Update on the Pathogenesis of Rheumatoid Arthritis

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1 Update on the Pathogenesis of Rheumatoid Arthritis Professor Ernest Choy Head of Rheumatology and Translational Research Institute of Infection and Immunity Director of Arthritis Research UK and Health and Care Research Wales CREATE Centre 1

2 Cytokines promote inflammatory synovitis DC IL-12, IL-23 chemokines, ECM, co-stimulation IL-17, IL-22 IFNγ Macrophage Th1/Th17 IL17 IL22 Cell contact, co-stimulation TNFα IL1 IL15 IL18 IL6 IL20 IL32 IL33 RANKL GM-CSF IL10 IL1Ra IL18BP sil1r stnfr IL27 IL35 TGFβ Synoviocytes B cell Neutrophil Mast cell Tissue cell Endothelial cell C H R O N I C I N F L A M M A T I O N Firestein GS, et al, eds. Kelley s Textbook of Rheumatology. 8th ed. Philadelphia: Saunders Elsevier; 2009:376. 2

Cytokines are implicated in each phase of RA pathogenesis Cellular recruitment Immunologic activation and organization Cellular retention and survival Tissue response McInnes IB, Liew FY.

3 Cytokines are implicated in each phase of RA pathogenesis Cellular recruitment Immunologic activation and organization Cellular retention and survival Tissue response McInnes IB, Liew FY. Nat Clin Pract Rheumatol. 2005;1:31-39; 2. Schett G, et al. Arthritis Rheum. 2008;58: Adapted and reprinted by permission from Macmillan Publishers Ltd: Nat Clin Pract Rheumatol

4 PsA and RA were originally treated as the same disease Not until the 1950s were the typical features of PsA described 1 Before Moll and Wright produced the first classification of PsA, disease descriptions included: 2 Arthritis confined to the DIP joints with psoriasis Atypical arthritis with atypical psoriasis Arthritis following prolonged, uncontrollable psoriasis Coincident psoriasis and RA there being no distinct entity Classification criteria have evolved to address the difficulty in PsA diagnosis 1,3 Still, joint involvement in psoriasis/psa is often treated in the same way as RA, with drugs known to be ineffective against some PsA symptoms 4 1. Moll J and Wright V. Semin Arthritis Rheum 1973;3:55 78; 2. Wright V. Arthritis & Rheumatology 1978;21:619 33; 3. Helliwell P, et al. Ann Rheum Dis 2005;64(Suppl II):ii3 ii8. doi: /ard ; 4. Kingsley G, et al. Rheumatology (Oxford) 2012;51: AS, ankylosing spondylitis; RA, rheumatoid arthritis; DIP, distal interphalangeal. 4

5 Class II genes account for about 30% of genetic susceptibility to RA α chain HLA-DR associations with rheumatoid arthritis defined by DR β 1 sequence position DR type Sequence Association β chain DR4 -W4 Q K R A A Positive -W14 Q R R A A Positive -W15 Q R R A A Positive DR1 Q R R A A Positive DR4 -W10 D E R A A Negative -W13 Q K R A A Negative Q=glutamine; K=lysine; R=arginine; A=alanine D=aspartic acid; E=glutamic acid Gregersen PK, et al. Arthritis Rheum 1987;30: HLA-DR=human leukocyte antigen D-related. 5

6 Current RA genetic risk loci from GWAS McAllister Open Access Rheumatol. 2011; 3:

7 Citrullination is a process of protein modification Van Venrooij WJ, et al. Arthritis Res. 2000;2: PAD, peptidyl arginine deiminase 7

8 PAD expression in the lung Luigli EB, et al. Arthritis Res Ther 2015;17:9 16 8

9 Citrullination improved peptide binding to come HLA class II alleles and leads to T-cell activation Adapted from Hill JA, et al. J Immunol 2003; 171:

10 ACPA and RF precede RA Adapted from 1. Nielen MM, et al. Arthritis Rheum 2004;50: Rantapaa-Dahlqvist S, et al. Arthritis Rheum 2003;48:

11 Evolution of rheumatoid arthritis Immune response develops Pathologic inflammatory response Humoral immunity Synovial inflammation ACPA Genetic and environmental factors RF Complications comorbidities Time T cell Joint destruction mφ B cell MHC II TCR Activated T cell Activated B cells Activated macrophages mφ Immune complexes ACPA=anti-citrullinated protein antibodies; mφ=macrophage; MHC=major histocompatibility complex; RF=rheumatoid factor; TCR=T-cell receptor. Adapted from Klareskog, et al. Lancet 2009;373:

12 Prognostic value of ACPA in patients with recent-onset RA Kroot EJ, et al. Arthritis Rheum 2000;43: Schellekens GA, et al. Arthritis Rheum 2000;43:

ACPA or CCP? 1. Van Gaalen FA, et al. Ann Rheum Dis 2005;64:1510 2.

