possibilities of Treatment Marina Frleta & Stefan Siebert & Iain B. McInnes
Published online: 26 February 2014 # Springer Science+Business Media New York 2014
Abstract Psoriasis and psoriatic arthritis (PsA) are pathophysiological enigmas among rheumatic diseases. Substantial clinical advances have been made with new therapy targeting different components of the IL-17 and IL-23 pathways. At the same time, an increase in research on the topic has provided new insights into the potential functional effects of treatments on cell types, pathways, and tissues of interest. Here we review our knowledge of all IL-17 family members, their relationships with the IL-23 pathway, and the outcomes of relevant clinical trials in which different strategies for targeting these molecules have been tested in the treatment of moderate to severe psoriasis and PsA. Keywords Psoriatic arthritis . Psoriasis . Interleukin-17 . IL-17 . Interleukin-23 . IL-23 . Biologic agents . Pathogenesis . Treatment
promising clinical trial data emerging in the last 2–3 years, particularly for cutaneous psoriasis. To mark the 20th anniversary of discovery of IL-17A, herein we review our understanding of its roles as one of the central pathophysiological cytokines in autoimmune diseases [1]. Advances in human genome sequencing and proteomics have now identified six members of the IL-17 family and led to the discovery of a new T helper cell lineage, TH17 cells, which have profoundly changed the traditional view of innate and adaptive immune systems. In the past decade, the functions of IL-17 cytokines and their receptors have been closely linked to the pathogenesis of complex inflammatory conditions, for example psoriasis and PsA, and led to several new types of successful therapy.
The IL-17 and IL-17 Receptor Family Introduction Few treatments are available for the range of psoriasis and psoriatic arthritis (PsA) diseases. Although a variety of new biological approaches in the last decade have led to progress, few highly effective options are available for treatment of chronic PsA. In this respect there has been increasing interest in the biology of the IL-17 superfamily, on the basis of This article is part of the Topical Collection on Psoriatic Arthritis M. Frleta : S. Siebert : I. B. McInnes University of Glasgow, Glasgow, UK I. B. McInnes (*) Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, Glasgow Biomedical Research Centre, Sir Graeme Davies Building, 120 University Place, Glasgow G12 8QQ, UK e-mail: [email protected]
IL-17A is a pro-inflammatory cytokine, and was the first member of the six-member interleukin family, which also contains IL-17B, IL-17C, IL-17D, IL-17E (or IL-25), and IL-17F, to be discovered. This unique group of cytokines bears no resemblance to previously known mammalian proteins, a fact which facilitated rapid discovery of all the members on the basis of the homology of their sequence. IL-17A and IL-17F share 50 % of their protein identity and, as a consequence, functional similarity [2]. Structurally, the IL17s contain five spatially conserved cysteine residues, which enable the formation of homodimers and IL-17A-F heterodimers with less affinity for their receptor. It is important to emphasise that, despite structural resemblance, the six members of the group usually have distinctly different activity during adaptive and innate immune responses. Diversity is ensured by the number of different cellular sources of these cytokines and by the variety of responsive cells expressing components of the five known IL-17 receptors (IL-17R).
414, Page 2 of 8
Of the IL-17 family members, the biology of IL-17A and IL-17F has been described in greatest detail. In the quiescent state, IL-17A (or IL-17) and IL-17F are primarily detected in hematopoietic cells of the spleen and small intestine lamina propria [3••]. During inflammation, activated T cells, and particularly CD4+ TH17 cells, are the main source of both, although expression by CD8+, NK T cells, γδ T cells, granulocytes, myeloid, and type 3 innate lymphoid cells in response to IL-23 is also significant [2, 4, 5]. Both IL-17A and IL-17F signal through the IL-17RA–IL-17RC complex, inducing expression of important chemoattractants (for example CXC chemokines CXCL8, CXCL1, and CXCL10), metalloproteinases, and proinflammatory cytokines, including IL-6. Ubiquitous tissue expression of the receptor ensures involvement of endothelium, epithelial cells, fibroblasts, keratinocytes, osteoblasts, and monocytes and/or macrophages. Finally, the principal activity of IL-17A and IL17F involves attraction of neutrophils to the site of inflammation, generating a powerful immune response against extracellular pathogens [6]. In psoriasis, IL-17A and F transcript and protein are significantly increased in lesional skin compared with non-lesional skin. IL-17RA expression is consistent under inflammatory conditions whereas that of IL-17RC is markedly reduced in lesional biopsies [7]. Other members of the IL-17 family have completely different functions. IL-17E (also known as IL-25) is produced by epithelial cells and signals through the IL-17RA–IL-17RB complex to elicit a TH2 cytokine response [8]. During inflammation, IL-17E induces expression of IL-4, IL-5, IL-9, and IL13, which