Autoimmunity Reviews 19 (2020) 102429 Contents lists available at ScienceDirect Autoimmunity Reviews journal homepage: www.elsevier.com/locate/autrev Review Critical role of interleukin (IL)-17 in inflammatory and immune disorders: T An updated review of the evidence focusing in controversies José María G. Ruiz de Moralesa, , Lluís Puigb,c, Esteban Daudénd, Juan D. Cañetee, ⁎ José Luis Pablosf, Antonio Olveira Martíng, Carlos González Juanateyh, Alfredo Adáni,j, Xavier Montalbánk,l, Natalia Borruelm, Guillermo Ortín, Esther Holgado-Martíno, Carolina García-Vidalp, Cynthia Vizcaya-Moralesq, Víctor Martín-Vázquezr, Miguel Ángel González-Gays,t a Inmunology Unit, Complejo Asistencial Universitario e Instituto de Biomedicina Universidad de León (IBIOMED), León, Spain b Department of Dermatology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain c Universitat Autònoma de Barcelona Medical School, Spain d Dermatology Department, Instituto de Investigación Sanitaria La Princesa (IIS-IP), Hospital Universitario de la Princesa, Madrid, Spain e Arthritis Unit, Rheumatology Dpt.,Hospital Clinic and IDIBAPS, Barcelona, Spain f Rheumatology Department, Hospital 12 de Octubre, Instituto de Investigación Hospital 12 de Octubre, Madrid, Spain g Gastroenterology Department, La Paz Universitary Hospital, Madrid, Spain h Cardiology Department, Hospital Universitario Lucus Augusti, c/Ulises Romero n°1. 27003, Lugo, Spain i Hospital Clinic, Institut Clínic d´Oftalmología (ICOF), Barcelona, Spain j University of Barcelona, Barcelona, Spain k Department of Neurology-Neuroimmunology, Centre d'Esclerosi Múltiple de Catalunya, (Cemcat), Vall d'Hebron Institut de Recerca, Hospital Universitari Vall d'Hebron, Barcelona, Spain l Division of Neurology, St. Michael's Hospital, University of Toronto, Toronto, Canada m Crohn's and colitis Attention Unit, Digestive System Research Unit, Hospital Vall d'Hebron, Barcelona, Spain n Hematology Department, Hospital Universitario Vall d'Hebron, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain o Oncología Médica, IOB, Complejo Ruber Juan Bravo, Ruber Internacional, Madrid, Spain p Infectious Diseases Department, Hospital Clinic-IDIBAPS, Universitat de Barcelona, Barcelona, Spain q Novartis Pharma, Basel, Switzerland r Novartis pharmaceuticals Spain, Barcelona, Spain s Rheumatology División, IDIVAL, Hospital Universitario Marqués de Valdecilla, Santander, Spain t University of Cantabria, Santander, Spain ARTICLE INFO ABSTRACT Keywords: Interleukin 17 (IL-17) is a proinflammatory cytokine that has been the focus of intensive research because of its IL17A crucial role in the pathogenesis of different diseases across many medical specialties. In this context, the present Psoriasis review in which a panel of 13 experts in immunology, dermatology, rheumatology, neurology, hematology, Inflammation infectious diseases, hepatology, cardiology, ophthalmology and oncology have been involved, puts in common Citoquine the mechanisms through which IL-17 is considered a molecular target for the development of novel biological Immunology Biological drugs therapies in these different fields. A comprehensive review of the literature and analysis of the most outstanding evidence have provided the basis for discussing the most relevant data related to IL-17A blocking agents for the treatment of different disorders, such as psoriasis, psoriatic arthritis, rheumatoid arthritis, ankylosing spondy- litis, cardiovascular disorders, non alcoholic fatty liver disease, multiple sclerosis, inflammatory bowel disease, uveitis, hematological and solid cancer. Current controversies are presented giving an opening line for future research. ⁎ Corresponding author at: Complejo Hospitalario Universitario de León, Altos de Nava S/N, 24080 León, Spain. E-mail address: jmgarciar@saludcastillayleon.es (J.M.G. Ruiz de Morales). https://doi.org/10.1016/j.autrev.2019.102429 Received 10 July 2019; Accepted 14 July 2019 Available online 15 November 2019 1568-9972/ © 2019 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/BY/4.0/). J.M.G. Ruiz de Morales, et al. Autoimmunity Reviews 19 (2020) 102429 1. Introduction tissue-resident innate cells such as NK, NKT, Tγδ, and ILC3 lympho- cytes, which are rapidly activated after injury or infection to secrete IL- The IL-17 family of cytokines consists of 6 proteins (IL-17A to IL- 17 in an HLA-independent fashion. In fact, from an evolutionary per- 17F) and 5 receptors (IL-17RA to IL-17RE) which are structurally un- spective, IL-17 is an ancient cytokine already identified in lampreys related to any other known cytokine receptor (Fig. 1) [1]. IL-17A and with little evolutionary variation over 360 million years and therefore IL-17F are produced by several types of immune cells, while IL-17B, IL- lacking an adaptive immune system [7]. Production of IL-17A by 17C and IL-17D are mostly produced by epithelial cells. IL-17 receptors myeloid cells (neutrophils, mastocytes) is controversial due to its cap- are widely distributed across common cell types at different tissues. ability for extracellular environmental IL-17A endocytosis [8]. Whether Depending on the nature of the responder cell, the ligation of IL-17R IL-17 production by the different types of innate immune cells is strictly initiates signaling pathways leading to activation of the transcription IL-23-dependent is a matter of intensive debate [9–11]. In this sense, it factors NFκB, IκBζ, AP1 and C-EBP, which induce transcription of has been shown that in persistent psoriatic manifestations and psoriatic several genes in a tissue-specific fashion [3]. Among the most relevant, arthritis, innate immune cells can be a non-IL-23 dependent source of inflammatory cytokines (TNF, IL-6, IL1β, G-CSF, GM-CSF), chemokines IL-17A, which can contribute to the pathogenesis of these diseases [12]. (IL8, CXCL1, CXCL2, CXCL5, CCL2, CCL7, CCL20), matrix metallopro- In the same way that monogenic defects in the IL-17 pathway – as teinases (MMP1, MMP3, MMP9, MMP12, and MMP13), and also dif- observed in Hyper-IgE syndrome, chronic muco-cutaneous candidiasis ferent proteins to preserve epithelial barrier function such as bacter- and APECED syndrome – are associated with increased susceptibility to icidal peptides (cathelicidins, α and β defensins), claudins and mucines infections mainly by Candida sp. and Staphylococcus aureus [13], un- [4] (Table 1). restrained IL-17 production has been demonstrated to be involved in Despite its proinflammatory effect, IL-17A and IL-17F alone are not the pathogenesis of several chronic inflammatory disorders, as well as powerful inflammatory cytokines. In fact, its potent inflammatory ac- organ-specific autoimmune diseases. Notwithstanding basic intensive tion is mostly related with its capability to recruit immune cells, and research, several gaps in the knowledge of the pathogenic role of IL-17 with its synergistic actions with other proinflammatory cytokines such cytokines exist. Among them, two important uncertainties have already as TNF, IL-1β, IFNγ, GM-CSF, IL-22 [5]. By recruiting and activating emerged. First at all, the relevance of distinctive IL-17-producing cells neutrophils, and at lesser extent monocytes, IL-17A and IL-17F cyto- and how they are locally activated in different pathologies is just be- kines are central players in the physiological immune response against ginning to be explored. For instance, ILC3 seems to be the key IL 17- extracellular bacteria and fungi. Its protective function is mostly re- producing cell at the enthesis in SpA [14], while tissue-resident levant at mucosal surfaces and skin where, upon appropriate stimuli, IL- memory CD8 T constitute the majority of intradermal T cells in psor- 17 cytokines are immediately released and contribute to epithelial iatic plaques [15]. Secondly, the role of Th17 cells in human diseases is homeostasis, to inflammatory acute responses and B cell stimulation difficult to establish because they do not display a terminal differ- [6], thus acting as a bridge between innate and acquired immune re- entiation phenotype, but characteristically exhibit instability, plasticity, sponses. and functional heterogeneity, including pathogenic and non-pathogenic IL-17A is the hallmark of the Th17 subset of CD4 lymphocytes, phenotypes. The distinctive features of the various Th CD4 effector/ which also produce IL-17F, IL-22 and IL-21. Th17 differentiation is regulatory subpopulations are determined largely by the set of lineage- dependent on the presence of proinflammatory IL-6 and IL-1β, but specific transcription factors they express and the cytokine genes they surprisingly also TGFβ, an anti-inflammatory cytokine produced by transcribe. The induction of the distinctive patterns of gene expression several non-immune cells. Th17 differentiation requires simultaneous is dependent on the local cytokine milieu during the antigen-presenting activation of the transcription factors STAT3 (IL-6 dependent) and cell mediated activation of a naïve T cell (Th0) (Fig. 2). Moreover, ti- ROR-c (TGFβ-dependent). After differentiation, Th17 express IL-23-R sular factors such as dysbiosis, pH modifications or dietary intakes, by and require IL-23 for proliferation and survival. However, it is now exerting epigenetic changes, can further promote transitory changes in recognized that IL-17 is also produced by CD8 lymphocytes and by Th differentiation programs [16]. Thus, Th17 cells expressing their Fig. 1. IL-17 Cytokine and receptor families [2].Note added in proof: it has recently been identified that IL17RB also uses ILRA chain for signal transduction of type 2 cytokines[184]. 2 J.M.G. Ruiz de Morales, et al. Autoimmunity Reviews 19 (2020) 102429 Table 1 2. Dermatology IL-17 functions in homeostatic conditions. Molecule Actions 2.1. Psoriasis IL-17 A − Stimulate the production of neutrophils The central role of IL-23/Th17 axis in the pathogenesis of psoriasis IL-17 F − Potent chemotactic effect on neutrophils (and monocytes) has been the focus of extensive research. Selective antagonists to IL-23, − Production of mucus − Production of antimicrobial peptides IL-17, IL-22, IFNγ, and IFNα have been examined as therapeutic targets. − Epithelial integrity with secretion of claudins Although several isoforms of IL-17 have been identified, IL-17A is the − Production of inflammatory chemokines/cytokines best characterized from a functional and pathogenic perspective. Blockade of IL-17A (ixekizumab and secukinumab), the IL-17 receptor A subunit (brodalumab) or IL-23p19 (guselkumab, risankizumab, til- signature transcription factor ROR-c and secreting IL-17A can si- drakizumab, mirikizumab) can reverse clinical, histologic, and mole- multaneously co-express Tbet and secrete also IFN-γ (dual Th lym- cular features of psoriasis. In contrast, IL-22 and IFN-γ have a smaller phocytes) (Fig. 2). Moreover the pro-inflammatory ROR-c Th17 cell pathogenic role, given that single antagonism of these cytokines with producing IL17 can simultaneously transcribe Fox-P3 and thus achieve neutralizing antibodies has not been associated with marked clinical the capability to co-produce IL10, an anti-inflammatory cytokine (15). improvement, highlighting the predominant pathogenic role of the IL- In healthy individuals, the majority of Th17 cells are nonpathogenic 23/IL-17 axis in patients with psoriasis [31]. and found at mucosal sites where they promote tissue repair and con- Blocking IL-17A with targeted treatments might be more far- tribute maintain barrier functions. It would therefore make sense that reaching than previously thought, and evidence is accumulating that the default Th17 differentiation program would favor a nonpathogenic cells of the innate immune system, like neutrophils, mast cells, γδ T phenotype that could be converted into a pathogenic phenotype in cells and innate lymphoid cells (ILC3) might also be an important presence of additional proinflammatory signals, such as IL-1β or IL-23 source of IL-17A in psoriasis [32]. Relevant finding is the presence of [17]. cells other than T lymphocytes (most likely innate immune cells) ex- Targeted manipulation of the immune system in animal models has pressing IL-17A independently from IL-23 in psoriatic plaques re- led to insights into disease pathogenesis, but is contribution to for- fractory to ustekinumab therapy [33]. mulate clinical and therapeutic concepts in humans has been much However, activated monocytes and T lymphocytes have been sug- more limited [18]. Thus, in experimental animal models of chronic gested to be the dominant source of IL-17A rather than neutrophils inflammatory diseases such as posterior uveitis, psoriasis, inflammatory [34]. Moreover, it has also been demonstrated that clinically resolved bowel disease, multiple sclerosis, collagen-induced arthritis and anky- psoriatic plaques contain psoriasis-specific IL17-producing long-lasting losing spondylitis, IL-17A appeared to be a crucial pathogenic molecule. resident memory T CD4 and T CD8 clones [35]. However, results of clinical trials with anti-IL-17 antibodies in Crohn Recent studies have provided interesting clinical data on drugs disease, RA and refractory posterior uveitis have been discouraging or targeting the IL-17-Th17 pathway. In a head-to-head, double-blind only partially effective in spite of strong evidence for a dominant pa- study, secukinumab demonstrated sustained superior efficacy than us- thogenic role of IL-17A in Crohn [19,20], RA [21] and posterior uveitis tekinumab in clearing skin of subjects with moderate-to-severe plaque [22,23] (Table 2). On the other hand, IL23/IL17 blockade is highly psoriasis through week 52, with greater reductions in psoriasis-related effective in Psoriasis, Ankylosing Spondylitis and Psoriatic arthritis, and pain, itching, and scaling, and greater improvement across all quality- therefore a few monoclonal antibodies selectively acting at different of-life measures evaluated, with a favorable safety profile [36]. Also, points of the IL23/IL17 axis are currently approved and marketed treatment with secukinumab 300 mg at a fixed-interval schedule (every (Fig. 3). 