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22-04-2016 | Spondyloarthropathies | Review | Article

The Bench-to-Bedside Story of IL-17 and the Therapeutic Efficacy of its Targeting in Spondyloarthritis

Journal: Current Rheumatology Reports

Author: Judith A. Smith

Abstract

TNF-blocking biologics have revolutionized the care of patients with spondyloarthritis, a group of clinically overlapping conditions that includes ankylosing spondylitis and psoriatic arthritis. However, incomplete response rates speak to the need for alternative therapeutic approaches. Over the last decade, animal models, genetics, and translational studies have implicated the excessive production of a pro-inflammatory cytokine interleukin-17 (IL-17) along with another IL-17-promoting cytokine IL-23 in the pathogenesis of spondyloarthritis. Genome-wide studies identified disease associations with multiple genes regulating IL-23/IL-17 immune pathway activity. Direct examination of the patient blood and tissues revealed excessive IL-17 and IL-23 production by diverse cell types. Murine models both underscored the sufficiency of excess IL-23 in driving disease phenotype and predicted utility in IL-23/IL-17 pathway blockade. However, the clinical efficacy of agents such as secukinumab and ustekinumab, which block IL-17 and IL-23/IL-12 respectively, provided exciting proof of concept.

Dougados M, Baeten D. Spondyloarthritis. Lancet. 2011;377:2127–37.CrossRefPubMed

van der Heijde D, Dijkmans B, Geusens P, Sieper J, DeWoody K, et al. Efficacy and safety of infliximab in patients with ankylosing spondylitis: results of a randomized, placebo-controlled trial (ASSERT). Arthritis Rheum. 2005;52:582–91.CrossRefPubMed

van der Heijde D, Kivitz A, Schiff MH, Sieper J, Dijkmans BA, et al. Efficacy and safety of adalimumab in patients with ankylosing spondylitis: results of a multicenter, randomized, double-blind, placebo-controlled trial. Arthritis Rheum. 2006;54:2136–46.CrossRefPubMed

Mosmann TR, Cherwinski H, Bond MW, Giedlin MA, Coffman RL. Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins. J Immunol. 1986;136:2348–57.PubMed

Seder RA, Paul WE. Acquisition of lymphokine-producing phenotype by CD4+ T cells. Annu Rev Immunol. 1994;12:635–73.CrossRefPubMed

Leonard JP, Waldburger KE, Goldman SJ. Prevention of experimental autoimmune encephalomyelitis by antibodies against interleukin 12. J Exp Med. 1995;181:381–6.CrossRefPubMed

Gran B, Zhang GX, Yu S, Li J, Chen XH, et al. IL-12p35-deficient mice are susceptible to experimental autoimmune encephalomyelitis: evidence for redundancy in the IL-12 system in the induction of central nervous system autoimmune demyelination. J Immunol. 2002;169:7104–10.CrossRefPubMed

Krakowski M, Owens T. Interferon-gamma confers resistance to experimental allergic encephalomyelitis. Eur J Immunol. 1996;26:1641–6.CrossRefPubMed

Murphy CA, Langrish CL, Chen Y, Blumenschein W, McClanahan T, et al. Divergent pro- and antiinflammatory roles for IL-23 and IL-12 in joint autoimmune inflammation. J Exp Med. 2003;198:1951–7.CrossRefPubMedPubMedCentral

10.

Cua DJ, Sherlock J, Chen Y, Murphy CA, Joyce B, et al. Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain. Nature. 2003;421:744–8.CrossRefPubMed

11.

Dallenbach K, Maurer P, Rohn T, Zabel F, Kopf M, et al. Protective effect of a germline, IL-17-neutralizing antibody in murine models of autoimmune inflammatory disease. Eur J Immunol. 2015;45:1238–47.CrossRefPubMed

12.••

Patel DD, Kuchroo VK. Th17 cell pathway in human immunity: lessons from genetics and therapeutic interventions. Immunity. 2015;43:1040–51. An excellent recent review of Th17 in human disease.CrossRefPubMed

13.