potentiate antibody class switching to IgG1 and IgE, and recruitment of such effector cells as eosinophils, basophils, mast cells, and CD4+ TH2 cells, which are involved in the control of parasitic infections. More importantly, IL17E facilitation of TH2-type responses is distinct from IL-17A and F-mediated TH17 immunity [2]. IL-17C was cloned by Li et al., who demonstrated stimulatory effects on THP-1 cells (a human monocytic cell line) and production of the inflammatory cytokines TNFα and IL1β [9, 10]. IL-17C is produced predominantly by intestinal epithelial cells and keratinocytes upon Toll-like receptor (TLR) stimulation, but not by hematopoietic cells [11, 12•]. Moreover, constitutive expression of IL-17C receptor, a heterodimer of IL-17RA–IL-17RE, on skin keratinocytes and epithelial cells enables autocrine signalling and promotes release of defensins and S100 proteins, required for clearance of such infections as C. rodentium; no other TH17-related cytokine, for example IL-23 or IL-22, function in this way [13]. Despite being absent under normal conditions, IL-17C is highly upregulated in synovial tissue, lung, and skin during inflammation [7, 14]. In addition, treatment of mice with the topical TLR7–TLR8 agonist imiquimod, potentiated IL-17C release by keratinocytes and induced psoriasis-like lesions.
Curr Rheumatol Rep (2014) 16:414
Moreover, TNFα also stimulates IL-17C production in MyD88-deficient mice in a TLR-independent manner, and establishes IL-17C as an epithelial cell-derived factor which is induced by a variety of danger signals and is widely present during skin infection and inflammation [10]. The functions of the other members, IL-17B and IL-17D, are still to be fully elucidated. IL-17B expression is predominantly detected in differentiated tissue cells, for example chondrocytes, with recently reported expression in synovial fibroblasts and, possibly, neutrophils of rheumatoid arthritis (RA) patients, where it enhances TNFα-induced G-CSF and IL-6 production [15, 16]. Because it shares the IL-17RA–IL17RB receptor with IL-17E, its relationship with TH2 type responses might be worth investigating. IL-17D is the most highly conserved member of the IL-17 family, which, with its broad expression pattern, including skeletal muscle, brain, and adipose tissues, suggests it may be of biological importance [2]. IL-17D is also present at low levels in resting CD4+ T cells and CD19+ B cells, but not during activation [17]. While the functional receptor complex for IL-17D remains unknown, it is difficult to interpret the nature of its functions. Considering the significant reduction of IL-17B and IL-17D transcript levels in lesional compared with non-lesional psoriatic skin, it is more likely they have a homeostatic rather than pro-inflammatory function in this pathology [7].
Relevant Pathogenesis of Psoriasis and PsA Psoriasis is a chronic inflammatory skin disease affecting 2– 3 % of the general population. The multifactorial nature of this disorder includes genetic and environmental factors leading to disease onset, frequently initiated by infection, local injury (“Köbner” phenomenon), or by rapid withdrawal of immunosuppressants [18]. The most common clinical form is “plaque” psoriasis, also known as psoriasis vulgaris, in which typical skin lesions are covered by several layers of thick scales. Histological onset is usually apparent from papillary oedema infiltrated with dendritic cells, macrophages, and activated resident and recruited lymphocytes. Maturing lesions develop significant epidermal changes with epidermal thickening (acanthosis) and elongated epidermal rete ridges. Various other forms of skin manifestation are recognised, and, if not adequately treated, the disease leads to recurrent chronic inflammation with multiple systemic features, increased comorbidity, and substantial disability [19]. In fact, psoriasis is an independent risk factor for myocardial infarction [20] and for psychological disease with severe skin presentation, revealing the great physical and psychological burden [21]. Furthermore, approximately 30 % of patients with psoriasis in secondary care settings develop psoriatic arthritis (PsA) [22]. Clinical features of PsA typically involve dactylitis, enthesitis, arthritis (“true” synovitis), and nail changes
Curr Rheumatol Rep (2014) 16:414
combined in a variety of symptomatic patterns from asymmetrical distal intraphalangeal arthritis to axial disease and sacroiliitis. Inflammation of the spine occurs in 40 % of the patients, with nail lesions observed in 87 % of cases and, frequently, radiographically visible joint erosion within two years of disease onset [23]. The high heritability of psoriasis and PsA provoked several large genome-wide studies in search of important risk loci. Among the first identified associations was the psoriasis susceptibility 1 locus (PSORS1) mapped to the MHC class I region. The presence of the HLA-Cw*0602 allele is estimated to account for from one-third to one-half of genetic susceptibility to psoriasis [18]. The association of the Cw06 loci with skin disease is stronger than that with PsA [24, 25]. Other MHC alleles are associated with spinal involvement, for example HLA-B27, or with peripheral polyarthritis, for