4 weeks) has demonstrated sustained efficacy in achieving ≥ 90% Fig. 2. Th differentiation patterns. After antigen processing, dendritic cells are activated and start secreting specific cytokines and present antigen peptides in a HLA-dependent fashion to Th0 naïve cells. According to the factors present at the im- munological synapse, Th0 initiate a program of lineage-specific transcription factor (TF) expression which allows for transcription of genes characteristic of each Th differentiation pathway: Tbet=Th1; Gata- 3=Th2; ROR-γT (ROR-c) = Th17; Fox-P3= Treg. However, depending on the local tisular and cyto- kine milieu, simultaneous transcription of more than a TF is possible, allowing for more than one lineage- specific cytokine production (“Dual“ Th cells). This possibility may render a Th17 cell pathogenic or not pathogenic. 3 J.M.G. Ruiz de Morales, et al. Autoimmunity Reviews 19 (2020) 102429 improvement in Psoriasis Area and Severity Index (PASI 90) and in Not approved (phase 3 ongoing) Not approved (phase 3 ongoing) Not approved (phase 3 ongoing) Not approved (phase 3 ongoing) overall and subscale scores on all quality-of-life instruments, which has been maintained through 5 years with no new safety concerns [37]. IL-17A-F (Bimekizumaba) Furthermore, three phase III trials have shown that ixekizumab, a Not approved (phase 2 monoclonal antibody against interleukin-17A, was superior to placebo and etanercept in the treatment of moderate-to-severe psoriasis through 60 weeks of treatment [38]. completed) Not tested Not tested Not tested Not tested Data from three prospective phase III studies of secukinumab with a follow-up of 2.5 years demonstrated long-lasting efficacy and safety in the complete spectrum of psoriasis manifestations, including palmo- plantar, nail, and scalp manifestations [39]. In moderate-to-severe genital psoriasis with ≥ 1% body surface area involved, ixekizumab Not approved (phase 3 Not approved (phase 2 Not approved (phase 2 Not approved (phase 2 Not approved (phase 2 IL-17RA (Brodalumab) has been shown to be superior to placebo at week 12 [40]. Aiming to understand the potential of IL-17 inhibitor secukinumab for disease modification and based on the fact that a portion of patients withdrawn) withdrawn) withdrawn) withdrawn) completed) did not relapse for at least 1 or 2 years post-discontinuation of secuki- Not tested Not tested Not tested Approved numab therapy [41], the ongoing STEPin study investigates whether early intervention with secukinumab versus narrow-band ultraviolet B (nb-UVB) phototherapy in subjects with new-onset psoriasis can modify the long-term natural course of the disease and thus become a novel Not approved (phase 3 ongoing) (phase 2 endpoint (phase 2 endpoint treatment strategy for patients with psoriasis [42]. To test the concept of a very early intervention in PsA, recent ex- (phase 3 (phase 2 IL-17A (Secukinumab, ploratory study has shown that in psoriatic patients with arthralgia and inflammatory changes in the joints very early treatment with secuki- numab led to resolution of inflammation and no progression of joint Not approved Not approved Not approved Not approved Ixekizumab) completed) completed) bone changes after 24 weeks [43]. However, additional research is Approvedc Not tested Approved Approved not met) not met) needed to further understand this approach. 2.2. Other diseases Not approved (phase 2 endpoint not met for IL-17A has also been linked to the pathogenesis of atopic dermatitis Not approved (phase 2 endpoint not met) IL-23 (p19) (Guselkumab, Tildrakizumab, (AD). In experimental AD models, IL-17A was shown to be an inducer of Th2-mediated immune response [44,45] and to contribute to the da- Not approved (phase 3 ongoing) Not approved (phase 3 ongoing) Not approved (phase 3 ongoing) mage of skin barrier proteins, with reduced expression of filaggrin and Risankizumab, Mirikizumaba) claudin 1 in lesional atopic skin; filaggrin expression and disease se- verity have been found to be inversely correlated [46]. Moreover, ele- vation of skin and serum levels of IL-17A in AD emphasizes the systemic inflammatory profile of this dermatosis. Although IL-17A may mediate risankizumab) AD-related immune dysregulation by amplifying the inflammatory re- Approvedb Not tested Not tested Not tested sponse [47], the proposal of IL-17A as an attractive target for AD is still unclear. AD is now considered to be heterogeneous, with additional activation of Th22, Th17/IL-23, and Th1 cytokine pathways depending on the subtype of the disease, and the immune activation seems to Not approved (phase 3 endpoint not met) Not approved (phase 2 endpoint not met) Not approved (phase 2 endpoint not met) Not approved (phase 2 endpoint not met extend beyond lesional AD, since non-lesional skin and the blood IL-12 + IL-23 (p40) (Ustekinumab) component harbor AD-specific inflammatory changes. Future therapies should probably focus on a systemic treatment approach, especially in patients with moderate-to-severe disease [48]. Mirikizumab is not currently approved for this indication. The precise pathogenesis of alopecia areata remains unknown. Clinical efficacy of IL-12/IL-23 pathway modulators [24–26]. Ixekizumab is not currently approved for this indication. However, this disease seems to be triggered by helper T cell infiltration for risankizumab) in hair follicles. Infiltration of CD4(+)IL-17A(+) Th17 cells in the dermis, particularly around hair follicles was found in patients with Not tested Not tested Approved Approved Approved alopecia areata, including single patch alopecia areata, multiple patch alopecia areata, alopecia totalis and alopecia universalis [49]. These findings suggest that alopecia areata is induced by a Th17-associated autoimmune mechanism. A quantitative analysis of IL-17-producing cells in different lesional skin of several forms of alopecia areata showed that the ratio of IL-17-producing cells in acute, diffuse and total alopecia was significantly lower than in patchy alopecia areata. Re- garding IL-12, IL-17, and IL-23 receptor gene polymorphisms, IL-12 and Uveitis (non-infectious) Non-radiographic Axial IL-23R polymorphisms did not show a significant association with Ankylosing spondylitis Spondyloarthritis Rheumatoid arthritis alopecia areata, but the IL-17 GG genotype was associated with sus- Multiple sclerosis Psoriatic arthritis ceptibility to the disease, even though this phenotype was present in a Crohn’s disease small number of patients [50]. Th17 cell counts have been found to be Phase 3. significantly higher than those of Treg in patients with alopecia areata Psoriasis Diseases Asthma Table 2 (45). Furthermore, Th17 cell counts in patients with disease of short b a duration or in active phase were significantly higher than their c 4 J.M.G. Ruiz de Morales, et al. Autoimmunity Reviews 19 (2020) 102429 Fig. 3. Different targets and antagonists of the IL-23/IL-17 pathway already approved [27–30]. respective counterparts, both in lesional skin and in peripheral blood 2.3. Controversies mononuclear cells. In another study, the expression of IL-17, IL-22, Foxp3 and B cell activating factor (BAFF), a regulator of T cell activa- In addition to the previously described diseases, it has been recently tion, was evaluated in tissue and sera of patients with alopecia areata suggested a role for IL-17 in the pathophysiology of a large number of [51].Tissue and serum levels of IL-17, and tissue levels of IL-22 and dermatological inflammatory dermatoses, such as lichen planus, pyo- BAFF were significantly higher in patients with alopecia areata than in derma gangrenosum, pemphigus vulgaris, pemphigoid, or dermatitis controls. A significant positive correlation was found between both herpetiformis. The potential activity of IL17A inhibitors in the control tissue levels of IL-17 and BAFF, and tissue levels of IL-22 and disease of these diseases, as well as their long-term efficacy and safety, and duration. These data draw attention to the possible synergistic in- their potential for psoriatic disease modification, is a challenge for the volvement of Th17 cells and BAFF in the pathogenesis of alopecia scientific community. areata. In tissue samples of hidradenitis suppurativa, IL-12 and IL-23 were found to be abundantly expressed by macrophages infiltrating papillary 3. Rheumatology and reticular dermis of lesional skin. In addition, IL-17-producing T helper cells were found to distinctly infiltrate the lesional dermis, The IL-23/IL-17/IL-22 cytokine axis has been shown to be involved suggesting the involvement of the IL-23/Th17 pathway [52]. In a study in the pathogenesis of chronic arthritis (Fig. 4) and structural damage of 86 patients with hidradenitis suppurativa and 86 matched healthy including bone erosion, and new bone formation in experimental volunteers aimed to determine serum levels of IL-17 in both groups, the models of spondyloarthritis (SpA) [54,55]. mean serum levels in patients were significantly higher than in healthy In animal models of inflammatory arthritis (collagen-induced ar- volunteers [53]. Also, a tendency toward higher serum IL-17 con- thritis), IL-17A gene transfer induced the expansion of IL- centrations in patients with more advanced disease was observed [53]. 17RA(+)CD11b(+)Gr1(low) osteoclast precursors and a concomitant According to current data, anti-IL-17 agents seem promising agents elevation of biomarkers indicative of bone resorption. This occurred at to treat hidradenitis suppurativa. An ongoing pilot study evaluates the a time preceding noticeable joint inflammation, suggesting that IL-17A safety and feasibility of secukinumab for patients with moderate-to- is critical for the induction of pathological bone resorption through severe hidradenitis suppurativa, as well as informs on the effect size direct activation of osteoclast precursors [56]. In validated animal that will be useful for future larger randomized control trial with an models of SpA, blockade of IL-17A, but not of TNF-α, reduced clinical active comparator (Clinical trial NCT 03099980). manifestations, with radioimaging and histological data showing that IL-17A blockade also impact structural damage, including pathologic new bone formation [54,57]. Also, IL-23 has been shown to be essential in the development of an experimental model of enthesitis acting on IL- 5 J.M.G. Ruiz de Morales, et al. Autoimmunity Reviews 19 (2020) 102429 Fig. 4. The inflammatory cascade resulting in the production of IL-17 cells originates in the macrophages and dendritic cells. Several types of cells of the innate and adaptive immune systems produce IL-17 which along IL-22 is involved in bone neoformation. *There is no clear evidence of IL-23R expression; IL, interleukin; ROR, RAR-related orphan receptor; Tc, cytotoxic T cell; Th, T-helper cell; TNF, tumor necrosis factor. 23 receptor, RAR-related orphan receptor γt (ROR-γt), and stem cell subpopulations are associated with clinical disease activity as well as antigen 1 (Sca1)(+) entheseal resident CD4-CD3-T cells [14]. Besides imaging signs of inflammation and structural damage. In clinically ac- evidence from animal models, it has been showed the in vitro capacity tive PsA, ILC3 (induced by IL-23 and synthesizing IL-17, IL-22) were of IL-17A to induce differentiation of osteoblasts from synovial biopsies significantly increased at the expense of ILC2s (synthesize IL-4, IL-5, IL- of SpA patients [57]. Moreover, local, but no systemic IL-17 A, induced 9 and IL-13), supporting the concept of IL-23/IL-17 pathway activation polarizacion of anti-inflammatory Mesenchymal stem cells type 2 is also the driving force of inflammation in PsA patients [65,66]. (MSC2) and bone neoformation in AS patients [58]. Although IL-23 is needed to the development of Th17 and Tc17 cells as well as to induce IL-17 and IL-22 production of innate immune cells 3.1. Psoriatic arthritis expressing the IL-23-receptor, there are many other innate immune cells producing IL-17 in an IL-23-independent manner. Depending of Psoriatic arthritis (PsA) is an immune-mediated inflammatory dis- the predominance of the subtype of IL-17A expressing cell in the dif- ease belonging to the concept of spondyloarthritis which is character- ferent tissues (gut, skin, musculoskeletal, etc) in PsA or AS patients, IL- ized by a wide musculoskeletal (arthritis, enthesitis, spondylitis, dac- 23 or IL-17A targeted therapies could be or no efficacious. Studies on tylitis) and cutaneous (skin and nail psoriasis) involvement with expression of IL-23/IL-17 cytokine axis are warranted to better define extrarticular features such as bowel inflammatory disease and uveitis. the more convenient target. Genetically and clinically is a very heterogeneous disease [59], and its In patients with active PsA treated with secukinumab, the extension pathophysiology, i.e, the relative expression of IL-23/IL-17 or TNF phase of the FUTURE 1 trial [67], confirms long term (156 weeks) ef- pathways, seems to be different in the distinct tissues involved [60]. ficacy in all endpoints, including (American College of Rheumatology) In synovial tissue and fluid samples from PsA, IL-23A mRNA ex- ARC20 response, quality of life, and radiographic progression [68]. pression correlated with C-reactive protein levels and swollen joint ARC20/50/70 responses were sustained through 5 years of treatment count [61]. Although Th17 cells were reported as the pathogenic cells [69]. On the other hand, the first RCT evaluating the efficacy of a implicated in animal models of arthritis, mast cells are the main cells biologic treatment in the management of axial manifestations in pa- expressing IL-17A in synovial tissue of patients with peripheral SpA, tients with PsA recently demonstrated rapid and significant improve- including PsA, while very few IL-17+ T cells were found [62]. How- ment in ASAS20 response through Week 12 of secukinumab vs. placebo ever, mast cells do not synthesize, but rather capture IL-17A from the [70]. extracellular medium and release it after an inflammatory/infectious The PSARTROS study was designed to elucidate the effects of IL-17A challenge [8]. Recent evidence supports the presence of IL-17A-positive inhibition on inflammation and bone changes in joints affected by PsA mast cells across different SpA-related target tissues (skin, gut, synovial [71]. In this open-label study, 20 patients with PsA received 24-week tissue), and the inverse correlation between its IL-17A content and in- treatment with secukinumab, which led to significant improvement of flammation indicate that IL-17A in mast cells can be regulated [63]. synovial inflammation (MRI, power Doppler ultrasound, and high-re- Therefore, tissue-resident mast cells may act as IL-17A-loaded sentinel solution peripheral quantitative computer tomography [72] of the cells and release IL-17A to amplify inflammation and should therefore hands), with no progression of catabolic and anabolic bone lesions. be further investigated to understand how IL-17A can be controlled locally during tissue inflammation [63]. 