13 ACPA or CCP? 1. Van Gaalen FA, et al. Ann Rheum Dis 2005;64: van Steendam K, et al. Rheumatology (Oxford). 2001;50:

14 Several epitopes are recognised by ACPAs Ioan-Facsinay, et al. Ann Rheum Dis. 2011;70:188 93; Wagner CA, et al. Ann Rheum Dis 2015;74:

15 Poor prognostic factors in RA Smolen JS, et al. Ann Rheum Dis 2013;3:

16 ACPAs form immune complexes to activate macrophages Adapted from Nimmerjahn F and Ravetch JV. Nat Rev Immunol 2008;8;

17 Percentage of early RA with erosions by serology Katchamart W et al. Rheumatol Int. 2015,35:

18 Percentage of early RA with erosions by serology after 1 year Katchamart W et al. Rheumatol Int. 2015,35:

19 Changes in cortical bone structure Reproduced from: Kleyer A, et al. Ann Rheum Dis. 2014;73:

20 ACPA and osteoclast differentiation Adapted from Harre U, et al. J Clin Invest 2012;122:

21 Interaction between ACPA and RF in RA-mediated bone loss Adapted from Hecht C, et al. Ann Rheum Dis 2015;74:

22 Moving from citrullination to ACPA Adapted from Klareskog L, et al. Annu Rev Immunol 2008;26:

23 Sputum ACPAs and NETs in FDRs of RA patients Demoruelle MK et al Arthritis Rheumatol; 2017; 69:

24 Sputum ACPAs and NETs in FDRs of RA patients Demoruelle MK et al Arthritis Rheumatol; 2017; 69:

25 Porphyrymonas gingivalis citrullinates bacterial and human proteins This organism and several other common infectious agents have been suggested to trigger RA Generally via molecular mimicry Wegner N, et al. Arthritis Rheum 2010;62:

26 Classification and disease duration Adapted from van Steenbergen HW, et al. Arthritis Rheum. 203;65: Raza K, et al. Ann Rheum Dis. 2012;71: Willemze A, et al. Nat Rev Rheumatol 2012;8:

27 The cells and cytokines involved in the pathogenesis of psoriasis, PsA, and RA Coates LC, et al. Semin Arthritis Rheum. 2016;46(3):

Clinical features of PsA and RA Typical features of RA 1,2 Rheumatoid nodules Rheumatoid vasculitis Serum rheumatoid factor Symmetric joint involvement Primarily hand and wrist involvement Pannus

28 Clinical features of PsA and RA Typical features of RA 1,2 Rheumatoid nodules Rheumatoid vasculitis Serum rheumatoid factor Symmetric joint involvement Primarily hand and wrist involvement Pannus Typical features of PsA 1 Dactylitis Enthesitis Spondylitis Asymmetric joint involvement DIP involvement Psoriasis Nail disease Radiographically evident enthesopathic changes 1. Gottlieb A, et al. J Am Acad Dermatol 2008; 58:851 64; 2. Scutellari P, et al. Eur J Radiol 1998; 27(suppl 1):S31 8. DIP, distal interphalangeal; RA, rheumatoid arthritis. 28

REL, PLCL2 and KIF5A. 1. Belasco J, et al. Arthritis Rheumatol 2015;67(4):934 44; 2. Bowes J, et al.

29 Genomic analysis highlights differences between PsA and RA OR plots for eight SNPs demonstrating evidence for association to PsA susceptibility, highlighting the opposing direction of effects for REL, PLCL2 and KIF5A. 1. Belasco J, et al. Arthritis Rheumatol 2015;67(4):934 44; 2. Bowes J, et al. Ann Rheum Dis 2012;71: OR, odds ratio; RA, rheumatoid arthritis, SNP, single nucleotide polymorphism. 29

