RA symposium 2023-24.pptx

Module 203 Systemic Inflammatory Disease Symposium Rheumatoid Arthritis (RA) pathophysiology Prof Sandra Sacre [email protected] Contents What is RA? Clinical tests for RA Etiology Molecular mechanisms of joint destruction RA is an autoimmune disease Autoimmunity (or autoreactivity)= immune respons...

Module 203 Systemic Inflammatory Disease Symposium Rheumatoid Arthritis (RA) pathophysiology Prof Sandra Sacre [email protected] Contents What is RA? Clinical tests for RA Etiology Molecular mechanisms of joint destruction RA is an autoimmune disease Autoimmunity (or autoreactivity)= immune responses to self-antigens Represents a breakdown of immunological tolerance Immune reactions to ‘self’ can occur as part of a controlled inflammatory reaction e.g. tissue repair acute Removal of pathogen/ Tissue repair Cytokines Tissue destruction Chronic RA is a chronic inflammatory disease of the synovial joints Usually multiple joints in a symmetrical fashion – Morning stiffness – Swelling, heat, redness and pain – Loss of function Destructive process – Bone erosion – Synovial and cartilage damage Characteristics of RA 3x more women than men with RA Affects 1% of the worldwide population (1:100 peop Autoantibodies are often present :  Rheumatoid factor (RF) Women have a higher risk of developing autoimmunity  Cyclic citrullinated peptide (anti-CCP) antibodies Inflammation in the synovial joint but also systemically Disability and a reduced quality of life Increased mortality – decreased life expectancy ‘Healthy’ Inflammation Pathological Inflammation Inflammation naturally fluctuates over time  Time Fluctuation in a person with chronic inflammatory disease e.g. RA Response to immune events in a healthy person Threshold for pathological inflammation Natural fluctuation in a healthy person Complete blockade of proinflammatory mediators Goal of treatment: restore natural fluctuations below threshold Image courtesy of Peter C. Taylor, personal communication 2018 Chronic Inflammation causes tissue damage Inflammation associated with autoimmunity is chronic, unregulated and persistent. Inflammation Co-morbidity Autoimmune diseases are often complex and can involve a specific site in the body or can be systemic. Damage Time Comorbidities in Patients with RA McInnes IB, Schett G. N Engl J Med 2011;365:2205-2219. Clinical markers of RA Elevated ESR (Erythrocyte sedimentation rate) Elevated CRP (C-reactive protein) Presence of autoantibodies:  Rheumatoid factor (RF)  Cyclic citrullinated peptide (anti-CCP) antibodies Rheumatoid factor (RF) Rheumatoid factor are antibodies directed against the Fc portion of another antibody, leading to immune complex Present information 60-70% of patients with RA Of some use in diagnosis, but:  Not specific for RA (only 86%), also present in other autoimmune diseases, infectious diseases and some healthy individuals  Some RA patients are ‘seronegative’  Levels do not correlate with disease activity  RF+ patients have a more erosive disease Image: laboratoryinfo.com Anti-cyclic citrullinated peptide (CCP) antibody Also known as ACPA (anti-citrullinated peptide antibodies) Antibodies directed against CCP are found in 70-80% of patients with RA (anti-CCP+) Very rarely found in healthy people who do not go on to develop RA (high specificity 98%) Detectable in the blood many years before disease onset Anti-CCP+ RA has a more aggressive clinical course of disease Citrullination Process of replacing protein arginine residues with citrulline residues Occurs normally in the body but if occurs on an unusual part of the protein, they may be recognised as foreign, leading to an antibody response Citrullinated self proteins are detected in RA patients by anti-CCP antibodies; examples are α-enolase, keratin, fibrinogen, fibronectin, collagen and vimentin Do anti-CCP antibodies have a pathogenic role? Unable to induce arthritis alone but can enhances the development and severity of inflammation in mice when a mild synovitis is already present. Possible mechanisms: 1)Activation of inflammatory cells by anti-CCP immune complexes 2)Induce neutrophil cell death producing NETs 3)Promote osteoclast differentiation and activation Krishnamurthy, et al Annals of the Rheumatic Diseases 2016;75:721-729. Etiology of RA Genes Autoimmune Disease Immune dysfunction Environment Images from wikimedia Commons Incidence of RA worldwide (cases per 100 inhabitants) Population North America Incidence USA (general 0.9–1.1 population) USA (native- 5.3–6.0 Americans) North Europe England Finland Sweden Norway Netherlands Denmark Ireland South Europe Spain France Italy Greece Yugoslavia 0.8–1.10 0.8 0.5–0.9 0.4–0.5 0.9 0.9 0.5 0.5 0.6 0.3 0.3–0.7 0.2 Population South America Argentina Brazil Colombia Asia Japan China Taiwan Indonesia Philippines Pakistan Middle East Egypt Israel Oman Turkey Africa Alamanos et al.Autoimmunity Reviews 4, Incidence 0.2 0.5 0.1 0.3 0.2–0.3 0.2–0.3 0.2 0.1 0.2 0.3 0.4 0.5 0–0.3 Genetics: Twin Studies (RA disease concordance) Monozygo tic ‘identical’ 12-15% Dizygotic ‘nonidentical’ 2-5% Values can differ between studies Genetics of RA Most genes show a relatively low gene penetrance. Variants are not found in many of the RA patients. No individual gene is necessary or sufficient Susceptibility and severity is determined by a combination of genes Must be other factors that in addition to genetics that have a role in the susceptibility and severity of autoimmune diseases. Many of the genes identified regulate the immune system, possibly in response to environmental