1. Rheumatoid Arthritis: Clinical Overview Roger Kornu, MD Associate Clinical Professor Division of Rheumatology University of California, Irvine

2. Take Home RA is a prevalent, inflammatory disease with potential of high morbidity both in articular and extra-articular manifestations. Symmetrical, small joint pain and morning stiffness with joint swelling on physical exam are the most important clinical features. Rheumatoid factor, anti-CCP antibody, and inflammatory markers are useful in diagnosis. Modern clinical criteria allows for earlier diagnosis and more aggressive therapy to minimize joint damage. Methotrexate is the standard disease modifying agent, but there is a low threshold to add combination therapy as we are in the era of treat to target.

3. Case Presentation 52 year old Caucasian female presents with 6 months of swelling and stiffness in her bilateral hands, wrists, and feet. She has one hour of morning stiffness. She is still able to work full-time as a supervisor, but has difficulty in grasping objects and opening doors.

4. Case Presentation She has no significant medical history and is taking OTC ibuprofen. Her mother may have had rheumatoid arthritis, but she is not sure. Physical exam shows joint swelling and tenderness in her bilateral 2 nd -5 th PIP and 2 nd -3 rd MCP joints with right wrist swelling. She has tenderness in bilateral MTP joints.

6. Case Presentation On work-up, she has a normal CBC, electrolytes, and LFTs ESR 46, CRP 1.5, RF negative, anti-CCP antibody 120 and ANA negative

8. Case Presentation What’s the diagnosis? Rheumatoid arthritis

10. “One must from time to time attempt things that are beyond one’s capacity.” —Pierre-Auguste Renoir

11. Epidemiology Prevalence up to 1% Annual incidence 40 per 100,000 Peak age of onset between 50-75 years Female:Male ratio, 2-3:1 Prevalence of RA in females over 65 years is up to 5% Monozygotic twins 13.5% vs dizygotic twins 3.5%

12. Genetics HLA-DRB1: “shared epitope” –Individuals with certain sequence found in DR4, DR14 and DR1 beta-chains have higher RA and anti-CCP positivity Risk of RA and Smoking –Men 2x higher and Women 1.3x higher –Also related to the shared epitope –No relationship of heavy or light smoking

13. McInnes and Schett, NEJM 2011

15. Clinical Presentation of RA Early RAIntermediate RA Severe RA Latinis KM, et al. The Washington Manual TM Rheumatology Subspecialty Consult. Philadelphia, Pa: Lippincott Williams & Wilkins; 2004.

16. Establishing a Diagnosis for RA Joint stiffness upon awakening Swelling in specific fingers or wrist joints, with or without pain Swelling in soft tissues around the joints Symmetrical pattern of affected joints Fatigue, depression, occasional fevers, anemia, general sense of malaise Symptoms may last for years and get progressively worse for the majority of patients

18. Diagnosis of RA: 2010 ACR Criteria

19. Diagnostic Tools in Rheumatoid Arthritis Rheumatoid factor Anti-CCP antibodies Plain X-ray MRI Ultrasound

20. Rheumatoid Factor Antibody directed against the Fc portion of IgG Present in approximately 80% of RA patients –Sensitivity for RA is ~80% –Specificity is 85-95% May be involved in disease pathogenesis Higher levels tend to be associated with poorer prognosis Found in other conditions, especially Hepatitis C

21. Anti-Cyclic Citrullinated Peptide (CCP) Antibodies in RA Anti-citrulline Abs produced in RA synovium Early RA Diagnosis –sensitivity 48%; specificity 96% –seen in 2% of pts with other autoimmune diseases and infections (vs. 14% for RF) –less than 1% of healthy controls Predicts erosive disease PPV - 63% and NPV - 90% Present years before the onset of symptoms. 34% of blood samples obtained 2.5 yr before onset of symptoms (vs. 1.8% of controls)

22. Plain X-ray

23. Magnetic Resonance Imaging as a Diagnostic Tool McQueen FM et al. Ann Rheum Dis. 1999;58:156-163. McQueen FM et al. Ann Rheum Dis. 1998;57:350-356. X-ray MRI Erosions Detected: X-rays vs MRI (%)

