3.

03 ACUTE RHEUMATIC FEVER

& VASCULITIS SYNDROME
DR. VILLAROSA, November 19, 2020
Elysian Trans by Linao & Lirazan INTERNAL MEDICINE

Outline PATHOGENESIS

I. Acute rheumatic fever

II. Epidemiology
III. Organism factors
IV. Pathogenesis
V. Clinical features
VI. Jones Criteria
VII. Treatment
VIII. Prognosis
IX. Primary Prevention
X. Secondary Prophylaxis

I.The Vasculitis Syndromes

I. Anti-neutrophilic Cytoplasmic Antibodies (ANCAs)
II. Granulomatosis with polyangitis (Wegener’s)
III. Polyarteritis Nodosa
IV. Giant Cell Arteritis and Polymyalgia Rheumatica
V. Takayasu Arteritis
VI. Henoch-Schonlein Purpura
VII. Behcet’s Syndrome
Reference: Invictus Trans & Harrison’s 20th Ed
ACUTE RHEUMATIC FEVER
• multisystem disease resulting from an autoimmune
reaction to infection with group A streptococci
• Almost all of the manifestations resolve completely
• Cardiac valvular damage [rheumatic heart disease (RHD)],
may persist after the other features have disappeared
• ARF and RHD are diseases of poverty
EPIDEMIOLOGY
• Mainly a disease of children aged 5–14 years
• Initial episodes become less common in older adolescents
and young adults and are rare in persons aged >30 years
• No clear gender association for ARF, but RHD more
commonly affects females, sometimes up to twice as
frequently as males
ORGANISM FACTORS
• Exclusively caused by infection of the upper respiratory
tract with group A streptococci
• Preceding streptococcal infections is needed to "prime" the
immune system prior to the final infection that directly
causes disease
• Approximately 3–6% of any population may be susceptible
to ARF
 Molecular mimicry- most widely accepted theory of
rheumatic fever pathogenesis whereby an immune response
targeted at streptococcal antigens also recognizes human
tissue.
 Cross-reactive antibodies bind to endothelial cells on the
heart valve, leading to activation of the adhesion molecule
VCAM-1, with resulting recruitment of activated lymphocytes
and lysis of endothelial cells in the presence of complement.
CLINICAL FEATURES
• Latent period of ~3 weeks (1–5 weeks) between the
precipitating group A streptococcal infection and the
appearance of the clinical features of ARF
• Chorea and indolent carditis: may follow prolonged latent
periods lasting up to 6 months
• Commonly subclinical but may report prior sore throat
• Most common clinical presentation of ARF: polyarthritis and
fever
• Polyarthritis - 60–75%
• Carditis - 50–60%
Heart Involvement
• Up to 60% of patients with ARF progress to RHD
• Endocardium, pericardium, or myocardium may be affected
• HALLMARK OF RHEUMATIC CARDITIS: Valvular
damage; mitral valve; early damage: regurgitation
• Damage to the pulmonary or tricuspid valves is usually
secondary to increased pulmonary pressures resulting from
left-sided valvular disease
• Pericarditis - most commonly causes a friction rub or a small
effusion on echocardiography and may occasionally cause
pleuritic central chest pain
• PR interval prolongation & soft S1 due to affected electrical
conduction pathways secondary to myocardial inflammation

1 of 6
 3.03 ACUTE RHEUMATIC FEVER & THE VASCULITIS SYNDROMES

Joint Involvement Laboratory: elevated erythrocyte

e
sedimentation rate or leukocyte count
• Polyarthritis (Major)
• Migratory Electrocardiogram: prolonged P-R
• Affects the large joints—most commonly the knees, interval
ankles, hips, and elbows—and is asymmetric
• Pain is severe and usually disabling until anti- Elevated or rising anti-streptolysin O or
inflammatory medication is commenced other streptococcal antibody, or
• Arthralgia (Minor criteria) Supporting evidence of a
• Highly responsive to salicylates and other nonsteroidal preceding A positive throat culture, or
anti-inflammatory drugs (NSAIDs) streptococcal infection Rapid antigen test for group A
within the last 45 days streptococcus, or
Chorea
e
Recent scarlet fever
• Sydenham's chorea commonly occurs in the absence of
other manifestations Must have: 2 MAJOR or
• Prolonged latent period after group A streptococcal 1 MAJOR plus 2 MINOR plus evidence of preceding
infection, and is found mainly in females Group A Strep infection
• Affect particularly the head (causing characteristic darting
movements of the tongue) and the upper limbs
• often associated emotional lability or obsessive-compulsive DIAGNOSTICS
traits
• Eventually resolves completely, usually within 6 weeks