example HLA-B38 and HLA-B39, revealing an association of PsA with the HLA class I region stronger than with any other loci in the genome [18, 26]. Despite the statistical strength of genetic studies, the mechanism(s) underlying disease association(s) with HLA variations is/are still unknown and require(s) further investigation. Conversely, the strong genetic association of psoriasis and PsA with variants of the IL-23 receptor (IL-23R) and the IL-23p40 subunit of its ligand has been demonstrated in many recent studies and strongly supports a central pathophysiological function of the IL-23/IL-17 axis in skin, gut, lung, and joint inflammation [18, 26–28]. IL-23 comprises a specific IL-23p19 subunit and an IL23p40 subunit shared with IL-12 and encoded by the IL12B gene. IL-23 is a mucosal tissue defence factor derived from resident lymphoid or epithelial cells in barrier tissues of the gut, lung, or skin after encounter with dangerous pathogens [29•]. IL-23 acts synergistically with IL-6 and TGFβ-1 to promote rapid TH17 development and IL-17A/F release [2]. In acute skin infection with C. albicans, high IL-17A expression is detected [3••]. However, the IL-23/IL-17 axis is important in poorly controlled chronic inflammation. New insights into TH17 cell behaviour in the context of chronicity were obtained by use of a mouse model of IL-17-dependent experimental autoimmune encephalomyelitis (EAE), in which the fate of all IL-17A-producing cells was traced [3••]. Surprisingly, when IL-17A+ cells reached the site of inflammation in the spinal cord, established CD4+ TH17 cells rapidly switched from IL-17A to abundant IFNγ expression to resemble a TH1 phenotype. The only differences seen were high expression of GM-CSF and TNFα, which are indicative of their ex-TH17 origin [3••, 30•]. In these mice, IL-23 was a crucial factor driving deviation toward the ex-TH17 phenotype, initiating Tbet transcription factor expression above RORγt levels, and sustaining chronic inflammation [3••]. The extent to which this newly exposed plasticity of TH cells is involved in the pathogenesis of the classical TH1 celldependent chronic conditions in humans remains unclear.
Page 3 of 8, 414
Whatever the source, the ninefold induction of IFNγ expression accompanies higher IL-17A and F levels detected in lesional compared with nonlesional psoriatic skin [7]. Although IL-23 is best known for its contribution to TH17 maturation, it potentiates IL-17A, IL-17F, and IL-22 release by many resident immune cells, including myeloid, type 3 innate lymphoid cells (ILC3), NKT, and, most importantly, γδT cells [31•]. The unique feature of γδT cells is expression of the γδ TCR receptor in combination with other innate receptors, for example TLR1 and 2, which directly sense a variety of danger signals or readily respond to IL-23 and IL-1β as an earlyresponse, tissue-resident T cell beacon [30•, 32]. Moreover, under quiescent conditions most IL-17A-producing cells in the skin are, in fact, γδT cells, rather than of αβ T cell origin [3••]. Peculiarly, in the EAE model of chronic inflammation, IL-17A production by γδT cells remained consistently high with no signs of plasticity [3••]. If CD4+ TH17 differentiation requires IL-6 signalling, it is dispensable for IL-17A expression by γδT cells and iNKT cells [33, 34]; this may be a factor contributing to the lack of response of ankylosing spondylitis to anti-IL-6 therapy in clinical trials; note that for PsA there is an absence of such trials [35]. Similar mechanisms are suspected for chronic synovial inflammation, because the IL-23/IL-17 genetic link and profile has been detected among patients with PsA [26]. Increased synovial expression of IL-17 and IL-22, downstream from IL23, predominantly in T cells and in some innate lineages in RA and PsA patients, is believed to stimulate proliferation of synovial fibroblasts [18, 36]. Some of the clinical features of spondyloarthropathies (SpA) are indicative of distorted innate immune activity rather than classical T/B-cell-mediated autoimmune pathogenesis [37•], further implicating innate IL-17producing cells, for example γδT cells. Moreover, RORγt+ CD3+ CD4− CD8− IL-23-responsive entheseal T cells resembling a γδT cell phenotype, have recently been described, and are believed to induce entheseal inflammation preceding arthritis in the collagen type II antibody-induced arthritis (CAIA) murine model of spondyloarthropathy [38•]. Interestingly, IL-23-induced IL-17 expression was responsible for inflammatory components whereas parallel IL-22 expression activated STAT3-dependent osteoblast-mediated bone remodelling. These features (early enthesitis, arthritis, and bone formation) were fully ameliorated by addition of anti-IL-23 antibodies [38•, 39]. The authors hypothesize that elevated levels of IL-23 originating from intestinal epithelial cells could result in the same inflammatory phenotype [38•]. Indeed, increased levels of IL-23 have been detected in the plasma of patients with SpA, and IL-22 is abundant in psoriatic serum samples with increased IL-22 message in lesional skin where it mediates IL-23-induced acanthosis [40–42]. Therapeutic targeting of IL-17/IL-23 was clinically efficacious in the treatment of psoriasis and PsA, and is discussed below.