30 MHC-1-opathy versus autoimmunity Comparison of the features of MHC-1-opathies and autoimmune diseases Feature MHC-I-opathy Autoimmune disease Sex No femalepredominance Femalepredominance Age of onset Generally young Wide age range Eye disease Anterior or posterior uveitis, or both Injury Linked to tissue-specific injury Nolink Barrier function perturbation Skin, mouth, gut Can includescleritis Absent Course without therapy Waxing and waning Progressive Genetics MHC-1, ERAP1/2, IL-23/IL-17 axis MHC-II Gut involvement Therapy Joint disease Clinical or subclinical gut disease is common Respond to anticytokine therapy, but not B-cell depletion Sites of mechanical stress (entheses and lower limbs) No link to gut disease (except coeliac disease) May respond to anticytokine therapy and B-cell depletion Polyarticular and synovial Underpinning. theory Danger as immunological driver Self versus non-self discrimination McGonagle D, et al. Nat Rev Rheum 2015;11: ERAP, endoplasmic reticulum aminopeptidase; IL, interleukin; MHC, major immunohistocompatibility complex. 30

31 Differentiation of RA and the diffuse inflammation in PsA Early in RA joint disease localisation is to the synovium Synovium the primary target organ In early PsA the inflammatory changes have a widespread distribution Appear to relate to patterns of joint stressing around ligaments, adjacent bone and soft tissues As opposed to a specific antigen territory PsA: DIP joint with extensive inflammatory changes in all tissues McGonagle D, et al. PLoS Medicine 2006;3(8): DIP, distal interphalangeal; RA, rheumatoid arthritis. 31

The physiology of entheses the enthesis organ (more than an insertion) Neighbouring tissues are also involved in the dissipation of stress 1 Periosteal and sesamoid fibrocartilage, bone, soft

enthesis by microdamage or other mechanisms can lead to inflammation of the SEC due to their close association 3 1. Benjamin M, et al. Arthritis & Rheumatism 2004;50:3306 313; 2. Eshed I, et al.

32 The physiology of entheses the enthesis organ (more than an insertion) Neighbouring tissues are also involved in the dissipation of stress 1 Periosteal and sesamoid fibrocartilage, bone, soft tissues, synovium Widespread stress dissipation may explain the diffuse tissue swelling observed in SpAs 2 The synovio-entheseal complex (SEC) can form part of the enthesis organ 3 Damage to the enthesis by microdamage or other mechanisms can lead to inflammation of the SEC due to their close association 3 1. Benjamin M, et al. Arthritis & Rheumatism 2004;50: ; 2. Eshed I, et al. Ann Rheum Dis 2007; 66(12): ; 3. McGonagle D, et al. Arthritis Rheum 2007;56(8): ; 4. McGonagle D. (Accessed Aug 2016). 32 SpA, spondyloarthropathy.

Model for how enthesitis leads to joint and bone damage Progression Cytokines/growth factor Enthesitis Primary enthesitis Mechanical stressing can

enthesis 3 Diffuse inflammation occurs across all structures of the entheseal organ and SEC 4 Osteolysis occurs from persistent inflammation 5 1.

html (accessed Oct 2016);3. McGonagle D, et al. Lancet 1998;352(9134):1137 140; 4. McGonagle D, et al. PLoS Medicine 2006;3(8):1242 248; 5.

33 Model for how enthesitis leads to joint and bone damage Progression Cytokines/growth factor Enthesitis Primary enthesitis Mechanical stressing can lead to microdamage and micro-inflammation at normal entheses 1,2 In psoriasis/psa patients, a dysregulated inflammatory response occurs at the enthesis 3 Diffuse inflammation occurs across all structures of the entheseal organ and SEC 4 Osteolysis occurs from persistent inflammation 5 1. McGonagle D. (accessed Oct 2016); 2. McGonagle D. (accessed Oct 2016);3. McGonagle D, et al. Lancet 1998;352(9134): ; 4. McGonagle D, et al. PLoS Medicine 2006;3(8): ; 5. Tan A, McGonagle D. Imaging of psoriatic arthritis in Atlas of PsA Mease & Helliwell, ed. 33 SEC, synovio-entheseal complex.

