DEMAM REMATIK dan PENYAKIT JANTUNG REMATIK

Abdullah Afif Siregar Departemen Kardiologi dan Kedokteran Vaskuler Fakultas Kedokteran USU Medan

Rheumatic fever is an immunologically mediated inflammatory disease, that occurs as a delayed sequel to group A streptococcal throat infection, in genetically susceptible individuals. Rheumatic heart disease is the most serious complication of rheumatic fever Acute rheumatic fever and rheumatic heart disease are thought to result from an autoimmune response, but the exact pathogenesis remains unclear

The rheumatic fever follows 0.3% of cases of group A beta-hemolytic streptococcal pharyngitis in children. As many as 39% of patients with acute rheumatic fever may develop varying degrees of pancarditis with associated valve insufficiency, heart failure, pericarditis, and even death. With chronic rheumatic heart disease, patients develop valve stenosis with varying degrees of regurgitation, atrial dilation, arrhythmias, and ventricular dysfunction. Chronic rheumatic heart disease remains the leading cause of mitral valve stenosis and valve replacement in adults and children

Pathophysiology:

Rheumatic fever develops in children and adolescents following pharyngitis with group A beta-hemolytic Streptococcus (ie, Streptococcus pyogenes). The organisms attach to the epithelial cells of the upper respiratory tract and produce a battery of enzymes allowing them to damage and invade human tissues. After an incubation period of 2-4 days, the invading organisms elicit an acute inflammatory response with 3-5 days of sore throat, fever, malaise, headache, and an elevated leukocyte count. In 0.3-3% of cases, infection leads to rheumatic fever several weeks after the sore throat has resolved. Only infections of the pharynx initiate or reactivate rheumatic fever. The organism spreads by direct contact with oral or respiratory secretions, and spread is enhanced by crowded living conditions.

Etiopathogenesis :
The pathogenic mechanisms involved in the development of RF remain

unclear. But it is evident that an abnormal humoral and cellular immune response occurs. Antigenic mimicry between streptococcal antigens, mainly M-protein epitopes and human tissues, such as heart valves, myosin and tropomyosin, brain proteins, synovial tissue and cartilage has been proposed as the triggering factor leading to autoimmunity in individuals with genetic predisposition. Several genetic markers of susceptibility have been studied but no consistent association found. Associations with different HLA class II antigens have been observed in several populations. Molecular mimicry was first demonstrated by humoral immune response. Streptococcal antibodies cross-react with several human tissues including heart, skin, brain, glomerular basement membrane, striated and smooth muscles. The presence of CD4+ T cells at lesions sites in the heart has been demonstrated, suggesting a direct role of these cells in the pathogenesis of RHD.

Etiopathogenesis :

Infiltrating T lymphocytes from

heart lesions of severe RHD patients and peripheral T lymphocytes were capable of recognising immunodominant myocardium M5 peptides and valve proteins. These results showed the significance of molecular mimicry between beta hemolytic streptococci and heart tissue assessing the T-cell repertoire leading to local tissue damage in RHD.
Figure 1: Schematic representation of the aetiopathogenic events occurring during the development of carditis

DIAGNOSIS :

Sambungan Tabel 4.1

Carditis (40% )

Carditis (40% )

Clinical picture of carditis :

The clinical picture includes high pulse rate, congestive heart failure, arrhytmias and pericardial friction rubs. On the first attack, valvulitis is suspected in the presence of a new apical systolic murmur of mitral regurgitation (associated or not with an apical mid-diastolic murmur) and/or a basal diastolic murmur of aortic regurgitation. Cardiomegaly is noted on X-Ray and on echocardiogram. Myocarditis and/or pericarditis in the absence of valvular involvement is unlikely due to acute RF

Polyarthritis (75%)
Arthritis is the most common manifestation, present in 60-80% of patients. It usually affects the peripheral large joints; small joints and axial skeleton are rarely involved. Knees, ankles, elbows and wrists are the most frequently affected. The joints are red, warm and swollen. Arthritis is characteristically asymmetrical, migratory, and very painful, although some patients may present mild joint complaints. It usually resolves spontaneously at the most in 2 or 3 weeks. Arthritis in ARF has an excellent response to salicylates

Sydenham Chorea :

Sydenhams chorea is characterized by involuntary movements, specially of the face and limbs, muscle weakness, disturbances of speech and gait. Children usually exhibit concomitant psychologic dysfunction, especially obsessive-compulsive disorder, increased emotional lability, hyperactivity, irritablility and age-regressed behavior. It is usually a delayed manifestation, and is often the sole manifestation of ARF.

