Rheumatoid arthritis

Rheumatoid arthritis a common autoimmune disease

1. RHEUMATOID ARTHRITIS a common autoimmune disease DIANA GIRNITA MD PhD RHEUMATOLOGY TRIHEALTH PHYSICIAN PARTNERS

2. Learning objectives Understanding the most common clinical presentation of RA, laboratory testing and differential diagnosis Understanding that RA is a systemic disease with emphasis on the increased cardiovascular risk Current treatment options in RA and the importance of early aggressive treatment

3. RA chronic, systemic disease Rheumatoid arthritis (RA) is a symmetric, inflammatory, peripheral polyarthritis If untreated, inflammation can lead to joint destruction, deformity, significant disability and shortened life expectancy.

4. Epidemiology Annual incidence: 30/ 100,000 persons worldwide . Female predominance ( F: M is 5:1 < age 50) C an develop at any age Peak age of onset 30 to 55 years

5. PATHOGENESIS

6. Genetic Factors Account for 60% of an individual’s susceptibility to RA HLA -DR genes (DR4, DR1, DR14) account for 30% to 40% of genetic predisposition G enetic loci outside the MHC have been associated with an increased risk Polymorphisms of PTPN22, TRAF1-C5, STAT4, TNFAIP3, and PADI4

7. Hormones? Reduced risk in women who have had children/ breastfed > 1 year Disease activity often subsides during pregnancy and flares postpartum

8. Environmental Factors Smoking the best characterized environmental risk factor increases the OR for developing RA 12-fold in susceptible monozygotic twins, 2.5-fold in dizygotic twins, and 1.8-fold in smokers (>20 pack- yrs ). This risk persists for 10 to 20 years after a person quits smoking. P eriodontal disease Asbestos/ silica exposure Parvovirus/ EBV virus –low evidence

9. RF and CCP The presence of Rheumatoid factor (RF) or anti- CCP (citric citrullinated peptides) antibodies in the blood is associated with increased risk of RA RF is absent in 30% of patients with rheumatoid arthritis; present in 10% of healthy individuals A nti -CCP antibodies are absent in 40% of patients with the disease.

10. CLINICAL PRESENTATION

11. RA is a systemic disease Joints Heart Lungs Brain Bones Eyes GI Skin Kidney

12. “Classic” RA Symmetric, bilateral polyarthritis of small , medium, and large joints M orning stiffness >1h Most common joints affected in RA Rheumatology secrets, 3 rd ed , 2016

13. Symmetric, bilateral synovitis PIPs, MCPs

14. MCPs and PIPs synovitis 35yo F with bilateral MCP, PIPs synovitis , especially 2 nd and 3 rd PIP Personal library of RA patients

15. Symmetric deformities 40yo female presented with bilateral MCP synovitis and “boutonniere” deformity of 4 th digit Personal library of RA patients

16. RA-deformities of the hands A.” Butonniere ” deformity“ B. “Swan neck deformity” -hyperextension of the PIP and extension of the DIP Kelleys ’ Rheumatology Chapter 70, Clinical RA

17. RA–late disease Personal library of RA patients “ Butonniere ” deformities in late RA disease

18. Hands - Ulnar deviation Rheumatology Image bank-ACR website

19. RA mutilans – late stage Rheumatology Image bank-ACR website

20. RA nodulosis Rheumatology Image bank-ACR website

21. Other forms of RA Palindromic rheumatism  —  episodic , one to several joints affected sequentially for hours to days, alternating with symptom-free periods Monoarthritis  — Persistent single joint arthritis (wrist , knee, shoulder, hip, or ankle)

22. RA extra-articular manifestations Ocular Brain Heart Pulmonary GI Renal Skin

23. Extra-articular manifestations

24. Ocular involvement Episcleritis Scleromalacia Rheumatology Image bank-ACR website

25. Scleromalacia perforans –severe, uncontrolled RA P ersonal library of RA patients

26. 78yo patient with longstanding RA. MRI of the brain showed diffuse leptomeningeal enhancement over the right frontal and parietal lobes. Leptomeningeal biopsy showed a granulomatous inflammatory reaction (arrow) consistent with rheumatoid pachymeningitis . Brain - Pachimeningitis Rheumatology Image bank-ACR website

27. Cardiac involvement Rheumatology Image bank-ACR website

28. Lung involvement –interstitial lung disease 52 YO M, seropositive RA who presented with dyspnea and hypoxemia. Chest X- ray w/ increased interstitial markings with volume loss and tracheal deviation. CT scan-honeycombing and traction bronchiectasis consistent with ILD associated with RA . Rheumatology Image bank-ACR website