3.2. Ankylosing spondylitis Other IL-17 A producing cells may also have pathogenic relevance in PsA. IL-17A+ CD8 T cells are enriched in synovial fluid of PsA pa- In ankylosing spondylitis (AS), serum concentrations of IL-23 are tients and correlate with disease activity, power Doppler signal and elevated and polymorphisms in the IL-23 receptor are associated with erosive disease [64]. Innate lymphocyte cells (ILC) are increased in AS and PsA. Other studies have shown increased numbers of circulating peripheral blood of PsA patients, and distinct changes of ILC Th17 cells in the peripheral blood of patients with SpA, included AS, 6 J.M.G. Ruiz de Morales, et al. Autoimmunity Reviews 19 (2020) 102429 which were also polyfunctional in terms of T cell receptor-driven cy- expressing IL-17A. Despite of these findings, clinical trials confirms that tokine production [73]. In addition, peripheral blood levels of Th22 and only TNF and IL-17 A are effective therapeutic targets in AS [25]. Th17 cells were reported to be elevated in patients with AS [74]. Dysbiosis is reported as the inducer of subclinical gut inflammation 4. Hepatology and production of IL-23 which actives ILC3, which are proposed to migrate to the joints where they may trigger inflammation and bone Liver is one of the main producers of IL-17A [82] and IL-17RA is neoformation through IL-17 and IL-22 release [75]. thoroughly expressed in liver cells as hepatocytes, sinusoidal cells, Results from clinical trials support the efficacy and safety of agents biliary cells, and stellate cells [82,83]. In mouse models, IL-17A that block IL-17 (secukinumab and ixekizumab) in AS patients [76]. In blockade (genetic deletion or antibody neutralization) protects from a 3-year extension study of the randomized MEASURE 1 trial [76] in liver injury [84] whereas its administration increases liver damage 274 patients with AS, secukinumab provided sustained efficacy in signs, [85]. In humans, IL-17A has been studied in hepatitis B [86] and C symptoms and physical function, without new safety signals [77]. The [87], alcohol [88], primary biliary cholangitis [89], acute rejection in efficacy and safety of secukinumab has been confirmed in 80% of pa- liver transplant [90], hepatocellular carcinoma [91], autoimmune he- tients who entered in the extension study and completed 5 years of patitis [92], and primary sclerosing cholangitis [92]. In all of them, the treatment [78]. In patients with AS treated with secukinumab for IL-17 axis is overexpressed and its blockade is suggested as of future 2 years (weekly after 4 weeks and every 4 weeks thereafter), improve- therapeutic benefit [83,86–92]. ment in pain and fatigue scores were documented, which were noted in Nowadays, the focus of interest is shifting to non-alcoholic fatty both subgroups of patients with hsCRP elevated or normal baseline liver disease (NAFLD) as it has become the most important and severe values, as well as in anti-TNF-naïve patients or with TNF inadequate liver disease leading to liver transplant [93,94]. NAFLD is characterized response [77]. by excessive hepatic fat accumulation defined by the presence of stea- Unexpectedly, neither risankizumab nor ustekinumab IL-23 an- tosis in > 5% of hepatocytes [95] and is considered the hepatic mani- tagonists, have shown efficacy in phase II study in patients with AS festation of the Metabolic Syndrome [95]. Other non-related diseases to [25], challenging the pathogenic role attributed to IL-23 in animal Metabolic Syndrome can provoke fatty liver, as excessive alcohol con- models of SpA [14] and providing evidence of the distinct roles of IL- sumption, and infrequent genetic diseases [95]. A strong association is 23/IL-17 axis components in the different tissues of different SpA recognized in the last years between fatty liver and psoriasis so that conditions. these patients suffer a higher prevalence and severity of both when they coexist [96]. 3.3. Rheumatoid arthritis NAFLD pathogenesis is complex and multifactorial. The disease is the final result of the not yet perfectly understood interaction between High levels of serum IL-17 A and increased number of Th17+ cir- lifestyle (diet, physical activity) and genetic background [96–98]. In- culating cells have been reported in RA. As in PsA, in RA synovial tissue sulin resistance is the key factor linking Metabolic Syndrome and mast cells are the main IL-17A+ cells, with less proportion of IL17A+ NAFLD [99]. The liver is influenced by peripheral insulin resistance, neutrophils and very few IL17A+ T cells. Peripheral blood levels of mainly mediated by proinflammatory cytokines as TNFα, IL-6 and IL-17 Th22 and Th17 cells were elevated and correlated with disease activity [99]. But the liver is also influenced by a specific process of intrahepatic in patients with RA [74]. insulin resistance mediated by an excess of free fatty acids released In a phase 3 randomized double-blind clinical trial, the anti-IL-17A from adipose tissue that became lipotoxic inducing accumulation of antibody, secukinumab, at a dose of 150 mg resulted in improvement in hepatic diacylglycerols and activation of inflammatory pathways that, signs and symptoms and reduced disease activity in patients with active in turn, inhibit insulin signaling and lead to hepatic insulin resistance RA who had an inadequate response to TNF inhibitors [79]. However, [99]. IL-17 plays a central role in this inflammatory hepatic response treatment with ustekinumab (anti-IL-12/23 p40 antibody) or guselk- [100]. There is an increase in IL-17 production driven by natural killer umab (anti-IL-23 antibody) did not significantly reduce the signs and (NK), natural killer T (NKT), and Th17 cells. NK cells represent one symptoms of RA [26]. third of liver lymphocytes and are the main source of liver IFNγ [100]. The modest response of RA to secukinumab could perhaps be ex- They have been shown to be involved in fatty liver progression [101]. plained by disease heterogeneity. Interestingly, the subgroup of RA NKT are also an important part of liver immunity as producers of IFNα, patients with synovial tissue ectopic lymphoid neogenesis (ELN) had a IFNγ, and IL-17 [102]. NKT cells modulate fibrogenic and inflammatory robust expression of IL-23 and its downstream cytokines, IL-17F, IL-22 responses in liver tumors, autoimmune hepatitis and viral hepatitis and IL-21. This observation raises the question of whether in the group although its role in NAFLD is yet unclear [102]. Th17 cells are the of patients with synovial ELN, targeting this pathway may specifically primary source of IL-17 [103]. Obesity drives increased levels of Th17 provide larger clinical benefits [80]. cells and IL-17 production whose levels are increased in fatty liver [104]. Increased levels of IL-17 induced by NK, NKT and Th17 cells 3.4. Controversies activate IL-17AR in a subset of liver cells, mainly hepatocytes, Kuppfer cells, and hepatic stellate cells. Triglyceride-stored hepatocytes in Although IL-23 is needed for development of Th17 and Tc17 cells as NAFLD are more susceptible to stress damage [105]. IL-17 over- well as to induce IL-17 and IL-22 production by innate immune cells expression further increases hepatocytes lipid uptake aggravating da- expressing the IL-23-receptor, there are many other innate immune mage and rendering hepatocytes prone to cell death and disease pro- cells producing IL-17 in an IL-23-independent manner. Depending on gression [105]. Kuppfer cells play a critical role in liver homeostasis as the predominance of the subtype of IL-17A producing cell in the dif- regulators of hepatic pathogenesis via activation of inflammation (IL-6, ferent tissues (gut, skin, musculoskeletal, etc) in PsA or AS patients IL-12, TNFα) [106]. The stimulation of Kuppfer cells by IL-17 results in and/or the clinical stage, IL-23 or IL-17A targeted therapies could be or intense production of IL-6 and TNFα [107] and its depletion protects no efficacious [81]. from liver damage [85]. IL-17- activated Kuppfer cells augment liver As an example, experimental models support the key pathogenic fibrosis [107]. Hepatic stellate cells (HSC) are the main source of ex- role of IL-23 in the development of enthesitis, spondylitis, bone neo- tracellular liver matrix, and hyperactivation induces liver fibrosis in formation and erosions through IL-23R+RORgt+CD3+CD4-CD8- en- almost all liver disorders [108]. IL-17 induced by Th17 cells and thesitis-resident cells [14]. In axial tissues of AS patients, it has been Kuppfer cells, in turn induced by IL-17, provoke HSC collagen pro- demonstrated that IL-23/IL-17 producing cells are macrophage and duction [107]. The IL-17 -mediated activation of hepatocytes, Kuppfer dendritic cells expressing IL-23 and myeloid cells (neutrophils) cells, and HSC leads to further proinflammatory cytokine and 7 J.M.G. Ruiz de Morales, et al. Autoimmunity Reviews 19 (2020) 102429 inflammatory chronic disease. 5. Cardiology There is evidence that Th17 cell response has a relevant role in several cardiovascular diseases [118,119]. Interestingly, in a model of IL-17−/− mice, hypertensive response to angiotensin II infusion was not sustained as compared with C57BL/6J wild type mice, which in- dicates that IL-17 is required for maintenance of angiotensin II-induced hypertension [118]. Also, IL-17 deficiency abrogated vascular con- traction of phenylephrine, with alterations in vascular tone thought to be at least partly mediated by alterations in superoxide production. IL- 17 levels are increased in human hypertension as shown in a study of type 2 diabetic patients with and without hypertension, in whom IL-17 levels in normotensive individuals were significantly lower than in those with hypertension [118]. Therefore, it may be plausible that targeting IL-17 and Th17 cells might help to control blood pressure and preserve vascular function without affecting global immunity. Over the past few years our understanding of the importance of adaptive immunity in acute coronary syndromes (ACS) has con- siderably increased. Profound abnormalities have been observed in specific subsets of CD4+T cells, including type 1 helper T (Th1) cells, CD4(+) CD28(null) T-cells, and naturally occurring regulatory T-cells Fig. 5. Pathogenic role of IL-17 in myocardial ischemia/reperfusion injury. IL- (Treg cells) [120]. The relevance of IL-17 to human atherosclerosis 17 is activated by signal transducer and activator of transcription 3 (STAT3), remains poorly defined because of conflicting results in animal studies. which in turn activates MAPK-PI(3)K/AKT leading to production of C-X-C While some studies have suggested a proatherogenic role for IL-17, an chemokine 1 and IL-6 causing neutrophil infiltration and cell apoptosis [121]. atheroprotective role for IL-17 through cross-regulation of IFN-γ-pro- ducing Th1 cells has also been proposed. IL-17 exerts proatherogenic chemokine production, neutrophil recruitment, reactive oxygen species effects by inducing the production of cytokines, chemokines, and matrix production and increased collagen deposition, processes known to metalloproteinases. IL-17 also promotes G-CSF-mediated granulopoiesis mediate NAFLD progression [100]. IL-17 excess in fatty liver is also and the recruitment of immune cells. Moreover, IL-17 induces apoptosis related to hepatocellular carcinoma risk. Unconventional prefoldin of endothelial cells and cardiomyocytes by activating caspase-3 and RPB5 interactor (URI) is a chaperone involved in cell signaling, tran- caspase-9, and up-regulating the Bax/Bcl-2 ratio [120]. The ather- scription processes, and DNA damage; it has been described in several oprotective effect of IL-17 seems to be mediated at least in part by the tumors. Overexpression of IL-17-induced URI has been associated to regulation of other cytokines (reduction of IFN-γ and enhancement of NASH and hepatocellular carcinoma and its blockade decreased liver IL-5) and by its inhibitory effect on VCAM-1 expression, an adhesion tumor risk. molecule mediating the accumulation of monocytes and T-cells within NAFLD lacks specific treatment [95]. Patients are advocated to lose the lesions [120]. weight by hypocaloric diet and aerobic exercise, although this goal is It has been shown that IL-17A contributes to myocardial ischemia/ rarely achieved [109]. IL-17 is relevant in the control of many immune- reperfusion (I/R) injury by regulating cardiomyocyte apoptosis and mediated diseases and therefore is an attractive candidate for NAFLD neutrophil infiltration (Fig. 5) [121]. treatment. Nevertheless, the evidence is still scarce although promising. In a mouse model of left coronary artery ligation and reperfusion, IL-17 blockade restores insulin resistance and prevents NAFLD in- IL-17A was demonstrated to play a critical role in mediating I/R [122]. flammation in mouse models [110]. The genetic ablation of IL-17RA It was found that myocardial infiltrated γδ T lymphocytes, but not Th17 also alleviates NAFLD [110]. In another mice model, IL-17 blockade cells, were a major source of IL-17A. Anti-IL-17A monoclonal antibody attenuated liver damage induced by lipopolysaccharide in baseline treatment or IL-17A knockout markedly ameliorated I/R injury, which normal livers as much as in fatty liver, evaluated by transaminase levels was associated with a reduction in cardiomyocyte apoptosis and neu- as well as by liver biopsy. Statins