414, Page 4 of 8
Clinical Implications of IL-23/IL-17 Axis Activity Management of patients with PsA is challenging and suboptimum. The efficacy of anti-TNFα agents for treatment of moderate to severe psoriasis and active, persistent PsA has been established in numerous clinical trials. The National Institute for Health and Clinical Excellence (NICE) currently approves four agents (infliximab, etanercept, adalimumab, and golimumab), and the RAPID-PsA study demonstrated the efficacy of another TNFα inhibitor, certolizumab pegol, which has recently received FDA approval for PsA and is currently under review by the EMA. Collective efficacy of TNFα blockers is such that approximately 60–70 % of patients with moderate to severe psoriasis achieve 75 % improvement in Psoriasis Area and Severity Index (PASI) 75 score within 12 weeks of treatment [36], and between 40 and 70 % of patients with active PsA achieve an American College of Rheumatology (ACR) 20 score in the same time period. Therefore, a significant proportion of patients do not respond to TNF inhibition, and even among most of those who do respond the response is only partial. Paradoxically, TNFα agents have also been reported to induce psoriasis-like lesions in approximately 5 % of patients with active inflammatory bowel disease (IBD) or RA [43], and recent reports have identified patients with resistant PsA who experience worsening of skin psoriasis after anti-TNFα treatment [44]. The crude incidence of psoriasis in RA patients treated with antiTNFα therapy was 1.04 (95 % CI 0.67–1.54) per 1000 person years compared with 0 (upper 97.5 % CI 0.71) per 1000 person years among patients treated with traditional DMARDs. The incidence of psoriasis was significantly higher for patients receiving adalimumab (IRR 9.6, 95 % CI 1.2– 77.8) than for patients treated with etanercept (IRR 3.1, 95 % CI 0.4–25.5) or infliximab (IRR 4.6, 95 % CI 0.6–38.2) [45]. Among patients with active IBD, a greater risk was also associated with smoking and increased body mass index [43]. A putative mechanistic and causative link was later established with demonstration of the ability of TNFα to repress IFNα secretion by plasmocytoid dendritic cells (pDCs). Anti-TNFα treatment releases this inhibition, leading to increased levels of IFNα, and of IL-17, IL-22, IL-20, and IFNγ, in psoriasis-like lesions [46]. Furthermore, there are indications that the efficacy of anti-TNFα treatment is also at least partly mediated by regulation of the IL-17/IL-23 pathway, with significant decreases in IL-23 p40 subunit expression by CD11c+ myeloid cells in psoriatic lesional skin after two weeks of etanercept treatment [36]. This more intimate link between IL-23/IL-17 expression and psoriatic skin pathology is supported not only by basic research but also by the observation that non-responders to etanercept treatment have a persistent IL-17 profile [36] and that 100 % response is observed when anti-TNFα-induced psoriasislike lesions are subsequently treated with ustekinumab, a
Curr Rheumatol Rep (2014) 16:414
fully human monoclonal antibody against the p40 subunit shared by interleukin-12/23 [43]. As a result of increased pathophysiological understanding and the ongoing unmet clinical need, agents targeting the IL12/23 pathway have been developed and the first clinical trial of ustekinumab for treatment of moderate to severe plaque psoriasis was completed in 2005 [47]. This randomized placebo-controlled clinical trial was designed with several groups, enabling dose adjustment from 45 mg and 90 mg received once or four-weekly, with PASI 75 improvement at week 12 as the primary endpoint. A PASI 75 score was achieved by 52 % of the patients receiving the single low dose and 81 % of those who received four-weekly 90-mg doses, compared with 2 % of patients who received placebo (p