McGeachy MJ, Chen Y, Tato CM, Laurence A, Joyce-Shaikh B, et al. The interleukin 23 receptor is essential for the terminal differentiation of interleukin 17-producing effector T helper cells in vivo. Nat Immunol. 2009;10:314–24.CrossRefPubMedPubMedCentral

14.

Ouyang W, Kolls JK, Zheng Y. The biological functions of T helper 17 cell effector cytokines in inflammation. Immunity. 2008;28:454–67.CrossRefPubMedPubMedCentral

15.

Awasthi A, Riol-Blanco L, Jager A, Korn T, Pot C, et al. Cutting edge: IL-23 receptor GFP reporter mice reveal distinct populations of IL-17-producing cells. J Immunol. 2009;182:5904–8.CrossRefPubMedPubMedCentral

16.

Adamopoulos IE, Chao CC, Geissler R, Laface D, Blumenschein W, et al. Interleukin-17A upregulates receptor activator of NF-kappaB on osteoclast precursors. Arthritis Res Ther. 2010;12:R29. doi:10.1186/ar2936.CrossRefPubMedPubMedCentral

17.

Chen L, Wei XQ, Evans B, Jiang W, Aeschlimann D. IL-23 promotes osteoclast formation by up-regulation of receptor activator of NF-kappaB (RANK) expression in myeloid precursor cells. Eur J Immunol. 2008;38:2845–54.CrossRefPubMed

18.

Yago T, Nanke Y, Ichikawa N, Kobashigawa T, Mogi M, et al. IL-17 induces osteoclastogenesis from human monocytes alone in the absence of osteoblasts, which is potently inhibited by anti-TNF-alpha antibody: a novel mechanism of osteoclastogenesis by IL-17. J Cell Biochem. 2009;108:947–55.CrossRefPubMed

19.

Kotake S, Udagawa N, Takahashi N, Matsuzaki K, Itoh K, et al. IL-17 in synovial fluids from patients with rheumatoid arthritis is a potent stimulator of osteoclastogenesis. J Clin Invest. 1999;103:1345–52.CrossRefPubMedPubMedCentral

20.

Huang H, Kim HJ, Chang EJ, Lee ZH, Hwang SJ, et al. IL-17 stimulates the proliferation and differentiation of human mesenchymal stem cells: implications for bone remodeling. Cell Death Differ. 2009;16:1332–43.CrossRefPubMed

21.

Burton PR, Clayton DG, Cardon LR, Craddock N, Deloukas P, et al. Association scan of 14,500 nonsynonymous SNPs in four diseases identifies autoimmunity variants. Nat Genet. 2007;39:1329–37.CrossRefPubMed

22.

Di Meglio P, Di Cesare A, Laggner U, Chu CC, Napolitano L, et al. The IL23R R381Q gene variant protects against immune-mediated diseases by impairing IL-23-induced Th17 effector response in humans. PLoS ONE. 2011;6, e17160.CrossRefPubMedPubMedCentral

23.

Davidson SI, Liu Y, Danoy PA, Wu X, Thomas GP, et al. Association of STAT3 and TNFRSF1A with ankylosing spondylitis in Han Chinese. Ann Rheum Dis. 2011;70:289–92.CrossRefPubMed

24.

Davidson SI, Jiang L, Cortes A, Wu X, Glazov EA, et al. Brief report: high-throughput sequencing of IL23R reveals a low-frequency, nonsynonymous single-nucleotide polymorphism that is associated with ankylosing spondylitis in a Han Chinese population. Arthritis Rheum. 2013;65:1747–52.CrossRefPubMed

25.

Reveille JD, Sims AM, Danoy P, Evans DM, Leo P, et al. Genome-wide association study of ankylosing spondylitis identifies non-MHC susceptibility loci. Nat Genet. 2010;42:123–7.CrossRefPubMedPubMedCentral

26.