have been shown to reduce liver in- trophil infiltration, but repletion of exogenous IL-17A induced the op- flammation in NAFLD [111]. Some studies highlight the im- posite effect. These data suggest a novel IL-17A-dependent pathway by munomodulatory capacity of statins by inhibiting the differentiation of which the immune system may influence the myocardial I/R injury. Th17 cells and decreasing its production [112,113]. Vitamin D levels Control of IL-17A production may be of benefit for minimizing I/R- are reduced in NAFLD, increasing its severity and fibrosis [114]. Vi- associated myocardial damage. tamin D participates in modulation of IL-17 axis [114] and its supple- In a study that investigated the relationship between serum levels of mentation in NAFLD reduces liver fibrosis, inflammatory response, and IL-17 and the risk of cardiovascular events in 981 patients enrolled in a insulin resistance [115]. Considering the key role in NAFLD, IL-17 in- prospective French registry of myocardial infarction, serum levels of IL- hibitors could have a protective effect in NAFLD. In experimental 17 were associated with the risk of all-cause death and recurrent models they improve hepatic steatosis [116] and could block the shift myocardial infarction at 2 years, with levels of IL-17 below the median from steatosis to steatohepatitis [117], although clinical studies are still indicative of a worse outcome [123]. It was also shown that the effect of lacking. IL-17 remained significant after adjusting for known cardiovascular risk factors, C-reactive protein, and treatments including statins. IL-17 in- 4.1. Controversies hibited mononuclear cell adhesion to endothelium and reduced en- dothelial vascular cell adhesion molecule (VCAM-1) expression. At Blockade of IL-17 axis needs to show clinical benefit in NAFLD 2 years, 43% of death and myocardial infarction occurred in patients beyond basic investigation. Prospective, well-designed trials are eagerly with low (below the median) baseline IL-17 and high (above the awaited. The main focus is probably psoriasis patients with NAFLD, as median) baseline sVCAM-1 levels compared with 12% in those patients they constitute a human model of IL-17-mediated systemic with high baseline IL-17 and low baseline sVCAM-1. The corresponding 8 J.M.G. Ruiz de Morales, et al. Autoimmunity Reviews 19 (2020) 102429 hazard ratio (HR) for event rates was 4.03 (95% CI 2.48-6.55) and re- studies with cell cultures and in vivo studies. A relevant involvement of mained significant in the Cox multivariate analysis. This study shows IL-17A has been postulated in the development and maintenance of that elevated levels of IL-17 are associated with a better outcome in arterial hypertension, endothelial dysfunction, myocardiocyte apop- patients with acute myocardial infarction, supporting a protective tosis and in the extent of myocardial infarction in ischemia/reperfusion regulatory role of IL-17 in coronary heart disease. Moreover, the models. Regarding IL-17A relationship with atherosclerosis, there are highest risk of death and recurrent infarction observed in patients with controversial aspects determined by its dual proatherogenic and anti- low levels of IL-17 and high levels of sVCAM-1, indicates an important atherogenic action, which in clinical models of chronic systemic in- modulatory role of IL-17 on vascular inflammation [123]. In a recent flammation could shift towards a preponderant proatherogenic effect study by Elnabawi and cols, they analyzed the total burden of athero- based on its synergistic action with TNTα. More clinical studies are sclerotic coronary artery plaques and the plaque subcomponents by needed to explore the therapeutic effect of blocking IL-17A in relation coronary CT in 290 psoriatic patients. The plaque burden was sig- to cardiovascular risk in patients with chronic inflammatory diseases nificantly correlated with traditional cardiovascular risk factors and such as psoriasis, psoriatic arteritis and ankylosing spondylitis. with the severity of the disease according to the PASI. A greater re- duction in the non-calcified plaque burden and necrotic core was ob- 6. Ophthalmology served in the anti-IL17 treated group, compared to other biologic treatments (anti-IL 12/23 and anti-TNF alpha groups). These findings A pathogenic role of Th17 cells in some ocular disorders, particu- highlight the importance of systemic inflammation in coronary artery larly uveitis, has been the focus of interest in recent years. Mucientes disease in psoriatic patients. The modulation of coronary plaque indices et al. [132] evaluated the possible influence of the IL-17A locus on using biologic treatment with anti-IL17 in severe psoriatic patients susceptibility to non-anterior uveitis. To this purpose five IL-17A shows an opportunity of reducing the cardiovascular risk in these pa- polymorphisms (rs4711998, rs8193036, rs3819024, rs2275913 and tients [124]. Targeting the IL-17 pathways appears a promising ther- rs7747909) were genotyped in 353 Spanish patients with non-anterior apeutic approach in the field of atherosclerosis and acute myocardial uveitis and 1851 ethnically matched controls. A consistent association infarction [125]. between two of the analyzed genetic variants, rs8193036 and On the other hand, IL-17A induces endothelial damage through rs2275913, and the presence of panuveitis and the diffuse form of the increased apoptosis by decreasing the mitochondrial transmembrane disease was found. These data agree with the elevated levels of this potential and have a synergistic effect with TNFα on endothelial cells cytokine that are found in patients with uveitis, supporting a crucial leading to pro-inflammatory and pro-thrombotic responses [126]. Re- role of Th17 cells in this pathology [132]. cently, in a 52-week randomized, double-blind, placebo-controlled In Behçet’s disease (BD) in which uveitis is characterized in its more study (CARIMA) in patients with plaque psoriasis without cardiovas- severe form by posterior or panuveitis and retinal vasculitis, a study of cular disease, secukinumab showed a beneficial effect on cardiovas- 37 patients with BD and uveitis showed that IFN-γ, IL-17A, TNF-α, and cular risk as improved significantly endothelial function measured by high-sensitive C-reactive protein (hsCRP) were increased, with sig- flow-mediated dilatation [127]. nificantly higher levels of IFN-γ and TNF-α compared to healthy sub- IL-17A induces apoptosis in cardiomyocytes by increasing the pro- jects, supporting a Th1 immune response [133]. The analysis of the to anti-apoptotic protein ratio (B-cell lymphoma-2-associated protein X cytokine profile in the subgroup of patients to whom serum samples Bax/Bcl-2 ratio) [128] and through iNOS (inducible nitric oxide syn- were obtained during both active and inactive stages also revealed that thase) activation [129]. Also, it has been suggested that immune acti- IFN-γ and TNF-α were significantly increased during the active stage of vation and genetic polymorphisms of IL-17 genes contribute to the the disease. Similarly, IL-17A was increased in patients with active pathogenesis and progression of heart failure. In a total of 1713 adult uveitis compared to healthy controls. However, this increase was sta- patients with congestive heart failure and 1713 age- and sex-matched tistically significant only in those patients without treatment, sug- controls, genotyping for promoter single nucleotide polymorphisms gesting the involvement of Th17 response in BD. Additionally, TNF-α (SNPs), rs2275913 and rs8193037 in IL-17A and rs4819554 in IL-17RA also correlated with IL-17A in these patients, supporting the idea that was examined in order to determine the relationship between in- BD is mediated simultaneously by both Th1 and Th17 responses [133]. dividual SNPs and the risk of congestive heart failure [130]. It was Moreover, IFN-γ, TNF-α, and IL-17A levels were higher in patients found that rs8193037 in IL-17A was associated with the risk of con- without treatment than in those with pharmacological treatment in gestive heart failure after adjustment for multiple cardiovascular risk both active and inactive patients, and therefore it may be speculated factors including age, sex, smoking status, diabetes, hypertension, and that successful therapies should be able to prevent recurrent in- dyslipidemia, and this association being evident in both ischemic and flammatory attacks by keeping under control the circulating levels of non-ischemic heart failure. In addition, rs4819554 in IL-17RA was as- these proinflammatory cytokines [133]. sociated with cardiovascular mortality after a follow-up of 12.7 months. However, information on the efficacy of anti-IL-17A antibodies in This study provided evidence for an association of rs8193037 in IL-17A the treatment of non-infectious uveitis is still limited. In patients with with the risk of heart failure, and of rs4819554 in IL-17RA with the risk psoriasis (n = 36), rheumatoid arthritis (n = 52), and chronic non- of cardiovascular mortality [130]. infectious uveitis (n = 16), the efficacy and safety of AIN457 (a human It is recognized that several immune-mediated chronic in- antibody to IL-17A) at doses of 3–10 mg/kg given intravenously (i.v.) flammatory diseases (IMIDs) such as Psoriasis, Rheumatoid Arthritis, was investigated [134]. Efficacy for uveitis was assessed by the number Ankylosing spondylitis, Crohn, share co-morbidities including meta- of responders defined by either vision improvement or reduction in bolic syndrome and accelerated atherosclerosis, that are associated ocular inflammation or corticosteroid dose. Variable responses were with increased cardiovascular risks. They all are considered to harbor a obtained probably due to heterogeneity in small patient populations, low-grade systemic inflammatory state that might be responsible for differential pathogenic roles of IL-17A in these diseases, and the dif- insulin-resistance and increased cardiovascular co-morbidities. In fact, ferent involvement or activation of IL-17A-producing cells [134]. release of pro-inflammatory cytokines ie TNF, IL-17, IL-6 and adipo- Results of three different randomized studies on the efficacy of se- cytokines from tissues into the circulation has been directly related with cukinumab in heterogeneous populations of uveitis patients (118 pa- accelerated atherosclerosis in Psoriasis [131]. tients with BD uveitis, 31 patients with active, noninfectious, non-BD uveitis, and 125 patients with quiescent, non-infectious, non-BD 5.1. Controversies uveitis), were disappointing as there were no statistically significant differences in uveitis recurrence between the secukinumab and placebo The role of IL-17A in cardiovascular risk has been suggested in groups in any study, although a beneficial effect of secukinumab in 9 J.M.G. Ruiz de Morales, et al. Autoimmunity Reviews 19 (2020) 102429 reducing the use of concomitant immunosuppressive medication was cells from the periphery – where they are activated – into the CNS is a recorded [135]. In a randomized, double-masked, dose-ranging, phase recognized early event in the development of MS. Natalizumab – a 2 clinical trial, with 37 patients with active non-infectious intermediate monoclonal antibody approved for severe RR MS directed to α4-in- uveitis, posterior uveitis, or panuveitis who required corticosteroid- tegrin that blocks mononuclear cell migration across endothelial cells – sparing immunosuppressive therapy, secukinumab iv (30 and 10 mg/ is a highly active drug that exerts its effects by inducing peripheral kg) compared with a standard 300 mg subcutaneous dose, produced accumulation of Th17, which returns to normal when relapses occur higher responder rates and remission rates [136]. Greater activity with [145]. i.v. dosing suggests that patients may not receive sufficient drug with In the experimental autoimmune encephalomyelitis (EAE), a mouse subcutaneous administration, and that high-dose i.v. secukinumab may model of the human MS where Th17-IL-17A induce disease, neu- be necessary to deliver the drug in therapeutic concentrations [136]. tralization of IL-17 results in resolution [146]. An ongoing double- The expression of Th 17-associated cytokines (IL-17, IL-23) has been blind, placebo-controlled proof-of-concept trial with the IL-17A– spe- studied in a small sample of 45 patents with dry eye disease [137]. cific antibody secukinumab in active relapsing-remitting multiple Protein and conjunctival mRNA IL17A and IL6 levels were both sig- sclerosis has now provided preliminary results supporting the role of IL- nificantly increased and correlated with ocular surface parameters. The 17A in multiple sclerosis in humans, as they showed a substantial re- expression of IL-23 was also significantly increased but did not correlate duction of the number of new lesions revealed by magnetic resonance with ocular surface parameters. The expressions of IL-17A and IL-6 in imaging (EudraCT number 2009- 011626-34) [147]. In this multicenter tears have potential to be diagnostic biomarkers for dry eye disease study carried out at 28 sites from the Czech Republic, Russia, and Uk- [137]. In ocular surface inflammatory pathologies, namely pterygium raine, patients aged 18–55 years diagnosed with RRMS with stable and inflamed juvenile conjunctival nevus (IJCN), IL-17 was im- disease at least 30 days before inclusion and not being currently treated munohistochemically detected in all IJCN specimens and in 84% of disease-modifying drugs were eligible. Other inclusion criteria were the pterygia samples, suggesting that IL-17 blockade may have a potential presence of one gadolinium (Gd) enhancing MRI lesion at screening/ role in management of these conditions [138]. baseline or one relapse in the last year or two relapses in the last In patients with type 2 diabetes mellitus and diabetic retinopathy 2 years. The objectives of the study were to assess efficacy, safety and (DR), the proportion of Th17 cells and IL17A production in peripheral tolerability. The primary endpoint was the cumulative number of blood mononuclear cell (PBMC) culture were significantly increased in combined unique active lesions (CUAL) observed on brain MRI scans patients without DR but decreased in those with DR, and were nega- from week 4 to week 24. Patients (n = 73) were randomized 1:1 to tively correlated with body mass index, duration of diabetes, and gly- secukinumab. Afterwards, patients were included in a 12-month open cated hemoglobin levels [139]. Additionally, vitreous fluid IL-17A le- extension study, in which they received secukinumab 10/mg/kg i.v. vels were significantly elevated in patients with DR compared with every 4 weeks. MRI scans were obtained within 30 days prior to ran- controls. It seems that disturbances in Th17 cells and IL-17A levels domization, on a monthly basis during the treatment period, and at might be associated with DR. study completion. In relation to efficacy, a significant reduction in new MRI lesion activity was found, including reduction in cumulative 6.1. Controversies CUALS and new T1-Gd+ lesions, with treatment benefits being ap- parent at week 12 and sustained through week 36. Also, a trend to- Nowadays, the advent of highly effective and targeted biotherapies wards clinical relapse reduction in the secukinumab group was ob- and the recent imaging technologies are improving the treatment and served. monitoring of patients with noninfectious uveitis. A personalized ap- In Guillain-Barre syndrome (GBS), an heterogeneous peripheral proach should take into consideration patient’s characteristics and neuropathy involving myelin and axons, recent immunological, genetic uveitis subtypes. Clinical and experimental observations suggest that iv and gene expression studies suggest evidence towards the involvement IL-17A may be an attractive therapeutic target in patients with non- of Th17 cells in the pathobiology of GBS. Han et al described increased infectious uveitis. However, new molecules and the design of new circulating Th17 cell numbers, elevated CSF IL-17 concentrations and clinical trials will be necessary to demonstrate its effectiveness in the increased ROR-γt and STAT-3 expression in peripheral mononuclear treatment of noninfectious uveitis. cells from patients with GBS [141,148]. Psoriasis and other chronic inflammatory diseases such as in- 7. Neurology flammatory bowel diseases and Spondyloarthropathies (IMIDs, im- munomediated inflammatory diseases) are now recognized as diseases The effect of IL-17 cytokines in central (CNS) and peripheral ner- in which a low-grade systemic chronic inflammatory state is associated vous system (PNS) inflammatory conditions is still not well defined. with the development of co-morbidities, including increased risk of Multiple sclerosis (MS) is associated with encephalitogenic Th17 cells cardiovascular events and psychiatric disorders i.e depression and an- [140]. Recently, Th17 and IL-17 have been suggested to be involved in xiety. In these patients, depression has been associated with increased the pathogenesis of post-infectious Guillain-Barre syndrome [141]. plasmatic levels of pro-inflammatory cytokines (TNF, IL-17, IL-22) High levels of IL-17 have also been linked to depression, a frequent [131]. However, the role of IL- 17 in depression has not been well comorbidity of several chronic inflammatory diseases, i.e. Psoriasis characterized. Of note, a recent study using mouse models of depression [131]. showed that administration of Th17 cells was directly correlated with MS is a chronic inflammatory disease characterized by the de- depression sensitivity suggesting that the Th17 axis may play a role in struction of myelin by peripherally activated autoreactive pathogenic T neuro- immune interactions [149,150]. cells. In patients with MS early results showed increased expression of IL-17 in the brain at autopsy, and abundant IL-17-expressing cells in 7.1. Controversies active CNS lesions [142,143]. In a seminal paper, Kebir et al [140] demonstrated in MS patients high IL-17R and IL-22R expression at BBB The pathogenic role of IL17A both in experimental models of MS (blood brain barrier)- endothelial cells, and that in vitro treatment with (EAE) and in MS is undisputed. Despite a small proof-of-concept trial IL-17A and IL-22 was able to induce BBB tight junction´s disruption. has already been published (137), strong evidence on the long-term Recently Th17 subpopulations producing low amounts of IL-10 were beneficial effects of IL17-blockade in MS is still needed. A clinical trial identified as pathogenic in MS, and IL-10 production correlated with with Secukinumab was terminated early in 2016 based upon develop- disease activity [144]. Further evidence for the pathogenic role of Th17 ment of another anti-IL17 monoclonal antibody with better potential cells in MS derives from therapies. Trafficking of MOG-reactive Th17 for treating MS patients (Clinical trial NCT01433250). Moreover, the 10 J.M.G. Ruiz de Morales, et al. Autoimmunity Reviews 19 (2020) 102429 promising results with Siponimod improving inflammation, disability explanation is that blocking IL-17A may interfere with the protective and brain atrophy in a large clinical trial in patients with secondary function of this cytokine in the intestine, i.e. maintenance of epithelial progressive MS stresses the importance of further exploring the re- integrity, showing the high complexity of IL-17 biology [160]. Other lationship among inflammation and neurodegeneration to achieve the approaches neutralizing IL-17 pathway in IBD patients have also failed. best treatment across the entire spectrum of the MS disease (EXPAND In a phase 2, randomized, double-blind, placebo-controlled, dose-ran- trial) [151]. Siponimod, an oral selective inhibitor of Sphingosine-1- ging study in patients with moderate-to-severe CD and evidence of phophatase receptors 1 and 5, has an anti-inflammatory effect on active inflammation, brodalumab (anti-IL-17RA antibody) provided neuroinflammation because reduces pathogenic Th17 lymphocyte disappointing results, with a disproportionate number of cases of egress from peripheral lymphoid tissue into the brain. In addition, and worsening CD and no evidence of meaningful efficacy [161]. because its ability to cross the blood-brain barrier, it can directly in- teract with non-lymphoid brain cells i.e astrocytes, microglia, oligo- 8.1. Controversies dendrocytes and neurons, potentially exerting direct neuroprotective effects via routes beyond its anti-inflammatory effect [152]. Inhibition of IL-17 has been ineffective to induce remission in trials of patients with Crohn's disease despite strong evidences that IL-23/IL- 8. Gastroenterology 17 axis plays an important role in disease mechanisms. IL-17 pathway regulation complexity and/or fungi overgrowth could explain lack of Different studies during the past decade demonstrate that IL-17/IL- efficacy. Further in-depth immunological studies should investigate 23 cytokines are overexpressed in Crohn’s disease patients, playing a intestinal pathophysiology by setting targeted molecules in the context critical role in disease mechanisms. In a study of ileal biopsies from of its real biological network. patients with active and inactive Crohn’s disease (CD) and control subjects, lamina propria IL-17 and IL-23-positive cells were higher in 9. Hematology patients with CD, both active and inactive, than in the controls. Furthermore, IL-17A mRNA expression was increased in biopsies from Allogeneic stem cell transplantation (Allo-HCT) is a curative im- both patients with active or inactive disease, whereas fecal IL-17 mRNA munotherapy for patients with blood-related diseases [162], but graft- was increased only in active disease [153]. In another study of tissue versus-host disease (GvHD) remains a major cause of transplant failure samples from patients with ulcerative colitis (UC), CD, infectious colitis, [163,164], and effective therapeutic options beyond systemic steroids ischemic colitis, and healthy controls, IL-17 expression evaluated by are limited. Recently, murine transplant research has shown that in immunohistochemical techniques was only present in IBD samples vitro differentiated Th17/Tc17 lineages cells alone could mediate [19]. In inflamed mucosa from active UC and CD patients, IL-17 ex- GvHD [165]. Highly in vitro purified Th17 cells are capable of inducing pression was detectable in CD3(+) T cells and CD68(+) monocytes/ lethal GvHD in a murine acute GvHD (aGvHD) model, hallmarked by macrophages with a significant increase in the number of IL-17(+) cells extensive cutaneous and pulmonary lesions. The majority of these Th17 in active UC and CD patients as compared with inactive patients. Al- cells retained the ability to produce IL-17A in an INFγ-independent though IL-17 was not detected in the sera from normal individuals, manner. Also, in a murine Allo-HCT model, targeted depletion of Tc17 infectious colitis, or ischemic colitis patients, IL-17 levels were sig- cells (a subset of CD8+ T cells) early after transplant protected from nificantly elevated in IBD patients. In another study assessing intestinal lethal aGvHD but failed to mediate graft-versus-leukemia effect [166], biopsies from 40 patients with UC, 20 with CD, and 20 healthy controls, suggesting that targeting these cells would not increase the relapse risk. Th17 cells abundance and IL-17A, IL-21 and IL-22 expression were A study of lesional skin biopsies in patients suffering from skin significantly increased in active IBD patients and correlated with dis- GvHD showed that distinct T-cell patterns characterized the acute and ease activity index and endoscopic and histological score [154]. These chronic forms of cutaneous GvHD [167]. Of note, chronic lichenoid results provide evidence about the important role of Th17 cells and GvHD showed a mixed Th1/Th17 response as evidenced by a pre- Th17-related cytokines in mucosal damage and disease activity in IBD. dominance of Th1 (IFN-γ, IL-12/IL-23p40) and Th17 cytokines (IL-17, A meta-analysis of UC and CD Genome-wide association studies IL-23p19) and a relative increase of IL-17 and IFN-γ single-producing (GWAS) in more than 75,000 cases and controls revealed a total of 163 CD8+ T cells. These findings allow to more accurately distinguish loci that meet genome-wide significance thresholds in patients with between GvHD manifestations, and further confirms that Th17/Tc17 IBD. An interesting finding was a strong association between variants in might play a key role in GvHD pathogenesis. IL-23R with susceptibility to CD, thus confirming the implication of the Over the last years several strategies such as B-cell depletion, JAK1/ IL-23/IL-17 axis in disease pathogenesis [155]. 2 pathway inhibition, or the infusion of mesenchymal stem cells and The efficacy of ustekinumab (a monoclonal antibody against IL-12/ regulatory T-cells have been developed to treat steroid refractory IL-23 p40) in Crohn’s disease in different studies also supports the idea GvHD. In line with this, targeting Th17 differentiation and function of the involvement of the IL23/IL17 axis in the pathogenesis of IBD with an anti-IL-17 monoclonal antibody might be a way to provide [156]. Moreover, published results from an open-label extension study better control for some GvHD manifestations such as pulmonary and with risankizumab, a monoclonal anti- IL23p19, in patients with Crohn cutaneous. Nevertheless, concerns have been raised regarding the use of disease are promising [157]. anti-IL-17 in the Allo-HCT setting, given the IL-10 dependent regulatory Taking into account all these evidences, IL-17 neutralization, theo- effect of Th17 in the gut and recent reports regarding the development retically, could be effective in the treatment of patients with Crohn’s of acute GvHD in IL-17 -/- knock-out murine model [168]. The in- disease. However, secukinumab, a human anti-IL-17A monoclonal an- hibition of IL-17 in AlloHCT could be a potential therapeutic path to tibody, was ineffective in a double-blind, randomized, placebo-con- treat GvHD. To date, anti-IL-17 MoAb have not been used to treat Al- trolled proof-of-concept study of 59 patients with moderate to severe loHCT patients and its role warrants further study. CD (secukinumab 39, placebo 20) [158]. Unexpectedly, the trial was stopped prematurely because predefined criterion of futility was met 10. Oncology (≤ 90% probabilities that secukinumab reduces Crohn’s Disease Ac- tivity Index by < 40 points more than placebo). Surprisingly, higher Recently, the inflammatory cytokine interleukin 17 (IL-17) and the rates of adverse events (Candida spp. infection) were observed in the IL-17-Th17 pathway have gained attention as promising therapeutic treatment group. To explain secukinumab's lack of efficacy in IBD, it targets in the immune-oncology field. Many studies have shown high has been postulated that overgrowth of Candida spp. might be re- levels of IL-17 in gastric carcinoma, colorectal cancer, non-small cell sponsible for the worsening of IBD patients, [159]. Another possible lung cancer, breast, ovarian and hematologic cancers [169–175]. The 11 J.M.G. Ruiz de Morales, et al. Autoimmunity Reviews 19 (2020) 102429 utility of anti-IL-17 mAb CJM112 alone or in combination with anti-PD- Abbvie, Almirall, Amgen, Baxalta, Biogen, Boehringer Ingelheim, 1 in multiple myeloma patients is being studied in a phase I clinical trial Celgene, Gebro, Janssen, Leo-Pharma, Lilly, Merck-Serono, MSD, (NCT 03111992). Mylan, Novartis, Pfizer, Regeneron, Roche, Sandoz, Samsung-Bioepis, IL-17 is a double-edged cytokine that acts in a cancer-type de- Sanofi, UCB and has participated in a company sponsored speaker’s pending manner as an anti- or protumor cytokine [176]. The oncogenic bureau for Celgene, Janssen, Lilly, MSD, Novartis, Pfizer. role of IL-17 is supported by studies that demonstrated an anti-apop- ED has been an advisory Board member, consultant, received grants, totic effect in mouse breast cancer models and sustaining self-renewal research support, participation in clinical trials, honorarium for properties of ovarian cancer stem cells [174,177]. In addition, it has speaking, research support, with: Abbvie/Abbott, Almirall, Amgen, shown to decrease the presence of CD4 and CD8 infiltrating cells in Janssen-Cilag, Leo Pharma, Novartis, Pfizer, MSD-Schering-Plough, tumor sites, to diminish the secretion of interferon gamma (IFN-γ) by Celgene and Lilly. CD8 T cells, to increase infiltrating T-regs and to promote angiogenesis JDC received consulting fees from Celgene, Janssen, Lilly, Mylan, [178], invasion and metastasis [179] recruiting tumor associated Novartis, Pfizedr and UCB. macrophages (TAM) and myeloid-derived suppressor cells (MDSC) JLP has received lecturing and consulting fees from Janssen, Pfizer, [180]. On the other hand, other authors have shown opposite effects. Lilly, Novartis, Roche, Celgene, Bristol, Gilead, Sanofi and Biogen. Indeed, the controversial role of IL-17 in cancer comes from the het- AOM has been an advisory board member and speaker for Abbvie erogeneity in how the IL-17 is measured in the different reports: as IL- and Novartis. 