Rheumatoid Arthritis

1. Rheumatoid Arthritis M Handel 1st Feb 2012

2. Definition of the Problem Rheumatoid Arthritis is a multi-system autoimmune disease of unknown cause characterized by inflammatory changes in the joints

3. Features of Rheumatoid Arthritis • Prevalence of approximately 1% in adult population • Age of onset usually between 30 – 50 years • Two- to three-fold more common in women • Chronic, progressive and disabling • Higher mortality rates • Shortens life span by 3 to 18 years Koopman WJ, et al. Arthritis & Allied Conditions. 13th ed. 1997.

4. FUSIFORM SWELLING MCP & PIP SWELLING

6. Hammer Toe Deformities MTP Erosive Disease

7. Potential Pathogenic Pathway in RA Initiating Event Inflammation Synovitis Pannus Pain and Stiffness Clinical Symptoms Swelling Joint Space Narrowing (JSN) X-rayChanges Joint Erosions (JE) Pain QoL Change Structural Damage Adapted from: Kirwan JR. Rheum Dis Clin North Am. 2001;27:389.

8. APC Ag MHC Immune-Mediated Inflammatory Process of RA CD4 Initiation CD4+ T cell TCR IL-1 TNF- IL-6 IL-8 IL-10 TGF- IL-2 IFN- TNF- IL-4 iNOS Perpetuation/ Regulation Inflammation/ Joint Destruction Adhesion molecule activation B cells Synoviocytes Lymphocytes, PMNs, macrophages Immunoglobulins Metalloproteinases APC = antigen-presenting cell; MHC = major histocompatibility complex; TCR = T-cell receptor;TGF = transforming growth factor; iNOS = inducible nitric oxide synthase; PMNs = polymorphonuclear cells Moreland LW, et al. Arthritis Rheum. 1997;40:397-409.

9. The Pathogenesis of Rheumatoid Arthritis Feldmann M, et al. Ann Rev of Immunol. 1996;14:397-440.

10. RA Synovium

11. RA Synovium Rosenberg A. In: Cotran RS et al, eds. Robbins Pathologic Basis of Disease. 6th ed. Philadelphia, PA: WB Saunders; 1999:1215.

12. Inflamed synovium invading and destroying cartilage and bone

13. Clinical Course of RA • Main presenting symptoms: • Swelling of the joint and/or joint margins • Joint tenderness • Systemic malaise • Loss of energy • Severe morning stiffness Joint involvement in RA 64 % 38 % 78 % 17 % 91% 65 % 50 % 43 % Guerne PA and Weisman MH. Am J Med 1992;16:451-460; Lee DM and Weinblatt E. The Lancet 2001; 358 : 903-911 “Kelley's Textbook of Rheumatology”, 2008; “Eular Compendium on Rheumatic Diseases”, Ed. Bijlsma JWJ, 2009

14. Clinical Course of RA • Clinical course of RA is highly variable • From mild arthritis • To rapidly progressive multisystem inflammation • With profound morbidity & mortality • Rate of disease progression • Variable presentation • periods of increasing disease activity (early years) • relentless linear progression • aggressive and malignant without remission • But always progress with irreversible destruction at all phase of disease Lee DM and Weinblatt E. The Lancet 2001; 358 : 903-911

15. Puffy, hands, early arthritis

16. Nodular, erosive rheumatoid arthritis

17. Joint Destruction and disability in RA

18. Progression of RA joint damage

19. Inflammation Disability Radiographs Relationship Between Inflammation, Radiographic Progression and Disability Severity (Arbitrary Units) 0 5 10 15 20 25 30 Duration of Disease (years) “In early RA irreversible damage is seen in 60% of patients within the first 2 years of diagnosis.” Kirwan J. Rheum 1999;26:720. Saleemet al. Clin Exp Rheum 2006;24:S33. Illustration source unknown.