Evans DM, Spencer CC, Pointon JJ, Su Z, Harvey D, et al. Interaction between ERAP1 and HLA-B27 in ankylosing spondylitis implicates peptide handling in the mechanism for HLA-B27 in disease susceptibility. Nat Genet. 2011;43:761–7.CrossRefPubMedPubMedCentral

27.

Cortes A, Hadler J, Pointon JP, Robinson PC, Karaderi T, et al. Identification of multiple risk variants for ankylosing spondylitis through high-density genotyping of immune-related loci. Nat Genet. 2013;45:730–8.CrossRefPubMedPubMedCentral

28.

Danoy P, Pryce K, Hadler J, Bradbury LA, Farrar C, et al. Association of variants at 1q32 and STAT3 with ankylosing spondylitis suggests genetic overlap with Crohn’s disease. PLoS Genet. 2010;6, e1001195.CrossRefPubMedPubMedCentral

29.••

Brown MA, Kenna T, Wordsworth BP. Genetics of ankylosing spondylitis—insights into pathogenesis. Nat Rev Rheumatol. 2016;12:81–91. An excellent, comprehensive recent review of ankylosing spondylitis genetics.CrossRefPubMed

30.

Coffre M, Roumier M, Rybczynska M, Sechet E, Law HK, et al. Combinatorial control of Th17 and Th1 cell functions by genetic variations in genes associated with the interleukin-23 signaling pathway in spondyloarthritis. Arthritis Rheum. 2013;65:1510–21.CrossRefPubMed

31.

McGovern DP, Kugathasan S, Cho JH. Genetics of inflammatory bowel diseases. Gastroenterology. 2015;149:1163–76. e1162.CrossRefPubMed

32.

O’Rielly DD, Rahman P. Genetics of psoriatic arthritis. Best Pract Res Clin Rheumatol. 2014;28:673–85.CrossRefPubMed

33.

Stuart PE, Nair RP, Tsoi LC, Tejasvi T, Das S, et al. Genome-wide association analysis of psoriatic arthritis and cutaneous psoriasis reveals differences in their genetic architecture. Am J Hum Genet. 2015;97:816–36.CrossRefPubMed

34.

Libioulle C, Louis E, Hansoul S, Sandor C, Farnir F, et al. Novel Crohn disease locus identified by genome-wide association maps to a gene desert on 5p13.1 and modulates expression of PTGER4. PLoS Genet. 2007;3, e58.CrossRefPubMedPubMedCentral

35.

Franke A, McGovern DP, Barrett JC, Wang K, Radford-Smith GL, et al. Genome-wide meta-analysis increases to 71 the number of confirmed Crohn’s disease susceptibility loci. Nat Genet. 2010;42:1118–25.CrossRefPubMedPubMedCentral

36.

Mielants H, Veys EM, Cuvelier C, de Vos M. Ileocolonoscopic findings in seronegative spondylarthropathies. Br J Rheumatol. 1988;27 Suppl 2:95–105.CrossRefPubMed

37.

Stolwijk C, Essers I, van Tubergen A, Boonen A, Bazelier MT, et al. The epidemiology of extra-articular manifestations in ankylosing spondylitis: a population-based matched cohort study. Ann Rheum Dis. 2015;74:1373–8.CrossRefPubMed

38.

Baraliakos X, Coates LC, Braun J. The involvement of the spine in psoriatic arthritis. Clin Exp Rheumatol. 2015;33:S31–5.PubMed

39.

Shen H, Goodall JC, Hill Gaston JS. Frequency and phenotype of peripheral blood Th17 cells in ankylosing spondylitis and rheumatoid arthritis. Arthritis Rheum. 2009;60:1647–56.CrossRefPubMed

40.

Benham H, Norris P, Goodall J, Wechalekar MD, FitzGerald O, et al. Th17 and Th22 cells in psoriatic arthritis and psoriasis. Arthritis Res Ther. 2013;15:R136. doi:10.1186/ar4317.CrossRefPubMedPubMedCentral

41.