17 mRNA or protein levels by western blotting and/or ELISA, as the AA has receipt grants/research supports or participation in clinical presence of Th17 tumor-infiltrating T cell. However, the fact is that the trials from Abbvie and Roche, has been an Advisory Boards member for role of IL-17 in different human cancers has been studied mostly in in Abbvie, Novartis, Santen, Alimera and Allergan and speaker for Abbvie, vitro cell models and human xenografts while it is known that this cy- Novartis and Alimera. tokine is just one of the plethora of interleukins at the interplay be- XM has received speaking honoraria and travel expenses for parti- tween cancer and the stromal cell compartment that indeed, is secreted cipation in scientific meetings, has been a steering committee member by several immune cells such as macrophages, dendritic cells, neu- of clinical trials or participated in advisory boards of clinical trials in trophils, natural killers, CD8 and regulatory T cells, MDSC as well as the past years with Actelion, Bayer, Biogen, Celgene, Genzyme, Merck, Th17 cells. Novartis, Roche, Sanofi-Genzyme, Teva Pharmaceutical, Excemed, Th17 cells are key players in inflammation and autoimmune dis- MSIF and NMSS. orders, but the clinical significance of their detection in the tumor NB received lecture fees from Abbvie, Merck, Janssen and Takeda microenvironment remains unclear. Actually, compared to conven- and consulting fees from Janssen in the last year. tional effector T cells, Th17 phenotype comprised low levels of gran- GO has been in a consulting or advisory Role: Bristol-Myers Squibb, zyme B and activation markers HLA-DR and CD25 [181]. This ob- Incyte, Novartis, Pfizer, received speakers' bureau from Bristol-Myers servation is in favor of an impossibility to initiate cytotoxic killing. Squibb, Incyte, Novartis, Pfizer and travel, Accommodations and ex- Although Th1 cells accumulate in the tumor microenvironment of most penses from Bristol-Myers Squibb, MSD, Pfizer and Takeda. solid tumors as compared to samples of normal tissues, distinct func- CGV has received speaker honoraria from Novartis, Janssen, Lilly, tions regarding their ability to promote or to eliminate tumors have Pfizer, MSD and Gilead. been reported, and it seems that this opposite functions depend on the MAGG received grants/research supports from AbbVie, MSD. features or the microenvironment, such as nature of the antigen-pre- Jansen and Roche and had consultation fees/participation in company senting cells, presence of TGF-β, IL-1β or IL-23. These cells can mediate sponsored speaker´s bureau from AbbVie, Pfizer, Roche, Sanofi, antitumoral effects by their ability to recruit immune effector cells Celgene, Sobi, Novartis and MSD. (cytotoxic T lymphocytes, natural killer cells, dendritic cells) into the CVM and VMV are employees of Novartis Pharmaceuticals. tumor bed and they can promote tumor growth by means of angio- CGJ and EHM have none conflict of interest to declare. genesis (production of VEGF, angiogenic chemokines) and/or through immunosuppression (Treg conversion, myeloid-derived suppressor cell References recruitment) [182,183]. [1] Gaffen SL. Life before seventeen: cloning of the IL-17 receptor. J Immunol 2011;187(9):4389–91. 10.1. Controversies [2] Beringer A, Noack M, Miossec P. IL-17 in chronic inflammation: from discovery to targeting. Trends Mol Med 2016;22(3):230–41. Targeting the Th17/IL-17 signaling axis in hematological and solid [3] Amatya N, Garg AV, Gaffen SL. IL-17 signaling: the Yin and the Yang. Trends Immunol 2017;38(5):310–22. cancers is an exciting strategy in the immune-oncology field although it [4] Veldhoen M. Interleukin 17 is a chief orchestrator of immunity. Nat Immunol remains controversial. The dual role of IL-17 observed depends on 2017;18(6):612–21. many factors, current sources of knowledge are based in heterogeneous [5] Onishi RM, Gaffen SL. Interleukin-17 and its target genes: mechanisms of inter- leukin-17 function in disease. Immunology 2010;129(3):311–21. experimental cancer models and the lack of data regarding IL-17 and [6] Okada S, Puel A, Casanova JL, Kobayashi M. Chronic mucocutaneous candidiasis cancer in humans requires well-designed clinical trials to guarantee the disease associated with inborn errors of IL-17 immunity. Clin Transl Immunol 2016;5(12):e114. safety and efficacy in cancer patients. [7] Guo P, Hirano M, Herrin BR, Li J, Yu C, Sadlonova A, et al. Dual nature of the adaptive immune system in lampreys. Nature 2009;459(7248):796–801. Funding/financial support [8] Noordenbos T, Blijdorp I, Chen S, Stap J, Mul E, Canete JD, et al. Human mast cells capture, store, and release bioactive, exogenous IL-17A. J Leukoc Biol 2016;100(3):453–62. This work was supported by Novartis Pharmaceuticals Spain. [9] Caccamo N, La Mendola C, Orlando V, Meraviglia S, Todaro M, Stassi G, et al. Differentiation, phenotype, and function of interleukin-17-producing human Vgamma9Vdelta2 T cells. Blood 2011;118(1):129–38. Declaration of competing interest [10] Lee JS, Tato CM, Joyce-Shaikh B, Gulen MF, Cayatte C, Chen Y, et al. Interleukin- 23-independent IL-17 production regulates intestinal epithelial permeability. Immunity 2015;43(4):727–38. JMGRM has been a lecturer and advisory board for Abbvie, an [11] Maxwell JR, Zhang Y, Brown WA, Smith CL, Byrne FR, Fiorino M, et al. Differential lecturer for Novartis, Takeda, Grifols, Merck Sharpe &Dohme. roles for interleukin-23 and interleukin-17 in intestinal immunoregulation. LPG has receipt grants/research supports or participation in clinical Immunity 2015;43(4):739–50. [12] Bissonnette R, Nigen S, Langley RG, et al. Increased expression of IL-17A and trials (paid to Institution) from Abbvie, Almirall, Amgen, Boehringer limited involvement of IL-23 in patients with palmo-plantar (PP) pustular psoriasis Ingelheim, Janssen, Leo-Pharma, Lilly, Novartis, Pfizer, Regeneron, or PP pustulosis; results from a randomised controlled trial. J Eur Acad Dermatol Venereol 2014;28(10):1298–3015. Roche, Sanofi, UCB, has receipt of honoraria or consultation fees from 12 J.M.G. Ruiz de Morales, et al. Autoimmunity Reviews 19 (2020) 102429 [13] Boisson B, Wang C, Pedergnana V, Wu L, Cypowyj S, Rybojad M, et al. An ACT1 [42] Iversen L, Eidsmo L, Austad J, de Rie M, Osmancevic A, Skov L, et al. Secukinumab mutation selectively abolishes interleukin-17 responses in humans with chronic treatment in new-onset psoriasis: aiming to understand the potential for disease mucocutaneous candidiasis. Immunity 2013;39(4):676–86. modification – rationale and design of the randomized, multicenter STEPIn study. [14] Sherlock JP, Joyce-Shaikh B, Turner SP, Chao CC, Sathe M, Grein J, et al. IL-23 J Eur Acad Dermatol Venereol 2018;32(11):1930–9. induces spondyloarthropathy by acting on ROR-gammat+ CD3+CD4-CD8- en- [43] Kampylafka E, d Oliveira I, Linz C, Lerchen V, Englbrecht M, Simon D, et al. theseal resident T cells. Nat Med 2012;18(7):1069–76. OP0305 Disease interception in psoriasis patients with subclinical joint in- [15] Di Meglio P, Villanova F, Navarini AA, Mylonas A, Tosi I, Nestle FO, et al. flammation by interleukin 17 inhibition with secukinumab – data from a pro- Targeting CD8(+) T cells prevents psoriasis development. J Allergy Clin Immunol spective open label study. Ann Rheum Dis 2018;77(Suppl. 2):199. 2016;138(1). 274-6 e6. [44] Heo WI, Lee KE, Hong JY, Kim MN, Oh MS, Kim YS, et al. The role of interleukin- [16] Burkett PR, Meyer zu Horste G, Kuchroo VK. Pouring fuel on the fire: Th17 cells, 17 in mouse models of atopic dermatitis and contact dermatitis. Clin Exp Dermatol the environment, and autoimmunity. J Clin Invest 2015;125(6):2211–9. 2015;40(6):665–71. [17] McAleer JP, Kolls JK. Mechanisms controlling Th17 cytokine expression and host [45] Nakajima S, Kitoh A, Egawa G, Natsuaki Y, Nakamizo S, Moniaga CS, et al. IL-17A defense. J Leukoc Biol 2011;90(2):263–70. as an inducer for Th2 immune responses in murine atopic dermatitis models. J [18] Ehrenstein MR, Mauri C. If the treatment works, do we need to know why?: the Invest Dermatol 2014;134(8):2122–30. promise of immunotherapy for experimental medicine. J Exp Med [46] Batista DI, Perez L, Orfali RL, Zaniboni MC, Samorano LP, Pereira NV, et al. Profile 2007;204(10):2249–52. of skin barrier proteins (filaggrin, claudins 1 and 4) and Th1/Th2/Th17 cytokines [19] Fujino S, Andoh A, Bamba S, Ogawa A, Hata K, Araki Y, et al. Increased expression in adults with atopic dermatitis. J Eur Acad Dermatol Venereol of interleukin 17 in inflammatory bowel disease. Gut 2003;52(1):65–70. 2015;29(6):1091–5. [20] Kerami Z, Duijvis NW, Vogels EW, van Dooren FH, Moerland PD, Te Velde AA. [47] Tan Q, Yang H, Liu EM, Wang H. Establishing a role for interleukin-17 in atopic Effect of interleukin-17 on gene expression profile of fibroblasts from Crohn's dermatitis-related skin inflammation. J Cutan Med Surg 2017;21(4):308–15. disease patients. J Crohns Colitis 2014;8(10):1208–16. [48] Brunner PM, Guttman-Yassky E, Leung DY. The immunology of atopic dermatitis [21] Ndongo-Thiam N, Miossec P. A cell-based bioassay for circulating bioactive IL-17: and its reversibility with broad-spectrum and targeted therapies. J Allergy Clin application to destruction in rheumatoid arthritis. Ann Rheum Dis Immunol 2017;139(4S):S65–76. 2015;74(8):1629–31. [49] Tanemura A, Oiso N, Nakano M, Itoi S, Kawada A, Katayama I. Alopecia areata: [22] Amadi-Obi A, Yu CR, Liu X, Mahdi RM, Clarke GL, Nussenblatt RB, et al. TH17 infiltration of Th17 cells in the dermis, particularly around hair follicles. cells contribute to uveitis and scleritis and are expanded by IL-2 and inhibited by Dermatology 2013;226(4):333–6. IL-27/STAT1. Nat Med 2007;13(6):711–8. [50] Aytekin N, Akcali C, Pehlivan S, Kirtak N, Inaloz S. Investigation of interleukin-12, [23] Chi W, Zhu X, Yang P, Liu X, Lin X, Zhou H, et al. Upregulated IL-23 and IL-17 in interleukin-17 and interleukin-23 receptor gene polymorphisms in alopecia areata. Behcet patients with active uveitis. Invest Ophthalmol Vis Sci J Int Med Res 2015;43(4):526–34. 2008;49(7):3058–64. [51] Elela MA, Gawdat HI, Hegazy RA, Fawzy MM, Abdel Hay RM, Saadi D, et al. B cell [24] Patel DD, Kuchroo VK. Th17 cell pathway in human immunity: lessons from ge- activating factor and T-helper 17 cells: possible synergistic culprits in the patho- netics and therapeutic interventions. Immunity 2015;43(6):1040–51. genesis of alopecia areata. Arch Dermatol Res 2016;308(2):115–21. [25] Baeten D, Østergaard M, Wei JC, Sieper J, Järvinen P, Tam LS, et al. Risankizumab, [52] Schlapbach C, Hanni T, Yawalkar N, Hunger RE. Expression of the IL-23/Th17 an IL-23 inhibitor, for ankylosing spondylitis: results of a randomised, double- pathway in lesions of hidradenitis suppurativa. J Am Acad Dermatol blind, placebo-controlled, proof-of-concept, dose-finding phase 2 study. Ann 2011;65(4):790–8. Rheum Dis 2018;77(9):1295–302. [53] Matusiak L, Szczech J, Bieniek A, Nowicka-Suszko D, Szepietowski JC. Increased [26] Smolen JS, Agarwal SK, Ilivanova E, Xu XL, Miao Y, Zhuang Y, et al. A randomised interleukin (IL)-17 serum levels in patients with hidradenitis suppurativa: im- phase II study evaluating the efficacy and safety of subcutaneously administered plications for treatment with anti-IL-17 agents. J Am Acad Dermatol ustekinumab and guselkumab in patients with active rheumatoid arthritis despite 2017;76(4):670–5. treatment with methotrexate. Ann Rheum Dis 2017;76(5):831–9. [54] Van Tok M, van Duivenvoorde L, Kramer I, Ingold P, Taurog J, Kolbinger F, et al. [27] Yeremenko N, Paramarta JE, Baeten D. The interleukin-23/interleukin-17 immune Anti-IL-17A treatment blocks inflammation, destruction and new bone formation axis as a promising new target in the treatment of spondyloarthritis. Curr Opin in experimental spondyloarthritis in HLA-B27 transgenic rats. Arthritis Rheumatol Rheumatol 2014;26(4):361–70. 2015;67(Suppl. 10). Abstract 981. [28] Bartlett HS, Million RP. Targeting the IL-17-T(H)17 pathway. Nat Rev Drug Discov [55] Shaw AT, Gravallese EM. Mediators of inflammation and bone remodeling in 2015;14(1):11–2. rheumatic disease. Semin Cell Dev Biol 2016;49:2–10. [29] Song IH, Hermann KG, Haibel H, Althoff CE, Poddubnyy D, Listing J, et al. [56] Adamopoulos IE, Suzuki E, Chao CC, Gorman D, Adda S, Maverakis E, et al. IL-17A Relationship between active inflammatory lesions in the spine and sacroiliac joints gene transfer induces bone loss and epidermal hyperplasia associated with psor- and new development of chronic lesions on whole-body MRI in early axial spon- iatic arthritis. Ann Rheum Dis 2015;74(6):1284–92. dyloarthritis: results of the ESTHER trial at week 48. Ann Rheum Dis [57] van Tok MN, van Duivenvoorde LM, Kramer I, Ingold P, Pfister S, Roth L, et al. 2011;70(7):1257–63. Interleukin-17A inhibition diminishes inflammation and new bone formation in [30] Nestle FO, Kaplan DH, Barker J. Psoriasis. N Engl J Med 2009;361(5):496–509. experimental spondyloarthritis. Arthritis Rheumatol 2019;71(4):612–25. [31] Noda S, Krueger JG, Guttman-Yassky E. The translational revolution and use of [58] He T, Huang Y, Zhang C, Liu D, Cheng C, Xu W, et al. Interleukin-17A-promoted biologics in patients with inflammatory skin diseases. J Allergy Clin Immunol MSC2 polarization related with new bone formation of ankylosing spondylitis. 