Skin Manifestations

• ERYTHEMA MARGINATUM - begins as pink macules that

clear centrally, leaving a serpiginous, spreading edge;
evanescent, appearing and disappearing before the
examiner's eyes; trunk, sometimes on the limbs, but almost
never on the face
• SUBCUTANEOUS NODULES - painless, small (0.5–2 cm),
mobile lumps beneath the skin overlying bony
prominences, particularly of the hands, feet, elbows,
occiput, and occasionally the vertebrae
• 2–3 weeks after the onset of disease, last for just a
few days up to 3 weeks, and are commonly
associated with carditis
Other Features

• Fever - usually high-grade fever (39°C)

• Elevated acute-phase reactants:
• C-reactive protein (CRP)
• Erythrocyte sedimentation rate (ESR)
• Peripheral leukocyte count is mildly elevated TREATMENT
• ANTIBIOTICS:
• Penicillin - drug of choice
Evidence of a preceding group A Streptococcal Infection
• Oral: 500 mg PO twice daily for 10 days
• Essential in making the diagnosis of ARF • Single dose IM: 1.2 million units
• Most common serologic tests: anti-streptolysin O (ASO) benzathine penicillin G
and anti-DNase B (ADB) titers • Erythromycin – for penicillin allergy
• 250 mg capsule bid
JONES CRITERIA
Carditis
• SALICYLATES AND NSAIDS
Polyarthritis • Treatment of arthritis, arthralgia, and fever
• No value in the treatment of carditis or chorea
Major manifestations Chorea • Aspirin - drug of choice
• Initial dose of 80–100 mg/kg per day in children
Erythema marginatum
(4– 8 g/d in adults) in 4–5 divided doses up to
Subcutaneous nodules 2 weeks
• Naproxen at a dose of 10–20 mg/kg per day
Minor manifestations Clinical: fever, polyarthralgia has been reported to lead to good
symptomatic response
2 of 6
 3.03 ACUTE RHEUMATIC FEVER & THE VASCULITIS SYNDROMES

PROGNOSIS I. THE VASCULITIS SYNDROMES

 Untreated: ARF lasts on average 12 weeks
 With treatment: within 1–2 weeks
 Inflammatory markers should be monitored every 1–2
weeks until they have normalized (usually within 4–6
weeks)
 Echocardiogram should be performed after 1 month
 Secondary antibiotic prophylaxis
 inflammation of and damage to blood vessels
 associated with ischemia of the tissues supplied by the
involved vessel
 PRIMARY vs SECONDARY VASCULITIS
 SINGLE ORGAN (e.g. skin) vs MULTISYSTEM
Classification

PRIMARY PREVENTION
• Elimination of the major risk factors for streptococcal
infection
• Primary prophylaxis: timely and complete treatment of
group A streptococcal sore throat with antibiotics
• commenced within 9 days of sore throat onset:
• 10 days of penicillin V (500 mg bid PO)
• Single IM injection of 1.2 million units of
benzathine penicillin G

SECONDARY PROPHYLAXIS
CATEGORY OF PATIENT DURATION OF PROPHYLAXIS

Patient without proven For 5 years after the last attack or 18

carditis years of age (whichever is longer)

Patient with carditis (mild For 10 years after the last attack, or 25
mitral regurgitation or years of age (whichever is longer)
healed carditis)

More severe valvular Lifelong

disease

Valvular surgery Lifelong

POST QUIZ Other classification

• Give the criteria in the diagnosis of the following
diseases and include the required number of criterion ANCA VESSEL SIZE
that will qualify the patient for the said disease:  Granulomatosis with Large: Giant Cell Arteritis
1. SLE Polyangiitis (Wegener’s) Medium: PAN
2. Rheumatoid arthritis (1987 Revised ACR)  Microscopic Polyangiitis Small: Microscopic
3. Acute Rheumatic Fever  Eosinophilic Polyangiitis
*See notes for SLE Criteria, 1987 Revised Criteria for RA or 2010 Granulomatosis with
ACR-EULAR Criteria, and Jones Criteria for ARF Polyangiitis (Churg-
Strauss)

Pathophysiology & Pathogenesis

1. Genetic predisposition
2. Environmental exposures
3. Regulatory mechanisms associated with immune response to
certain antigens
 Mechanisms:
 Immune Complex formation
 Antineutrophil Cytoplasmic Antibodies (ANCAs)
 Pathogenic T lymphocyte responses
-Vascular endothelial cells can express HLA class II
molecules following activation by cytokines such as
interferon (IFN) γ
-cells interact with CD4+ T cells
-Endothelial cells can secrete IL-1, activates T cells and
initiate or propagate in situ immunologic processes within
the blood vessel.

