Update on the Pathogenesis of Rheumatoid Arthritis

Professor Ernest ChoyHead of Rheumatology and Translational Research

Institute of Infection and ImmunityDirector of Arthritis Research UK and Health and Care

Research Wales CREATE Centre

1

C

H

R

O

N

I

C

I

N

F

L

A

M

M

A

T

I

O

N

TNFα

IL1

IL15

IL18

IL6

IL20

IL32

IL33

RANKL

GM-CSF

IL10

IL1Ra

IL18BP

sIL1R

sTNFR

IL27

IL35

TGFβ

Cytokines promote inflammatory synovitis

Firestein GS, et al, eds. Kelley’s Textbook of Rheumatology. 8th ed. Philadelphia: Saunders Elsevier; 2009:376.

B cell

Endothelial

cell

Tissue

cell

Mast cell

Neutrophil

Synoviocytes

Cell contact, co-stimulation

Macrophage

IL17

IL22

IL-17, IL-22

IFNγ

IL-12, IL-23

chemokines, ECM,

co-stimulation

Th1/Th17

DC

2

Cytokines are implicated in each phase of RA pathogenesis

3

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;58:2936-2948.

Adapted and reprinted by permission from Macmillan Publishers Ltd: Nat Clin Pract Rheumatol. 2005.

PsA and RA were originally treated as the same disease• Not until the 1950s were the typical features of PsA described1

• 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 diagnosis1,3

• Still, joint involvement in psoriasis/PsA is often treated in the same way as RA, with drugs known to be ineffective against some PsA symptoms4

AS, ankylosing spondylitis;

RA, rheumatoid arthritis; DIP, distal interphalangeal.

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: 10.1136/ard.2004.032318; 4. Kingsley G, et al. Rheumatology (Oxford) 2012;51:1368–377.

4

α chain

β chain

Gregersen PK, et al. Arthritis Rheum 1987;30:1205–13.

DR type Sequence Association

70 71 72 73 74

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

HLA-DR associations with

rheumatoid arthritis defined by DR

β1 sequence position 70–74

Q=glutamine; K=lysine; R=arginine; A=alanine

D=aspartic acid; E=glutamic acid

Class II genes account for about 30% of genetic susceptibility to RA

5

HLA-DR=human leukocyte antigen D-related.

Current RA genetic risk loci from GWAS

6

McAllister Open Access Rheumatol. 2011; 3: 31–46.

Citrullination is a process of protein modification

7

Van Venrooij WJ, et al. Arthritis Res. 2000;2:249-51 PAD, peptidyl arginine deiminase

16

PAD expression in the lung

8

Luigli EB, et al. Arthritis Res Ther 2015;17:9

Citrullination improved peptide binding to come HLA class II alleles and leads to T-cell activation

9

Adapted from Hill JA, et al. J Immunol 2003; 171:538–41.

20

ACPA and RF precede RA

Adapted from 1. Nielen MM, et al. Arthritis Rheum 2004;50:380–6. 2. Rantapaa-Dahlqvist S, et al. Arthritis Rheum 2003;48:2741–9.

Immune response develops Pathologic inflammatory response

Genetic and environmental factors

Synovial inflammation

Humoral

immunity

Complications

comorbidities

Joint destruction

Time

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;373:659–72.

ACPA

RF

Evolution of rheumatoid arthritis

mφ

Immune

complexes

Activated

macrophages

T cell

B cell

Activated

T cell

mφ

Activated

B cells

TCR

MHC II

11

Prognostic value of ACPA in patients with recent-onset RA

12

Kroot EJ, et al. Arthritis Rheum 2000;43:1831–5. Schellekens GA, et al. Arthritis Rheum 2000;43:155–63.

ACPA or CCP?

13

1. Van Gaalen FA, et al. Ann Rheum Dis 2005;64:1510–2. 2. van Steendam K, et al. Rheumatology (Oxford). 2001;50:830–7.

1

Several epitopes are recognised by ACPAs

14

Ioan-Facsinay, et al. Ann Rheum Dis. 2011;70:188–93; Wagner CA, et al. Ann Rheum Dis 2015;74:579–86.

Poor prognostic factors in RA

15

Smolen JS, et al. Ann Rheum Dis 2013;3:529–35.

ACPAs form immune complexes to activate macrophages

16

Adapted from Nimmerjahn F and Ravetch JV. Nat Rev Immunol 2008;8;34–47

Percentage of early RA with erosions by serology

Katchamart W et al. Rheumatol Int. 2015,35:1693-1699

17

Percentage of early RA with erosions by serology after 1 year

18

Katchamart W et al. Rheumatol Int. 2015,35:1693-1699

23

19

Reproduced from: Kleyer A, et al. Ann Rheum Dis. 2014;73:854–60

Changes in cortical bone structure

ACPA and osteoclast differentiation

20

Adapted from Harre U, et al. J Clin Invest 2012;122:1791–802.