24. Ultrasound as a Diagnostic Tool Keen et al. Rheum Dis Clinic N Am 31 (2005) 699-714

25. Adapted from Kirwan JR. J Rheumatol. 1999;26:720-725. Severity (Arbitrary Units) 0 Duration of Disease (Years) 51015202530Inflammation Relationship of Radiographic Joint Damage to DisabilityDisability Radiograph Scores

26. Features Related to Poor Outcomes  Extra-articular disease  High rheumatoid factor titer, positive anti-CCP antibody  Poor functional status  Involvement of multiple joints  Radiographic erosions  Sustained elevation of acute-phase reactants (eg, ESR)  Low socioeconomic status/educational level  Increased genetic risk of developing RA plus smoking Anaya JM, et al. Ann Rheum Dis. 1994;53:782-783. Pincus T, et al. Balliere’s Clin Rheumatol. 1992;6:161-191. Furst DE. Rheum Dis Clin North Am. 1994;20:309-319. Padyukov L, et al. Arthritis Rheum. 2004;50:3085-3092.

28. Copyright © 1972-2004 American College of Rheumatology Slide Collection. All rights reserved. Rheumatoid arthritis: episcleritis

29. Copyright © 1972-2004 American College of Rheumatology Slide Collection. All rights reserved. Rheumatoid arthritis: scleromalacia perforans

30. RA: Pulmonary Manifestations Interstitial lung disease may appear in 2- 5% of RA patients –Nonspecific interstitial pneumonitis (NSIP) Homogeneous mononuclear infiltrate Ground glass infiltrate on HRCT Better prognosis –Usual interstitial pneumonitis (UIP) Non productive cough and dyspnea Honeycombing of HRCT Worse prognosis

32. RA: Pleural Disease Males > females In <5% of patients Long-standing disease Low pleural fluid glucose Must exclude infections, malignancy

33. RA: Felty’s Syndrome Seropositive rheumatoid arthritis –Long standing RA, can have bland synovitis Splenomegaly Leukopenia –WBC < 4000 –Neutropenia <1500 Recurrent infections

34. Large Granular Lymphocyte (LGL) Syndrome Neutropenia, splenomegaly, and recurrent infections Clinical features may mimic Felty’s syndrome (“pseudo” Felty’s) Neutropenia with normal or increased total WBC due to lymphocytosis May have associated anemia, thrombocytopenia Clonal populations of LGL in some patients may represent neoplastic proliferation and some patients ultimately develop leukemia or lymphoma

35. RA and Lymphoma Majority Non-Hodgkin’s Lymphoma (NHL) –Diffuse Large B cell type –MALT (mucosal associated lymphoid tissue) EBV association in 12% Higher incidence with age In early biologic trials with TNF alpha inhibitors, increased incidence of NHL

36. Adult Still’s Disease Triad –Quotidian fever –evanescent salmon rash –inflammatory arthritis High acute phase reactants –High ferritin (>4000) –Elevated CRP Lymphadenopathy, heptomegaly

38. Treatment NSAIDs, glucocorticoids Biologics –TNF alpha inhibition –T-cell inhibition –B cell inhibition –IL-6 inhibition Small molecules –JAK kinase inhibition

39. Joint Erosions Occur Early in Rheumatoid Arthritis van der Heijde DM, et al. J Rheumatol. 1995;22:1792-1796. Fuchs HA, et al. J Rheumatol. 1989;16:585-591. McQueen FM, et al. Ann Rheum Dis. 1998;57:350-356. Year 0 10 20 30 0123 Maximum Percentage of Joints Affected Metatarsophalangeal joint Total Hand

40. Change in Median Sharp Score 0 2 4 6 8 10 12 14 06121824 Time (Months) *Patients were treated with chloroquine or sulfasalazine Lard LR, et al. Am J Med. 2001;111:446-451. Treatment: The Earlier, the Better Delayed treatment 1993-1995* (median lag time to treatment=123 days; n=109) Early treatment 1996-1998* (median lag time to treatment=15 days; n=97)