3 of 6
 3.03 ACUTE RHEUMATIC FEVER & THE VASCULITIS SYNDROMES

- Lung involvement typically appears as multiple, bilateral,

nodular cavitary infiltrates ->cough, hemoptysis, dyspnea, and
chest discomfort
- Renal involvement: focal and segmental glomerulitis that may
evolve into a rapidly progressive crescentic glomerulonephritis

Clinical & Laboratory Manifestations

-Involvement of the upper airways occurs in 95% of patients (e.g.

 II. ANTI-NEUTROPHILIC CYTOPLASMIC ANTIBODIES
(ANCA)
 Antibodies directed against certain proteins in the cytoplasmic
granules of neutrophils and monocytes
 High percentage:
 Active Granulomatosis with Polyangiitis (Wegener’s)
 Microscopic Polyangiitis
 Lower percentage:
 Eosinophilic Granulomatosis with Polyangiitis (Churg-
Strauss)
2 major categories of ANCA
 cytoplasmic ANCA (cANCA)
- diffuse, granular cytoplasmic staining pattern observed
by immunofluorescence microscopy when serum
antibodies bind to indicator neutrophils
-Proteinase-3- major cANCA antigen
-> 90% of patients with Wegener’s have
detectable abs
 perinuclear ANCA (pANCA)
-more localized perinuclear or nuclear staining pattern of
the indicator neutrophils
-major target for pANCA is the enzyme myeloperoxidase
-Abs found in Churg-Strauss, isolated necrotizing
crescentic glomerulonephritis, and Wegener’s
paranasal sinus pain, drainage and purulent or bloody nasal
discharge)
-saddle nose deformity, serous otitis media, Subglottic tracheal
stenosis
-eye involvement, skin lesions
-Cardiac involvement (pericarditis, coronary vasculitis,
cardiomyopathy)
-Nervous System (cranial neuritis, mononeuritis multiplex, or,
rarely, cerebral vasculitis and/or granuloma)
-Renal Disease (mild glomerulitis with proteinuria, hematuria, and
red blood cell casts)
-Active dse: malaise, weakness, arthralgias, anorexia, and weight
loss
-Lab findings:
markedly elevated ESR
mild anemia and leukocytosis
mild hypergammaglobulinemia (IgA class)
mildly elevated rheumatoid factor.
Thrombocytosis
positive antiproteinase-3 ANCA
Diagnosis
-tissue biopsy: necrotizing granulomatous vasculitis
-Pulmonary tissue offers the highest dx yield
-positive antiproteinase-3 ANCA
IV. POLYARTERITIS NODOSA
 Necrotizing vasculitis of small and medium-sized muscular
arteries in which involvement of the renal and visceral arteries
 ABSENCE: granulomas, significant eosinophilia, and an
allergic diathesis


CHURG-
III. GRANULOMATOSIS WITH POLYANGITIS (WEGENER’S) WEGENER’S MPA
STRAUSS
- granulomatous vasculitis of the upper and lower respiratory Organ Involvement Upper Airways Lungs Asthma
tracts together with glomerulonephritis Lungs Kidneys Eosinophilia
- variable degrees of disseminated vasculitis involving both Kidneys
small arteries and veins may occur Prevalence 3 per 100,000 NA 1-3/Million
-Prevalence: 3 per 100,000 Mean Age of Onset 40 yo 57 yo 48 yo
Vessel Small Small – Medium Small – Medium
- rare in blacks compared with whites
Arteries & Veins Capillaries
- male-to-female ratio is 1:1 Venules
- ~15% of patients are <19 y.o.; rare before adolescents Arterioles
- mean age of onset is ~40 years Hallmark Necrotizing Absence of Granulomatous
vasculitis with granuloma reactions
granuloma Eosinophilia
Gross Appearance Saddle-nose NA NA
Pathophysiology & Pathogenesis Deformity
ANCA Antiproteinase – 3 Antimyeloperoxidase
-necrotizing vasculitis of small arteries and veins together with (c-ANCA) (p-ANCA)
granuloma formation, which may be either intravascular or Treatment Glucocorticoid; Cyclophosphamide
extravascular Methotrexate; Rituximab
Complete Remission 75% Relapse: 34% NA
5-year Survival > 80% 74% 25%