24

Interaction between ACPA and RF in RA-mediated bone loss

21

Adapted from Hecht C, et al. Ann Rheum Dis 2015;74:2151–6.

19

Moving from citrullination to ACPA

22

Adapted from Klareskog L, et al. Annu Rev Immunol 2008;26:651–75.

23

Demoruelle MK et al Arthritis Rheumatol; 2017; 69:1165-75

Sputum ACPAs and NETs in FDRs of RA patients

Sputum ACPAs and NETs in FDRs of RA patients

24

Demoruelle MK et al Arthritis Rheumatol; 2017; 69:1165-75

Porphyrymonas gingivalis citrullinatesbacterial 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;62:2662–72.

25

18

Classification and disease duration

26Adapted from van Steenbergen HW, et al. Arthritis Rheum. 203;65:2219–32. Raza K, et al. Ann Rheum

Dis. 2012;71:1921–3. Willemze A, et al. Nat Rev Rheumatol 2012;8:144–52.

The cells and cytokines involved in the pathogenesis of psoriasis, PsA, and RA

Coates LC, et al. Semin Arthritis Rheum. 2016;46(3):291-304.

27

Clinical features of PsA and RA

DIP, distal interphalangeal;

RA, rheumatoid arthritis.

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.

Dactylitis

Enthesitis

Spondylitis

Asymmetric joint involvement

DIP involvement

Psoriasis

Nail disease

Radiographically evident enthesopathic changes

Rheumatoid nodules

Rheumatoid vasculitis

Serum rheumatoid factor

Symmetric joint involvement

Primarily hand and wrist involvement

Pannus

Typical features of PsA1Typical features of RA1,2

28

Genomic analysis highlights differences between PsA and RA

OR, odds ratio; RA, rheumatoid arthritis,

SNP, single nucleotide polymorphism.

1. Belasco J, et al. Arthritis Rheumatol 2015;67(4):934–44;

2. Bowes J, et al. Ann Rheum Dis 2012;71:1350–354.

OR plots for eight SNPs demonstrating evidence for association to PsAsusceptibility, highlighting the opposing direction of effectsfor REL, PLCL2 and KIF5A.

29

MHC-1-opathy versusautoimmunity

30ERAP, endoplasmic reticulum aminopeptidase; IL, interleukin;

MHC, major immunohistocompatibility complex.

Feature MHC-I-opathy Autoimmune disease

Sex No femalepredominance Femalepredominance

Age of onset Generally young Wide agerange

Eye disease Anterior or posterior uveitis, orboth

Can includescleritis

Injury Linked to tissue-specific injury No link

Barrierfunction perturbation

Skin, mouth, gut Absent

Course without therapy Waxing and waning Progressive

Genetics MHC-1, ERAP1/2, IL-23/IL-17 axis MHC-II

Gut involvement Clinical or subclinical gutdisease iscommon

No link to gut disease(except coeliac disease)

Therapy Respond to anticytokine therapy, but not B-cell depletion

May respond to anticytokine therapy and B-celldepletion

Joint disease Sites of mechanical stress(entheses and lower limbs)

Polyarticular and synovial

Underpinning theory Danger as immunologicaldriver Self versus non-self discrimination

Comparison of the features of MHC-1-opathies and autoimmune diseases

.

McGonagle D, et al. Nat Rev Rheum 2015;11:731–740.

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

DIP, distal interphalangeal;

RA, rheumatoid arthritis.McGonagle D, et al. PLoS Medicine 2006;3(8):1242–248.

PsA: DIP joint with extensive inflammatory

changes in all tissues

31

The physiology of entheses‒ the enthesis organ (more than an insertion)• Neighbouring tissues are also involved in the dissipation of stress1

• Periosteal and sesamoid fibrocartilage, bone, soft tissues, synovium

• Widespread stress dissipation may explain the diffuse tissue swelling observed in SpAs2

SpA, spondyloarthropathy.

1. Benjamin M, et al. Arthritis & Rheumatism 2004;50:3306–313;

2. Eshed I, et al. Ann Rheum Dis 2007; 66(12):1553-559 ;

3. McGonagle D, et al. Arthritis Rheum 2007;56(8):2482–491;

4. McGonagle D. http://enthesis.info/anatomy/synovio-entheseal_complex.html (Accessed Aug 2016).

• The synovio-entheseal complex (SEC) can form part of the enthesis organ3

• Damage to the enthesis by micro-damage or other mechanisms can lead to inflammation of the SEC due to their close association3

32

Model for how enthesitis leads to joint and bone damage

SEC, synovio-entheseal complex.