Erythema marginatum : This is an evanescent, erythematous, non-pruritic rash with pale centers and rounded or serpiginous margins. Lesions occur mainly on the trunk and proximal extremities and may be induced by application of heat

Diagnosis :

Based on Jones Criteria, 1992 Update : - 2 Major criteria + 1 Minor criteria, or - 1 Major criteria + 2 minor criteria
infection

* plus supporting evidence of preceding GAS

Table : Differential diagnosis of rheumatic fever

Juvenile rheumatoid arthritis Systemic lupus erythematosus

Infective endocarditis
Reactive arthritis Sickle cell disease Drug reactions

Other connective tissue diseases

Septicaemia Leukaemia Gonoccocal arthritis

Tuberculosis
Lyme disease Serum sickness

Treatment :
Medical therapy involves the following 5 areas: 1. Treat group A streptococcal infection regardless of organism detection. 2. Steroids and salicylates are useful in the control of pain and inflammation. The nonsteroidal anti-inflammatory drug (NSAID) naproxen has also been studied. It is effective and may be easier to use than aspirin. 3. Heart failure may require digitalis. 4. Administer prophylaxis to patients who have developed ARF. Patients with ARF should receive prophylaxis against future GABHS infections. Available regimens include benzathine penicillin G 1.2 million U IM every month, penicillin V 200,000 U or 250 mg PO bid, or erythromycin 250 mg PO bid. Most authorities suggest that prophylaxis be given for 5 years. For those who have rheumatic carditis, some authorities suggest lifelong prophylaxis. 5. Haloperidol may be helpful in controlling chorea.

Drug Name Description

Penicillin G benzathine (Bicillin LA) Interferes with synthesis of cell wall mucopeptide during active multiplication resulting in bactericidal activity against susceptible bacteria. Because of its prolonged blood level, several authors believe this to be the DOC. Others prefer daily injections. 2.4 million U IM once Infants and children <30 lb: 600,000 U IM once Children 30-60 lb: 900,000 to 1.2 million U IM once

Penicillin G procaine (Crysticillin, Wycillin) Long-acting parenteral penicillin (IM only) indicated in the treatment of moderately severe infections caused by penicillin G-sensitive microorganisms. Some prefer 10-d therapy. Administer by deep IM injection only into the upper outer quadrant of the buttock. 2.4 million U IM once Infants and children <30 lb: 600,000 U IM Children 30-60 lb: 900,000 to 1.2 million U IM

Penicillin VK (Beepen-VK, Betapen-VK, Robicillin VK, Veetids) Inhibits the biosynthesis of the cellwall mucopeptide and is effective during the stage of active multiplication. Inadequate concentrations may produce only bacteriostatic effects. Penicillin VK is the oral alternative for the treatment of rheumatic fever. 500 mg PO q6h for 10 d <12 years: 25-50 mg/kg/d PO divided tid/qid; not to exceed 3 g/d >12 years: Administer as in adults

Adult Dose Pediatric Dose

Contraindications
Interactions

Documented hypersensitivity
Probenecid can increase penicillin effectiveness by decreasing its clearance; coadministration of tetracyclines can decrease penicillin effectiveness

Documented hypersensitivity
Increases risk of bleeding when administered concurrently with warfarin; ethacrynic acid, aspirin, indomethacin, and furosemide may compete with penicillin G for renal tubular secretion increasing penicillin serum concentrations B - Usually safe but benefits must outweigh the risks. Never use IV route to adminis ter penicillin G procaine; admi nister >10 d to eliminate orga nism and prevent complications.

