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 arthritis is. Chronic, systemic, and inflammatory disorder with predominantly affecting diathroidial joints Characterized by Symmetric synovitis leading to joint destruction Multi-systemic extra-articular manifestations Auto-antibodies such as RF and anti-ccp/acpa But, unknown etiology Autoimmune mechanisms could be involved. A prototype of chronic inflammatory disease with features of autoimmunity

Prevalence of RA Worldwise prevalence 0.5-1.0% More common in females than males Nat Rev Rheumatol 2010;6:468-76.; Ann N Y Acad Sci. 2006;1069:212-22.

Articular manifestations of RA Time

Pathological change in the RA joints Normal RA Normal joint Early RA Late RA Osteoclasts Pannus Normal RA T cells Inflammatory cells B cells Normal RA Synovial hyperplasia Fibroblastlike synoviocytes Macrophagelike synoviocytes

Extra-articular manifestations

Typical auto-antibodies in RA Rheumatoid factor (RF) Auto-antibodie against the Fc portion of IgG. Anti-CCP / ACPA Anti-cyclic citrullinated peptide / anti-citrullinated protein andibodies. Conformational change Altered proteolytic degradation Changed protein function

Clinical course of RA Joint symptoms of RA is up and down, but joint damage is progressively accumulated.

Evolution of hypothesis in RA pathogenesis Synoviocyte transformations interaction with macrophage, cartilage, and bone Cellular immune mechanisms (T cells, monocyte, cytokines) Genetic factors Humoral immune mechanisms (B cells, RF, immune complex compliment) Infection 1920 1940 1960 1980 2000

Evolution of hypothesis Synoviocyte transformations interaction with macrophage, cartilage, and bone Cellular immune mechanisms (T cells, monocyte, cytokines) Genetic factors Humoral immune mechanisms (B cells, RF, immune complex compliment) Infection 1920 1940 1960 1980 2000

Infection and RA No evidence of direct invasion by microbes into the joint Indirect immune-medicated mechanisms

Possible infectious agents in RA Microbes Clinical associations Animal study Porphyromonas Proteus EBV Mycoplasma Clinical association between RA and periodontitis. Presence of P. gingivalis DNA in RA patients. Anti-P. gingivalis in RA patients. Increased anti-p. gingivalis antibodies in subjects with high risk of RA. Clinical association between RA and urinary tract infection. Immune responses to P. mirabilis in RA patients. Clinical association between RA and EBV infection. Presence of EBV DNA and protein in RA patients. Immune responses to EBV in RA patients. Presence of DNA and GGPL (glycoglycerophospholipids) in RA patients. Immune responses to mycoplasma in RA patients. Immunization with P. gingivalis or P. gingivalis enolase induced or exacerbated arthritis. P. gingivalis facilitated destructive arthritis in CIA mice dependent on its peptidylarginine deiminase. EBV induced arthritis in humanized mice. Immunization with mycoplasma arthritidis induced or exacerbated arthritis. J Clin Cell Immunol. 2013;4(6). pii: 174.

P. gingivalis Periodontitis and RA PAD enzyme, which makes citrullinated protein, is produced from P. gingivalis. Peptidyl-Arginine Deiminase from P. gingivalis Tissue injury Citrullination of host proteins Anti-citrullinated peptide Epitope spreading Pathogenic Anti-CCP/CPA Nat Rev Immunol. 2015;15(1):30-44.

Microbiota & RA Over 10 times more microbial cells than human cells (1~3% of total body mass) Science. 2010;330(6012):1768-7

Microbiota & RA Intestinal microbiota in RA patients Germ-free cage Germ-free cage Active RA Inactive RA Elife. 2013;2:e01202.; Nat Med. 2015;21(8):895-905

B cells in the RA pathogenesis A prominent participation of the B cell has long been appreciated since the discovery of RF. However, since 1980`s when T cell hypothesis developed, B cell models has been less attracted. B cells have been recently reevluated. The effectiveness of anti-b cell therapy such as anti-cd20 (rituximab). Induction of RA-like disease in BL6 mice with a transfer of antiglucose-6 phosphate isomerase (without T cells). The amplification of tissue injury by ACPA.