20. EXTRA-ARTICULAR MANIFESTATIONS Ocular – Episcleritis Neurologic – Neuritis, Stroke Heart – Pericarditis Lungs – Pulmonary Nodules, Effusions Vascular – Vasculitis Skin - Nodules

21. Rheumatoid Nodule

22. Episcleritis Scleromalacia Perforans

23. Periungual Infarcts and Digital Gangrene Associated with Severe Rheumatoid Vasculitis.

24. Atlanto axial subluxation

25. Rheumatoid Arthritis Classification

26. 1987 ACR Classification Criteria for RA At least 4 of the following criteria must be met: • AM stiffness lasting > 1 hour* • Swelling of  3 joints* • Swelling of hand joints* • Symmetric joint involvement* • Radiographic changes (erosion or bony decalcification) • Presence of rheumatoid nodules • Rheumatoid factor in serum *Must be present for at least 6 weeks. Arnett FC et al. Arthritis Rheum. 1988:31:315-324.

27. 2010 ACR Classification Criteria for RA Synovitis plus score of ≥6/10 needed for the classification of definite RA *With or without involvement of large joints. # at least one test result needed for classification . ACPA: Anti-citrullinated protein/peptide antibodies; CRP: C-reactive protein; ESR: Erythrocyte sedimentation rate Aletaha et al. Ann Rheum Dis 2010;69:1580-1588

28. Tree Algorithm to Classify Definite RA or to Exclude its Current Presence APR: acute-phase response; Serology+: low-positive for RF or ACPA; serology++: high-positive for RF or ACPA;serology+/++: serology either + or ++ Aletaha et al. Ann Rheum Dis 2010;69:1580-1588

29. Rheumatoid Arthritis Disease assessment tools

30. Measuring Treatment Outcomes: Common Clinical Trial Endpoints FDA, Center for Drug Evaluation and Research. Guidance for Industry. http://www.fda.gov/cder/guidance/1203fnl.htm. February 1999.

31. Definition of ACR 20, 50, or 70 • Measures response to treatment in a clinical trial: • Is the patient an ACR 20 responder or not • A 20%, 50%, or 70% reduction in • the number of swollen joints and • the number of tender joints and • the same degree of improvement inat least 3 of 5 other variables: • pain • degree of disability according to the HAQ • patient’s global assessment • physician’s global assessment • erythrocyte sedimentation (ESR)/ C-reactive protein (CRP) level

32. Disease Activity Score (DAS) and Definition of Response • Continuous variable: • Patient’s disease activity is described on a scale of 1 to 10 using a composite index • Composite Index incorporating: • ESR • Number of Swollen joints (SJC) (1-28) • Number of Tender joints (TJC) (1-28) • Assessment of patient’s general health (VAS 1-100) den Broeder, A. et al., Rheumatology. 2002; 41:638-42.

33. Health Assessment Questionnaire (HAQ) Widely accepted, validated, rheumatology-specific instrument to assess physical function in RA • 20 questions covering eight types of activities • Dressing and grooming, arising, eating, walking, hygiene, reaching, gripping, activities of daily living • A mean decrease of at least0.22 in HAQ score is considered a minimum clinically important difference (MCID) HAQ Disability Index (HAQ-DI) • Scores the worst items within each of the eight scales • Based on use of aids and devices Buchbinder R, et al. Arthritis Rheum. 1995;38:1568–1580; Sullivan FM, et al. Ann Rheum Dis. 1987;46:598–600; Kosinski M, et al. Arthritis Rheum. 2000;43:1478–1487.

34. Range: 0 – 528 Modified van der Heijde-Sharp Scoring Method (vdHSS) Schema of Radiographic Joint Evaluation =Joint narrowing Erosions 20 joints evaluated 20 joints evaluated 6 joints evaluated 6 joints evaluated Van der Heijde D, et al. Ann Rheum Dis. 2005;64(Suppl II):ii61-ii64.

35. 0 1 2 3 4 0 1 2 3 4 5 VdHSS: Joint Erosions Scored 0 – 5 and Joint Space Narrowing Scored 0 – 4 EROSIONS NARROWING

36. Continuation of DMARDs Parenteral gold (269) Oral gold (84) Azathioprine (56) Methotrexate (253)* HCQ (228) D-Pen (193) 100 80 60 40 20 0 MTX vs all other drugs Estimated continuation (%) (P < 0.001) Oral gold vs all other drugs (P < 0.001) 0 12 24 36 48 60 Months *Numbers represent courses of therapy Pincus T et al, J Rheumatol 19:1885–1894, 1992