PSORIATIC ARTHRITIS (O FITZGERALD AND P HELLIWELL, SECTION EDITORS)
The Interleukin-17 Pathway in Psoriasis and Psoriatic Arthritis: Disease Pathogenesis and Possibilities of Treatment Marina Frleta & Stefan Siebert & Iain B. McInnes
Published online: 26 February 2014 # Springer Science+Business Media New York 2014
Abstract Psoriasis and psoriatic arthritis (PsA) are pathophysiological enigmas among rheumatic diseases. Substantial clinical advances have been made with new therapy targeting different components of the IL-17 and IL-23 pathways. At the same time, an increase in research on the topic has provided new insights into the potential functional effects of treatments on cell types, pathways, and tissues of interest. Here we review our knowledge of all IL-17 family members, their relationships with the IL-23 pathway, and the outcomes of relevant clinical trials in which different strategies for targeting these molecules have been tested in the treatment of moderate to severe psoriasis and PsA. Keywords Psoriatic arthritis . Psoriasis . Interleukin-17 . IL-17 . Interleukin-23 . IL-23 . Biologic agents . Pathogenesis . Treatment
promising clinical trial data emerging in the last 2–3 years, particularly for cutaneous psoriasis. To mark the 20th anniversary of discovery of IL-17A, herein we review our understanding of its roles as one of the central pathophysiological cytokines in autoimmune diseases [1]. Advances in human genome sequencing and proteomics have now identified six members of the IL-17 family and led to the discovery of a new T helper cell lineage, TH17 cells, which have profoundly changed the traditional view of innate and adaptive immune systems. In the past decade, the functions of IL-17 cytokines and their receptors have been closely linked to the pathogenesis of complex inflammatory conditions, for example psoriasis and PsA, and led to several new types of successful therapy.
The IL-17 and IL-17 Receptor Family Introduction Few treatments are available for the range of psoriasis and psoriatic arthritis (PsA) diseases. Although a variety of new biological approaches in the last decade have led to progress, few highly effective options are available for treatment of chronic PsA. In this respect there has been increasing interest in the biology of the IL-17 superfamily, on the basis of This article is part of the Topical Collection on Psoriatic Arthritis M. Frleta : S. Siebert : I. B. McInnes University of Glasgow, Glasgow, UK I. B. McInnes (*) Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, Glasgow Biomedical Research Centre, Sir Graeme Davies Building, 120 University Place, Glasgow G12 8QQ, UK e-mail: [email protected]
IL-17A is a pro-inflammatory cytokine, and was the first member of the six-member interleukin family, which also contains IL-17B, IL-17C, IL-17D, IL-17E (or IL-25), and IL-17F, to be discovered. This unique group of cytokines bears no resemblance to previously known mammalian proteins, a fact which facilitated rapid discovery of all the members on the basis of the homology of their sequence. IL-17A and IL-17F share 50 % of their protein identity and, as a consequence, functional similarity [2]. Structurally, the IL17s contain five spatially conserved cysteine residues, which enable the formation of homodimers and IL-17A-F heterodimers with less affinity for their receptor. It is important to emphasise that, despite structural resemblance, the six members of the group usually have distinctly different activity during adaptive and innate immune responses. Diversity is ensured by the number of different cellular sources of these cytokines and by the variety of responsive cells expressing components of the five known IL-17 receptors (IL-17R).