Jansen DT, Hameetman M, van Bergen J, Huizinga TW, van der Heijde D, et al. IL-17-producing CD4+ T cells are increased in early, active axial spondyloarthritis including patients without imaging abnormalities. Rheumatology (Oxford). 2015;54:728–35.CrossRef

42.

Kenna TJ, Davidson SI, Duan R, Bradbury LA, McFarlane J, et al. Enrichment of circulating interleukin-17-secreting interleukin-23 receptor-positive gamma/delta T cells in patients with active ankylosing spondylitis. Arthritis Rheum. 2012;64:1420–9.CrossRefPubMed

43.

Cai Y, Shen X, Ding C, Qi C, Li K, et al. Pivotal role of dermal IL-17-producing gammadelta T cells in skin inflammation. Immunity. 2011;35:596–610.CrossRefPubMedPubMedCentral

44.

Bowness P, Ridley A, Shaw J, Chan AT, Wong-Baeza I, et al. Th17 cells expressing KIR3DL2+ and responsive to HLA-B27 homodimers are increased in ankylosing spondylitis. J Immunol. 2011;186:2672–80.CrossRefPubMedPubMedCentral

45.

Ridley A, Hatano H, Wong-Baeza I, Shaw J, Matthews KK, et al. Activation-induced KIR3DL2 binding to HLA-B27 licenses pathogenic T cell differentiation in spondyloarthritis. Arthritis Rheum. 2015. doi:10.1002/art.39515.

46.

Noordenbos T, Yeremenko N, Gofita I, van de Sande M, Tak PP, et al. Interleukin-17-positive mast cells contribute to synovial inflammation in spondylarthritis. Arthritis Rheum. 2012;64:99–109.CrossRefPubMed

47.

Appel H, Maier R, Wu P, Scheer R, Hempfing A, et al. Analysis of IL-17(+) cells in facet joints of patients with spondyloarthritis suggests that the innate immune pathway might be of greater relevance than the Th17-mediated adaptive immune response. Arthritis Res Ther. 2011;13:R95. doi:10.1186/ar3370.CrossRefPubMedPubMedCentral

48.

Ciccia F, Bombardieri M, Principato A, Giardina A, Tripodo C, et al. Overexpression of interleukin-23, but not interleukin-17, as an immunologic signature of subclinical intestinal inflammation in ankylosing spondylitis. Arthritis Rheum. 2009;60:955–65.CrossRefPubMed

49.

Ciccia F, Accardo-Palumbo A, Alessandro R, Rizzo A, Principe S, et al. Interleukin-22 and interleukin-22-producing NKp44+ natural killer cells in subclinical gut inflammation in ankylosing spondylitis. Arthritis Rheum. 2012;64:1869–78.CrossRefPubMed

50.•

Ciccia F, Guggino G, Rizzo A, Saieva L, Peralta S, et al. Type 3 innate lymphoid cells producing IL-17 and IL-22 are expanded in the gut, in the peripheral blood, synovial fluid and bone marrow of patients with ankylosing spondylitis. Ann Rheum Dis. 2015;74:1739–47. Provides a gut-joint pathogenetic link.CrossRefPubMed

51.

Appel H, Maier R, Bleil J, Hempfing A, Loddenkemper C, et al. In situ analysis of interleukin-23- and interleukin-12-positive cells in the spine of patients with ankylosing spondylitis. Arthritis Rheum. 2013;65:1522–9.CrossRefPubMed

52.

Mashiko S, Bouguermouh S, Rubio M, Baba N, Bissonnette R, et al. Human mast cells are major IL-22 producers in patients with psoriasis and atopic dermatitis. J Allergy Clin Immunol. 2015;136:351–9. e351.CrossRefPubMed

53.•

Barnas JL, Ritchlin CT. Etiology and pathogenesis of psoriatic arthritis. Rheum Dis Clin N Am. 2015;41:643–63. A good recent review of psoriatic arthritis pathogenesis.CrossRef

54.