2015;135(2):324–36. Oncotarget 2017;8(57):96993–7008. [32] Keijsers RR, Joosten I, van Erp PE, Koenen HJ, van de Kerkhof PC. Cellular sources [59] Kirkham BW, Kavanaugh A, Reich K. Interleukin-17A: a unique pathway in im- of IL-17 in psoriasis: a paradigm shift? Exp Dermatol 2014;23(11):799–803. mune-mediated diseases: psoriasis, psoriatic arthritis and rheumatoid arthritis. [33] Jack C, Mashiko S, Arbour N, Bissonnette R, Sarfati M. Persistence of interleukin Immunology 2014;141(2):133–42. (IL)-17A+ T lymphocytes and IL-17A expression in treatment-resistant psoriatic [60] Belasco J, Louie JS, Gulati N, Wei N, Nograles K, Fuentes-Duculan J, et al. plaques despite ustekinumab therapy. Br J Dermatol 2017;177(1):267–70. Comparative genomic profiling of synovium versus skin lesions in psoriatic ar- [34] Yamanaka K, Yamagiwa A, Akeda T, Kondo M, Kakeda M, Habe K, et al. thritis. Arthritis Rheumatol 2015;67(4):934–44. Neutrophils are not the dominant interleukin-17 producer in psoriasis. J Dermatol [61] Celis R, Planell N, Fernandez-Sueiro JL, Sanmarti R, Ramirez J, Gonzalez-Alvaro I, 2017;44(7). e170-e1. et al. Synovial cytokine expression in psoriatic arthritis and associations with [35] Matos TR, O'Malley JT, Lowry EL, Hamm D, Kirsch IR, Robins HS, et al. Clinically lymphoid neogenesis and clinical features. Arthritis Res Ther 2012;14(2):R93. resolved psoriatic lesions contain psoriasis-specific IL-17-producing αβ T cell [62] Noordenbos T, Yeremenko N, Gofita I, van de Sande M, Tak PP, Caňete JD, et al. clones. J Clin Invest 2017;127(11):4031–41. Interleukin-17-positive mast cells contribute to synovial inflammation in spondy- [36] Blauvelt A, Reich K, Tsai TF, Tyring S, Vanaclocha F, Kingo K, et al. Secukinumab larthritis. Arthritis Rheum 2012;64(1):99–109. is superior to ustekinumab in clearing skin of subjects with moderate-to-severe [63] Chen S, Noordenbos T, Blijdorp I, van Mens L, Ambarus CA, Vogels E, et al. plaque psoriasis up to 1 year: results from the CLEAR study. J Am Acad Dermatol Histologic evidence that mast cells contribute to local tissue inflammation in 2017;76(1). 60-9 e9. peripheral spondyloarthritis by regulating interleukin-17A content. Rheumatology [37] Bissonnette R, Luger T, Thaçi D, Toth D, Lacombe A, Xia S, et al. Secukinumab (Oxford) 2019;58(4):617–27. demonstrates high sustained efficacy and a favourable safety profile in patients [64] Menon B, Gullick NJ, Walter GJ, Rajasekhar M, Garrood T, Evans HG, et al. with moderate-to-severe psoriasis through 5 years of treatment (SCULPTURE Interleukin-17+CD8+ T cells are enriched in the joints of patients with psoriatic Extension Study). J Eur Acad Dermatol Venereol 2018;32(9):1507–14. arthritis and correlate with disease activity and joint damage progression. Arthritis [38] Gordon KB, Blauvelt A, Papp KA, Langley RG, Luger T, Ohtsuki M, et al. Phase 3 Rheumatol 2014;66(5):1272–81. trials of ixekizumab in moderate-to-severe plaque psoriasis. N Engl J Med [65] Soare A, Weber S, Maul L, Rauber S, Gheorghiu AM, Luber M, et al. Cutting edge: 2016;375(4):345–56. homeostasis of innate lymphoid cells is imbalanced in psoriatic arthritis. J [39] Reich K, Gottlieb A, Lebwohl M, Kisa R, Frueh J. Secukinumab provides long Immunol 2018;200(4):1249–54. lasting complete relief for patients with difficult-to-treat palmoplantar, nail, and [66] Sakkas LI, Bogdanos DP. Are psoriasis and psoriatic arthritis the same disease? The scalp psoriasis: results from 3 phase III placebo-controlled randomized trials. San- IL-23/IL-17 axis data. Autoimmun Rev 2017;16(1):10–5. Diego, California: American Academy of Dermatology Association, Annual [67] Kavanaugh A, Mease PJ, Reimold AM, Tahir H, Rech J, Hall S, et al. Secukinumab Meeting; 2018. for long-term treatment of psoriatic arthritis: a two-year followup from a phase III, [40] Ryan C, Menter A, Guenther L, Blauvelt A, Bissonnette R, Meeuwis K, et al. Efficacy randomized, double-blind placebo-controlled study. Arthritis Care Res (Hoboken) and safety of ixekizumab in a randomized, double-blinded, placebo-controlled 2017;69(3):347–55. phase IIIb study of patients with moderate-to-severe genital psoriasis. Br J [68] Mease PJ, Kavanaugh A, Reimold A, Tahir H, Rech J, Hall S, et al. Secukinumab in Dermatol 2018;179(4):844–52. the treatment of psoriatic arthritis: efficacy and safety results through 3 years from [41] Lebwohl M, Iversen L, Eidsmo L, Messina I, You R, Milutinovic M. Long-term the year 1 extension of the randomised phase III FUTURE 1 trial. RMD Open psoriasis control following secukinumab discontinuation indicates disease mod- 2018;4(2):e000723. ification of moderate to severe psoriasis. Presented as a poster presentation at the [69] Mease P, Kavanaugh A, Reimold A, Tahir H, Rech J, Hall S, et al. Secukinumab 13th Annual Maui Derm for Dermatologists (2017). J Clin Aesthet Dermatol provides sustained improvements in the signs and symptoms in psoriatic arthritis: 2017;10:S7–31. final 5 year efficacy and safety results from a phase 3 trial. 2018 ACR/ARHP 13 J.M.G. Ruiz de Morales, et al. Autoimmunity Reviews 19 (2020) 102429 Annual Meeting: Arthritis Rheumatol. 2018. 2013;10(6):330–44. [70] Baraliakos X, Coates LC, Gossec L, Jeka S, Mera Varela A, Schulz B, et al. [99] Asrih M, Jornayvaz FR. Metabolic syndrome and nonalcoholic fatty liver disease: is Secukinumab improves axial manifestations in patients with psoriatic arthritis and insulin resistance the link? Mol Cell Endocrinol 2015;418(Pt 1):55–65. inadequate response to NSAIDS: primary analysis of the maximise trial. Am Coll [100] Giles DA, Moreno-Fernandez ME, Divanovic S. IL-17 axis driven inflammation in Rheumatol 2019;78(Suppl. 2):195–6. non-alcoholic fatty liver disease progression. Curr Drug Targets [71] Kampylafka E, d'Oliveira I, Linz C, Lerchen V, Stemmler F, Simon D, et al. 2015;16(12):1315–23. Resolution of synovitis and arrest of catabolic and anabolic bone changes in pa- [101] Kahraman A, Schlattjan M, Kocabayoglu P, Yildiz-Meziletoglu S, Schlensak M, tients with psoriatic arthritis by IL-17A blockade with secukinumab: results from Fingas CD, et al. Major histocompatibility complex class I-related chains A and B the prospective PSARTROS study. Arthritis Res Ther 2018;20(1):153. (MIC A/B): a novel role in nonalcoholic steatohepatitis. Hepatology [72] Egeberg A, Thyssen JP, Jensen P, Gislason GH, Skov L. Risk of myocardial in- 2010;51(1):92–102. farction in patients with psoriasis and psoriatic arthritis: a nationwide cohort [102] Xu CF, Yu CH, Li YM, Xu L, Du J, Shen Z. Association of the frequency of per- study. Acta Derm Venereol 2017;97(7):819–24. ipheral natural killer T cells with nonalcoholic fatty liver disease. World J [73] Jandus C, Bioley G, Rivals JP, Dudler J, Speiser D, Romero P. Increased numbers of Gastroenterol 2007;13(33):4504–8. circulating polyfunctional Th17 memory cells in patients with seronegative [103] Ahmed M, Gaffen SL. IL-17 in obesity and adipogenesis. Cytokine Growth Factor spondylarthritides. Arthritis Rheum 2008;58(8):2307–17. Rev 2010;21(6):449–53. [74] Zhang L, Li YG, Li YH, Qi L, Liu XG, Yuan CZ, et al. Increased frequencies of Th22 [104] Tang Y, Bian Z, Zhao L, Liu Y, Liang S, Wang Q, et al. Interleukin-17 exacerbates cells as well as Th17 cells in the peripheral blood of patients with ankylosing hepatic steatosis and inflammation in non-alcoholic fatty liver disease. Clin Exp spondylitis and rheumatoid arthritis. PLoS One 2012;7(4):e31000. Immunol 2011;166(2):281–90. [75] Ciccia F, Rizzo A, Triolo G. Subclinical gut inflammation in ankylosing spondylitis. [105] Berlanga A, Guiu-Jurado E, Porras JA, Auguet T. Molecular pathways in non-al- Curr Opin Rheumatol 2016;28(1):89–96. coholic fatty liver disease. Clin Exp Gastroenterol 2014;7:221–39. [76] Braun J, Baraliakos X, Deodhar A, Baeten D, Sieper J, Emery P, et al. Effect of [106] Wenfeng Z, Yakun W, Di M, Jianping G, Chuanxin W, Chun H. Kupffer cells: in- secukinumab on clinical and radiographic outcomes in ankylosing spondylitis: 2- creasingly significant role in nonalcoholic fatty liver disease. Ann Hepatol year results from the randomised phase III MEASURE 1 study. Ann Rheum Dis 2014;13(5):489–95. 2017;76(6):1070–7. [107] Meng F, Wang K, Aoyama T, Grivennikov SI, Paik Y, Scholten D, et al. Interleukin- [77] Baraliakos X, Kivitz AJ, Deodhar AA, Braun J, Wei JC, Delicha EM, et al. Long-term 17 signaling in inflammatory, Kupffer cells, and hepatic stellate cells exacerbates effects of interleukin-17A inhibition with secukinumab in active ankylosing liver fibrosis in mice. Gastroenterology 2012;143(3). 765-76.e3. spondylitis: 3-year efficacy and safety results from an extension of the Phase 3 [108] Weiskirchen R, Tacke F. Cellular and molecular functions of hepatic stellate cells MEASURE 1 trial. Clin Exp Rheumatol 2018;36(1):50–5. in inflammatory responses and liver immunology. Hepatobiliary Surg Nutr [78] Baraliakos X, Braun J, Deodhar A, Poddubnyy D, Kivitz A, Tahir H, Van den Bosch 2014;3(6):344–63. F, Delicha EM, Talloczy Z, Fierlinger A. Long-term efficacy of secukinumab 150 mg [109] Vilar-Gomez E, Martinez-Perez Y, Calzadilla-Bertot L, Torres-Gonzalez A, Gra- in ankylosing spondylitis: 5-year results from the phase 3 MEASURE 1 extension Oramas B, Gonzalez-Fabian L, et al. Weight loss through lifestyle modification study. RMD Open. 2019 Sep 3;5(2):e001005. https://doi.org/10.1136/rmdopen- significantly reduces features of nonalcoholic steatohepatitis. Gastroenterology 2019-001005. 2015;149(2). 367-78.e5; quiz e14-5. [79] Blanco FJ, Moricke R, Dokoupilova E, Codding C, Neal J, Andersson M, et al. [110] Gomes AL, Teijeiro A, Burén S, Tummala KS, Yilmaz M, Waisman A, et al. Secukinumab in active rheumatoid arthritis: a phase III randomized, double-blind, Metabolic inflammation-associated IL-17A causes non-alcoholic steatohepatitis active comparator- and placebo-controlled study. Arthritis Rheumatol and hepatocellular carcinoma. Cancer Cell 2016;30(1):161–75. 2017;69(6):1144–53. [111] Sanyal AJ, Chalasani N, Kowdley KV, McCullough A, Diehl AM, Bass NM, et al. [80] Canete JD, Celis R, Yeremenko N, Sanmarti R, van Duivenvoorde L, Ramirez J, Pioglitazone, vitamin E or placebo for nonalcoholic steatohepatitis. N Engl J Med et al. Ectopic lymphoid neogenesis is strongly associated with activation of the IL- 2010;362(18):1675–85. 23 pathway in rheumatoid synovitis. Arthritis Res Ther 2015;17:173. [112] Li XL, Dou YC, Liu Y, Shi CW, Cao LL, Zhang XQ, et al. Atorvastatin ameliorates [81] van Tok MN, Na S, Lao CR, Alvi M, Pots D, van de Sande MGH, et al. The initiation, experimental autoimmune neuritis by decreased Th1/Th17 cytokines and up- but not the persistence, of experimental spondyloarthritis is dependent on inter- regulated T regulatory cells. Cell Immunol 2011;271(2):455–61. leukin-23 signaling. Front Immunol 2018;9:1550. [113] Zhang X, Markovic-Plese S. Statins' immunomodulatory potential against Th17 [82] Gaffen SL. Structure and signalling in the IL-17 receptor family. Nat Rev Immunol cell-mediated autoimmune response. Immunol Res 2008;41(3):165–74. 2009;9(8):556–67. [114] Barchetta I, Angelico F, Del Ben M, Baroni MG, Pozzilli P, Morini S, et al. Strong [83] Beringer A, Miossec P. IL-17 and IL-17-producing cells and liver diseases, with association between non alcoholic fatty liver disease (NAFLD) and low 25(OH) focus on autoimmune liver diseases. Autoimmun Rev 2018;17(12):1176–85. vitamin D levels in an adult population with normal serum liver enzymes. BMC [84] Nagata T, McKinley L, Peschon JJ, Alcorn JF, Aujla SJ, Kolls JK. Requirement of IL- Med 2011;9:85. 17RA in Con A induced hepatitis and negative regulation of IL-17 production in [115] Hasegawa T, Yoneda M, Nakamura K, Makino I, Terano A. Plasma transforming mouse T cells. J Immunol 2008;181(11):7473–9. growth factor-beta1 level and efficacy of alpha-tocopherol in patients with non- [85] Yan S, Wang L, Liu N, Wang Y, Chu Y. Critical role of interleukin-17/interleukin-17 alcoholic steatohepatitis: a pilot study. Aliment Pharmacol Ther receptor axis in mediating Con A-induced hepatitis. Immunol Cell Biol 2001;15(10):1667–72. 2012;90(4):421–8. [116] Shi W, Zhu Q, Gu J, Liu X, Lu L, Qian X, et al. Anti-IL-17 antibody improves [86] Du WJ, Zhen JH, Zeng ZQ, Zheng ZM, Xu Y, Qin LY, et al. Expression of inter- hepatic steatosis by suppressing interleukin-17-related fatty acid synthesis and leukin-17 associated with disease progression and liver fibrosis with hepatitis B metabolism. Clin Dev Immunol 2013;2013:253046. virus infection: IL-17 in HBV infection. Diagn Pathol 2013;8:40. [117] Rolla S, Alchera E, Imarisio C, Bardina V, Valente G, Cappello P, et al. The balance [87] Bălănescu P, Lădaru A, Voiosu T, Nicolau A, Ene M, Bălănescu E. Th17 and IL-17 between IL-17 and IL-22 produced by liver-infiltrating T-helper cells critically immunity in chronic hepatitis C infection. Rom J Intern Med 2012;50(1):13–8. controls NASH development in mice. Clin Sci (Lond) 2016;130(3):193–203. [88] Lemmers A, Moreno C, Gustot T, Maréchal R, Degré D, Demetter P, et al. The [118] Madhur MS, Lob HE, McCann LA, Iwakura Y, Blinder Y, Guzik TJ, et al. Interleukin interleukin-17 pathway is involved in human alcoholic liver disease. Hepatology 17 promotes angiotensin II-induced hypertension and vascular dysfunction. 2009;49(2):646–57. Hypertension 2010;55(2):500–7. [89] Shi T, Zhang T, Zhang L, Yang Y, Zhang H, Zhang F. The distribution and the [119] Savioli B, Abdulahad WH, Brouwer E, Kallenberg CGM, de Souza AWS. Are cy- fibrotic role of elevated inflammatory Th17 cells in patients with primary biliary tokines and chemokines suitable biomarkers for Takayasu arteritis? Autoimmun cirrhosis. Medicine (Baltimore) 2015;94(44):e1888. Rev 2017;16(10):1071–8. [90] Fábrega E, López-Hoyos M, San Segundo D, Casafont F, Pons-Romero F. Changes in [120] Liuzzo G, Trotta F, Pedicino D. Interleukin-17 in atherosclerosis and cardiovas- the serum levels of interleukin-17/interleukin-23 during acute rejection in liver cular disease: the good, the bad, and the unknown. Eur Heart J 2013;34(8):556–9. transplantation. Liver Transpl 2009;15(6):629–33. [121] Chen M, Yu L, Liu Q, Jiang H, Zhou S. Interleukin-17 inhibition: an important [91] Kang Y, Su G, Sun J, Zhang Y. Activation of the TLR4/MyD88 signaling pathway target for attenuating myocardial ischemia and reperfusion injury. Int J Cardiol contributes to the development of human hepatocellular carcinoma via upregu- 2015;198:89–90. lation of IL-23 and IL-17A. Oncol Lett 2018;15(6):9647–54. [122] Liao YH, Xia N, Zhou SF, Tang TT, Yan XX, Lv BJ, et al. Interleukin-17A con- [92] Zhang H, Bernuzzi F, Lleo A, Ma X, Invernizzi P. Therapeutic potential of IL-17- tributes to myocardial ischemia/reperfusion injury by regulating cardiomyocyte mediated signaling pathway in autoimmune liver diseases. Mediators Inflamm apoptosis and neutrophil infiltration. J Am Coll Cardiol 2012;59(4):420–9. 