1. RHEUMATIC FEVER Rheumatology Research Center

2. Definition A multisystem disease resulting from an autoimmune reaction to infection with group A streptococci A multisystem disease resulting from an autoimmune reaction to infection with group A streptococci

3. ARF & RHD is disease of poverty ARF & RHD is disease of poverty 15- 19 million people affected by RHD 15- 19 million people affected by RHD Prevalence of RHD in Iran: 2/1000 (5-14 y) Prevalence of RHD in Iran: 2/1000 (5-14 y) Sex : Similar Sex : Similar Age: 5-14 Y Age: 5-14 Y

4. Important Resolve completely except cardiac valvular damage (RHD) Resolve completely except cardiac valvular damage (RHD) Most common cause of heart disease in children Most common cause of heart disease in children 250000 death/ y 250000 death/ y ARF RHD Mortality & Morbidity

5. Microbe PATHOGENESIS

6. Immune system Activation PATHOGENESIS

7. Microbe Immune system Activation

8. Microbe Immune system Activation HEART JOINT BRAIN SKIN

9. Microbe Immune system Activation HEART JOINT BRAIN SKIN GAS URTI (M1,, 5, 6, 18)

10. Microbe Immune system Activation HEART JOINT BRAIN SKIN - 3-6% - Familial clustering - Monozygotic twins GAS URTI (M1,, 5, 6, 18)

11. Microbe Immune system Activation HEART JOINT BRAIN SKIN 3-6% Familial aggregation Monozygotic twine GAS URTI (M1,, 5, 6, 18) HLA class II TGF-1 and Ig genes High expression on B cells, D8-17

12. PATHOGENESIS Group A Streptococcus Rheumatogenic Strains: M1,, 5, 6, 18 mucoid phenotype Susceptible Host HLA DR4, 2, 1, 3, 7 Dw10, DRw53 Immune Response Cross-Reactive Humoral (Antibody) and/or Cell- Mediated (T cell) Immunity Target Tissue/ organ Inflammation of Heart, Joints, Brain, Connective Tissue Acute Rheumatic Fever

13. Clinical Presentation

14. A children (5-15 Y) with: A children (5-15 Y) with: Fever Fever Polyarthritis Polyarthritis

15. Clinical Presentation A children (5-15 Y) with fever & Arthritis A children (5-15 Y) with fever & Arthritis Joint: 75% Joint: 75% Polyarthritis Polyarthritis Migratory Migratory Large joint Large joint Asymmetric Asymmetric Sever and disabling Sever and disabling Dramatic response to ASA Dramatic response to ASA

16. Clinical Presentation A children (5-15 Y) with fever & Arthritis A children (5-15 Y) with fever & Arthritis Joint: 75% Joint: 75% Heart (pancarditis): 60% Heart (pancarditis): 60% New murmur ( hallmark ) : MR New murmur ( hallmark ) : MR Pericarditis Pericarditis First degree AV block First degree AV block

17. Valvular Involvement (MR) RHD (MS)

18. Clinical Presentation A children (5-15 Y) with fever & Arthritis A children (5-15 Y) with fever & Arthritis Joint: 75% Joint: 75% Heart (carditis): 60% Heart (carditis): 60% Skin: Skin:

19. Clinical Presentation A children (5-15 Y) with fever & Arthritis A children (5-15 Y) with fever & Arthritis Joint: 75% Joint: 75% Heart (carditis): 60% Heart (carditis): 60% Skin: Skin: Erythema marginatum : Erythema marginatum : Classic rash Classic rash <5% <5% evanescent evanescent spare face spare face exacerbate with warmth exacerbate with warmth

20. Clinical Presentation A children (5-15 Y) with fever & Arthritis A children (5-15 Y) with fever & Arthritis Joint: 75% Joint: 75% Heart (carditis): 60% Heart (carditis): 60% Skin: Skin: Subcutaneous nodule Subcutaneous nodule <5% <5% Delayed manifestation Delayed manifestation Firm, non tender Firm, non tender <2cm <2cm Last a few days up to 3 weeks Last a few days up to 3 weeks Associated with carditis Associated with carditis

