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1987 Revised Criteria for classification of RA

1987 Revised Criteria for classification of RA. Morning stiffness * Arthritis ≥ 3 joints * Arthritis of PIP, MCP or Wrist * Arthritis is Symmetric* Subcutaneous nodules RF Radiographic Changes Patient must meet ≥ 4 criteria of the above. N.B: sensitivity 92% and specificity is 89%.

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1987 Revised Criteria for classification of RA

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  1. 1987 Revised Criteria for classification of RA • Morning stiffness * • Arthritis ≥ 3 joints * • Arthritis of PIP, MCP or Wrist * • Arthritis is Symmetric* • Subcutaneous nodules • RF • Radiographic Changes Patient must meet ≥ 4 criteria of the above. N.B: sensitivity 92% and specificity is 89%. * More Than 6 Weeks

  2. What is rheumatoid arthritis ? It ‘s a chronic systemic autoimmune inflammatory disease affecting all joints covered by synovium leading to destructive polyarthritis

  3. 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

  4. 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

  5. Etio-pathogenesis of RA No clear aetiology Multi-factorial Genetic factors Auto-Immunity

  6. 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 20-25 % 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

  7. 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

  8. Exogenous EBV Mycoplasma Hepatitis MycoBacterium Paro Virus B19 Yarsenia Streptococcus Endogenous Citrullinated Peptide Arthritogenic Antigen Bacterial viral

  9. Pathogenesis of Rheumatoid Arthritis (RA)

  10. B Cell Macrophage T Cell Pannus IL-1 TNF Cartilage 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

  11. Mechanisms of Structural Damage in Rheumatoid Arthritis1 Osteoclasts Joint erosion Bone destruction TNFa IL-1 Synoviocytes Macrophage CD4+ T lymphocyte Joint-space narrowing Cartilage destruction TNFa IL-1 Chondrocytes Adhesion molecule expression Endothelial cell Adapted from Arend WP.  J Rheumatol Suppl. 2002;65:16-21. Permission to reproduce granted by Journal of Rheumatology and Dr WP Arend.

  12. Anti-inflammatory sTNFR IL-4 IL-10 sIL-1R IL-11 IL-1Ra TGF- Proinflammatory TNF IL-8 IL-1 IFN- IL-2 LT IL-6 Cytokine Disequilibrium in the Disease Process of RA1,2

  13. TNF Proinflammatory Anti-inflammatory IL-6, IL-8, GM-CSF IL-10, sTNFR, IL-1Ra IL-1 , TNF – A Logical Target • Helps drive events in the inflammatory cascade1-3 • Triggers production of other cytokines, including IL-11,2

  14. Activates monocytes/macrophages Activates chondrocytes, releasing collagenases Activates osteoclasts, suppresses osteoblasts Inflammation Cartilage breakdown Bone resorption and erosions Three Destructive Effects of TNF1-5

  15. The role of B cells in the pathophysiology of RA 16

  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

  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

  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

  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

  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

  21. Steps in the maturation of B cellsCD20 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 EFFECTORS

  23. Conclusion of Pathogenesis • 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(

  24. presentation • 70% insidious onset (weeks to mnths) • 10% acute (fulminant onsent) • 20% sub acute onset

  25. 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

  26. 1987 Revised Criteria for classification of RA • Morning stiffness * • Arthritis ≥ 3 joints * • Arthritis of PIP, MCP or Wrist * • Arthritis is Symmetric* • Subcutaneous nodules • RF • Radiographic Changes Patient must meet ≥ 4 criteria of the above. N.B: sensitivity 92% and specificity is 89%. * More Than 6 Weeks

  27. Precipitating factors? • Emotional stress • Infection • Immunization • Pregnancy • Fibromyalgia • Reynaud's phenomenon • Family history (of autoimmune disease )

  28. Extraarticular manifestation of RA Skin Pulmonary Cardiovascular Hematological Ocular CNS Bone Amyloidosis Filty’s Syndrome

  29. 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

  30. pulmonary Manifistaions • Pleurisy (with or without effusion) (frequent-often mild-) 25% bilateral • Rheumatoid pleural nodules 5% caplan syndrome (coin shape lesions) • Diffuse interstitial fibrosis –Rare-- • Cricoartynoid involvment (hoarsness,dysphagia,inspiration dificulty)

  31. Cardiovascular • Pericarditis 10%, Myocarditis 5%, Valvulitis (aortic incompitance)<1% • Coronary artery disease (40% of RA have prematue atherosclerosis) • Nodule formation • Amylodosis

  32. 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

  33. Ocular • keratocongunctivitisSicca (xeropthalmia) secondary to sjögren’s syndrome xerostomia,dyspareunia • Episcleritis benign • Scleritisscleromalcia 1% • Nodules <2% scleromalciaperforance • Uveitis &Congunctivitis are rare

  34. Bone • Osteoperosis • AVN(avascular necrosis) • osteoarthritis

  35. 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

  36. Secondary amyloidosis • Renal is the most common • Skin,liver,GI can be affected

  37. Bad Prognostic Factors • Early onset • Fulminant course • Seropositive RF • Anti CCP positve • Rheumatoid nodules • Sjogron’s syndrome • Feltty syndrome • Vasculitis • Limtation of biologics

  38. 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.

  39. 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

  40. Managing RA – Therapeutic Goals • Control symptoms • Minimize loss of function • Reduce progression of disease

  41. RA Disease Management

  42. Inflammation Disability Radiographic Scores Schematic Representation of the Course of RA Over 30 Years Kirwan J. J Rheumatol. 1999;26:720-5.

  43. Current RA Treatment Strategy for 2009 • DMARD (Step-up/triple therapy) • MTX • SSZ • Biologic 1 • Anti-TNF • Etanercept • Infliximab • Adalimumab • Biologic 2 • Rituximab • Abatacept DAS28 driven

  44. 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.

  45. Early referal Reliable diagnosis Prognostic predictors Effective & safe therapies Disease activity measures For early aggressive treatment we need the following Decrease disease activity & prevent joint damage

  46. Progress in management of RA in recent years

  47. Exp methods MTX, axathioprine Glucocorticoid (systemic or intra-articular) Surgery Penicillamine, gold, hydroxychloroquine Physcial medicine, rehabilitation Salicylates, NSAIDs Patient education, rest, application of heat or cold Traditional Therapies Wilske and Haeley. J Rheumatol 1989

  48. Treatment of RA With DMARDs • Traditional DMARDs1 • MTX • Hydroxychloroquine • Sulfasalazine • Leflunomide • “Biologics DMARDs”2-5 • Etanercept • Infliximab • Adalimumab • Anakinra • Abatacept • Rituximab Combination Treatment2 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.

  49. 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

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