Disease mechanisms in Spondyloarthritis. Joerg Ermann, MD Brigham and Women s Hospital Harvard Medical School
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1 Disease mechanisms in Spondyloarthritis Joerg Ermann, MD Brigham and Women s Hospital Harvard Medical School
2 Disclosures Scientific Advisory Boards: Abbvie, Janssen, Novartis, UCB, Takeda, Eli Lilly Research Grants: Boehringer Ingelheim, Pfizer Speaker: SPARTAN-GRAPPA Education Symposia
3 Ermann Nat Immunol 2001; 2:759-6
4 Ermann Nat Immunol 2001; 2:759-6
5 HLA-B27 is strongly associated with Ankylosing spondylitis and other spondyloarthritides Schlosstein NEJM 1973; 288:704-6, Caffrey Nature 1973; 242:121
6 HLA-B27 association with AS and SpA in populations of Northwestern European extraction ankylosing spondylitis ~90% reactive arthritis 30-70% IBD-associated SpA 30-70% psoriatic SpA 40-50% undifferentiated SpA ~70% acute anterior uveitis ~50% general population ~8% Khan Curr Rheumatol Rev 2010; 12:337-41
7 Prevalence of HLA-B27 in indigenous populations Khan Curr Opin Rheumatol 1995; 7:4, 263-9
8 HLA-B27 epidemiology prevalence of SpA correlates with frequency of HLA-B27 in the population: very high - indigenous circumpolar populations, Navajo very low - South America, Southern Africa, Australia, Japan HLA-B27+ in general US population 6.1% overall 7.5% non-hispanic White 4.6% Mexican American 1.1% non-hispanic Black Reveille Arthritis Rheum 2011, 64:5,
9 HLA-B is a gene in the Class I MHC locus Every individual has - 2 HLA-A genes - 2 HLA-B genes - 2 HLA-C genes Gutierrez-Arcelus Nat Rev Genet 2016; 17:160-74
10 Bowness Annu Rev Immunol 2015; 33:29-48
11 Neefjes Nat Rev Immunol 2011; 11:823-3 ERAP1/2
12 How is HLA-B27 determined? cytotoxicity assay flow cytometry PCR-SSP (sequence-specific primers) PCR-SSO (sequence-specific oligonucleotides) PCR-SBT (sequence-based typing = sequencing)
13 How is HLA-B27 determined? cytotoxicity assay cell/protein flow cytometry cell/protein PCR-SSP (sequence-specific primers) DNA PCR-SSO (sequence-specific oligonucleotides) DNA PCR-SBT (sequence-based typing = sequencing) DNA
14 HLA-B27 - cytotoxicity assay
15 HLA-B27 - flow cytometry
16 HLA-B27 - PCR-based techniques HLA-B
17 Understanding HLA nomenclature (4-letter code) HLA-B*27:05 gene allele family serotype allele (aa sequence) detectable by serology requires DNA-based typing Marsh Tissue Antigen 2010; 75:
18 >100 protein coding HLA-B27 variants, not all are associated with AS associated: 2705, 2702, 2704 NOT associated: 2706 (SE Asia), 2709 (Sardinia) uncertain: most others Mathieu Autoimmun Rev 2009; 8:420-5
19 Disease-associated HLA-B27 polymorphisms map to the peptide binding grove AA 45, 46 (B pocket) 45 (Glu), 67 (Cys) in all HLA-B27 preference for P2 = Arg AA 97, 114, 116 (F pocket) 97 (Asp) strongly associated with AS p< (Asp) Asp (B*27:05) His (B*27:09) susceptible non susceptible 114 (His), 116 (Asp) His (B*27:04) Asp (B*27:06) Asp (B*27:04) Tyr (B*27:06) van Deutekom Immunogenetics 2015; 67:425-36, Cortes Nat Commun; 6,7146
20 Hypotheses for HLA-B27 disease association 1. peptide hypothesis molecular mimicry autoimmune response (CD8+ T cells) 2. misfolding hypothesis unfolded protein response (UPR) inflammation 3. NK receptor hypothesis aberrant forms (homodimers, free heavy chain) lymphocyte activation via NK receptors (KIR) 4. microbiome hypothesis HLA-B27 gut microbiome inflammation
21 Ankylosing spondylitis HLA-B27 HLA-B51, HLA-B47, HLA-B40, HLA-B13 One mechanisms or many? Psoriasis HLA-C06 HLA-C12 Psoriatic Arthritis HLA-B27 HLA-B38 HLA-B39 HLA-B08
