Rheumatoid Arthritis (RA) I. General Considerations Systemic autoimmune disease

1. Rheumatoid Arthritis • (RA) I. General Considerations Systemic autoimmune disease Chronic poly-arthritis, usually symmetric Mainly involve peripheral joints

2. II. Etiology Genetic Background HLA-DR Infections Agents especially Epstein-Barr Virus

3. III. Pathogenesis Activation of both B and T lymphocytes

4. Synovitis: Infiltrates of inflammatory cells Angiogenesis Synovial cell proliferations Formation of Pannus Destruction of cartilage and Subchondral bone ↓ Narrowing of joint space and bone erosion IV. Pathology

5. Pathology • IV. Pathology

6. V. Clinical Features of RA 1. Articular Manifestations a. polyarthritis: (1)symmetrical (2)≥6 weeks (3)wrists, hand joints, knee, feet joints commonly affected (4)erosive (5)deformity b. motion of joints limited

7. PIP proximal interphalangeal joint DIP Distant Interphalangeal joint MCP Metacarpophalangeal joint Wrist MTP Metatarsophalangeal joint Frequently involved joints

8. Swollen of the PIP joints makes the finger spindle shape Spindle finger

10. Swan-neck deformity: Hyperextension of the PIP in conjunction with flexion of DIP joint . Common deformities

11. Boutonniere deformity: Flexion of PIP joints and extension of the DIP joints.

12. frequently accompanied by palmar subluxation of the proximal phalanges. ulnar deviation

13. Ulnar deviation with muscle atrophy

14. 2. Extra-articular Manifestations Skin: (1) Subcutaneous nodules (2) Vasculitis

16. Subcutaneous nodules with muscle atrophy

17. ulnar deviation with the vasculitis-induced finger necrosis after surgical resection

18. ischemic necrosis due to vasculitis

19. Cardiac Manifestations • (1)Pericarditis • (2)myocarditis • (3)valvular insufficiency

20. Pulmonary Manifestations 1. Rheumatoid pleural disease: pleural effusion: exudative, low glucose, LDH elevated, Low complement, RF+ Multiple subpleural nodules. 2. Nodular change: Rheumatoid nodule in the lung. 3. Diffuse interstitial fibrosis

21. Neurologic Manifestations (1) Mononeuritis Multiplex: Sensory loss, foot, wrist drop (2) Carpal tunnel Syndrome Ocular Manifestations: Sjogren Syndrome Causing corneal and conjunctival lesions along with dryness of the eyes. episcleritis, scleritis

22. Felty Syndrome: Splenomegaly, lymphadenopathy, anemia, Bpc ↓ WBC ↓ , RF positive

23. VI. Lab Findings in RA Test Characteristic Results Blood Elements Moderate normochromic, normocytic anemia Erythrocytes Low plasma iron, decreased total iron binding Capacity Leukocytes Normal or slightly elevated Leukopenia rare ( Felty Syn. ) Acute-phase Reactants and immunoglobulin ESR Increased C-Reactive Protein (CRP): positive Ig. IgG increased, IgA, M increased Immune Factors ANA Present in 15% RF Present in 70% Complement Normal or slightly elevated

24. Rheumatoid Factors RF are now defined as antibodies specific to antigenic determinants on the Fc fragments of human or animal immunoglobulin. Seropositivity of patients with RA or with other disease is usually defined by the latex fixation test or red cell agglutination tests. These assays reflect the presence of IgM Rheumatoid factors (IgM-RFs). The presence of RF is not unique to RA, and a positive RF should not be used as the sole criterion for the diagnosis of RA.

25. Occurrence of RF in various Dis IgM-RF + Negative Rheumatoid Arthritis Osteoarthritis Other rheumatic Diseases Ankylosing Spondylitis Sjogren*s Syn SLE, PSS, PM Gout Infections Diseases Psoriatic arthritis SBE TB Non-infections Disease Normal individuals (Aged) Chronic active hepatitis Diffuse Interstitial pulmonary fibrosis

26. Radiological Examination: S-soft tissue A-alignment B-bone C-cartilage

30. erosion

31. Classification of Progression of RA Stage 1, Early 1. No destructive changes on X-ray film 2. Radiological evidence of osteoporosis Stage II, moderate Osteoporosis with Slight Subchondral bone destruction, No joint deformities Stage III, Severe 1. Radiological evidence of cartilage and bone destruction 2. Joint deformity without ankylosis Stage IV 1. Fibrous or bony ankylosis 2. Criteria of Stage III.

