1. Rheumatoid Arthritis Update Ivonne Herrera, MD Rheumatologist July 20, 2013

2. Disclosure Nothing to be disclosed

3. Outline Clinical presentation Diagnosis: New diagnostic criteria for RA (2010) Morbidity and Mortality Treatment options

4. Pierre Auguste Renoir 1841-1919

5. Rheumatoid Arthritis Disabling Destructive Cause of mortality as well as morbidity

6. Rheumatoid Arthritis RA is a symmetric, peripheral polyarthritis of unknown etiology. If untreated, leads to joint deformity and destruction.

7. Rheumatoid Arthritis Arthritis that affects the MCP and/or PIP joints of both hands, strongly suggests RA

8. Rheumatoid Arthritis Early Intermediate Late

9. Changes in the joint

11. RA:Laboratory Features Rheumatoid Factor (RF) – 70-80% RA patients. – Virtually all patients with Mixed Cryoglobulinemia – Sjogren’s Syndrome 70 % – Hepatitis C/B or other chronic infections 50% – SLE 30% – Healthy individuals 5-10% Anti-CCP: – Similar sensitivity to RF for RA – 95%-98% specificity – Useful to differentiate RA from infections

12. Other Laboratory Features Elevated acute phase reactants: – ESR – CRP – Leukocytosis – Thrombocytosis Anemia of chronic disease Hypoalbuminemia ANA + Inflammatory Synovial Fluid: White cells >2000

13. Imaging Studies Plain film radiography Color Doppler Ultrasonography MRI

14. Plain Film Radiography in RA Soft tissue swelling Peri-articular osteopenia Decrease joint space Bony erosions

15. Plain Film Radiography in RA MCP and PIP erosions: – 1 st year: 15-30% of patients – 2 nd year: 90% of patients

16. Atlantoaxial Subluxation in RA

17. MRI Allows early detection of: – Synovitis – Bone edema – Erosions More sensitive and specific than XRays to identify erosions – 4 months: 45% of patients have erosions

18. Ultrasonography AAAAA

19. RA Diagnosis: 1987 ACR Criteria Morning Stiffness: at least 1 hour Arthritis of 3 or more joints Arthritis of at least 1 joint in the hand Symmetric arthritis Rheumatoid nodules Serum Rheumatoid Factor (+) Radiographic changes: erosions RA Diagnosis: 4 out of 7 criteria

20. 2010 ACR/EULAR Criteria

21. Differential Diagnosis Acute viral polyarthritis: – Parvovirus B 19 – Hepatitis B or C – HTLV-1 CTD: SLE, Sjogren’s, etc – Overlap syndrome – Jaccoud’s arthropathy Psoriatic arthritis Gout and Pseudogout Myelodysplasia Erosive OA PMR Sarcoidosis

22. RA: Morbidity and Premature Mortality Cardiovascular Disease Infections Lymphoproliferative disorders Gastrointestinal Interstitial Lung Disease

23. CARDIOVASCULAR DISEASE IN RA EPIDEMIOLOGY RA ↑ risk of premature death. The risk of CAD mortality was 59 % higher in patients with RA than in the general population (1) The risk of CAD in RA patients precedes the ACR criteria-based diagnosis of RA (2) (1)Aviña-Zubieta JA, et al, Arthritis Rheum. 2008;59(12):1690. (2) Maradit-Kremers H, et al, Arthritis Rheum. 2005;52(2):402.

24. RISK OF CVD DM type II 2-fold increase risk RA2.2-fold increase risk

25. The increase incidence of cardiovascular events in RA patients can not be completely explained by traditional cardiovascular risk factors

26. CARDIOVASCULAR DISEASE IN RA: PATHOGENESIS In the general population inflammation has a significant role in the development of CAD Chronic inflammation in RA may enhance the development of atherosclerosis - Cytokines - Immune complexes - Coagulation abnormalities

27. Biomarkers for atherosclerosis in patients with RA ↑ CRP (1) ↑ ESR (2) ↑ IL-6 (3) ↑ TNF α (3) ↑ Von Willebrand factor, Plasminogen activator inhibitor- 1, Fibrinogen (4) ↓ Endothelial cell progenitors (5) ↑ Ox-LDL-ab (6) ↑ Proinflammatory high-density lipoprotein. (7) (1)Solomon DH, et al, Arthritis Rheum. 2004;50(11):3444. (2)Maradit-Kremers H, et al, Arthritis Rheum. 2005;52(3):722. (3)Rho YH, et al, Arthritis Rheum. 2009;61(11):1580 (4)Wållberg-Jonsson S, et al, J Rheumatol. 2000;27(1):71. (5)Grisar J,et al, Circulation. 2005;111(2):204. (6)Peters MJ, J Rheumatol. 2008;35(8):1495. (7)Charles-Schoeman et al, Arthritis Rheum. 2009;60(10):2870

29. CVD IN RA: PATHOGENESIS Medications used in RA patients: – Glucocorticoids Prednisone >7.5mg/day: ↑ MI, CVA, CHF, Mortality – NSAIDs: Diclofenac Ibuprofen Naproxen – COX-2 inhibitors: Celecoxib Risk of MI: ibuprofen ˃ Celecoxib ˃ diclofenal ˃ naproxen Naproxen and Ibuprofen attenuate the antiplatelet effect of aspirin

30. Traditional Risk Factors for CAD Hypertention Smoking Dyslipidemia Obesity Diabetes Age Sedentary lifestyle Family history CAD Rheumatoid Arthritis..!