Documented hypersensitivity
Probenecid may increase effectiveness by decreasing clearance; tetracyclines are bacteriostatic, causing a decrease in the effectiveness of penicillins when administered concurrently B - Usually safe but benefits must outweigh the risks Caution in renal impairment

Pregnancy Precautions

B - Usually safe but benefits must outweigh the risks. Caution in impaired renal function

Drug Name Description

Erythromycin (EES, E-Mycin, Ery-Tab, Erythrocin) DOC for patients allergic to penicillin; inhibits RNA-dependent protein synthesis, possibly by stimulating the dissociation of peptidyl t-RNA from ribosomes, which inhibits bacterial growth. In children, age, weight, and the severity of infection determine the proper dosage. When bid dosing is desired, one-half the daily dose may be administered q12h. For more severe infections, the dose may be doubled. 1 g/d PO divided bid for 10 d 30-50 mg/kg/d PO divided bid Documented hypersensitivity; hepatic impairment Coadministration may increase toxicity of theophylline, digoxin, carbamazepine, and cyclosporine; may potentiate anticoagulant effects of warfarin; coadministration with lovastatin and simvastatin, increases risk of rhabdomyolysis B - Usually safe but benefits must outweigh the risks. Caution in liver disease; estolate formulation may cause cholestatic jaundice; GI adverse effects are common (give doses pc); discontinue use if nausea, vomiting, malaise, abdominal colic, or fever occur

Adult Dose Pediatric Dose Contraindications Interactions

Pregnancy Precautions

Drug Category: Glucocorticoids

Drug Name Prednisone (Deltasone, Sterapred) Patients with carditis require prednisone instead of aspirin. The goal is to decrease myocardial inflammation. Useful in treatment of inflammatory and autoimmune disorders. Reversing increased capillary permeability and suppressing PMN activity may decrease inflammation. 60-80 mg/d PO 2 mg/kg/d PO Documented hypersensitivity; viral, fungal, or tubercular skin infections Coadministration with estrogens may decrease clearance; concurrent use with digoxin, may cause digitalis toxicity secondary to hypokalemia; phenobarbital, phenytoin, and rifampin may increase metabolism of glucocorticoids (consider increasing maintenance dose); monitor for hypokalemia with coadministration of diuretics B - Usually safe but benefits must outweigh the risks. Abrupt discontinuation of glucocorticoids may cause adrenal crisis; hyperglycemia, edema, osteonecrosis, myopathy, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, myasthenia gravis, growth suppression, and infections may occur with glucocorticoid use

Description

Adult Dose Pediatric Dose Contraindications

Interactions

Pregnancy

Precautions

Anti inflammatory.
Drug Name
Description Adult Dose Pediatric Dose Contraindications

Aspirin (Ascriptin, Bayer Buffered Aspirin, Ecotrin)

Treats mild to moderate pain. Inhibits prostaglandin synthesis, which prevents formation of platelet-aggregating thromboxane A2. 6-8 g/d PO for 2 mo or until ESR has returned to normal 80-100 mg/kg/d PO for 2 mo or until ESR has returned to normal Documented hypersensitivity; liver damage, hypoprothrombinemia, vitamin K deficiency, bleeding disorders, asthma; because of association with Reye syndrome, do not use in children ( <16 y) with flu Effects may decrease with antacids and urinary alkalinizers; corticosteroids decrease salicylate serum levels; additive hypoprothrombinemic effects and increased bleeding time may occur with coadministration of anticoagulants; may antagonize uricosuric effects of probenecid and increase toxicity of phenytoin and valproic acid; doses > 2 g/d may potentiate glucose lowering effect of sulfonylurea drugs C - Safety for use during pregnancy has not been established. Pregnancy category D if full dose given during third trimester; may cause transient decrease in renal function and aggravate chronic kidney disease; avoid use in patients with severe anemia, with history of blood coagulation defects, or taking anticoagulants

Interactions

Pregnancy

Precautions

Drug Category: Neuroleptic agents May help to control the chorea associated with ARF.
Drug Name Description Adult Dose Haloperidol (Haldol) A dopamine receptor blocker useful in the treatment of irregular spasmodic movements of limbs or facial muscles. 0.5-2 mg PO bid/tid <3 years: Not established 3-12 years: 0.05 mg/kg/d or 0.25-0.5 mg/d bid/tid; increase by 0.25-0.5 mg q5-7d Maintenance dose: 0.05-0.15 mg/kg/d bid/tid; not to exceed 0.15 mg/kg/d >12 years: Administer as in adults Documented hypersensitivity; narrow-angle glaucoma; bone marrow suppression; severe cardiac and liver disease; severe hypotension; subcortical brain damage May increase tricyclic antidepressant serum-concentrations and hypotensive action of antihypertensive agents; phenobarbital or carbamazepine may decrease effects; coadministration with anticholinergics may increase intraocular pressure; encephalopathy-like syndrome associated with concurrent administration of lithium and haloperidol

Pediatric Dose

Contraindications

Interactions

Pregnancy

C - Safety for use during pregnancy has not been established.