32. VII. Proposed 1987 Revised ARA criteria for RA 1. Morning stiffness for at least one hour and Present for at least six weeks 2. Swelling of three or more joint≥6 weeks 3. Swelling of wrist, MCP or PIP joints≥6 weeks 4. Symmetric Joint swelling 5. Hand X-ray changes typical of RA that must include erosions or unequivocal bony decalcification 6. Rheumatoid nodules 7. Serum RF positive Four or more criteria must be present to diagnose RA

33. Differential Diagnosis Rheumatic Fever Osteoarthritis SLE Ankylosing Spondylitis ( AS )

34. The Hand in Rheumatoid Arthritis and in Osteoarthritis Criteria Rheumatoid Arthritis Osteoarthritis Character of Swelling Synovial, Capsular, Bony with Soft-tissue, bony irregular only in late stages Spurs Tenderness Usual None or mild except during occasional acute onset DIP involvement Not usual, except Characteristic thumb PIP involvement Characteristic Frequent MCP involvement Characteristic Rare Wrist involvement Usual or common Rare, except base of thumb

35. Clinical Course of RA Progressive Chronic disease with remission and exacerbations but continuing disease activity (70%) Intermittent Brief attacks with intermittent remissions with no disease activity (25%) Malignant Severe disease with extra-articular manifestations, especially vasculitis

36. VIII. Treatment Objective of treatment • 1. relief of pain • 2. reduction or suppression of inflammation • 3. minimizing undesirable effects • 4. preservation of muscle and joint function • 5. return to a desirable and productive life

37. Drug Therapy 1. Non-steroid Anti-inflammatory Drugs ( NSAIDs ) • a. Analgesic • b. Anti-inflammatory • c. Anti-pyrexia

38. Processes influenced by NSAIDs Prostaglandin Production Leukotriene Synthesis* Superoxide Generation Lysosomal enzyme release Neutrophil aggregation

39. Adverse effects of NSAIDs • a. Gastrointestinal effects • b. Hepatic effects • c. Renal effects • d. others: skin rash

40. COX-1 Constitutive Homeostatic functions GI tract Renal function Platelet function COX-2 Regulated Inflammation COX-1/COX-2 Theory

41. The advantage of selective COX-2 inhibition • NSAIDs with a good GI side effect profile have been • shown to have lower ratios of COX-2/COX-1 inhibition • Newly designed selective COX-2 inhibitors have • significantly fewer GI side effects compared with traditional • NSAIDs

42. 2. Disease - Modifying Anti-rheumatic Drugs ( DMARDs) Features of DMARDs: • a. Modifying the progression of RA • b. Slow acting • c. More adverse effects

43. Disease-Modified Anti-rheumatic Drugs ( DMARDs) Drug Major adverse reaction Methotrexate (MTX) Hepatic fibrosis, Nausea, Cytopenia Anti-malanial (CQ & HCQ) Visual disturbance Leflunomide (LEF) Hepatic damage Sulfasalazine (SASP) GI irritation, rashes D-penicillamine (D-PA) Rashes, Proteinuria, Cytopenia, Taste disturbance

44. Principles for DMARDs therapy • 1. early use • 2. combination therapy

45. Common combination therapy • MTX+CQ(HCQ) • MTX+SASP • MTX+LEF

46. 3. Corticosteroids usually low dose (below 10mg/day) combined with DMARDs Indications for Large doses: Rheumatoid vasculitis Felty Syn High fever (Systemic Onset)

47. Biological agents • Anti-TNFα preparations Infleximab and Etanercept

48. Surgical treatment • Synovectomy • Joint replacement

49. Comprehension questions • female, 30 years old , joint pain with low fever for two months, RF (+) • diagnosis : RA ? • Choice: yes ,no, uncertain

50. Thank you