21. Clinical Presentation A children (5-15 Y) with fever & Arthritis A children (5-15 Y) with fever & Arthritis Joint: 75% Joint: 75% Heart (carditis): 60% Heart (carditis): 60% Skin: Skin: CNS (Sydenham’s chorea ) CNS (Sydenham’s chorea ) <2% - 30% <2% - 30% Mainly in female Mainly in female Prolong latent period (up to 6 months) Prolong latent period (up to 6 months) Purposeless involuntary movement Purposeless involuntary movement Basal ganglia Basal ganglia Self limited (6 weeks) Self limited (6 weeks)

22. ORGAN DAMAGE HEART

23. DIAGNOSIS

24. DIAGNOSIS Combination of typical clinical features together with evidence of the precipitating group A streptococcal infection Combination of typical clinical features together with evidence of the precipitating group A streptococcal infection

25. 2002-2003 WHO criteria (based on the 1992 Revised Jones Criteria) Major criteria: Major criteria: Carditis Carditis Polyarthritis Polyarthritis Chorea Chorea Erythema marginatum Erythema marginatum Subcutaneous nodules Subcutaneous nodules

26. 2002-2003 WHO criteria (based on the 1992 Revised Jones Criteria) Major criteria: Major criteria: Minor criteria: Minor criteria: Fever Fever Polyarthralgia Polyarthralgia Elevated CRP or ESR or Leukocyte count Elevated CRP or ESR or Leukocyte count Prolonged P-R interval Prolonged P-R interval

27. 2002-2003 WHO criteria (based on the 1992 Revised Jones Criteria) Supporting GAS: Supporting GAS: Positive throat culture or rapid antigen test Positive throat culture or rapid antigen test Elevated or rising: Elevated or rising: ASO ASO Children > 320 Todd units Children > 320 Todd units Adult > 240 Todd units Adult > 240 Todd units Anti-DNase B Anti-DNase B Antistreptokinase Antistreptokinase Antihyaluronidase Antihyaluronidase Recent scarlet fever Recent scarlet fever

28. DIAGNOSIS First episode or recurrent attack without RHD: First episode or recurrent attack without RHD: 2 major + antecedent GAS 2 major + antecedent GAS 1 major +2 minor + antecedent GAS 1 major +2 minor + antecedent GAS Recurrent attack with RHD Recurrent attack with RHD 2 minor + antecedent GAS 2 minor + antecedent GAS Exception: Exception: Chorea Chorea Insidious onset rheumatic carditis Insidious onset rheumatic carditis Chronic valve lesion Chronic valve lesion

29. TREATMENT

30. Microbe Immune system Activation HEART JOINT BRAIN SKIN ANTIBIOTIC ANTIINFLAMMATORY

31. Anti-inflammatory: Anti-inflammatory: Arthritis: Arthritis: ASA: 80- 100mg/kg/d (2 w) ASA: 80- 100mg/kg/d (2 w) 60- 70 mg/kg/d (2-4w) 60- 70 mg/kg/d (2-4w) Carditis: Carditis: Prednisolone 1-2mg/kg d ( 3 w) Prednisolone 1-2mg/kg d ( 3 w)

32. Anti-inflammatory: Anti-inflammatory: Antibiotic: Antibiotic: Benzathine penicillin 1.2 million units Benzathine penicillin 1.2 million units Oral penicillin: 500 mg bid 10 days Oral penicillin: 500 mg bid 10 days Erytromycin: 250 bid (penicillin allergy) Erytromycin: 250 bid (penicillin allergy)

33. Anti-inflammatory: Anti-inflammatory: Antibiotic Antibiotic Symptomatic Care: Carditis: Bed rest, Diuretic, ACEI Chorea: Carbamazepine, Sodium valproate, IVIG

34. Discharge from hospital within 1-2 weeks Discharge from hospital within 1-2 weeks Normalization of acute phases within 4-6 weeks Normalization of acute phases within 4-6 weeks

35. Prevention

36. Prevention Antibiotic: Antibiotic: Benzathine penicillin every 3-4 weeks Benzathine penicillin every 3-4 weeks Oral penicillin V 250mg po bid Oral penicillin V 250mg po bid Erythromycin (250 mg) twice daily Erythromycin (250 mg) twice daily

37. Prevention Antibiotic: Antibiotic: Benzathine penicillin every 3-4 weeks Benzathine penicillin every 3-4 weeks Erythromycin (250 mg) twice daily Erythromycin (250 mg) twice daily Antibiotic prophylaxis against endocarditis Antibiotic prophylaxis against endocarditis