2015;2015:436450. [123] Simon T, Taleb S, Danchin N, Laurans L, Rousseau B, Cattan S, et al. Circulating [93] Younossi ZM, Stepanova M, Afendy M, Fang Y, Younossi Y, Mir H, et al. Changes in levels of interleukin-17 and cardiovascular outcomes in patients with acute the prevalence of the most common causes of chronic liver diseases in the United myocardial infarction. Eur Heart J 2013;34(8):570–7. States from 1988 to 2008. Clin Gastroenterol Hepatol 2011;9(6). 524-30.e1; quiz [124] Elnabawi YA, Dey AK, Goyal A, Groenendyk JW, Chung JH, Belur AD, et al. e60. Coronary artery plaque characteristics and treatment with biologic therapy in [94] Wong RJ, Aguilar M, Cheung R, Perumpail RB, Harrison SA, Younossi ZM, et al. severe psoriasis: results from a prospective observational study. Cardiovasc Res Nonalcoholic steatohepatitis is the second leading etiology of liver disease among 2019;115(4):721–8. adults awaiting liver transplantation in the United States. Gastroenterology [125] Robert M, Miossec P. Effects of interleukin 17 on the cardiovascular system. 2015;148(3):547–55. Autoimmun Rev 2017;16(9):984–91. [95] EASL-EASD-EASO Clinical Practice Guidelines for the management of non-alco- [126] Zhu F, Wang Q, Guo C, Wang X, Cao X, Shi Y, et al. IL-17 induces apoptosis of holic fatty liver disease. J Hepatol 2016;64(6):1388–402. vascular endothelial cells: a potential mechanism for human acute coronary syn- [96] Ganzetti G, Campanati A, Offidani A. Non-alcoholic fatty liver disease and psor- drome. Clin Immunol 2011;141(2):152–60. iasis: so far so near. World J Hepatol 2015;7(3):315–26. [127] von Stebut E, Reich K, Thaçi D, Koenig W, Pinter A, Körber A, et al. Impact of [97] Gerber L, Otgonsuren M, Mishra A, Escheik C, Birerdinc A, Stepanova M, et al. secukinumab on endothelial dysfunction and other cardiovascular disease para- Non-alcoholic fatty liver disease (NAFLD) is associated with low level of physical meters in psoriasis patients over 52 weeks. J Invest Dermatol activity: a population-based study. Aliment Pharmacol Ther 2012;36(8):772–81. 2019;139(5):1054–62. [98] Anstee QM, Targher G, Day CP. Progression of NAFLD to diabetes mellitus, car- [128] Zhou SF, Yuan J, Liao MY, Xia N, Tang TT, Li JJ, et al. IL-17A promotes ventricular diovascular disease or cirrhosis. Nat Rev Gastroenterol Hepatol remodeling after myocardial infarction. J Mol Med (Berl) 2014;92(10):1105–16. 14 J.M.G. Ruiz de Morales, et al. Autoimmunity Reviews 19 (2020) 102429 [129] Su SA, Yang D, Zhu W, Cai Z, Zhang N, Zhao L, et al. Interleukin-17A mediates 2016;11. CD007572. cardiomyocyte apoptosis through Stat3-iNOS pathway. Biochim Biophys Acta [157] Feagan BG, Panés J, Ferrante M, Kaser A, D'Haens GR, Sandborn WJ, et al. 2016;1863(11):2784–94. Risankizumab in patients with moderate to severe Crohn's disease: an open-label [130] Sandip C, Tan L, Huang J, Li Q, Ni L, Cianflone K, et al. Common variants in IL- extension study. Lancet Gastroenterol Hepatol 2018;3(10):671–80. 17A/IL-17RA axis contribute to predisposition to and progression of congestive [158] Hueber W, Sands BE, Lewitzky S, Vandemeulebroecke M, Reinisch W, Higgins PD, heart failure. Medicine (Baltimore) 2016;95(27):e4105. et al. Secukinumab, a human anti-IL-17A monoclonal antibody, for moderate to [131] Krueger JG, Brunner PM. Interleukin-17 alters the biology of many cell types in- severe Crohn's disease: unexpected results of a randomised, double-blind placebo- volved in the genesis of psoriasis, systemic inflammation and associated co- controlled trial. Gut 2012;61(12):1693–700. morbidities. Exp Dermatol 2018;27(2):115–23. [159] Colombel JF, Sendid B, Jouault T, Poulain D. Secukinumab failure in Crohn's [132] Mucientes A, Marquez A, Cordero-Coma M, Martin-Villa JM, Gorrono-Echebarria disease: the yeast connection? Gut 2013;62(5):800–1. MB, Blanco R, et al. Specific association of IL17A genetic variants with panuveitis. [160] Raine T, Kaser A. Seventeen in Crohn's disease: less prime than we thought? Gut Br J Ophthalmol 2015;99(4):566–70. 2012;61(12):1653–4. [133] Mesquida M, Molins B, Llorenc V, Sainz de la Maza M, Hernandez MV, Espinosa G, [161] Targan SR, Feagan B, Vermeire S, Panaccione R, Melmed GY, Landers C, et al. A et al. Proinflammatory cytokines and C-reactive protein in uveitis associated with randomized, double-blind, placebo-controlled phase 2 study of brodalumab in Behcet's disease. Mediat Inflamm 2014;2014:396204. patients with moderate-to-severe Crohn's disease. Am J Gastroenterol [134] Hueber W, Patel DD, Dryja T, Wright AM, Koroleva I, Bruin G, et al. Effects of 2016;111(11):1599–607. AIN457, a fully human antibody to interleukin-17A, on psoriasis, rheumatoid [162] Jenq RR, van den Brink MR. Allogeneic haematopoietic stem cell transplantation: arthritis, and uveitis. Sci Transl Med 2010;2(52). 52ra72. individualized stem cell and immune therapy of cancer. Nat Rev Cancer [135] Dick AD, Tugal-Tutkun I, Foster S, Zierhut M, Melissa Liew SH, Bezlyak V, et al. 2010;10(3):213–21. Secukinumab in the treatment of noninfectious uveitis: results of three rando- [163] Arai S, Jagasia M, Storer B, Chai X, Pidala J, Cutler C, et al. Global and organ- mized, controlled clinical trials. Ophthalmology 2013;120(4):777–87. specific chronic graft-versus-host disease severity according to the 2005 NIH [136] Letko E, Yeh S, Foster CS, Pleyer U, Brigell M, Grosskreutz CL, et al. Efficacy and Consensus Criteria. Blood 2011;118(15):4242–9. safety of intravenous secukinumab in noninfectious uveitis requiring steroid- [164] Flowers ME, Martin PJ. How we treat chronic graft-versus-host disease. Blood sparing immunosuppressive therapy. Ophthalmology 2015;122(5):939–48. 2015;125(4):606–15. [137] Liu R, Gao C, Chen H, Li Y, Jin Y, Qi H. Analysis of Th17-associated cytokines and [165] Carlson MJ, West ML, Coghill JM, Panoskaltsis-Mortari A, Blazar BR, Serody JS. In clinical correlations in patients with dry eye disease. PLoS One vitro-differentiated TH17 cells mediate lethal acute graft-versus-host disease with 2017;12(4):e0173301. severe cutaneous and pulmonary pathologic manifestations. Blood [138] Jabarin B, Solomon A, Amer R. Interleukin-17 and its correlation with vascular 2009;113(6):1365–74. endothelial growth factor expression in ocular surface pathologies: a histologic [166] Gartlan KH, Markey KA, Varelias A, Bunting MD, Koyama M, Kuns RD, et al. Tc17 study. Eur J Ophthalmol 2016;26(4):283–6. cells are a proinflammatory, plastic lineage of pathogenic CD8+ T cells that in- [139] Chen H, Ren X, Liao N, Wen F. Th17 cell frequency and IL-17A concentrations in duce GVHD without antileukemic effects. Blood 2015;126(13):1609–20. peripheral blood mononuclear cells and vitreous fluid from patients with diabetic [167] Bruggen MC, Klein I, Greinix H, Bauer W, Kuzmina Z, Rabitsch W, et al. Diverse T- retinopathy. J Int Med Res 2016;44(6):1403–13. cell responses characterize the different manifestations of cutaneous graft-versus- [140] Kebir H, Kreymborg K, Ifergan I, Dodelet-Devillers A, Cayrol R, Bernard M, et al. host disease. Blood 2014;123(2):290–9. Human TH17 lymphocytes promote blood-brain barrier disruption and central [168] Varelias A, Ormerod KL, Bunting MD, Koyama M, Gartlan KH, Kuns RD, et al. nervous system inflammation. Nat Med 2007;13(10):1173–5. Acute graft-versus-host disease is regulated by an IL-17-sensitive microbiome. [141] Debnath M, Nagappa M, Subbanna M, Sundaravadivel P, Talukdar PM, Blood 2017;129(15):2172–85. Shivakumar V, et al. Th17 pathway signatures in a large Indian cohort of Guillain [169] Liu X, Jin H, Zhang G, Lin X, Chen C, Sun J, et al. Intratumor IL-17-positive mast Barré syndrome. J Neuroimmunol 2018;323:125–30. cells are the major source of the IL-17 that is predictive of survival in gastric [142] Durelli L, Conti L, Clerico M, Boselli D, Contessa G, Ripellino P, et al. T-helper 17 cancer patients. PLoS One 2014;9(9):e106834. cells expand in multiple sclerosis and are inhibited by interferon-beta. Ann Neurol [170] Liu J, Duan Y, Cheng X, Chen X, Xie W, Long H, et al. IL-17 is associated with poor 2009;65(5):499–509. prognosis and promotes angiogenesis via stimulating VEGF production of cancer [143] Tzartos JS, Friese MA, Craner MJ, Palace J, Newcombe J, Esiri MM, et al. cells in colorectal carcinoma. Biochem Biophys Res Commun 2011;407(2):348–54. Interleukin-17 production in central nervous system-infiltrating T cells and glial [171] Chen X, Wan J, Liu J, Xie W, Diao X, Xu J, et al. Increased IL-17-producing cells cells is associated with active disease in multiple sclerosis. Am J Pathol correlate with poor survival and lymphangiogenesis in NSCLC patients. Lung 2008;172(1):146–55. Cancer 2010;69(3):348–54. [144] Hu D, Notarbartolo S, Croonenborghs T, Patel B, Cialic R, Yang TH, et al. [172] Zhu X, Mulcahy LA, Mohammed RA, Lee AH, Franks HA, Kilpatrick L, et al. IL-17 Transcriptional signature of human pro-inflammatory T. Nat Commun expression by breast-cancer-associated macrophages: IL-17 promotes invasiveness 2017;8(1):1600. of breast cancer cell lines. Breast Cancer Res 2008;10(6):R95. [145] Haas J, Schneider K, Schwarz A, Korporal-Kuhnke M, Faller S, von Glehn F, et al. [173] Kato T, Furumoto H, Ogura T, Onishi Y, Irahara M, Yamano S, et al. Expression of Th17 cells: a prognostic marker for MS rebound after natalizumab cessation? Mult IL-17 mRNA in ovarian cancer. Biochem Biophys Res Commun Scler 2017;23(1):114–8. 2001;282(3):735–8. [146] Pandiyan P, Yang XP, Saravanamuthu SS, Zheng L, Ishihara S, O'Shea JJ, et al. The [174] Xiang T, Long H, He L, Han X, Lin K, Liang Z, et al. Interleukin-17 produced by role of IL-15 in activating STAT5 and fine-tuning IL-17A production in CD4 T tumor microenvironment promotes self-renewal of CD133+ cancer stem-like cells lymphocytes. J Immunol 2012;189(9):4237–46. in ovarian cancer. Oncogene 2015;34(2):165–76. [147] Havrdova E, Belova A, Goloborodko A, Tisserant A, Wright A, Wallstroem E, et al. [175] Ciree A, Michel L, Camilleri-Broet S, Jean Louis F, Oster M, Flageul B, et al. Activity of secukinumab, an anti-IL-17A antibody, on brain lesions in RRMS: re- Expression and activity of IL-17 in cutaneous T-cell lymphomas (mycosis fun- sults from a randomized, proof-of-concept study. J Neurol 2016;263(7):1287–95. goides and Sezary syndrome). Int J Cancer 2004;112(1):113–20. [148] Han RK, Cheng YF, Zhou SS, Guo H, He RD, Chi LJ, et al. Increased circulating [176] Qian X, Chen H, Wu X, Hu L, Huang Q, Jin Y. Interleukin-17 acts as double-edged Th17 cell populations and elevated CSF osteopontin and IL-17 concentrations in sword in anti-tumor immunity and tumorigenesis. Cytokine 2017;89:34–44. patients with Guillain-Barré syndrome. J Clin Immunol 2014;34(1):94–103. [177] Nam JS, Terabe M, Kang MJ, Chae H, Voong N, Yang YA, et al. Transforming [149] Waisman A, Hauptmann J, Regen T. The role of IL-17 in CNS diseases. Acta growth factor beta subverts the immune system into directly promoting tumor Neuropathol 2015;129(5):625–37. growth through interleukin-17. Cancer Res 2008;68(10):3915–23. [150] Beurel E, Harrington LE, Jope RS. Inflammatory T helper 17 cells promote de- [178] Hirahara N, Nio Y, Sasaki S, Minari Y, Takamura M, Iguchi C, et al. Inoculation of pression-like behavior in mice. Biol Psychiatry 2013;73(7):622–30. human interleukin-17 gene-transfected Meth-A fibrosarcoma cells induces T cell- [151] Kappos L, Bar-Or A, Cree BAC, Fox RJ, Giovannoni G, Gold R, et al. Siponimod dependent tumor-specific immunity in mice. Oncology 2001;61(1):79–89. versus placebo in secondary progressive multiple sclerosis (EXPAND): a double- [179] Li J, Lau GK, Chen L, Dong SS, Lan HY, Huang XR, et al. Interleukin 17A promotes blind, randomised, phase 3 study. Lancet 2018;391(10127):1263–73. hepatocellular carcinoma metastasis via NF-kB induced matrix metalloproteinases [152] Behrangi N, Fischbach F, Kipp M. Mechanism of siponimod: anti-inflammatory 2 and 9 expression. PLoS One 2011;6(7):e21816. and neuroprotective mode of action. Cells 2019;8(1). [180] He D, Li H, Yusuf N, Elmets CA, Li J, Mountz JD, et al. IL-17 promotes tumor [153] Holtta V, Klemetti P, Sipponen T, Westerholm-Ormio M, Kociubinski G, Salo H, development through the induction of tumor promoting microenvironments at et al. IL-23/IL-17 immunity as a hallmark of Crohn's disease. Inflamm Bowel Dis tumor sites and myeloid-derived suppressor cells. J Immunol 2010;184(5):2281–8. 2008;14(9):1175–84. [181] Bailey SR, Nelson MH, Himes RA, Li Z, Mehrotra S, Paulos CM. Th17 cells in [154] Jiang W, Su J, Zhang X, Cheng X, Zhou J, Shi R, et al. Elevated levels of Th17 cells cancer: the ultimate identity crisis. Front Immunol 2014;5:276. and Th17-related cytokines are associated with disease activity in patients with [182] Llosa NJ, Geis AL, Thiele Orberg E, Housseau F. Interleukin-17 and type 17 helper inflammatory bowel disease. Inflamm Res 2014;63(11):943–50. T cells in cancer management and research. Immunotargets Ther 2014;3:39–54. [155] Jostins L, Ripke S, Weersma RK, Duerr RH, McGovern DP, Hui KY, et al. Host- [183] Murugaiyan G, Mittal A, Lopez-Diego R, Maier LM, Anderson DE, Weiner HL. IL-27 microbe interactions have shaped the genetic architecture of inflammatory bowel is a key regulator of IL-10 and IL-17 production by human CD4+ T cells. J disease. Nature 2012;491(7422):119–24. Immunol 2009;183(4):2435–43. [156] MacDonald JK, Nguyen TM, Khanna R, Timmer A. Anti-IL-12/23p40 antibodies [184] Ramirez-Carrozzi V, Ota N, Sambandan A, Wong K. J Immunol2019;202:1935–41. for induction of remission in Crohn's disease. Cochrane Database Syst Rev 15