Severe neurotoxicity manifesting as rigidity, or inability to walk or talk may occur in patients with thyrotoxicosis also receiving antipsychotics; if IV/IM, watch for hypotension; caution in CNS depression or cardiac disease; if history of seizures, benefits must outweigh risks; significant increase in body temperature may indicate intolerance to antipsychotics (discontinue if this occurs)

Precautions

Drug Category: Inotropic agents Some believe that digoxin may be helpful in congestive heart failure.
Drug Name Description Adult Dose
Digoxin (Lanoxin)

Cardiac glycoside with direct inotropic effects and indirect effects on the cardiovascular system. Effects on the myocardium involve a direct action on cardiac muscle that increases myocardial systolic contractions and indirect actions that result in increased carotid sinus nerve activity and enhanced sympathetic withdrawal for any given increase in mean arterial pressure.
0.125-0.375 mg PO qd Digitalizing dose: 2-5 years: 30-40 mcg/kg PO 5-10 years: 20-35 mcg/kg PO >10 years: 10-15 mcg/kg PO Maintenance dose: 25-35% of PO loading dose Documented hypersensitivity; beriberi heart disease; idiopathic hypertrophic subaortic stenosis; constrictive pericarditis; carotid sinus syndrome Medications that may increase digoxin levels include alprazolam, benzodiazepines, bepridil, captopril, cyclosporine, propafenone, propantheline, quinidine, diltiazem, aminoglycosides, oral amiodarone, anticholinergics, diphenoxylate, erythromycin, felodipine, flecainide, hydroxychloroquine, itraconazole, nifedipine, omeprazole, quinine, ibuprofen, indomethacin, esmolol, tetracycline, tolbutamide, and verapamil; medications that may decrease serum digoxin levels include aminoglutethimide, anti histamines, cholestyramine, neomycin, penicillamine, aminoglycosides, oral colestipol, hydantoins,hypo glycemic agents, antineoplastic treatment combinations (including carmustine, bleomycin, methotre xate, cytarabine, doxorubicin, cyclophosphamide, vincristine, procarbazine), aluminum or magnesium antacids, rifampin, sucralfate, sulfasalazine, barbiturates, kaolin/pectin, and aminosalicylic acid C - Safety for use during pregnancy has not been established. Hypokalemia may reduce positive inotropic effect of digitalis; IV calcium may produce arrhythmias ; hypercalcemia predisposes patient to digitalis toxicity, and hypocalcemia can make digoxin ineffective; magnesium replacement therapy must be instituted in patients with hypomagnesemia; patients diagnosed with incomplete AV block may progress to complete block when treated with digoxin; exercise caution in hypothyroidism, hypoxia, and acute myocarditis

Pediatric Dose

Contraindications

Interactions

Pregnancy

Precautions

Table : Secondary prevention of rheumatic fever.

Agent

Therapeutic Scheme
or

Benzathine penicillin G 1,200,000 U every 4 weeks*, IM Penicillin V Sulfadiazine

250mg twice daily, PO or 500mg once daily for patients < 27kg; 1g once daily for patients > 27kg, PO 250mg twice daily, PO

For individuals allergic to penicillin and sulfadiazine:

Erythromycin

*In high-risk situations, administration every 3 weeks is recommended.

Table. Guidelines for Bed Rest and Ambulation and Recommended antiinflammatory agents
Arthritis alone Bed Rest Indoor ambulation Outdor activity (school) Full activity Prednisone Aspirin 1-2 wk 1-2 wk 1-2 wk 1-2 wk 0 0 Carditis minimal 2-3 wk 2-3 wk 2-3 wk 2-3 wk 0 0 Carditis Carditis moderate severe 4-6 wk 4-6 wk 4-6 wk 4-6 wk 2-4 wk 2-4 wk 2-4 mo 2-3 mo 2-3 mo 2-3 mo 2-6 wk 2-6 wk

Minimal Carditis Questionable cardiomegaly ; Moderate carditis definite but mild cardiomegaly, Severe carditis, marked cardiomegaly or CHF

Complications
Carditis Mitral stenosis Congestive heart failure (CHF)

Prognosis
Sequelae are limited to the heart and are dependent upon the severity of the carditis during the acute attack. .