38. Duration of Antimicrobial Prophylaxis Without Carditis: Without Carditis: 5 Y, or 18 Y of age 5 Y, or 18 Y of age Mild Carditis (mild MR or healed carditis) Mild Carditis (mild MR or healed carditis) For 10 Y, or 25 years of age For 10 Y, or 25 years of age More sever valvular disease: More sever valvular disease: Lifelong Lifelong Valvular surgery: Valvular surgery: Lifelong Lifelong

40. INTERMITTENT ARTHRITIS

41. 1. FMF 2. Palindromic rheumatism 3. Crystal-induced disease 4. SLE, Behcet’s disease

42. FMF Familial Mediterranean Fever

43. INTRODUCTION An auto inflammatory and inherited disease. An auto inflammatory and inherited disease.

44. EPIDEMIOLOGY Race: Arab, Jewish, Armenian, Turkish Race: Arab, Jewish, Armenian, Turkish Age: children - 20 Y Age: children - 20 Y Sex: modest male predominance Sex: modest male predominance Inherited: Recessive Inherited: Recessive Gene: MEFV (short arm of chromosome 16) Gene: MEFV (short arm of chromosome 16) Pyrin: regulation of inflammation and apoptosis Pyrin: regulation of inflammation and apoptosis

45. PATHOPHYSIOLOGY INFLAMMATION

46. PATHOPHYSIOLOGY Anti Inflammatory Factors

47. PATHOPHYSIOLOGY INFLAMMATION Anti Inflammatory Factors PYRIN IL1 

48. PATHOPHYSIOLOGY INFLAMMATION Anti Inflammatory Factors PYRIN IL1 

49. Clinical Manifestations (Attacks) A children with episodic Fever + A children with episodic Fever + Serositis Serositis Synovitis Synovitis Skin rash Skin rash Onset: Acute Onset: Acute Trigger: often unpredictable Trigger: often unpredictable Duration of attacks: 1- 3 days Duration of attacks: 1- 3 days Frequency: varies Frequency: varies

50. Fever Nearly always Nearly always Some time only manifestation in children Some time only manifestation in children

51. Abdominal pain 90% 90% Mild to sever Mild to sever Acute abdomen Acute abdomen

52. Pleural involvement Unilateral Unilateral Sharp chest pain Sharp chest pain

53. Arthritis Acute Monoarthritis Acute Monoarthritis Knee, Ankle, Hip Knee, Ankle, Hip Synovial fluid may appear septic Synovial fluid may appear septic Longer than serosal attack Longer than serosal attack ~ 5% chronic arthritis ~ 5% chronic arthritis

54. Skin Erysipelas-like eryrhema Erysipelas-like eryrhema Dorsum of Foot, Ankle, lower leg Dorsum of Foot, Ankle, lower leg

56. OTHER Myalgia (lasting a few weeks) Myalgia (lasting a few weeks) Testicular involvement Testicular involvement Vasculitis (Henoch- PAN) Vasculitis (Henoch- PAN)

57. COMPLICATION

58. AMYLOIDOSIS Most serious complication Most serious complication Serum Amyloid A Serum Amyloid A Proteinuria (renal failure) Proteinuria (renal failure) Risk Factor: Risk Factor: M694V homozygous M694V homozygous Family history Family history Male Male Noncompliance with Colchicin Noncompliance with Colchicin

59. LAB Test ESR ESR CRP CRP Leukocytosis Leukocytosis

60. DIAGNOSIS High risk ethnic group High risk ethnic group Typical symptoms Typical symptoms Therapeutic response to colchicine Therapeutic response to colchicine Clinical judgment maintains a central role. Clinical judgment maintains a central role.

61. Differential Diagnosis Other hereditary periodic fever syndromes Other hereditary periodic fever syndromes Systemic onset JRA Systemic onset JRA Porphyria Porphyria Hereditary angioedema Hereditary angioedema

62. TREATMENT Colchicin (choice) Colchicin (choice) Dose: 1.2-1.8 mg/d Dose: 1.2-1.8 mg/d Daily prophylaxis Daily prophylaxis Decrease the frequency and Intensity Decrease the frequency and Intensity Prevent the amyloidosis Prevent the amyloidosis