Rheumatoid arthritis

rheumatology lectures

1. RHEUMATOID ARTHRITIS By Dr.ESSAM T. ATWA PROFESSOR OF RHEUMATOLOGY & REHABILITATION

2. Rheumatoid arthritis (RA) is a systemic disease characterized predominantly by a chronic inflammatory polyarthritis , with frequent progression to joint destruction and disability. The clinical picture seen in RA is the result of a complex cascade involving T cells, B cells, antigen-presenting cells, and a complex set of costimulation signals that lead to the production of proinflammatory cytokines, including tumor necrosis factor (TNF)-alpha, interleukins, and other mediators. Definition

3. The hallmarks of RA are inflammation and synovitis leading to joint damage, and an overexpression of inflammatory cytokines, such as TNF-alpha, IL-1, and IL-6. Although disease activity is the major cause for active joint damage in RA leading to disability, measuring disease activity in patients with RA remains a challenging issue. A number of composite disease scoring systems have been developed over the past decade, which consider physical and radiographic evaluations as well as overall physician and patient assessment. In addition, acute-phase reactant inflammatory markers, such as CRP and ESR, can provide additional information of the disease state.

4. RA Is Characterized by Synovitis and Joint Destruction NORMAL RA Synovial membrane Cartilage Capsule Synovial fluid Inflamed synovial membrane Pannus Major cell types T lymphocytes macrophages Minor cell types fibroblasts plasma cells endothelium dendritic cells Major cell type neutrophils Feldmann M, et al. Annu Rev Immunol . 1996;14:397-440. Cartilage thinning

5. Pannus formation Expansion of the synovial membrane forms an invasive pannus 1 Synovial cells and chondrocytes release destructive enzymes that degrade cartilage 1 Pannus invades cartilage, leading to bone erosion and joint instability 1 1 Harris ED Jr. N Engl J Med . 1990;322:1277-1289. Surgically resected pannus from a patient with advanced RA

6. Antigen presentation Foreign antigens bind to receptors on antigen-presenting cells 1 Complementary receptors on T cells recognize the antigens, triggering an immune response 1 1 Harris ED Jr. N Engl J Med . 1990;322:1277-1289.

7. The inflammatory cascade Activation of T cells triggers a series of intercellular reactions 1 Lymphocytes and macrophages release proinflammatory cytokines 1,2 Cytokines induce synovial proliferation and release of destructive enzymes 1,2 1 Rosenberg AE. In: Cotran RS, Kumar V, Robbins SL, eds. Robbins Pathologic Basis of Disease . 5th ed. Philadelphia, Pa: W.B. Saunders Company; 1994:1213-1271. 2 Goronzy JJ, Weyand CM. In: Klippel JH, ed. Primer on the Rheumatic Diseases . 11th ed. Atlanta, Ga: Arthritis Foundation; 1997:155-161.

8. Protein Inflammation Cytokines

9. Cytokine in Inflammation PROINFLAMMATORY ANTI-INFLAMMATORY TNF IL-1 IL-6 IL-8 IFN-  LT  IL-4 IL-10 TGF  sTNFR sIL-1R IL-1Ra Adapted from Feldmann M et al. Cell 85 :307-310, 1996 and Moreland LW et al. Arthritis Rheum 40 :397-409, 1997. disequilibrium

10. TNF Is a Key Pathogen in Rheumatic Disease TNF Macrophages Endothelium Hepatocytes Synoviocytes ­ Pro-inflammatory cytokines ­ Chemokines ­ Adhesion molecules ­ Acute phase response ­ Metalloproteinase synthesis ­ Vascular endothelial growth factor (VEGF) Articular cartilage degradation Increased CRP in serum Increased angiogenesis Increased cell infiltration Increased inflammation Osteoclast Progenitors ­ RANKL expression Bone erosions

11. TNF osteoclasts synoviocytes chondrocytes bone resorption bone erosion joint inflammation cartilage degradation joint space narrowing pain/joint inflammation Central Role of TNF in Rheumatoid Arthritis

12. The diagnosis of RA is made using : The patient's history and examination results In conjunction with laboratory and radiographic data.

