RHEUMATIC FEVER Rheumatology Research Center

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

ARF & RHD is disease of poverty ARF & RHD is disease of poverty million people affected by RHD 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

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 death/ y death/ y ARF RHD Mortality & Morbidity

Microbe PATHOGENESIS

Immune system Activation PATHOGENESIS

Microbe Immune system Activation

Microbe Immune system Activation HEART JOINT BRAIN SKIN

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

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

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

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

Clinical Presentation

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

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

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

Valvular Involvement (MR) RHD (MS)

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:

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

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

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)

ORGAN DAMAGE HEART

DIAGNOSIS

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

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

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

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

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

TREATMENT

Microbe Immune system Activation HEART JOINT BRAIN SKIN ANTIBIOTIC ANTIINFLAMMATORY

Anti-inflammatory: Anti-inflammatory: Arthritis: Arthritis: ASA: mg/kg/d (2 w) ASA: mg/kg/d (2 w) mg/kg/d (2-4w) mg/kg/d (2-4w) Carditis: Carditis: Prednisolone 1-2mg/kg d ( 3 w) Prednisolone 1-2mg/kg d ( 3 w)

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)

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

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

Prevention

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

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

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

INTERMITTENT ARTHRITIS

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

FMF Familial Mediterranean Fever

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

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

PATHOPHYSIOLOGY INFLAMMATION

PATHOPHYSIOLOGY Anti Inflammatory Factors

PATHOPHYSIOLOGY INFLAMMATION Anti Inflammatory Factors PYRIN IL1 

PATHOPHYSIOLOGY INFLAMMATION Anti Inflammatory Factors PYRIN IL1 

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

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

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

Pleural involvement Unilateral Unilateral Sharp chest pain Sharp chest pain

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

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

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

COMPLICATION

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

LAB Test ESR ESR CRP CRP Leukocytosis Leukocytosis

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.

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

TREATMENT Colchicin (choice) Colchicin (choice) Dose: mg/d Dose: mg/d Daily prophylaxis Daily prophylaxis Decrease the frequency and Intensity Decrease the frequency and Intensity Prevent the amyloidosis Prevent the amyloidosis