Clinical arthritis scores Clinical arthritis scores Clinical arthritis scores The role of B cells in collagen-induced arthritis (CIA) B cell deficient mice Anti-CD20 treated mice Anti-CD22 treated mice Days after immunization Days after immunization Days after immunization Clin Exp Immunol. 1998;111(3):521-6; J Immunol. 2007;179(2):1369-80.; Blood. 2005;106(7):2235-43.

ACPA and Bone loss Before the clinical onset of RA ACPA negative ACPA positive ACPA, a predictor of erosive RA Osteoclastogenesis Bone resorption After treatment with anti-citrullinated vimetin Harre U et al. J Clin Invest 2012;122(5):1791-802.; Kleyer A, et al. Ann Rheum Dis 2014;73:854 60.

B cell targeting therapy The multiple roles of B cells in RA B cell-targeting agents Biomed Res Int. 2014;2014:681678; Nat Rev Rheumatol 2014;10:77 88.

Who gets RA Susceptible genes in RA Gene variants within the HLA locus account for 30% to 50% of overall genetic susceptibility to RA. Clin Genet. 2014 Jul 25. doi: 10.1111/cge.12465.

The Shared Epitope Hypothesis The RA-associated HLA-DRB1 alleles encode a common sequence of amino acids in the 3 rd HVR of the DRβ1 chain the shared epitope (Gregersen et al., 1987) 70-74 DRB1 allels Classification RA risks D-E-RAA *0103, *0402, *1102, *1103, *1301, *1302, *1304, *1323 S1 (L) Low Q-A-RAA *15 S1 (L) Low Q-K-RAA *0401 S2 High D-K-RAA *1303 S2 High D-R-RAA *1101, *1104, *12, *1305, *1306, *1325, *1422, *16 S3D (L) No Q-R-RAA *0101, *0102, *0404, *0405, *0408 S3P Intermediate R-R-RAA *1001 S3P Intermediate Q-K-RGR *03 X (L) No Q-R-RAE *0403, *0407, *0411 X (L) No D-R-RGQ *07 X (L) No D-R-RAL *08 X (L) No R-R-RAE *0901, *1401, *1404 X (L) No Q :Glutaimine K : Lysine R : Arginine A : Alanine D : Aspartic acid E : glutamic acid

Assoication between SE and ACPA Shared epitope are more likely to develop anti-citrulline response Anti-CCP Anti-cit-Fbg Anti-cit-αENO Anti-cit-Col2 J Rheumatol 2004;31;1471-1473; Arthritis Rheum. 2010;62(1):117-25

Who gets RA RA genetic susceptibility loci and their ORs Nat Rev Rheumatol 2013;9:141-53;

Environmental versus Genetic factors Among 12,590 twins 350 (2.8%) were ACPA positive. 124 (1.0%) had ACPA positive RA. ACPA positive ACPA (+) RA ACPAs without RA Concordant Disconcordant Concordant Disconcordant Concordant Disconcordant MZ 3 72 1 22 1 52 SSDZ 3 111 1 43 1 70 OSDZ 0 90 0 33 0 57 100% 50% Unique environmental Shared environmental Herritability 0% ACPA ACPA (+) RA ACPAs without RA Ann Rheum Dis 2015;74:375 380

Environmental factors of RA Risk factors Odds ratio / Relative risk Ever smoked 1.40 (1.25-1.58) High alcohol intake 0.50 (0.40-0.60) Obesity 1.57 (1.01-2.44) High vitamin D intake 0.67 (0.44-1.00) High birthweight 2.10 (1.40-3.30) Breastfeeding 13 mo 0.46 (0.24-0.91) Smoking & alcohol intake associated with ACPA (+) RA. Obesity associated with ACPA (-) RA. Scott IC et al. Best Pract Res Clin Rheumatol. 2011;25(4):447-68

Environmental factor as smoking in RA Smoking is the best-known environmental risk factor. It interacts with genetic factors, esp. seropositive RA Higher prevalence of ACPA in patients with smoking and/or shared epitope Sugiyama D et al. Ann Rheum Dis 2010;69:70 81.