29. RA pulmonary nodules Rheumatology Image bank-ACR website

30. Caplan’s syndrome refers to a type of large nodule formation found in lungs of patients, many of whom are coal miners with rheumatoid arthritis ( Multiple nodules ( 3 cm or more in diameter in both lungs) . The remaining pulmonary parenchyma demonstrates micronodularity typical of pneumoconiosis and fibrosis. There is marked prominence of hilar and perihilar structures. RA- Caplan’s Syndrome

31. Skin involvement – vasculitis Images demonstrates of the finger from a woman with RA complicated by systemic vasculitis numerous ischemic lesions. Note the swan-neck deformity from erosive RA. Rheumatology Image bank-ACR website

32. Sternoclavicular Joint Girnita DM- Case Report: Sternoclavicular Erosions in a Patient with Uncontrolled RA; The Rheumatologist, December 17, 2015 issue

33. Renal involvement Girnita DM et al. Case report: Rheumatoid Arthritis & Autoimmune Glomerulonephritis; The Rheumatologist; June 13, 2016 69-year-old African American female with 25 years’ history of seropositive , erosive RA with nephrotic syndrome and worsening Cr. Renal Biopsy : immune mediated MPGN, no signs of vasculitis

34. RA - DIAGNOSIS

35. ACR 2010 Criteria for RA Classification RA>= 6/10 criteria ARTHRITIS & RHEUMATISM Vol. 62, No. 9, September 2010, pp 2569–2581

36. Imaging in RA

37. Plain XRAYs Marginal erosions Symmetric joint-space narrowing Periarticular osteopenia Baseline and every 2 years

38. RA at diagnosis and 10 years later 1 0 years later -progression of osteopenia, development of ulnar deviation, subluxation of MCP and loss of joint space. Rheumatology Image bank-ACR website At diagnosis : juxtaarticular osteopenia.

39. Feet involvement Marginal erosions Osteopenia L ateral deviation, and subluxation of all the MTPs Hallux valgus Rheumatology Image bank-ACR website

40. Elbows and Knees Elbow erosion Knee erosion Rheumatology Image bank-ACR website

41. Ultrasound detects synovitis and early bone erosions . Rheumatology Image bank-ACR website

42. MRI detects bone erosions earlier than Xrays Rheumatology Image bank-ACR website

43. Cervical spine involvement MRI cervical spine demonstrating pannus formation of the C1–C2 articulation (long arrow) and impingement of the odontoid on the spinal cord (arrow). Rheumatology Image bank-ACR website

44. Cervical Spine, Atlantoaxial Subluxation The lateral radiograph in flexion shows separation between the anterior inferior aspect of C1 and the odontoid process of greater than 2.5 mm. Rheumatology Image bank-ACR website

45. Differential diagnosis

46. Rheumatoid arthritis vs Osteoarthritis

47. The significance of RF and anti-CCP

48. Rheumatoid factor (RF) RF -70 % to 80% with a specificity of 86% for RA High -titer RF appears to be a better predictor of a severe disease course Stronger correlation with extraarticular manifestations (ILD) and subcutaneous nodules, and with increased mortality The RF titer does not correlate with disease activity so it does not have to be repeated Positive RF - hepatitis C (40%), SLE (20%), Sjögren’s syndrome (70%), and subacute bacterial endocarditis

49. High titer of RF more erosive disease van Zeben D et al. Clinical significance of rheumatoid factors in early rheumatoid arthritis: results of a follow up study. Ann Rheum Dis. 1992;51(9):1029.  Number of erosions

50. Anti-CCP better specificity than RF Nishimura K et al. Meta -analysis: diagnostic accuracy of anti-cyclic citrullinated peptide antibody and rheumatoid factor for rheumatoid arthritis . Ann Intern Med.  2007 Jun 5;146(11):797-808 . Zeng X et al. Diagnostic value of anti-cyclic citrullinated Peptide antibody in patients with rheumatoid arthritis. J Rheumatol . 2003;30(7):1451.  Ann Rheum Dis . 2006 Jul; 65(7): 845–851. 

51. Other autoimmune tests ANA: + 30%; patients tend to have more severe disease and a poorer prognosis;+ secondary Sjögren’s syndrome. ANCA: usually negative. If it is positive, it should not have specificity against PR3 or myeloperoxidase. Complement (C3, C4, CH50): normal or elevated. If it is low, consider a disease other than RA.