22 Non-MHC risk genes in SpA multiple GWAS studies since 2007, Immunochip (common SNP s >5%) significant overlap between AS, psoriasis, PsA, IBD many disease-associated variants with low effect size AS (n=31), psoriasis (n=63), IBD (n=163) only a fraction of heritability explained ( missing heritability ) few examples of rare genetic variants - SEC16A/MAMDC4 (AS, increased susceptibility) - IFIH1 (PsA, protective) O Rielly Curr Opin Rheumatol 2016; 28:4, , Ellinghaus Scand J Gastroenterol 2015; 50:1, 13-23, O Rielly Ann Rheum Dis. 2016; 75:772-9 Budu-Aggrey Ann Rheum Dis 2017; 76:
23 Pathways implicated by SpA genetics antigen peptide processing and presentation IL-23 receptor signaling lymphocyte development and differentiation NFκB/IFNγ signaling barrier function O Rielly Curr Opin Rheumatol 2016; 28:4, , Ellinghaus Scand J Gastroenterol 2015; 50:1, 13-23
24 Ermann Nat Immunol 2001; 2:759-6
25 Environmental factors in SpA pathogenesis interface inflammation is common - PsA, IBD-associated SpA, reactive arthritis - (subclinical) intestinal inflammation in ~2/3 of AS patients critical role for microbiota - dysbiosis more likely than specific pathogens - mechanism? diet? smoking? - not a risk factor for AS incidence but increased severity - controversial in psoriasis/psa
26 Ermann Nat Immunol 2001; 2:759-6
27 TNF and not TNF-α. Not IL-17 but IL-17A.
28 Patel Ann Rheum Dis 2013; 72:ii IL-17 is a family of 6 related cytokines
29 Secukinumab Ixekizumab Bimekizumab Brodalumab Patel Ann Rheum Dis 2013; 72:ii
30 IL-23 receptor signaling p40 p19 IL-12Rβ2 IL-23R Jak2, Tyk2 Stat3
31 IL-23 receptor signaling p40 p19 polymorphisms associated with SpA IL-12Rβ2 IL-23R Jak2, Tyk2 Stat3 Burton Nat Genet 2007; 39: , Evans Nat Genet 2011; 43:761-7, Cortes Nat Genet 2013; 45:730-8
32 IL-23 receptor signaling anti-p40 abs block IL-12 and IL-23 p40 p19 anti-p19 abs only block IL-23 IL-12Rβ2 IL-23R Jak2, Tyk2 Stat3
33 IL-23 receptor signaling p40 p19 IL-12Rβ2 IL-23R Jak2, Tyk2 Tofacitinib preferentially inhibits Jak1/3 Stat3
34 The IL-23/IL-17A axis dendritic cells, MΦ IL-23 IL-23R positive cells Th17 cells γδ T cells DN αβ T cells innate lymphoid cells IL-17A
35 IL-23 minicircle arthritis osteoproliferation spondylitis enthesitis IL-23 expression in the liver psoriasis aortic root inflammation
36 IL-23 mincircle-induced arthritis is (partially) mediated by IL-17A, IL-22 tissue-resident IL-23R+RORγt+ DN T cells secrete IL-17A, IL-22 Sherlock Nat Med 2012; 18:
37 Does mechanical stress contribute to SpA pathogenesis? entheses transmit mechanical force enthesitis as the primary lesion in SpA pathogenesis? clinical enthesitis is common in all variants of SpA (axial and peripheral), more often subclinical (U/S) Ball Ann Rheum Dis 1971, McGonagle Arthritis Rheum 2007, d Agostino Arthritis Rheum 2003
38 iliac crest major trochanter enthesitis: - pain - swelling - local tenderness tibial tuberosity quadriceps tendon insertion plantar fascia insertion Achilles tendon insertion
39 Syndesmophyte formation in AS - the result of enthesitis? Tan Ann Rheum Dis 2015; 74:437-43
40 TNF ΔARE mice - dysregulated expression of TNF - spontaneous SpA-like disease tail suspension for unloading of ankle joints Jacques Ann Rheum Dis 2013; 73:437-45
41 Jacques Ann Rheum Dis 2013; 73: control TNF ΔARE TNF ΔARE TS
42 Ermann Nat Immunol 2001; 2:759-6
43 SpA pathogenesis (a rough model) stimulus IL-23 immune cell * immune cell ** IL-17A target organ inflammation damage