Rheumatic Heart Disease

Rheumatic heart disease is the most serious complication of rheumatic fever. Acute rheumatic fever follows 0.3% of cases of group A beta-hemolytic streptococcal pharyngitis in children. As many as 39% of patients with acute rheumatic fever may develop varying degrees of pancarditis with associated valve insufficiency, heart failure, pericarditis, and even death. With chronic rheumatic heart disease, patients develop valve stenosis with varying degrees of regurgitation, atrial dilation, arrhythmias, and ventricular dysfunction. Chronic rheumatic heart disease remains the leading cause of mitral valve stenosis and valve replacement in adults

Frequency:
In the US: Prevalence of rheumatic heart disease in the United States now is less than 0.05 per 1000 population Internationally: The incidence of rheumatic fever and rheumatic heart disease has not decreased in developing countries. Retrospective studies reveal developing countries to have the highest figures for cardiac involvement and recurrence rates of rheumatic fever. Estimations worldwide are that 5-30 million children and young adults have chronic rheumatic heart disease, and 90,000 patients die from this disease each year. There were no data available in Indonesia

Mortality/Morbidity:
Rheumatic heart disease is the major cause of morbidity from rheumatic fever and the major cause of mitral insufficiency and stenosis in the Indonesia and the world. Variables that correlate with severity of valve disease include the number of previous attacks of rheumatic fever, the length of time between the onset of disease and start of therapy, and sex. (The disease is more severe in females than in males.) Insufficiency from acute rheumatic valve disease resolves in 60-80% of patients who adhere to antibiotic prophylaxis.

Race:
The race (when controlled for socioeconomic variables) has not been documented to influence disease incidence.

Sex:
Rheumatic fever occurs in equal numbers in males and females, but the prognosis is worse for females than for males.

Age: Rheumatic fever is principally a disease of childhood, with a median age of 10 years, although it also occurs in adults (20% of cases). Socio-economic factors : It is well known that socioeconomic and environmental factors play an indirect, but important, role in the magnitude and severity of RF and RHD. Such factor as a shortage of resources for providing quality health care, inadequate expertise of health-care providers, and a low level of awareness of the disease in the community can all impact the expression of the disease in populations. Crowding adversely affects rheumatic fever incidence

Cardiac manifestations of chronic rheumatic heart disease : Valve deformities, thromboembolism, cardiac hemolytic anemia, and atrial arrhythmias are the most common cardiac manifestations of chronic rheumatic heart disease.
Valve deformities Mitral stenosis Mitral regurgitasi occurs in 25% of patients with chronic rheumatic heart disease and in association with mitral insufficiency in another 40%. Aortic regurgitasi Aortic stenosis are typically from chronic rheumatic heart disease. The valve commissures and cusps become adherent and fused, and the valve orifice becomes small with a round or triangular shape.

 Thromboembolism occurs as a complication of mitral

stenosis. It is more likely to occur when the left atrium is dilated, cardiac output is decreased, and the patient is in atrial fibrillation. Cardiac hemolytic anemia is related to disruption of the red blood cells by a deformed valve. Increased destruction and replacement of platelets also may occur. Atrial arrhythmias typically are related to a chronically enlarged left atrium (from a mitral valve abnormality). Successful cardioversion of atrial fibrillation to sinus rhythm is more likely to be successful if the left atrium is not markedly enlarged, the mitral stenosis is mild, and the patient has been in atrial fibrillation for less than 6 months.

TREATMENT

1.

Medical Care:
Medical therapy is directed toward eliminating the group A strepto coccal pharyngitis Treatment of the acute inflammatory manifestations of acute rheumatic fever consists of administering salicylates and steroids. If moderate-to-severe carditis is indicated by cardiomegaly, congestive heart failure, or third-degree heart block, oral prednisone should be added to salicylate therapy. Preventive and prophylactic therapy is indicated after rheumatic fever and rheumatic heart disease to prevent further damage to valves.

2.

3.

4.

TREATMENT
Surgical Care: When heart failure persists or worsens after aggressive medical therapy for acute rheumatic heart disease, surgery to decrease valve insufficiency may be lifesaving. Forty percent of patients with acute rheumatic fever subsequently develop mitral stenosis as adults. In patients with critical stenosis, mitral valvulotomy, percutaneous balloon valvuloplasty, or mitral valve replacement may be indicated. Due to high rates of recurrent symptoms after annuloplasty or other repair procedures, valve replacement appears to be the preferred surgical option.

Thank You