Menon B, Gullick NJ, Walter GJ, Rajasekhar M, Garrood T, et al. Interleukin-17+CD8+ T cells are enriched in the joints of patients with psoriatic arthritis and correlate with disease activity and joint damage progression. Arthritis Rheum. 2014;66:1272–81.CrossRef

55.

Raychaudhuri SP, Raychaudhuri SK, Genovese MC. IL-17 receptor and its functional significance in psoriatic arthritis. Mol Cell Biochem. 2012;359:419–29.CrossRefPubMed

56.

Celis R, Planell N, Fernandez-Sueiro JL, Sanmarti R, Ramirez J, et al. Synovial cytokine expression in psoriatic arthritis and associations with lymphoid neogenesis and clinical features. Arthritis Res Ther. 2012;14:R93. doi:10.1186/ar3817.CrossRefPubMedPubMedCentral

57.•

Ciccia F, Guggino G, Ferrante A, Raimondo S, Bignone R, et al. IL-9 over-expression and Th9 polarization characterize the inflamed gut, the synovial tissue and the peripheral blood of patients with psoriatic arthritis. Arthritis Rheum. 2016. doi:10.1002/art.39649. Though Th9 cells are not reviewed here, this is a novel subset implicated in spondyloarthritis. This study is also one of the first descriptions of immune IL-17/IL-22 overexpression in subclinical gut inflammation associated with psoriatic arthritis.

58.

Hammer RE, Maika SD, Richardson JA, Tang JP, Taurog JD. Spontaneous inflammatory disease in transgenic rats expressing HLA-B27 and human beta 2m: an animal model of HLA-B27-associated human disorders. Cell. 1990;63:1099–112.CrossRefPubMed

59.

DeLay ML, Turner MJ, Klenk EI, Smith JA, Sowders DP, et al. HLA-B27 misfolding and the unfolded protein response augment interleukin-23 production and are associated with Th17 activation in transgenic rats. Arthritis Rheum. 2009;60:2633–43.CrossRefPubMedPubMedCentral

60.

Turner MJ, Sowders DP, DeLay ML, Mohapatra R, Bai S, et al. HLA-B27 misfolding in transgenic rats is associated with activation of the unfolded protein response. J Immunol. 2005;175:2438–48.CrossRefPubMed

61.

van der Fits L, Mourits S, Voerman JS, Kant M, Boon L, et al. Imiquimod-induced psoriasis-like skin inflammation in mice is mediated via the IL-23/IL-17 axis. J Immunol. 2009;182:5836–45.CrossRefPubMed

62.

Ruutu M, Thomas G, Steck R, Degli-Esposti MA, Zinkernagel MS, et al. Beta-glucan triggers spondylarthritis and Crohn’s disease-like ileitis in SKG mice. Arthritis Rheum. 2012;64:2211–22.CrossRefPubMed

63.•

Benham H, Rehaume LM, Hasnain SZ, Velasco J, Baillet AC, et al. Interleukin-23 mediates the intestinal response to microbial beta-1,3-glucan and the development of spondyloarthritis pathology in SKG mice. Arthritis Rheum. 2014;66:1755–67. This study implicates different roles for IL-17 and IL-22 in SpA pathogenesis.CrossRef

64.

Rehaume LM, Mondot S, Aguirre de Carcer A, Velasco J, Benham H, et al. ZAP-70 genotype disrupts the relationship between microbiota and host leading to spondyloarthritis and ileitis. Arthritis Rheum. 2014;66:2780–92.CrossRef

65.

Taurog JD, Richardson JA, Croft JT, Simmons WA, Zhou M, et al. The germfree state prevents development of gut and joint inflammatory disease in HLA-B27 transgenic rats. J Exp Med. 1994;180:2359–64.CrossRefPubMed

66.••

Sherlock JP, Joyce-Shaikh B, Turner SP, Chao CC, Sathe M, et al. IL-23 induces spondyloarthropathy by acting on ROR-gammat+ CD3+CD4-CD8- entheseal resident T cells. Nat Med. 2012;18:1069–76. Though not published in the last 3 years, this is a landmark study establishing the sufficiency and importance of IL-23 in producing a SpA phenotype.CrossRefPubMed

67.