34 IL-23 induces spondyloarthropathy by acting on ROR-γt+ CD3+CD4 CD8 entheseal resident T cells Sherlock JP et al. Nat Med Jul 1;18(7):

35 IL-23 drives entheseal-resident T cells in the pathogenesis of spondyloarthritis Lories RJ and McInnes IB Nat Med 2012;18:

36 Kirkham B et al. Immunology Feb;141(2):

37 Cytokine targets in inflammatory arthritis RA PsA AS TNF IL IL IL12/ JAK : approved treatment or positive phase III trial ++: not approved but positive phase III trial +: not approved but limited efficacy from phase II or III clinical trials -: negative clinical trial 1. Mease PJ, et al. Arthritis Rheum 2016;68: Sieper J, et al. Ann Rheum Dis 2014;73: Rheumatol Ther. 2017;4: Smolen J, et al. Ann Rheum Dis. 2017;76: Poddubnyy D, et al. Ann Rheum Dis. 2014;73: van der Heijde D, et al. Ann Rheum Dis 2017;0:1 8 37

38 Regulation of autoantibody activity by the IL-23-Th17 axis determines the onset of autoimmune disease Collagen induced arthritis IL-23-/- WT Pfeifle R et al. Nat Immunol 2017;18:

39 Regulation of autoantibody activity by the IL-23-Th17 axis determines the onset of autoimmune disease Pfeifle R et al. Nat Immunol 2017;18:

40 TNF T cells IL-6 B cells

41 Ideally, biomarkers would help clinicians select an optimal therapeutic strategy for patients Allocation of ideal treatment: Treat right the first time Therapy 1 Analysis of predictive biomarkers Prediction algorithm used to assess treatment response Therapy 2 Patient presents with inflammatory arthritis or new-onset RA Therapy 3 Adapted from Plant D, et al. Nat Rev Rheumatol 2014; 10:

42 Mean change in DAS28 at 6 months Patients with EULAR Good/Moderate response (%) RF and/or anti-ccp seropositivity enriches response to rituximab CERERRA 1 RABBIT registry 2 Positive Negative Positive Negative * ** ** *** RF Anti-CCP RF and anti- CCP 10 0 RF status Anti-CCP status *p = 0.009; **p = vs. seronegative patients; ***p = vs. RF. 1. Chatzidionysiou K, et al. Ann Rheum Dis 2011; 70: ; 2. Strangfeld A, et al. Arthritis Rheum 2009; 60(Suppl. 10):1695.

43 Boolean remission to abatacept in biologic-naïve RA patients at 6 months (ACTION study) Patients (%) p=0.008 p=0.096 p=0.013 p= RF (+) (n=318) RF (-) (n=128) Anti-CCP (+) (n=287) Anti-CCP (-) (n=141) RF (+) and anti-ccp (+) (n=243) RF (-) and anti-ccp (-) (n=100) RF (+) or anti-ccp (+) (n=362) Error bars represent 95% CI. Alten R, et al. Arthritis Rheumatol 2015; 67(Suppl. 10); Abstract 551

44 Dennis et al. Arthritis Research & Therapy 2014, 16:R90

Pathogenesis of RA is driven by complex interactions of immune cells and cytokines Early synovial histopathology Fibroblast Myeloid Lymphoid OSM, IL-11, IL-17, IL-18, IFN-γ, IL-19, IL-20, IL-22,

45 Pathogenesis of RA is driven by complex interactions of immune cells and cytokines Early synovial histopathology Fibroblast Myeloid Lymphoid OSM, IL-11, IL-17, IL-18, IFN-γ, IL-19, IL-20, IL-22, TGF-β Macrophage, dendritic cell IL-11, IL-10, IL-12, IL-27, IL-32, OSM, GM-CSF, M-CSF, IFN-γ, PDGF, RANKL, TGF-β Synoviocyte Cytokine interplay T cell, B cell Bone and cartilage IL-2, IL-4, IL-7, IL-9, IL- 10, IL-12, IL-13, IL-15, IL-21, IL-23, IL-27, IFN-γ,TGF-β Choy EH, et al. Nat Rev Rheumatol 2013; 9: Choy Rheumatol EH, et 2013; al. Nat 9:154 Rev 163.

46 Conclusion Pathogenesis of RA and PsA are different Different cytokines have different pathogenic roles in inflammatory rheumatic diseases Cytokines have different roles during different stages of inflammatory arthritis In RA, immune activation as evident by ACPA serpositivity, is present before symptoms In HLA-DR4 positive individual, citrullinated peptide are more potent antigens Infection can leads to development and amplification of ACPA response leading to disease RA are heterogenous: ACPA +ve and ACPA-ve diseases may be fundamentally different and associated with difference in response to rituximab and abatacept 46

PATHOGENESIS OF RHEUMATOID ARTHRITIS

PATHOGENESIS OF RHEUMATOID ARTHRITIS Division of Rheumatology Department of Internal Medicine College of Medicine Seoul National University Seoul National University Bundang Hospital Yun Jong Lee Rheumatoid