What is rheumatoid arthritis ?
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1987 Revised Criteria for classification of RA 1. Morning stiffness * 2. Arthritis ≥ 3 joints * 3. Arthritis of PIP, MCP or Wrist * 4. Arthritis is Symmetric* 5. Subcutaneous nodules 6. RF 7. Radiographic Changes Patient must meet ≥ 4 criteria of the above. N.B: sensitivity 92% and specificity is 89%. * More Than 6 Weeks What is rheumatoid arthritis ? It ‘s a chronic systemic autoimmune inflammatory disease affecting all joints covered by synovium leading to destructive polyarthritis RA is the most common inflammatory arthritis • • • • • causes severe joint destruction is a systemic disease with systemic damage leads to disability Is associated with significant costs Is an immune mediated disease driven by inflammatory cytokines Incidence , prevalence & morbidity • • • • • • • • • • • • • World wide prevalence: 1-3% Age distribution: 4F:1M Peak onset: (35-50) It can affect any age from childhood up to the age of 75 Life expectancy is reduced by approximately 7 yrs (♂) 3 yrs (♀) Due to : Cardiovascular disease Infection Renal disease Respiratory disease Vasculitis Malignancy GI disease Etio-pathogenesis of RA No clear aetiology Multi-factorial Genetic factors Auto-Immunity A- Genetics • HLA class II is strongly linked to RA. • HLA DR4 is the major halo-type in ethnic group, HLA DR1 in Indians and HLA DW15 in Japanese. N.B : • 50-70 % of caucasian RA patients are HLA DR4, Compared to 2025 % of the population at large. • 1st degree relatives of RA patients are 4x . • 25 % F frequency in identical twins •5% Frequency in non-identical twins B- Auto-Immunity There is substantial evidence that the initiation of RA is T-cell mediated. Antigen Specific Process Once T-Lymphocyte recognize antigens (Arthritogenic antigen) Therefore: Auto Immunity Cascade Started Arthritogenic Antigen Endogenous Bacterial viral Exogenous EBV Mycoplasma Hepatitis MycoBacterium Paro Virus B19 Yarsenia Streptococcus Citrullinated Peptide Pathogenesis of Rheumatoid Arthritis (RA) The Inflammatory Cascade in RA Activation of T cells triggers a • series of intercellular reactions1 Lymphocytes, monocytes/ • macrophages, and synovial fibroblasts are stimulated to release proinflammatory cytokines2 Cytokines induce synovial • proliferation and release of destructive enzymes1-3 B Cell Macrophage T Cell Pannus IL-1 TNF Cartilage Mechanisms of Structural Damage in Rheumatoid Arthritis1 Osteoclasts Bone destruction TNFa IL-1 CD4+ T lymphocyte Joint erosion Synoviocytes Macrophage Cartilage destruction TNFa IL-1 Chondrocytes Endothelial cell Adhesion molecule expression Adapted from Arend WP. J Rheumatol Suppl. 2002;65:16-21. Permission to reproduce granted by Journal of Rheumatology and Dr WP Arend. Joint-space narrowing Cytokine Disequilibrium in the Disease Process of RA1,2 TNF – A Logical Target Helps drive events in the inflammatory • cascade1-3 Triggers production of other cytokines, • including IL-11,2 TNF Anti-inflammatory Proinflammatory IL-1 IL-6, IL-8, GM-CSF IL-10, sTNFR, IL-1Ra , Three Destructive Effects of TNF1-5 Activates monocytes/macrophages Activates chondrocytes, releasing collagenases Activates osteoclasts, suppresses osteoblasts Inflammation Cartilage breakdown Bone resorption and erosions The role of B cells in the pathophysiology of RA 16 B cells: key players in RA pathophysiology • For the past 20 years, RA has been considered a T cell-mediated disease • Recently, the important role of B cells in the pathophysiology of RA has been revealed • This new discovery has led to a breakthrough in the management of RA (Dörner & Burmester, 2003) 17 B cells: key players in RA pathophysiology (cont’d) • There is an abundance of B cells in the synovium of RA-affected joints – These lymphocytes can be organised into lymphoid structures • Three critical roles of B cells in RA pathogenesis: – Antigen presentation and T cell activation – Autoantibody production – Cytokine production 18 Role of B cells in RA: (1) antigen presentation leading to T cell activation • B cells are highly efficient antigen-presenting cells (APCs) • Antigen presentation leads to T cell activation • Activated T cells produce cytokines that activate macrophages to produce pro-inflammatory cytokines Results in inflammation and joint destruction 19 Role of B cells in RA: (2) autoantibody production • Auto reactive B cells produce auto anti-bodies, including RF. • Formation of RF immune complexes