agents Genes associated with RA HLA-DRB1 SE Human leukocyte antigen (HLA), accounts for 30-50% of the overall genetic risk PTPN22 Negative regulator of antigen receptor signalling in T and B cells (protein tyrosine phosphatase 22) CTLA4 Co-stimulation suppressor that regulates interactions between T cells and antigen presenting cells (downregulated in RA) TNFAIP3 (A20) Inhibitor of NF-κB and TNFα mediated apoptosis (downregulated in RA) Testosterone Hormones Men who get RA usually have low testosterone levels RA patients often experience remission during pregnancy Early menopause (age 50 years of age, many other studies show no effect Smoking Heavy smoking of both sexes increase the risk of RA among persons with susceptibility HLA-DR4 alleles. Twin studies have demonstrated the gene–environment interaction by showing the effect of smoking is greater in genetically susceptible individuals, particularly for HLA DRB1 alleles Smoking and HLA-DRB1 alleles increase the risk of being anti-CCP+ Image from wikimedia Commons Suggested infectious trigger of RA Viral/bacterial infections have been suggested for many decades as an initiating cause of Infections autoimmunity Human parvovirus Evidence has proved difficult to find. The B19 infection may no longer be present once Human Retrovirus 5 the disease is established Bacterial components have been identified in Alphaviruses Hepatitis joint tissue from RA patients but also in Chronic hepatitis C healthy joint tissue virus No evidence of a seasonal influence on Epstein–Barr Virus incidence of autoimmune diseases Mycoplasma Escherichia coli Rubella virus Periodontitis Molecular mechanisms of joint destruction Synovitis Image source: VisualDx (www.visualdx.com) Swelling over extensor tendons, wrist and MCP joints Synovium hyperplasia (an increase in cell numbers) Synovial fibroblasts have reduced apoptosis, enhanced anchorage, upregulated adhesion molecules and increased proliferation Structural joint damage in RA Baseline + 5 years Damage is early and progressive Rheumatoid Arthritis Pathology Normal Joint Rheumatoid Joint Pannus (inflamed synovial membrane) Synovial membrane Synovial fluid rich in neutrophils Cartilage Synovitis Capsule Cartilage erosion Cartilage loss Bone erosion Composition of synovial tissue macrophages (40%) fibroblast and endothelial cells (10 -15%) T lymphocytes (40%) B lymphocytes and plasma cells (5%) Disequilibrium in inflammation Image from SpringerImages Cartilage erosion Chondrocytes undergo apoptosis Fibroblasts adhere to and invade the cartilage Fibroblasts make matrix metalloproteases (MMPs) which break down the collagen network in the cartilage Leads to biomechanical dysfunction and joint space narrowing Osteoclast bone erosion Cytokines (IL-17, RANKL, TNF-α, IL-1β and IL-6) and α-CCP antibodies promote osteoclast differentiation and activation Deep bone resorption pits develop, which become filled with inflammatory tissue Worse at mechanically vulnerable sites, such as the 2nd/ 3rd metacarpal Little repair as cytokines inhibit the differentiation of osteoblasts Affects 80% RA patients within 1 year of diagnosis Bony erosions in periarticular regions of toes Neutrophils Neutrophils infiltrate synovial fluid When activated neutrophils can undergo a special form of cell death termed ‘NETosis’ releasing nuclear chromatin Enhanced NETosis correlates with the presence of anti-CCP antibodies NETs release citrullinated proteins T Cells Human leukocyte antigen (HLA) associations suggest T cell role RA synovium is rich in activated T cells - Th17 cells and Th1 cells predominate Increasingly, Th17 cells suggested as a major pathogenic subset. IL-17 activates synovial fibroblasts and osteoclasts IL-17 favours cartilage resorption T regulatory cells are enriched in the RA joint but have a defect in their suppressive function. This defect is reversed by blocking TNF. B Cells Auto-antibodies associated with disease are usually present before onset of symptom diffuse B cells form diffuse or follicular infiltrates in the RA synovium B cell depletion using monoclonal anti-CD20 is effective treatment follicula r B cells also produce cytokines and are important for antigen presentation Panayi et al 2004 Rheumatology. 44(Suppl. 2):ii3–ii7 Innate immune cells Infiltrating macrophages, mast cells, NK cells in synovium Macrophages appear to be key effectors Phagocytosis Antigen presentation TNF, IL-1 and IL-6 Most therapies decrease macrophage cytokine production Decreased macrophage infiltration strongly correlates with the degree of clinical improvement to therapies Images from wikimedia Commons Complex cellular interactions in RA Genetic and non-genetic risk factors contribute to RA Smolen, J., Aletaha, D., Barton, A. et al. Rheumatoid arthritis. Nat Rev Dis Learning outcomes You should be able to:  Describe the characteristics of RA  Describe the clinical tests for RA  Explain which genetic and environmental factors are linked to RA  Describe the role of the cells of the innate and adaptive immune system in RA  Understand the pathogenic role of cytokines in RA Further Reading Smolen JS1, Aletaha D2, McInnes IB3.Rheumatoid arthritis. Lancet. 2016; 388(10055):2023-2038. McInnes, I. and Schett, G. The pathogenesis of rheumatoid arthritis. N. Engl. J. Med. (2011) 365;2205-19 Firestein GS, McInnes IB. Immunopathogenesis of Rheumatoid Arthritis. Immunity. 2017 Feb 21;46(2):183-196. doi: 10.1016/j.immuni.2017.02.006. Okada Y, Eyre S, Suzuki A, et al. Genetics of rheumatoid arthritis: 2018 status. Annals of the Rheumatic Diseases 2019;78:446-453.