414, Page 2 of 8
Of the IL-17 family members, the biology of IL-17A and IL-17F has been described in greatest detail. In the quiescent state, IL-17A (or IL-17) and IL-17F are primarily detected in hematopoietic cells of the spleen and small intestine lamina propria [3••]. During inflammation, activated T cells, and particularly CD4+ TH17 cells, are the main source of both, although expression by CD8+, NK T cells, γδ T cells, granulocytes, myeloid, and type 3 innate lymphoid cells in response to IL-23 is also significant [2, 4, 5]. Both IL-17A and IL-17F signal through the IL-17RA–IL-17RC complex, inducing expression of important chemoattractants (for example CXC chemokines CXCL8, CXCL1, and CXCL10), metalloproteinases, and proinflammatory cytokines, including IL-6. Ubiquitous tissue expression of the receptor ensures involvement of endothelium, epithelial cells, fibroblasts, keratinocytes, osteoblasts, and monocytes and/or macrophages. Finally, the principal activity of IL-17A and IL17F involves attraction of neutrophils to the site of inflammation, generating a powerful immune response against extracellular pathogens [6]. In psoriasis, IL-17A and F transcript and protein are significantly increased in lesional skin compared with non-lesional skin. IL-17RA expression is consistent under inflammatory conditions whereas that of IL-17RC is markedly reduced in lesional biopsies [7]. Other members of the IL-17 family have completely different functions. IL-17E (also known as IL-25) is produced by epithelial cells and signals through the IL-17RA–IL-17RB complex to elicit a TH2 cytokine response [8]. During inflammation, IL-17E induces expression of IL-4, IL-5, IL-9, and IL13, which potentiate antibody class switching to IgG1 and IgE, and recruitment of such effector cells as eosinophils, basophils, mast cells, and CD4+ TH2 cells, which are involved in the control of parasitic infections. More importantly, IL17E facilitation of TH2-type responses is distinct from IL-17A and F-mediated TH17 immunity [2]. IL-17C was cloned by Li et al., who demonstrated stimulatory effects on THP-1 cells (a human monocytic cell line) and production of the inflammatory cytokines TNFα and IL1β [9, 10]. IL-17C is produced predominantly by intestinal epithelial cells and keratinocytes upon Toll-like receptor (TLR) stimulation, but not by hematopoietic cells [11, 12•]. Moreover, constitutive expression of IL-17C receptor, a heterodimer of IL-17RA–IL-17RE, on skin keratinocytes and epithelial cells enables autocrine signalling and promotes release of defensins and S100 proteins, required for clearance of such infections as C. rodentium; no other TH17-related cytokine, for example IL-23 or IL-22, function in this way [13]. Despite being absent under normal conditions, IL-17C is highly upregulated in synovial tissue, lung, and skin during inflammation [7, 14]. In addition, treatment of mice with the topical TLR7–TLR8 agonist imiquimod, potentiated IL-17C release by keratinocytes and induced psoriasis-like lesions.
Curr Rheumatol Rep (2014) 16:414
Moreover, TNFα also stimulates IL-17C production in MyD88-deficient mice in a TLR-independent manner, and establishes IL-17C as an epithelial cell-derived factor which is induced by a variety of danger signals and is widely present during skin infection and inflammation [10]. The functions of the other members, IL-17B and IL-17D, are still to be fully elucidated. IL-17B expression is predominantly detected in differentiated tissue cells, for example chondrocytes, with recently reported expression in synovial fibroblasts and, possibly, neutrophils of rheumatoid arthritis (RA) patients, where it enhances TNFα-induced G-CSF and IL-6 production [15, 16]. Because it shares the IL-17RA–IL17RB receptor with IL-17E, its relationship with TH2 type responses might be worth investigating. IL-17D is the most highly conserved member of the IL-17 family, which, with its broad expression pattern, including skeletal muscle, brain, and adipose tissues, suggests it may be of biological importance [2]. IL-17D is also present at low levels in resting CD4+ T cells and CD19+ B cells, but not during activation [17]. While the functional receptor complex for IL-17D remains unknown, it is difficult to interpret the nature of its functions. Considering the significant reduction of IL-17B and IL-17D transcript levels in lesional compared with non-lesional psoriatic skin, it is more likely they have a homeostatic rather than pro-inflammatory function in this pathology [7].
Relevant Pathogenesis of Psoriasis and PsA Psoriasis is a chronic inflammatory skin disease affecting 2– 3 % of the general population. The multifactorial nature of this disorder includes genetic and environmental factors leading to disease onset, frequently initiated by infection, local injury (“Köbner” phenomenon), or by rapid withdrawal of immunosuppressants [18]. The most common clinical form is “plaque” psoriasis, also known as psoriasis vulgaris, in which typical skin lesions are covered by several layers of thick scales. Histological onset is usually apparent from papillary oedema infiltrated with dendritic cells, macrophages, and activated resident and recruited lymphocytes. Maturing lesions develop significant epidermal changes with epidermal thickening (acanthosis) and elongated epidermal rete ridges. Various other forms of skin manifestation are recognised, and, if not adequately treated, the disease leads to recurrent chronic inflammation with multiple systemic features, increased comorbidity, and substantial disability [19]. In fact, psoriasis is an independent risk factor for myocardial infarction [20] and for psychological disease with severe skin presentation, revealing the great physical and psychological burden [21]. Furthermore, approximately 30 % of patients with psoriasis in secondary care settings develop psoriatic arthritis (PsA) [22]. Clinical features of PsA typically involve dactylitis, enthesitis, arthritis (“true” synovitis), and nail changes
Curr Rheumatol Rep (2014) 16:414
