BIOM Firestein, Winter Rheumatoid arthritis. Page 1

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1 Rheumatoid arthritis Page 1

2 Vascular events in RA Synovium in rheumatoid arthritis Non-extra articular RA Extra articular RA Turesson, et al. Ann Rheum Dis. 2007;66:60 Normal Rheumatoid Arthritis Major Cell Types in RA Macrophage B cell B PMN Neutrophil FLS M T T cell C Fibroblast-like Chondrocyte synoviocyte OC Osteoclast Immunopathogenesis of RA Rheumatoid factors and immune complexes Rheumatoid factors produced by RA synovium Rheumatoid factors fix complement Complement consumed in RA joint Complement fragments recruit and activate PMNs New antibodies now implicated, especially to citrullinated peptides Hypothesis: RA represents a localized immune complex disease (Zvaifler, 1973) Page 2

3 Autoimmunity precedes synovitis in RA Percentage of positive patients IgM-RF or anti-cp anti-cp IgM-RF 49% 49% 28% Autoantibodies in RA Autoreactivity can precede RA by years Initiating and perpetuating antigens might differ Joint Type II collagen Proteoglycans Aggrecan Systemic IgG Fc (RF) CCPs Heat shock proteins Cartilage link protein GPI Years before the start of symptoms Nielen, et al, Arth Rheum 2004, 50:380 Anti-CCP antibodies and disease severity in RA Immunopathogenesis of RA HLA associations and the role of T cells Specific class II MHC alleles associated with RA e.g., HLA-DR 0401, rd hypervariable region of ß chain Q-K-R-A-A Increased susceptibility and severity Possibly related to binding of arthritogenic peptide Arthritis Res Ther. 2005; 7: R949 Issues: No specific peptide identified May play a role in T cell repertoire or TCR contacts Many other genes involved (PADI4, TNF promoter,ctla4, PTPN22, etc.) Page 3

4 The environment in RA: Activation of innate immunity Smoking induces citrullination in BAL cells Primitive arm of immune system Toll-like receptors expressed in synovium Repeated TLR activation might break tolerance TLR agonists in RA tissue Peptidoglycan Bacterial DNA Viral nucleotides Necrotic particles in synovial fluid Endogenous ligands Klareskog, et al.arthritis Rheum. 2006;54:38 Smoking as a risk factor for RA Role of Cytokines in RA TNF IL-1 Soluble TNF receptor IL-10 IL-1 receptor antagonist Combination of genes + environmental stress = RA No specific RA pathogen Initiation of disease is a continuum Repeated stress breaks immune tolerance Becomes increasingly complex as disease progresses Klareskog, et al.arthritis Rheum. 2006;54:38 IL-6 Feldmann M et al. Cell. 1996; 85: Pro-inflammatory Anti-inflammatory Page 4

5 Cytokine Networks in RA Model for the etiology of RA Autoreactivity/ genetics Activation of innate immunity DC FLS M Periphery Joint damage Synovial Inflammation/ Cytokines Lymph node Nature. 2003;423: Migration DC T T T T B Recruitment Autoantibodies Methotrexate in rheumatoid arthritis Effect of anti-tnf in RA Infliximab Placebo Lancet Dec 4;354(9194): Page 5

6 Targeting T cells: Abatacept Abatacept (CTLA4-Ig) Clinical Efficacy 80 ACR20 ACR50 ACR70 60 Patients (%) Placebo + MTX Abatacept 10 mg/kg + MTX N Engl J Med. 2005;353: Anti-B cell therapy in RA: Rituximab What is signal transduction? % of patients ACR20 ACR50 ACR MTX + placebos * Rituximab 1000 mg + placebos * 23 Rituximab 1000 mg + MTX Relays information from environment to nucleus Regulates cell function: mrna transcription/ stability, protein production/stability Many mechanisms, especially kinases that phosphorylate Tyrosine, Serine, Threonine Likely the next generation of anti-rheumatic drugs after biologics Page 6

7 Why signal transduction? How signal transduction works Orally bioavailable drugs Less expensive Broader effects than biologics Regulates pathways implicated in RA Inhibit production of multiple cytokines Inhibit action of multiple cytokines Target Kinase OH Kinase ATP Target Kinase OH Drug ATP Competitive inhibitor Target O-Phos ADP O-Phos Target OH Kinase ATP Drug Allosteric Inhibitor Why NOT signal transduction? Very complex 518 kinases! Redundant pathways Many compounds act at ATP site Specificity difficult to achieve and prove Toxicity if key pathways blocked Many of these same objections were raised about cytokine inhibitors. Success in signal transduction: The good Gleevec (Imatinib)--Tyrosine kinase inhibitor Chronic myelogenous leukemia?scleroderma and fibrosing diseases Iressa (gefitinib)--tyrosine kinase inhibitor Lung cancer JAK3 and Syk in RA Page 7

8 Syk regulation of FcR signaling Syk inhibitor in RA Other kinases & adaptors ITAM MAP kinases PI3 kinases NF-kB ITAM=Immunoreceptor tyrosine activating motif Responders (%) 12-week phase 2 study add on to MTX Hypertension, hepatotoxicity, and neutropenia 2008 ACR meeting, San Francisco Janus kinases: Regulation of cytokine signaling JAK3 inhibition in RA Responders (%) JAK1 IL-2 family, IL-6 family, IL-10 family and IFNs JAK2 Type II cytokines (IFNs, GM-CSF receptor family, EPO) JAK3 IL-2, 4, 7, 9, 15, and 21 (T cells and NK cells) week phase II study with CP added on to MTX Anemia, hepatotoxicity, neutropenia Kermer, et al. ACR Annual Meeting; 2008, San Francisco Page 8

9 MAP kinases: a model for targeting kinases Signal transduction pathway regulates inflammation and matrix turnover Three families: ERK, JNK and p38 Goal: To evaluate the hierarchy and organization of kinases in the MAP kinase pathway MAPK Cascade MAPKKK MAPKK MAPK Transcription factors Cytokines, MMPs The MAP kinase pathway MAP3Ks p38 inhibitor in adjuvant arthritis 1.8 MEK1/2 MKK4/7 MKK3/6 ERK1/2 JNK1/2/3 p38 / / / Elk1 c-jun ATF2 c-myc ATF2 MAPKAP2 Change in Paw Volume SB (mg/kg) Cell growth Matrix regulation Inflammation Differentiation Cytokines Badger AM et al. Arthritis Rheum. 2000;43: Page 9

10 p38 inhibitors in human LPS responses RWJ SCIO469: ACR20 Response Week 12 Proportion of Subjects Who Achieved ACR20 Fever Serum cytokines Placebo n =75 30mg Tid-IR n =73 P= mg Tid-IR n =73 P= mg ER n =78 P=0.898 Fijen, J. W., Clin Exp Immunol 124:16, 2001 Genovese, et al. National ACR meeting, 2008 Page 10

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