41. Goals of Therapy Treat early Treat to limit and/or prevent –Pain –Joint damage –Extra-articular disease –Disability –Premature death Treat to target

42. Traditional DMARD Selection Agent Time to Benefit Potential Toxicity Toxicities to Monitor Methotrexate1–2 moModerate Myelosuppression, hepatic fibrosis and cirrhosis, pulmonary infiltrates Hydroxychloroquine 2–6 moLow Macular damage Sulfasalazine1–3 moLow Myelosuppression Leflunomide 4–12 wk Low Diarrhea, alopecia, rash, headache, risk of immunosuppression infection Minocycline1–3 moLow Hyperpigmentation, dizziness, vaginal yeast infections

43. McInnes and Schett, NEJM 2011

44. RA Biologics: TNF alpha blockers TNF alpha is expressed on surface of macrophages Binding to its receptors trigger a variety of other inflammatory cytokines Appears to have improved efficacy in combination with methotrexate and lowers immunogenicity Receptor blocker –Etanercept (Enbrel) Monoclonal antibody –Infliximab (Remicade) –Adalimumab (Humira) –Golimumab (Simponi) –Certilizumab (Cimzia)

45. RA Biologics: B and T cells B-cell targeted therapy –Rituximab (Rituxan) is anti CD20 Eliminates peripheral B cells within days FDA approved in TNF alpha failures T-cell targeted therapy –Abatacept (Orencia) is CTLA4Ig Interferes with optimal T cell activation which results in decreased proinflammatory cytokines

46. RA Biologics: Interleukin inhibitors IL-1 inhibition –Anakinra (Kineret) First biologic for RA Not as effective in RA Used more in JIA, Adult Still’s disease IL-6 inhibition –Tocilizumab (Actemra) Inhibits IL-6 signaling on cells which lowers proinflammatory cytokines

47. RA Nonbiologics: JAK inhibitors JAK1/JAK3 inhibition –Tofacitinib (Xeljanz) JAK proteins are intracellular that associate with and transduce signals from several cytokine and growth factor receptors Oral therapy, FDA approved JAK1/JAK 2 inhibition –Baricitinib –Just finished Phase III trials

48. RA Therapies: The Next Generation Biosimilars Anti-IL-6 receptor –Sarilumab Anti-IL-17A –Secukinumab Anti-IL-20 Anti-CD22 –Epratuzamab Chemokine inhibitor: CCX354-L2 PDE4 inhibitor: aprimilast

49. RA Therapies: Infections Serious bacterial infection: 3-4% TB especially in TNF alpha blockers as TNF is important in granuloma formation Increased risk of fungal infections Active hepatitis B

50. Safety Issue: TB Bieber and Kavanaugh, Rheum Dis Clin N Am 30 (2004) 257-270

51. RA Therapies: Malignancies TNF is important in inducing apoptosis in tumor cells Long term use has not shown increase in solid tumors and still controversial with lymphoma Increased risk of melanoma and non- meloma skin cancers

52. RA Therapies: Vaccines Non-live vaccines recommended –Influenza injection –DTap –Pneumococcal vaccine –Hepatitis B –HPV Live vaccines –Not recommended with biologics Shingles, MMR, flu nasal, yellow fever, oral typhoid –Ok if prednisone <20mg, Methotrexate <0.4mg/week, azathioprine <3 mg/kg/day

53. Together we can work to prevent this:

54. Take Home RA is a prevalent, inflammatory disease with potential of high morbidity both in articular and extra-articular manifestations. Symmetrical, small joint pain and morning stiffness with joint swelling on physical exam are the most important clinical features. Rheumatoid factor, anti-CCP antibody, and inflammatory markers are useful in diagnosis. Modern clinical criteria allows for earlier diagnosis and more aggressive therapy to minimize joint damage. Methotrexate is the standard disease modifying agent, but there is a low threshold to add combination therapy as we are in the era of treat to target.