1. 1 Rheumatoid Arthritis M Handel 1 st Feb 2012

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

3. 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. 13 th ed. 1997.

4. FUSIFORM SWELLING MCP & PIP SWELLING

6. Hammer Toe Deformities MTP Erosive Disease

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

8. 8 Immune-Mediated Inflammatory Process of RA Initiation Perpetuation/ Regulation Inflammation/ Joint Destruction IL-1 TNF-  IL-6 IL-8 IL-10 TGF-  IL-2 IFN-  TNF-  IL-4 iNOS B cells Synoviocytes Adhesion molecule activation ImmunoglobulinsMetalloproteinases Lymphocytes, PMNs, macrophages TCR CD4 + T cell CD4 APC MHC Ag 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. 9 Feldmann M, et al. Ann Rev of Immunol. 1996;14:397-440. The Pathogenesis of Rheumatoid Arthritis

10. 10 RA Synovium

11. 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. 12 Inflamed synovium invading and destroying cartilage and bone

13. Clinical Course of RA 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 91% 78 % 64 % 65 % 50 % 43 % 38 % 17 % Joint involvement in RA Main presenting symptoms: –Swelling of the joint and/or joint margins –Joint tenderness –Systemic malaise –Loss of energy –Severe morning stiffness

14. 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 1.Variable presentation  periods of increasing disease activity (early years)  relentless linear progression  aggressive and malignant without remission 2.But always progress with irreversible destruction at all phase of disease Lee DM and Weinblatt E. The Lancet 2001; 358 : 903-911

15. 15 Puffy, hands, early arthritis

16. 16 Nodular, erosive rheumatoid arthritis

17. 17 Joint Destruction and disability in RA

18. 18 Progression of RA joint damage

19. Intended for internal use only. Subject to local regulatory review prior to external use Relationship Between Inflammation, Radiographic Progression and Disability Severity (Arbitrary Units) 0 Duration of Disease (years) 51015202530 Inflammation Disability Radiographs “In early RA irreversible damage is seen in 60% of patients within the first 2 years of diagnosis.” Kirwan J. Rheum 1999;26:720. Saleem et al. Clin Exp Rheum 2006;24:S33. Illustration source unknown.

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

21. Rheumatoid Nodule

22. EpiscleritisEpiscleritis Scleromalacia Perforans

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

24. Atlanto axial subluxation

25. 25 Rheumatoid Arthritis Classification

26. Arnett FC et al. Arthritis Rheum. 1988:31:315-324. *Must be present for at least 6 weeks. 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

27. Aletaha et al. Ann Rheum Dis 2010;69:1580-1588 2010 ACR Classification Criteria for RA Joint involvementOne large joint0 2-10 large joints1 1-3 small joints*2 4-10 small joints*3 >10 joints (at least one small joint)5 Serology # RF- and ACPA-0 Low RF+ or low ACPA+2 High RF+ or high ACPA+3 Acute-phase reactants # Normal CRP and normal ESR0 Abnormal CRP or abnormal ESR1 Duration of symptoms<6 weeks0 ≥6 weeks1 *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 Synovitis plus score of ≥6/10 needed for the classification of definite RA

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

29. 29 Rheumatoid Arthritis Disease assessment tools

30. 30 Measuring Treatment Outcomes: Common Clinical Trial Endpoints Requirements Improvement in Signs/Symptoms Prevention of Structural Damage Prevention of Disability Trial Duration  6 mo  1 y 2-5 y Validated Measure ACR 20 (or other composite endpoint) Larsen Sharp scores HAQ SF-36 OtherPain, tenderness, swelling Global assessments ACR core set Response over time preferred Prevention of new erosions Maintenance of erosion-free state “Patients should not worsen on these measures over the duration of the trial” FDA, Center for Drug Evaluation and Research. Guidance for Industry. http://www.fda.gov/cder/guidance/1203fnl.htmhttp://www.fda.gov/cder/guidance/1203fnl.htm. February 1999.

31. 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 in at 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. 32 Disease Activity Score (DAS) and Definition of Response Improvement in DAS or DAS28 from Baseline DAS 28 at Endpoint  1.2 (clinically significant)  0.6 and  1.2  0.6 (within error)  3.2 (low activity) Good None  3.2 and  5.1 (moderate activity) Moderate  5.1 (high activity) den Broeder, A. et al., Rheumatology. 2002; 41:638-42. 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)

33. 33 Health Assessment Questionnaire (HAQ) 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. 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 least 0.22 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

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

35. 35 VdHSS: Joint Erosions Scored 0 – 5 and Joint Space Narrowing Scored 0 – 4 154320 14320 EROSIONS NARROWING

36. 36 Continuation of DMARDs Pincus T et al, J Rheumatol 19:1885–1894, 1992 100 80 60 40 20 0 01224364860 Parenteral gold (269) Oral gold (84) Azathioprine (56) Methotrexate (253)* HCQ (228) D-Pen (193) Estimated continuation (%) Months (P < 0.001) MTX vs all other drugs Oral gold vs all other drugs *Numbers represent courses of therapy