combined in a variety of symptomatic patterns from asymmetrical distal intraphalangeal arthritis to axial disease and sacroiliitis. Inflammation of the spine occurs in 40 % of the patients, with nail lesions observed in 87 % of cases and, frequently, radiographically visible joint erosion within two years of disease onset [23]. The high heritability of psoriasis and PsA provoked several large genome-wide studies in search of important risk loci. Among the first identified associations was the psoriasis susceptibility 1 locus (PSORS1) mapped to the MHC class I region. The presence of the HLA-Cw*0602 allele is estimated to account for from one-third to one-half of genetic susceptibility to psoriasis [18]. The association of the Cw06 loci with skin disease is stronger than that with PsA [24, 25]. Other MHC alleles are associated with spinal involvement, for example HLA-B27, or with peripheral polyarthritis, for example HLA-B38 and HLA-B39, revealing an association of PsA with the HLA class I region stronger than with any other loci in the genome [18, 26]. Despite the statistical strength of genetic studies, the mechanism(s) underlying disease association(s) with HLA variations is/are still unknown and require(s) further investigation. Conversely, the strong genetic association of psoriasis and PsA with variants of the IL-23 receptor (IL-23R) and the IL-23p40 subunit of its ligand has been demonstrated in many recent studies and strongly supports a central pathophysiological function of the IL-23/IL-17 axis in skin, gut, lung, and joint inflammation [18, 26–28]. IL-23 comprises a specific IL-23p19 subunit and an IL23p40 subunit shared with IL-12 and encoded by the IL12B gene. IL-23 is a mucosal tissue defence factor derived from resident lymphoid or epithelial cells in barrier tissues of the gut, lung, or skin after encounter with dangerous pathogens [29•]. IL-23 acts synergistically with IL-6 and TGFβ-1 to promote rapid TH17 development and IL-17A/F release [2]. In acute skin infection with C. albicans, high IL-17A expression is detected [3••]. However, the IL-23/IL-17 axis is important in poorly controlled chronic inflammation. New insights into TH17 cell behaviour in the context of chronicity were obtained by use of a mouse model of IL-17-dependent experimental autoimmune encephalomyelitis (EAE), in which the fate of all IL-17A-producing cells was traced [3••]. Surprisingly, when IL-17A+ cells reached the site of inflammation in the spinal cord, established CD4+ TH17 cells rapidly switched from IL-17A to abundant IFNγ expression to resemble a TH1 phenotype. The only differences seen were high expression of GM-CSF and TNFα, which are indicative of their ex-TH17 origin [3••, 30•]. In these mice, IL-23 was a crucial factor driving deviation toward the ex-TH17 phenotype, initiating Tbet transcription factor expression above RORγt levels, and sustaining chronic inflammation [3••]. The extent to which this newly exposed plasticity of TH cells is involved in the pathogenesis of the classical TH1 celldependent chronic conditions in humans remains unclear.
Page 3 of 8, 414
Whatever the source, the ninefold induction of IFNγ expression accompanies higher IL-17A and F levels detected in lesional compared with nonlesional psoriatic skin [7]. Although IL-23 is best known for its contribution to TH17 maturation, it potentiates IL-17A, IL-17F, and IL-22 release by many resident immune cells, including myeloid, type 3 innate lymphoid cells (ILC3), NKT, and, most importantly, γδT cells [31•]. The unique feature of γδT cells is expression of the γδ TCR receptor in combination with other innate receptors, for example TLR1 and 2, which directly sense a variety of danger signals or readily respond to IL-23 and IL-1β as an earlyresponse, tissue-resident T cell beacon [30•, 32]. Moreover, under quiescent conditions most IL-17A-producing cells in the skin are, in fact, γδT cells, rather than of αβ T cell origin [3••]. Peculiarly, in the EAE model of chronic inflammation, IL-17A production by γδT cells remained consistently high with no signs of plasticity [3••]. If CD4+ TH17 differentiation requires IL-6 signalling, it is dispensable for IL-17A expression by γδT cells and iNKT cells [33, 34]; this may be a factor contributing to the lack of response of ankylosing spondylitis to anti-IL-6 therapy in clinical trials; note that for PsA there is an absence of such trials [35]. Similar mechanisms are suspected for chronic synovial inflammation, because the IL-23/IL-17 genetic link and profile has been detected among patients with PsA [26]. Increased synovial expression of IL-17 and IL-22, downstream from IL23, predominantly in T cells and in some innate lineages in RA and PsA patients, is believed to stimulate proliferation of synovial fibroblasts [18, 36]. Some of the clinical features of spondyloarthropathies (SpA) are indicative of distorted innate immune activity rather than classical T/B-cell-mediated autoimmune pathogenesis [37•], further implicating innate IL-17producing cells, for example γδT cells. Moreover, RORγt+ CD3+ CD4− CD8− IL-23-responsive entheseal T cells resembling a γδT cell phenotype, have recently been described, and are believed to induce entheseal inflammation preceding arthritis in the collagen type II antibody-induced arthritis (CAIA) murine model of spondyloarthropathy [38•]. Interestingly, IL-23-induced IL-17 expression was responsible for inflammatory components whereas parallel IL-22 expression activated STAT3-dependent osteoblast-mediated bone remodelling. These features (early enthesitis, arthritis, and bone formation) were fully ameliorated by addition of anti-IL-23 antibodies [38•, 39]. The authors hypothesize that elevated levels of IL-23 originating from intestinal epithelial cells could result in the same inflammatory phenotype [38•]. Indeed, increased levels of IL-23 have been detected in the plasma of patients with SpA, and IL-22 is abundant in psoriatic serum samples with increased IL-22 message in lesional skin where it mediates IL-23-induced acanthosis [40–42]. Therapeutic targeting of IL-17/IL-23 was clinically efficacious in the treatment of psoriasis and PsA, and is discussed below.