52. Poor outcome/ severe disease

53. Increased cardiovascular risk in RA

54. US - Mortality Data 1997 , RA accounted for 22% of all deaths due to arthritis and other rheumatic conditions in the US 40 % of all deaths in RA patients are due to CV causes (ischemic heart disease, stroke, premature death)   Sacks JJ, Helmick CG, Langmaid G. Deaths from arthritis and other rheumatic conditions, United States, 1979-1998 1. J.Rheumatol . 2004;31(9):1823- 1828; Symmons DP, Gabriel SE. Epidemiology of CVD in rheumatic disease, with a focus on RA and SLE. Nat Rev Rheumatol . 2011;7(7):399-408.

55. Wolfe F et al. The mortality in RA. Arthritis & Rheumatism; 37 (4) 481-494, 1994 Increased mortality in RA patients

56. Premature atherosclerosis MI, Stroke in RA Roman MJ. Preclinical carotid atherosclerosis in patients with RA Ann Intern Med. 2006;144:249-256. Solomon DH et al, Circulation . 2003;107:1303-1307

57. Unrecognized MI in RA patients Maradit- Kremers et al. Arthritis Rheum . 2005 Mar;52(3):722-32.

58. Increased risk of MI, stroke and CV death in RA patients Solomon DH et al. Ann Rheum Dis 2006; 65:1608-1612

59. Increased risk of Heart failure in RA Nicola PJ et al. The risk of congestive heart failure in rheumatoid arthritis : a population-based study over 46 years . Arthritis Rheum . 2005 Feb;52(2):412-20 . Crowson C et al. ARTHRITIS & RHEUMATISM 2005(10:52), pp 3039–3044

60. Treatment in RA

61. Early, aggressive treatment is the key in RA Once the diagnosis of RA is established, all patients (with rare exception) should begin DMARD therapy Bone erosions and joint space narrowing develop within the first 2 years of disease in most patients and are progressive from that point onward Patients with evidence of active disease ( synovitis , morning stiffness, etc.), bony erosions or deformities, or extraarticular disease

62. DMARD (disease modifying anti-rheumatic drugs) D rug must change the course of the disease for at least 1 year as evidenced by sustained improvement in physical function decreased inflammatory synovitis slowing or prevention of joint destruction

63. DMARDs

64. Abbas AK et al, Basic Immunology: Functions and Disorders of the Immune System

65. Cytokine-targeted therapies TNF inhibitors Etanercept , Infliximab, Adalimumab , Golimumab , Certolizumab IL-1 inhibitors Anakinra IL-6 inhibitors Tocilizumab , Sarilumab IL12/23 IL-17 Ustekinumab Secukinumab , Ixekizumab Jak inhibitors Tofacitinib , Baricitinib B-cell targeted therapies Rituximab (anti-CD 20) B cell growth factor inhibitors: Belimumab T-cell targeted therapies Abatacept (anti-CD80/ 86)

66. TNF alpha -inhibitors

67. IL-6 inhibitors ( Tocilizumab )

68. JAK inhibitors ( Tofacinib ) Koenders MI et al.Novel therapeutic targets in rheumatoid arthritis, Trends in Pharmacological Science, 2015, vol36:4, p189-195

69. T cell targeted therapy ( Abatacept )

70. B-cell targeted therapy (Rituximab)

71. 2015 ACR guidelines for RA treatment Singh JI et al, Arthritis Care & Research 2015 , American College of Rheumatology

72. Wheel of empiric therapy Kelley's Textbook of Rheumatology, 9 th edition, Treatment in RA

73. Triple therapy HCQ+SSZ+MTX Improved disease activity of triple therapy vs monotherapy

74. TEAR trial - Etanercept vs triple therapy Moreland LW et al. A  randomized comparative effectiveness study of oral triple therapy  vs etanercept  plus methotrexate in early aggressive rheumatoid arthritis: the treatment of Early Aggressive Rheumatoid Arthritis Trial .   Arthritis Rheum . 2012 September ; 64(9): 2824–2835 .

75. PREMIER trial- Adalimumab+methotrexate is superior to either alone Breedveld FC, Weisman MH, Kavanaugh AF, et al: A multicenter, randomized, double-blind clinical trial of combination therapy with adalimumab plus methotrexate versus methotrexate alone or adalimumab alone in patients with early, aggressive rheumatoid arthritis who had not had previous methotrexate treatment, Arthritis Rheum 54:26–37, 2006

76. Effect of Biologic therapies in RA

77. T argeted therapies changed the course of RA

78. The role of the PCP

79. Rheumatoid arthritis: SUMMARY Autoimmune disease -SYSTMIC effect (joints, heart, lung, eyes, etc ) RF and CCP are helpful in diagnosis, but remains a CLINICAL diagnosis Treatment needs to start early and had been proven to help restore the functional capacity of patients Targeted therapies have changed the course of Rheumatoid arthritis Arthritis foundation website www.arthritis.org

80. THANK YOU!