31. RA AS AN INDEPENDENT RISK FACTOR OF CAD ↑ Prevalence of traditional risk factors (1) ↑ Prevalence of preclinical atherosclerosis independent of traditional risk factors (2) Coronary artery calcification on CT scanning is more prevalent in RA patients independent of other CAD risk factors (3) (1)Chung CP, et al, Arthritis Rheum. 2005;52(10):3045 (2)Roman MJ, et al, Ann Intern Med. 2006;144(4):249. (3)Kao AH, et all, J Rheumatol. 2008;35(1):61.

32. Clinical manifestations of CAD in RA patients ↑ unrecognized MI and sudden cardiac death (1) Patients with RA are less likely to report chest pain during an acute coronary event (2) (1)Maradit-Kremers H, et all, Arthritis Rheum. 2005;52(2):402 (2)Douglas KM, et all, Ann Rheum Dis. 2006;65(3):348.

33. Prevention of CHD in RA patients Smoking cessation Dyslipidemia control Healthy diet Exercise Weight control Blood pressure control

34. Prevention of CHD in RA patients: Early aggressive therapy for RA MTX is associated with a reduced risk of CVD events in patients with RA (1) Risk of MI is markedly reduced in those who respond to TNF blockers by 6 months compared with nonresponders (2) Risk of CVD is lower in patients with RA treated with TNF blockers (3) (1) Westlake SL, et al, Rheumatology (Oxford). 2010;49(2):295. (2) Dixon WG, et al, Arthritis Rheum. 2007;56(9):2905. (3) Jacobsson LT, et al, J Rheumatol. 2005;32(7):1213

35. Early and aggressive therapy in patients with Rheumatoid Arthritis Prevent severe joint destruction and deformities Reduce the risk of CVD and CAD

36. Treatment Goal in RA Prevent Joint damage and disability Prevent Comorbidities Prevent premature death. Improve quality of life Relief symptoms Achieve clinical REMISSION

37. Treatment: The Earlier the Better Sharp Score Patients were treated with chloroquine or azathioprine Lard LR, et al. Am J Med. 2001;111:446-451.

38. Therapeutic Window of Opportunity Erosive changes occur EARLY in disease Delay of therapy can have a significant impact Early DMARD treatment that suppresses the disease appears to reset the rate of progression for years to come O’Dell JR. Arthritis Rheum. 2002;46:283-285. Van der Heijde DM. J Rheum. 1995:34 (suppl 2):74-78.

39. RA: TREATMENT OPTIONS DMARDs Agents Prednisone Methotrexate Hydroxychloroquine Sufasalazine Leflunomide Cyclosporine Azathioprine BIOLOGIC Agents Etanercept (ENBREL) Infliximab (REMICADE) Adalimumab (HUMIRA) Golimumab (SIMPONI) Certolizumab (CIMZIA) Anakinra (KINERET) Abatacept (ORENCIA) Rituximab (RITUXAN) Tocilizumab (ACTEMRA) Tofacitinib (XELJANZ)

40. Several Treatment Options Where should we start? Methotrexate (MTX) is the most widely used DMARD – SWEFOT *: Monotherapy with MTX 30% patients responded to initial 3-4months of MTX 16% in remission 75% MTX patients maintain low disease activity at 12 months (DAS28<3.2) *Van Vollenhoven RF, et al. Lancet. 2009;374(9688):459-466

41. Efficacy of Biologic Agents Efficacy often superior to DMARDs Rapid onset of action Well tolerated Sustained response in many

42. Evidence Based Medicine with Biologic Agents The initial use of TNFi or biologic agents with MTX in early RA resulted in significant decreases in radiographic progression in early RA patients (1) Initial use of TNFi + MTX is more effective clinically than MTX monotherapy in early RA patients (2) ABA+MTX is more effective clinically and radiographically than MTX monotherapy in early RA patients (3) (1)Smolen JS, et al. Lancet. 2007;370(9602):1861-1874) (2)Breedveld FC, et al.Arthritis Rheum.2006;54(1):26-37) (3)Westhovens R, et al.Ann Rheum Dis. 2009;68(12):1870-77

43. Evidence Based Medicine with Biologic Agents In patients with early RA who do not achieve LDA with MTX monotherapy, adding a TNFi results in less radiographic progression than adding of non-biologic DMARD(1) Rituximab is clinically and radiographically effective in TNF- I R patients(2) Abatacet is clinically effective in TNF-IR patients(3) Tocilizumab is clinically effective in TNF-IR patients(4) (1)Van Vollenhoven RF, et al. Presented at: 2009 ACR Scientific meeting; October17- 21,2009;Philladelphia, PA. Abstract LB6. (2)Cohen SB, et al. Arthritis Rheum. 2006;54(9):2793-2806. (3)Genovesse MC, et al. Ann Rheum Dis. 2008;67(4):547-554. (4)Emery P, et al. Ann Rheum Dis. 2008;67:1516-1523.

44. Safety considerations with Biologics Serious infections Opportunistic infections (TB) Malignancies Demyelination Hematologic abnormalities COPD Administration reactions CHF Hepatic impairment Autoantibodies and Drug induced Lupus GI perforation Progressive multifocal leukoencephalopathy

45. Rheumatoid Arthritis: Summary Early Diagnosis: Apply the new 2010 Diagnostic criteria for RA Early aggressive intervention: in patients with RA, critical to best possible outcome The combination of MTX plus a biologics is frequently more effective than either agent alone Tight control of traditional risk factors for CAD and early aggressive therapy for RA may reduce the risk of CVD

46. QUESTIONS Thank you