414, Page 4 of 8
Clinical Implications of IL-23/IL-17 Axis Activity Management of patients with PsA is challenging and suboptimum. The efficacy of anti-TNFα agents for treatment of moderate to severe psoriasis and active, persistent PsA has been established in numerous clinical trials. The National Institute for Health and Clinical Excellence (NICE) currently approves four agents (infliximab, etanercept, adalimumab, and golimumab), and the RAPID-PsA study demonstrated the efficacy of another TNFα inhibitor, certolizumab pegol, which has recently received FDA approval for PsA and is currently under review by the EMA. Collective efficacy of TNFα blockers is such that approximately 60–70 % of patients with moderate to severe psoriasis achieve 75 % improvement in Psoriasis Area and Severity Index (PASI) 75 score within 12 weeks of treatment [36], and between 40 and 70 % of patients with active PsA achieve an American College of Rheumatology (ACR) 20 score in the same time period. Therefore, a significant proportion of patients do not respond to TNF inhibition, and even among most of those who do respond the response is only partial. Paradoxically, TNFα agents have also been reported to induce psoriasis-like lesions in approximately 5 % of patients with active inflammatory bowel disease (IBD) or RA [43], and recent reports have identified patients with resistant PsA who experience worsening of skin psoriasis after anti-TNFα treatment [44]. The crude incidence of psoriasis in RA patients treated with antiTNFα therapy was 1.04 (95 % CI 0.67–1.54) per 1000 person years compared with 0 (upper 97.5 % CI 0.71) per 1000 person years among patients treated with traditional DMARDs. The incidence of psoriasis was significantly higher for patients receiving adalimumab (IRR 9.6, 95 % CI 1.2– 77.8) than for patients treated with etanercept (IRR 3.1, 95 % CI 0.4–25.5) or infliximab (IRR 4.6, 95 % CI 0.6–38.2) [45]. Among patients with active IBD, a greater risk was also associated with smoking and increased body mass index [43]. A putative mechanistic and causative link was later established with demonstration of the ability of TNFα to repress IFNα secretion by plasmocytoid dendritic cells (pDCs). Anti-TNFα treatment releases this inhibition, leading to increased levels of IFNα, and of IL-17, IL-22, IL-20, and IFNγ, in psoriasis-like lesions [46]. Furthermore, there are indications that the efficacy of anti-TNFα treatment is also at least partly mediated by regulation of the IL-17/IL-23 pathway, with significant decreases in IL-23 p40 subunit expression by CD11c+ myeloid cells in psoriatic lesional skin after two weeks of etanercept treatment [36]. This more intimate link between IL-23/IL-17 expression and psoriatic skin pathology is supported not only by basic research but also by the observation that non-responders to etanercept treatment have a persistent IL-17 profile [36] and that 100 % response is observed when anti-TNFα-induced psoriasislike lesions are subsequently treated with ustekinumab, a
Curr Rheumatol Rep (2014) 16:414
fully human monoclonal antibody against the p40 subunit shared by interleukin-12/23 [43]. As a result of increased pathophysiological understanding and the ongoing unmet clinical need, agents targeting the IL12/23 pathway have been developed and the first clinical trial of ustekinumab for treatment of moderate to severe plaque psoriasis was completed in 2005 [47]. This randomized placebo-controlled clinical trial was designed with several groups, enabling dose adjustment from 45 mg and 90 mg received once or four-weekly, with PASI 75 improvement at week 12 as the primary endpoint. A PASI 75 score was achieved by 52 % of the patients receiving the single low dose and 81 % of those who received four-weekly 90-mg doses, compared with 2 % of patients who received placebo (p