1. McGonagle D. http://enthesis.info/damage/fibrocartilage_microdamage.html (accessed Oct 2016); 2. McGonagle D.

http://enthesis.info/damage/microscopic_inflammation_in_normal_insertions.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. Tan A, McGonagle D. Imaging of psoriatic arthritis in Atlas of PsA. 2005. Mease & Helliwell, ed.

Progression

Mechanical stressing can lead to micro-

damage and micro-inflammation

at normal entheses1,2

Diffuse inflammation occurs across all structures of the

entheseal organ and SEC4

In psoriasis/PsA patients, a dysregulated inflammatory

response occurs at the enthesis3

Enthesitis

Cytokines/growth factor

Primary enthesitis

Osteolysis occurs from persistent inflammation5

33

IL-23 induces spondyloarthropathy by acting on ROR-γt+ CD3+CD4−CD8− entheseal resident T cells

Sherlock JP et al. Nat Med. 2012 Jul 1;18(7):1069-76.

34

IL-23 drives entheseal-resident T cells in the pathogenesis of spondyloarthritis

Lories RJ and McInnes IB Nat Med 2012;18:1018-9

35

Kirkham B et al. Immunology. 2014 Feb;141(2):133-42.

36

Cytokine targets in inflammatory arthritisRA PsA AS

TNF +++ +++ +++

IL-6 +++ +1 - 2

IL-17 +3 +++ +++

IL12/23 - 4 +++ +5

JAK +++ +++ +6

37

+++: 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;68:2163–73. 2. Sieper J, et al. Ann Rheum Dis 2014;73:95–100. 3. Rheumatol Ther. 2017;4:475-488.

4. Smolen J, et al. Ann Rheum Dis. 2017;76:831-839. 5. Poddubnyy D, et al. Ann Rheum Dis. 2014;73:817-23. 6. van der Heijde D, et al. Ann Rheum Dis 2017;0:1–8

Regulation of autoantibody activity by the IL-23-Th17 axis determines the onset of autoimmune disease

38

Collagen induced arthritis

WT

IL-23-/-

Pfeifle R et al. Nat Immunol 2017;18:104-113

Regulation of autoantibody activity by the IL-23-Th17 axis determines the onset of autoimmune disease

39

Pfeifle R et al. Nat Immunol 2017;18:104-113

TNF

B cells

T cellsIL-6

Ideally, biomarkers would help clinicians select an optimal therapeutic strategy for patients

Adapted from Plant D, et al. Nat Rev Rheumatol 2014; 10:329–337.

Analysis of predictive biomarkers

Prediction algorithm used to assess treatment response

Therapy 1

Therapy 2

Therapy 3

Patient presents with inflammatory arthritis or

new-onset RA

Allocation of ideal treatment: Treat right the

first time

RF and/or anti-CCP seropositivity enriches response to rituximab

*p = 0.009; **p = 0.002 vs. seronegative patients; ***p = 0.001 vs. RF–.1. Chatzidionysiou K, et al. Ann Rheum Dis 2011; 70:1575–1580; 2. Strangfeld A, et al. Arthritis Rheum 2009; 60(Suppl. 10):1695.

64.4 62.6

45.3

54.9

0

10

20

30

40

50

60

70

RF status Anti-CCP status

Positive Negative

2* 2.1** 2.1**

1.61.4

1.1

0

0.5

1

1.5

2

2.5

RF Anti-CCP RF and anti-CCP

Positive Negative

Me

an c

han

ge in

DA

S28

at

6

mo

nth

s

Pat

ien

ts w

ith

EU

LAR

G

oo

d/M

od

era

te r

esp

on

se (

%)

***

CERERRA1 RABBIT registry2

Boolean remission to abatacept inbiologic-naïve RA patients at 6 months (ACTION study)

Error bars represent 95% CI. Alten R, et al. Arthritis Rheumatol 2015; 67(Suppl. 10); Abstract 551

0

3

6

9

12

15

18

RF (+)(n=318)

RF (-)(n=128)

Anti-CCP (+)(n=287)

Anti-CCP (-)(n=141)

RF (+) andanti-CCP (+)

(n=243)

RF (-) andanti-CCP (-)

(n=100)

RF (+) oranti-CCP (+)

(n=362)

Pat

ien

ts (

%)p=0.008 p=0.096 p=0.013 p=0.025

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

Pathogenesis of RA is driven by complex interactions of immune cells and cytokines

• Choy EH, et al. Nat Rev Rheumatol 2013; 9:154–163.

Cytokine

interplay

Bone and cartilage

T cell,

B cell

Macrophage,

dendritic cell

Synoviocyte

Early synovial histopathology

Fibroblast Myeloid Lymphoid

IL-11, IL-10, IL-12, IL-27,

IL-32, OSM, GM-CSF,

M-CSF, IFN-γ, PDGF,

RANKL, TGF-β

OSM, IL-11, IL-17,

IL-18, IFN-γ, IL-19,

IL-20, IL-22, TGF-β

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; 9:154–163.

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