1. 1 IN THE NAME OF GOD

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3. Rheumatoid Arthritis A chronic inflammatory disease A systemic disease Characteristic feature: Persistent inflammatory synovitis Peripheral joints Symmetric Cartilage damage and bone erosions Destruction 3

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5. Epidemiology Most common form of chronic inflammatory arthritis Prevalence :~1% (range 0.3–2.1%) women: 3 times more often than men Throughout world; all races 5

6. Epidemiology Incidence between 25 and 55 y Plateaus until 75 Then decrease 6

7. Genetics First-degree relative 2-10 times> NL papulation Concordant in monozygotic twins 15–20% 7

8. Genetics Major genetic risk factors class II HLA HLA- DRB1(0401): - Shared epitope(70-74) - Anti-CCP - Worse outcome 8

9. Environmental factors Smoking : More common environmental factor Relative Risk: 1.5-3.5 Severe RA with antibodies to CCP Extraarticular In particular women (2.5 times) Persist 15 years after cessation 9

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11. 11 ANTIGEN Genetic Background MACROPHAGE

12. 12 DR MACROPHAGE TLR

13. 13 ANTIGEN DR MACROPHAGET-CELL CD4+ IL -1 CD80/86 CD 28 TH1TH17 IFN-γ, TNF-aIL-17, TNF-a, IL6, GM-CSF

14. 14 B-Cell CD40 CD40L AntiCCP RF

15. 15 Teff Macrophage TNF-a Wnt Dkk-1

16. 16 Genetic Background IL- 1 ANTIGEN MACROPHAGE T CELL IL 2 B Cell ANTIBODY

17. 17 AUTOIMMUNE REACTION Genetic Background IL- 1 ANTIGEN MACROPHAGE T CELL IL 2 B Cell IMMUNE COMPLEX ANTIBODY

18. 18 AUTOIMMUNE REACTION Genetic Background IL- 1 ANTIGEN MACROPHAGE T CELL IL 2 B Cell ANTIBODY IMMUNECOMPLEX COMPLEMENT TARGET INFLAMMATION

19. 19 PROTEINS Citrulination PAD4 Auto Ag MacrophageT cellB cellAb Anti CCP Immune complex clearance InflammationHumoral ANTI-CCP

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22. Onset In 2/3 of patients begins with: - Fatigue, anorexia, generalized weakness This prodrome may persist for weeks or months 22

23. Onset Specific symptoms appear gradually - Earliest joints: small joints of hands and feet -Especially: hands, wrists, knees, feet - Symmetric 1/3 of patients Initially one or a few joints 23

24. Articular Most common manifestation: - Pain An almost invariable feature: - Morning stiffness of >1-h 24

25. Articular Synovial inflammation causes: Swelling Tenderness Limitation of motion Warmth 25

26. Articular Symmetric Certain specific joints: - Wrist joints - MCP, PIP - Elbow - Knee - Forefoot, ankles, and subtalar - Hip & shoulder DIP: rare (OA) Rarely affect lumbar and thoracic spine 26

27. Articular Synovial joints of C1-C2: - Prevalence: decrease -< 10% of patients - Atlantoaxial subluxation - Pain in the occiput - Rarely: compression of the cord 27

28. Articular Characteristic joint changes: Hand: - "Z" deformity Radial deviation at wrist Ulnar deviation digits 28

29. Articular Characteristic joint changes: Hand: - Swan-neck deformity PIP hyperextension DIP Flexion 29

30. Articular Characteristic joint changes: Hand: - Boutonnière deformity PIP flexion DIP extension 30

31. Articular Characteristic joint changes: Hand: - Thumb Hyperextension of the first IP Flexion of the first MCP 31

32. Articular Characteristic joint changes: Foot: - Hallux valgus - Eversion at hindfoot - Plantar subluxation of the metatarsal heads - Widening of the forefoot - Lateral deviation and dorsal subluxation of the toes 32

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34. Extraarticular Manifestation RA is a systemic disease 40% of patients May be prior to arthritis 34

35. Extraarticular Manifestation More commonly in: History of smoking Early onset of disability RF or antiCCP positive 35

36. Rheumatoid nodule In 30–40% On areas subjected to mechanical pressure Elsewhere Firm, nontender, adherent 36

37. Rheumatoid nodule Common locations: Olecranon bursa, proximal ulna, Achilles tendon, occiput 37

38. Pleuropulmonary Pleuritis: - Most common pulmonary manifestation - Autopsy Common - Symptomatic Infrequent 38

39. Pleuropulmonary ILD: Dry cough Progressive shortness of breath Pulmonary nodules 39

40. Cardiovascular Pericarditis: - Asymptomatic - 50% by echo Congestive heart failure (cardiomyopathy) IHD 40

41. Cardiovascular Most common cause of death Inflammatory markers 41

42. Nervous system Central nervous system Spare Vasculitis Peripheral neuropathy Atlantoaxial subluxation Nerve entrapment 42

43. Eye <1% Long-standing disease and nodules Episcleritis, scleritis 15–20% of patients Sjögren's syndrome 43

44. Vasculitis Severe RA and high titers of RF Long-standing disease Hypocomplementemia Can affect nearly any organ Polyneuropathy and mononeuritis multiplex Cutaneous ulceration and dermal necrosis Digital gangrene Visceral infarction 44

45. Felty’s syndrome Consists of: - Splenomegaly - Neutropenia - Nodular RA Leukopenia is selective neutropenia (PMN <1500 cells/L) Late stage of sever RA High titers of RF 45

46. Lymphoma 2-4 fold Diffuse large B cell Risk: - High disease activity - Felty 46

47. 47 THANKS