PAD2 PAD4 PAD4 PAD2 Environmental factor as smoking in RA Bronchoalveolar lavage fluid Smoker Non-smoker Makrygiannakis D et al. Ann Rheum Dis. 2008;67(10):1488-9; Catrina AI, et al. Nat Rev Rheumatol. 2014 Jul 29.

Evidence of T cell involvement in RA T cells are one of the most abundant cell types in RA synovium (30~50% of cells) Mostly CD4+ memory T cells (CD45RO+) with an activated phenotype (HLA-DR+, CD69+, and CD27+) and chemokine receptors (CCR5, CCR6, and CXCR4). The presence of T-cell dependent autoantibodies Association with T cell related genes such as HLA-DR Low prevalence of RA-like features in T cell deficient animal models. Abatacept, a CD80/86-CD28 T cell costimulatioin modulator, is therapeutically effective in RA.

RA as a T cell-mediated disease Old Th1/Th2 paradigm RA as a Th1 dominant disease But. Aggravation of collagen-induced arthritis in IFNγ deficient mice. Quite low levels of Th1 cytokines, (IFNγ or IL-2), in the RA synovium.

RA as a T cell-mediated disease New paradigm of Th cell subsets Th17 cells in RA pathogenesis IFN and Th17 cells Th1 or Th17 Plasticity of Th17 cells The major subtype of T cells in RA is a complex issue because Th cells are plastic. The presence of IFNγ+ IL-17+ T cells in RA synovial fluid. Foxp3+ Treg cells lose Foxp3 and then differentiated into Th17 cells in RA (exfoxp3th17 cells).

Cytokines in the RA pathogenesis McInnes IB et al. Nature Reviews Immunology 7, 429-442

Cytokine imbalance in RA synovium

Cytokine-mediated regulation of synovitis McInnes IB et al. Nature Reviews Immunology 7, 429-442

Anti-cytokine agents in RA Dark green: efficacy in independent observational studies Light green : Preliminary data on clinical efficacy Gray: No or mild clinical efficacy or no data on efficacy Red: Disease-aggravating effect Trends Pharmacol Sci. 2015;36(4):189-95.; Nat Medicine. 2013;19(7):822-4.

Fibroblast-like Synoviocyte in RA Synovial fibroblasts are key effectors cells in the pathogenesis of RA since they produce a wide variety of mediators of inflammation and joint destruction. RA-FLSs have an activated phenotype that is independent of further activation by immune cells. Epigenetic changes have been found to lead to changes in gene expression in RA-FLSs and to shape the pathogenic phenotype of these cells.22

RA-FLS can spread to unaffected joints. Cell Cycle. 2010;9(12):2286-91.; Nat Med 2009;15:1414-20.

Disturbed joint tissue repair & remodeling in RA Erosion of periarticular bone, the typical feature observed in RA patients, results from excessive local bone resorption and inadequate bone formation.

Factors related to bone remodeling in RA Increased osteoclast enhancing factors Increased anti-osteoblastic factors Arthritis Research & Therapy 2011, 13:235; Nat. Rev. Rheumatol. 7, 700 707 (2011); Nat Med. 2007;13(2):133-4.

Hypothetic model RA Genetic Rheumatoid Arthritis Environmental Synoviocytes Osteoclassts Th1 or Th17 cells B cells

Autoantibodies & synovitis development in RA RA-related autoantibodies precede the onset of RA. Subclinical synovitis does not coincide with the appearance of serum autoantibodies during the pre-ra stage. Arthritis Rheum 2004;50(2):380-6..; Ann Rheum Dis 2011;70:772 7. Arthritis Rheumatol. 2014;66:513-22.

Multistep progression to RA development Nat Rev Rheumatol 2015;11:261 62.; Nat Rev Immunol. 2007;7(6):429-42

Multistep progression to RA development Auto-immune response in the extra-articular organs/tissues Immune inflammation in the joints Chemokines and cytokines Epitope spreading Fc glycosylation status; sialyation & galactosylation Microbiota change

Conclusion The recent progress in RA research has leaded to the introduction of new, effective therapies and remarkable improvement in clinical outcomes. However, much remains to be resolved. We need to understand the factors that lead to loss of tolerance and that cause localization of inflammation in the joint. We need to find ways to promote immunologic resolution or repair of damaged joints. We must strive to develop curative and preventive therapeutics of RA.