Bal A, Unlu E, Bahar G, Aydog E, Eksioglu E, et al. Comparison of serum IL-1 beta, sIL-2R, IL-6, and TNF-alpha levels with disease activity parameters in ankylosing spondylitis. Clin Rheumatol. 2007;26:211–15.CrossRefPubMed

68.

Sieper J, Porter-Brown B, Thompson L, Harari O, Dougados M. Assessment of short-term symptomatic efficacy of tocilizumab in ankylosing spondylitis: results of randomised, placebo-controlled trials. Ann Rheum Dis. 2014;73:95–100.CrossRefPubMedPubMedCentral

69.

Hueber W, Sands BE, Lewitzky S, Vandemeulebroecke M, Reinisch W, et al. Secukinumab, a human anti-IL-17A monoclonal antibody, for moderate to severe Crohn’s disease: unexpected results of a randomised, double-blind placebo-controlled trial. Gut. 2012;61:1693–700.CrossRefPubMed

70.

Sandborn WJ, Feagan BG, Fedorak RN, Scherl E, Fleisher MR, et al. A randomized trial of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with moderate-to-severe Crohn’s disease. Gastroenterology. 2008;135:1130–41.CrossRefPubMed

71.•

Langley RG, Elewski BE, Lebwohl M, Reich K, Griffiths CE, et al. Secukinumab in plaque psoriasis—results of two phase 3 trials. N Engl J Med. 2014;371:326–38. A definitive study documenting tremendous efficacy in cutaneous psoriasis.CrossRefPubMed

72.

Thaci D, Blauvelt A, Reich K, Tsai TF, Vanaclocha F, et al. Secukinumab is superior to ustekinumab in clearing skin of subjects with moderate to severe plaque psoriasis: CLEAR, a randomized controlled trial. J Am Acad Dermatol. 2015;73:400–9.CrossRefPubMed

73.

Lebwohl M, Strober B, Menter A, Gordon K, Weglowska J, et al. Phase 3 studies comparing brodalumab with ustekinumab in psoriasis. N Engl J Med. 2015;373:1318–28.CrossRefPubMed

74.•

Mease PJ, McInnes IB, Kirkham B, Kavanaugh A, Rahman P, et al. Secukinumab inhibition of interleukin-17A in patients with psoriatic arthritis. N Engl J Med. 2015;373:1329–39. Definitive clinical trials of secukinumab in psoriatic arthritis.CrossRefPubMed

75.•

McInnes IB, Mease PJ, Kirkham B, Kavanaugh A, Ritchlin CT, et al. Secukinumab, a human anti-interleukin-17A monoclonal antibody, in patients with psoriatic arthritis (FUTURE 2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2015;386:1137–46. A definitive report in psoriatic arthritis published contemporaneously with Mease et al. CrossRefPubMed

76.

Antoni CE, Kavanaugh A, Kirkham B, Tutuncu Z, Burmester GR, et al. Sustained benefits of infliximab therapy for dermatologic and articular manifestations of psoriatic arthritis: results from the infliximab multinational psoriatic arthritis controlled trial (IMPACT). Arthritis Rheum. 2005;52:1227–36.CrossRefPubMed

77.

Antoni C, Krueger GG, de Vlam K, Birbara C, Beutler A, et al. Infliximab improves signs and symptoms of psoriatic arthritis: results of the IMPACT 2 trial. Ann Rheum Dis. 2005;64:1150–7.CrossRefPubMedPubMedCentral

78.

Mease PJ, Goffe BS, Metz J, VanderStoep A, Finck B, et al. Etanercept in the treatment of psoriatic arthritis and psoriasis: a randomised trial. Lancet. 2000;356:385–90.CrossRefPubMed

79.

Gottlieb A, Menter A, Mendelsohn A, Shen YK, Li S, et al. Ustekinumab, a human interleukin 12/23 monoclonal antibody, for psoriatic arthritis: randomised, double-blind, placebo-controlled, crossover trial. Lancet. 2009;373:633–40.CrossRefPubMed

80.