44 SpA pathogenesis (a rough model) stimulus stimulus immune cell ** TNF IL-23 immune cell * immune cell ** IL-17A target organ inflammation damage
45 SpA pathogenesis (a rough model) stimulus HLA-B27 microbiota mechanical stress stimulus immune cell ** TNF IL-23 immune cell * immune cell ** IL-17A target organ inflammation damage
46 SpA pathogenesis (a rough model) stimulus HLA-B27 microbiota mechanical stress stimulus immune cell ** synergy TNF IL-23 immune cell * immune cell ** IL-17A target organ inflammation damage
47 SpA pathogenesis (a rough model) stimulus HLA-B27 microbiota mechanical stress stimulus immune cell ** synergy TNF IL-23 IL-17A immune cell * immune cell ** target organ inflammation damage
48 SpA pathogenesis (a rough model) stimulus HLA-B27 microbiota mechanical stress stimulus immune cell ** synergy TNF IL-23 IL-17A immune cell * immune cell ** target organ IL-1α/β IL-17F PGE2 GM-CSF IL-22 PGE2 inflammation damage
49 SpA pathogenesis (implications for therapy) stimulus HLA-B27 microbiota mechanical stress stimulus immune cell ** synergy TNF IL-23 IL-17A immune cell * immune cell ** target organ IL-1α/β IL-17F PGE2 GM-CSF IL-22 PGE2 inflammation damage
50 SpA pathogenesis (implications for therapy) stimulus HLA-B27 microbiota mechanical stress stimulus immune cell ** synergy TNF IL-23 IL-17A immune cell * immune cell ** target organ IL-1α/β IL-17F PGE2 GM-CSF IL-22 PGE2 inflammation damage
51 SpA pathogenesis (implications for therapy) stimulus HLA-B27 microbiota mechanical stress stimulus immune cell ** synergy TNF IL-23 IL-17A immune cell * immune cell ** target organ IL-1α/β IL-17F PGE2 GM-CSF IL-22 PGE2 inflammation damage
52 SpA pathogenesis (implications for therapy) stimulus HLA-B27 microbiota mechanical stress stimulus immune cell ** synergy TNF IL-23 IL-17A immune cell * immune cell ** target organ IL-1α/β IL-17F PGE2 GM-CSF IL-22 PGE2 inflammation damage
53 Three final points (instead of a summary) 1. Mice and rats do not develop ankylosing spondylitis. Animal model are pathway models. 2. Disease models are attempts to explain disease development based on current knowledge. disease model disease 3. Clinical trials with highly specific drugs (biologics!) are experiments that interrogate disease pathogenesis.
54 Three final points (instead of a summary) 1. Mice and rats do not develop ankylosing spondylitis. Animal model are pathway models. 2. Disease models are attempts to explain disease development based on current knowledge. disease model disease 3. Clinical trials with highly specific drugs (biologics!) are experiments that interrogate disease pathogenesis.
55 Schett Nat Rev Rheumatol 2017; 13:731-41
56 genetics epidemiology animal models clinical trials pathogenesis in vitro studies imaging biomarkers histopathology
57 Bone marrow edema in sacroiliitis is anatomically remote from any enthesis STIR
58 Erosions are present in early sacroiliitis baseline Year 2 T1 MRI Maksymowych Arthritis Rheumatol 2015
59 Pencil in cup erosions are characteristic in PsA
60 Three final points (instead of a summary) 1. Mice and rats do not develop ankylosing spondylitis. Animal model are pathway models. 2. Disease models are attempts to explain disease development based on current knowledge. disease model disease 3. Clinical trials with highly specific drugs (biologics!) are experiments that interrogate disease pathogenesis.
61 Clinical trials with selective cytokine inhibitors target AS PsA psoriasis IBD RA TNF IL IL-17A IL-6 - +?? ++
62 Questions?
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