in the synovium leads to production of pro-inflammatory cytokines through: – Complement activation – Macrophage activation (Abrahams et al, 2000; Silverman & Carson, 2003; Sutton et al, 2000) 20 Role of B cells in RA: (3) cytokine production • Activated B cells produce cytokines (e.g. TNF-α, interleukin [IL]-6, lymphotoxin) which are known to promote inflammation and joint damage in RA • Lymphotoxin promotes the formation of new lymphoid structures in the synovium, thus helping to perpetuate autoimmune reactions (Duddy et al, 2004; Lund et al, 2005) 21 Steps in the maturation of B cells CD20 only expressed in a subset of B cells (Roitt et al, 2002; Sell & Max, 2001; Silverman & Weisman, 2003) 22 Pro-inflammatory Cytokines Stimulate the secretion of: MMP: degrade matrix and complement protein MTP “ Acute phase protein” Prostaglandins “ O2 free radicals” Heat shock proteins and others! And these are the major That mediate tissue destruction Conclusion of Pathogenesis • 1. 2. 3. Whatever the initiating stimulus….. RA is characterized by : Persistent cellular activation Genetically susceptible host Auto-immunity At the site of articular and extra-articular tissue chronic inflammation (PANUS) and (JOINT DESTRUCTION( presentation • 70% insidious onset (weeks to mnths) • 10% acute (fulminant onsent) • 20% sub acute onset Patterns of joints involvement • Oligoarticular 45% • Polyarticular • • 35% 60% small joints 30 % large joints 10 % Both • Monoarticular 20% 50% knee only • • • • • • 50% wrist elbow shoulder ankle hips 1987 Revised Criteria for classification of RA 1. Morning stiffness * 2. Arthritis ≥ 3 joints * 3. Arthritis of PIP, MCP or Wrist * 4. Arthritis is Symmetric* 5. Subcutaneous nodules 6. RF 7. Radiographic Changes Patient must meet ≥ 4 criteria of the above. N.B: sensitivity 92% and specificity is 89%. * More Than 6 Weeks Precipitating factors? • • • • • • • Emotional stress Infection Immunization Pregnancy Fibromyalgia Reynaud's phenomenon Family history (of autoimmune disease ) Extraarticular manifestation of RA Skin Pulmonary Cardiovascular Hematological Ocular CNS Bone Amyloidosis Filty’s Syndrome Skin • Palmer erythema • Reynaud's phenomena • Rheumatoid nodules up to 25 % of patients (firm,nontender,single or multiple) • Vasculaitis 1% PAN like vasculitis • lekuocytoclastic vasculitis • cryoglobulonemia • pulmonary Manifistaions • Pleurisy (with or without effusion) (frequentoften mild-) 25% bilateral • Rheumatoid pleural nodules 5% caplan syndrome (coin shape lesions) • Diffuse interstitial fibrosis –Rare-• Cricoartynoid involvment (hoarsness,dysphagia,inspiration dificulty) Cardiovascular • Pericarditis 10%, Myocarditis 5%, Valvulitis (aortic incompitance)<1% • Coronary artery disease (40% of RA have prematue atherosclerosis) • Nodule formation • Amylodosis Hematological complications • • • • • • • • Lymph node enlargment 50 % Anemia of chronic disease Iron defficency anemia Autoimmune heamolytic anemia(uncommon) Drug induced marrow supression anemia Thrombocytosis Cytopenia secondary filty’s syndrome splenomegaly Ocular • keratocongunctivitis Sicca (xeropthalmia) secondary to sjögren’s syndrome xerostomia,dyspareunia • • • • Episcleritis benign Scleritisscleromalcia 1% Nodules <2% scleromalcia perforance Uveitis &Congunctivitis are rare Bone • Osteoperosis • AVN(avascular necrosis) • osteoarthritis CNS • • • • Carpal tunnel syndrome (common) Tarsal tunnel syndrome(rare) Mono neuritis multiplex Atlantoaxial subluxation 1/3 of patients (usually assymptomatic chronic cases) • CNS Vasculitis • Depression, Psychosis • FMS Secondary amyloidosis • Renal is the most common • Skin,liver,GI can be affected Bad Prognostic Factors • • • • • • • • • Early onset Fulminant course Seropositive RF Anti CCP positve Rheumatoid nodules Sjogron’s syndrome Feltty syndrome Vasculitis Limtation of biologics Unlikely to be RA • • • • • • • • Asymmetric Arthritis Migratory pattern Predominantly large joints DIP involvement Rash, High fever Back complain RF Negative status-CCP negative No erosions in X rays if more than 2 years since presentation. Are you a safe physician? Is the patient with RA fit for the OR? • Can the Patient get pregnant? • How to asses activity of the disease by : • history • physical exam • lab • When to start DMARDS • When to start Anti TNF • When to start Anti B-cell • How to follow up a patient Managing RA – Therapeutic Goals • Control symptoms • Minimize loss of function • Reduce progression of disease RA Disease Management Schematic Representation of the Course of RA Over 30 Years Inflammation Disability Severity (Arbitrary Units) Radiographic Scores 0 5 10 15 20 Disease duration (years) Kirwan J. J Rheumatol. 