13. CLINICAL

14. Symmetric joint pain Swelling of small peripheral joints Morning joint stiffness of variable duration Other diffuse aching Fatigue, malaise, and depression may precede other symptoms by weeks or months Grassi W et al. Eur J Radiol . 1998;27(suppl 1):S18–S24. RHEUMATOID ARTHRITIS Presenting Signs and Symptoms

15. INVESTIGATIONS

16. RADIOLOGY

17. 1987 Revised American Rheumatism Association Criteria for the Classification of Rheumatoid Arthritis Definition Criterion Morning stiffness in and around the joints, lasting at least 1 h. 1. Morning stiffness At least three joint areas simultaneously have had soft tissue swelling or fluid (not bony overgrowth alone) observed by a physician. The 14 possible areas are right or left PIP, MCP, wrist, elbow, knee, ankle, and MTP joints. 2. Arthritis in three or more joint areas At least one area swollen (as defined above) in a wrist, MCP, or PIP joint. 3. Arthritis of hand joints Simultaneous involvement of the same joint areas (as defined in Criterion 2) on both sides of the body (bilateral involvement of PIPs, MCPs, or MTPs is acceptable without absolute symmetry). 4. Symmetric arthritis

18. Cont. Definition Criterion Subcutaneous nodules over bony prominences or extensor surfaces or juxtaarticular regions observed by a physician. 5. Rheumatoid nodules Demonstration of abnormal amounts of serum rheumatoid factor by any method for which the result has been positive in <5% of normal control subjects. 6. Serum rheumatoid factor Radiographic changes typical of rheumatoid arthritis on the posteroanterior hand and wrist radiographs, which must include erosions or unequivocal decalcification localized in, or most marked adjacent to, the involved joints (osteoarthritis changes alone do not qualify). 7. Radiographic changes MCP, metacarpophalangeal ; MTP, metatarsophalangeal ; PIP, proximal interphalangeal .

19. For classification purposes, a patient shall be said to have rheumatoid arthritis if he or she has satisfied at least four of these seven criteria. Criteria 1 through 4 must have been present for at least 6 weeks. Patients with two clinical diagnoses are not excluded. Designation as classic, definite, or probable rheumatoid arthritis is not to be made.

20. The 2010 American College of Rheumatology/European League Against Rheumatism classification criteria for rheumatoid arthritis Target population (Who should be tested?): Patients who 1) have at least 1 joint with definite clinical synovitis (swelling) 2) with the synovitis not better explained by another disease Classification criteria for RA (score-based algorithm: add score of categories A–D; a score of 6/10 is needed for classification of a patient as having definite RA)

21. A-Joint Involvement Score 1- large joint. 2- 10 large joints 1 1-3 small joints (with or without involvement of large joints) 2 4-10 small joints (with or without involvement of large joints) 3 >10 joints (at least 1 small joint) 5

22. B. Serology (at least 1 test result is needed for classification ) Score Negative RF and negative ACPA Low-positive RF or low-positive ACPA 2 High-positive RF or high-positive ACPA 3

23. C . Acute-phase reactants (at least 1 test result is needed for classification) Score Normal CRP and normal ESR Abnormal CRP or abnormal ESR 1

24. D.Duration of symptoms Score < 6 weeks > 6 weeks 1

25. TREATMENT

26. Characteristics of ideal RA therapy ° Provides both rapid and sustained efficacy ° Highly effective for symptom relief ° Leads to prevention of joint destruction ° Prevents functional disability ° Useful in combination treatment ° Well tolerated , with minimal monitoring required ° Allows for simple dosing and administration

27. Modern history of RA treatment 1928 1948 1985 2000 Milestones Steps foreward Parenteral Gold Corticosteroids Methotrexate TNF blockers Antimalarials Modern NSAIDs Azathioprine D-Penicillamine Sulfasalazine Cyclosporin A Leflunomide COXIBS DMARD Combination

28. If Disease Controlled Wolfe F, et al. J Rheumatol . 2001;28:1704-11. Fleischmann RM. Clin Ther . 1999;21:1429-42. Matteson EL. Mayo Clin Proc . 2000;75:69-74. The Evolving RA Treatment Paradigm Initial Treatment Initial Treatment Monotherapy or Combination Current Approach Evolving Paradigm Conventional DMARDs DMARD Biologic agent If Poor Response Add additional DMARDs Add biologic agent If Poor Response Combination therapy Discontinuation/ reduction of DMARDs

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