McInnes IB, Kavanaugh A, Gottlieb AB, Puig L, Rahman P, et al. Efficacy and safety of ustekinumab in patients with active psoriatic arthritis: 1 year results of the phase 3, multicentre, double-blind, placebo-controlled PSUMMIT 1 trial. Lancet. 2013;382:780–9.CrossRefPubMed

81.••

Baeten D, Sieper J, Braun J, Baraliakos X, Dougados M, et al. Secukinumab, an interleukin-17A inhibitor, in ankylosing spondylitis. N Engl J Med. 2015;373:2534–48. IL-17 blockade may be the most viable biologic option for AS since the TNFs became available.CrossRefPubMed

82.

Baraliakos X, Borah B, Braun J, Baeten D, Laurent D, et al. Long-term effects of secukinumab on MRI findings in relation to clinical efficacy in subjects with active ankylosing spondylitis: an observational study. Ann Rheum Dis. 2016;75:408–12.CrossRefPubMed

83.

Poddubnyy D, Hermann KG, Callhoff J, Listing J, Sieper J. Ustekinumab for the treatment of patients with active ankylosing spondylitis: results of a 28-week, prospective, open-label, proof-of-concept study (TOPAS). Ann Rheum Dis. 2014;73:817–23.CrossRefPubMed

84.

Lee E, Trepicchio WL, Oestreicher JL, Pittman D, Wang F, et al. Increased expression of interleukin 23 p19 and p40 in lesional skin of patients with psoriasis vulgaris. J Exp Med. 2004;199:125–30.CrossRefPubMedPubMedCentral

85.

Baeten D, Baraliakos X, Braun J, Sieper J, Emery P, et al. Anti-interleukin-17A monoclonal antibody secukinumab in treatment of ankylosing spondylitis: a randomised, double-blind, placebo-controlled trial. Lancet. 2013;382:1705–13.CrossRefPubMed

86.

McInnes IB, Sieper J, Braun J, Emery P, van der Heijde D, et al. Efficacy and safety of secukinumab, a fully human anti-interleukin-17A monoclonal antibody, in patients with moderate-to-severe psoriatic arthritis: a 24-week, randomised, double-blind, placebo-controlled, phase II proof-of-concept trial. Ann Rheum Dis. 2014;73:349–56.CrossRefPubMed

87.•

Belasco J, Louie JS, Gulati N, Wei N, Nograles K, et al. Comparative genomic profiling of synovium versus skin lesions in psoriatic arthritis. Arthritis Rheum. 2015;67:934–44. A study suggesting why secukinumab may be more efficacious in treating psoriatic skin than joints.CrossRef

88.

Ward MM, Deodhar A, Akl EA, Lui A, Ermann J, et al. American College of Rheumatology/Spondylitis Association of America/Spondyloarthritis Research and Treatment Network 2015 recommendations for the treatment of ankylosing spondylitis and nonradiographic axial spondyloarthritis. Arthritis Rheum. 2016;68:282–98.CrossRef

89.

Gossec L, Smolen JS, Ramiro S, de Wit M, Cutolo M, et al. European League Against Rheumatism (EULAR) recommendations for the management of psoriatic arthritis with pharmacological therapies: 2015 update. Ann Rheum Dis. 2016;75:499–510.CrossRefPubMed

90.

Agarwal S, Misra R, Aggarwal A. Interleukin 17 levels are increased in juvenile idiopathic arthritis synovial fluid and induce synovial fibroblasts to produce proinflammatory cytokines and matrix metalloproteinases. J Rheumatol. 2008;35:515–19.PubMed

91.

Gaur P, Misra R, Aggarwal A. Natural killer cell and gamma delta T cell alterations in enthesitis related arthritis category of juvenile idiopathic arthritis. Clin Immunol. 2015;161:163–9.CrossRefPubMed

Medicine Matters Rheumatology

Abstract