1999;26:720-5. 25 30 Current RA Treatment Strategy for 2009 DMARD (Step-up/triple therapy) MTX SSZ Biologic 1 Anti-TNF Biologic 2 Rituximab Abatacept DAS28 driven Etanercept Infliximab Adalimumab ACR Goals of Therapy in RA Symptom relief Improvement in physical function Reduce physical disability Slowing/arresting progression of structural damage Guidelines for the Management of RA. Arthritis Rheum. 1996; 39:713-22. For early aggressive treatment we need the following Early referal Reliable diagnosis Prognostic predictors Effective & safe therapies Disease activity measures Decrease disease activity & prevent joint damage Progress in management of RA in recent years Drugs Objectives 1985 MTX/SSZ Signs & symptoms 1995 Combination 2000 Concepts Leflunomide joint damage TNF blockers Stop joint damage Early treatment Prevent joint damage Tight control Early intensive ttt 2008 Remission Traditional Therapies Exp methods MTX, axathioprine Penicillamine, gold, hydroxychloroquine Physcial medicine, rehabilitation Salicylates, NSAIDs Patient education, rest, application of heat or cold Wilske and Haeley. J Rheumatol 1989 Treatment of RA With DMARDs Traditional DMARDs1 MTX Hydroxychloroquine Sulfasalazine Leflunomide • • • •Combination Treatment2 “Biologics DMARDs”2-5 Etanercept Infliximab Adalimumab Anakinra Abatacept Rituximab • • • • • • 1. ACR Subcommittee on Rheumatoid Arthritis Guidelines. Arthritis Rheum. 2002;46:328-346. 2. Combe B, et al. Ann Rheum Dis. 2007;66:34-45. 3. Kineret® (anakinra) Prescribing Information, Amgen Corporation. Thousand Oaks, Calif. 4. Orencia® (abatacept) Prescribing Information, Bristol-Myers Squibb Company, Princeton, NJ. 5. Rituxan® (rituximab) Prescribing Information, Genentech, Inc., South San Francisco, Calif. The Famous Combination Studies • ARC low dose glucocorticoid study group trial • Methotrexate-Cyclosporin combination study • RAIN study of Methotrexate + SSP + HCQ: (triple therapy) • COBRA study: SSP + MTX + Prednisolone or SSP alone • Fin-RACo Trial: SSP+MTX+HCQ+Prednisolone vs single drug +/- Prednisolone Key Anti-TNF Trials Late ARMADA ATTRACT TEMPO Adalimumab Infliximab Etanercept Early ASPIRE ERA PREMIER Infliximab Etanercept Adalimumab When to use anti-TNF? Straight away • Synthesis and Function of TNFa Soluble TNFa After DMARD failure • DAS28 >5.1 or less • Macrophage or activated T-cell Receptor-bound TNFa Transmembrane TNFa Signal Induction TNFa Receptor Late • Target Cell Key Messages Set clear disease activity targets TICORA TEAR CAMERA Earlier treatment PROMPT COMET Therapeutic memory BeST B cell targeting Definition of Remission Clinical Remission – ACR/DAS criteria, or normal acute phase response, no clinical synovitis Imaging Remission – No radiographic damage progression – No significant synovitis on sensitive imaging True Remission – A state of low disease activity with no progression of structural damage Clinical Remission by DAS28 DAS28 Score Disease Activity Severe 5.1 Moderate 3.2 2.6 Low Remission DAS28 <2.6 Based on VAS of 100mm Prevoo MLL et al. Arthritis Rheum 1995;38:44-8. van Gestel AM et al. J Rheumatol 1999;26:705-11. Remission in RA Importance of Structural Damage Determinants of Structural Damage – Interrelationship synovitis and damage Remission Clinical and Imaging – Impact of DMARDs – Effect of TNF antagonists Remission on DMARDs DMARDs frequently produce clinical remission DMARDs rarely produce imaging remission Hence DMARDs rarely produce true remission Explains progression of damage in patients in clinical remission on DMARDs? What happens with TNF antagonists? Algorithm for Achieving Therapeutic Success in RA Early RA: Early DMARD therapy MTX dose 15-20 mg/week (within 1-2 months) + glucocorticoid Cobra? Long-standing RA: If previosuly inadequate dose: Optimize DMARD (MTX) dose + glucocorticoid DAS28 improvement >1.2 or HAQ improvement >0.5 within 3-4 months YES NO SDAI <3.3 or DAS28 < 2.4 or HAQ <0.5 within 4 months by adjusting dosages X-rays YES NO Switch to another DMARD + glucocorticoid or Add a biologic agent (eg, TNF- antagonist) Smolen, Sokka, Pincus, Breedveld, Clin Exp Rheumatol 2003 Add another DMARD + glucocorticoid or Add a biologic agent (eg,TNF- antagonist) Continue DMARD therapy, lower corticosteroids