4 of 6
 3.03 ACUTE RHEUMATIC FEVER & THE VASCULITIS SYNDROMES
Pathogenesis
 Necrotizing inflammation of small and medium-sized muscular
arteries
 Lesions are segmental and ten to involve bifurcations and
branchings or arteries
 Aneurysmal dilation up to 1 cm in size along the involved
arteries
 Kidney: arteritis without glomerulonephritis
 Strong association with Hepatitis B and Hepatitis C
Clinical & Laboratory Manifestations
 Fever, Weight Loss, Malaise > 50%
 Antibodies against myeloperoxidase or proteinase-3 (ANCA)
are rarely found
 All patients should be screened for Hepatitis B and C
Diagnosis
 Arteriographic demonstration of involved vessels
 Biopsy of symptomatic organs such as nodular skin lesions,
painful testes and nerve/muscle provides the highest
diagnostic yields
Prognosis
 5-year survival rate between 10 and 20%
 Death: Gastrointestinal Complications, particularly bowel
infarcts and perforation, and Cardiovascular causes
 Following successful treatment: relapse – 10-20% of patients
V. GIANT CELL ARTERITIS & POLYMYALGIA RHEUMATICA
 GIANT CELL ARTERITIS (TEMPORAL ARTERITIS)
 Medium and large-sized arteries
 One or more branches of the carotid artery (temporal
artery)
 Can involve the aorta and its main branches
 POLYMYALGIA RHEUMATICA
 Stiffness, aching, and pain in the muscles of the neck,
shoulders, lower back, hips and thighs
 Occurs in isolation, but it may be seen in 40-50% of
patients with giant cell arteritis
 ~10-20% of patients – develop giant cell arteritis
 Age: >50 years old
 More common in women than in men
 Annual incidence rates in individuals ≥ 50 years range from 6.9
to 32.8 per 100,000 population
 Familial aggregation: association with HLA-DR4
 Complex of fever, anemia, high ESR, and headaches in a
patient over the age of 50 years old
 Tender, thickened or nodular artery, which may pulsate
early in the disease but may become occluded later
 Ischemic Optic Neuropathy – dreaded complication
 Biopsy: Temporal Artery 3 – 5 cm
 Acute disease-related mortality – very uncommon
 Mortality: Cerebrovascular events or myocardial infarction
 At risk of late mortality: Aortic Aneurysm Rupture or Dissection
 18 times more likely to develop thoracic aortic aneurysms
than the general population
 Goals of Treatment:
1 To reduce symptoms
2 To prevent visual loss
 Glucocorticoid
VI. TAKAYASU ARTERITIS
 Inflammatory and stenotic disease
 Medium and large-sized arteries
 Strong predilection for the aortic arch and its branches
 Incidence rate: 1.2 – 2.6 cases per million
 Most prevalent in adolescent girls and young women
 More common in Asia
Diagnosis
Young woman: decrease or absence of peripheral pulses.
Discrepancies in blood pressure and arterial bruits
 Characteristic pattern on arteriography: irregular vessel walls,
stenosis, post stenotic dilation, aneurysm formation, occlusion
and evidence of increased collateral circulation
 Histopathologic demonstration: vessel wall inflammation
predominately lymphocytic with granuloma formation and
giant cells involving the media and adventitia adds
confirmatory data
 Overall survival: ≥ 94%
 5-year mortality rate: 0 to 35%
5 of 6
 3.03 ACUTE RHEUMATIC FEVER & THE VASCULITIS SYNDROMES

 Disease-related mortality: Congestive Heart Failure,

Cerebrovascular events; Myocardial Infarction, Aneurysm
Rupture or Renal Failure
 Associated with significant morbidity
 Course of the disease is variable
 Spontaneous remissions may occur; most often chronic and
relapsing
Glucocorticoid therapy in doses of 40-60 mg prednisone per
day

VI. HENOCH-SCHONLEIN PURPURA

 IgA vasculitis (Henoch-Schonlein)
 Small-vessel vasculitis characterized by:
 Palpable purpura
 Arthralgias
 GI signs and symptoms
 Glomerulonephritis
 Usually seen in children (4-7 yrs old) but may also be seen in
infants adults
 Male to female ratio is 1.5:1
 Peak incidence in spring
 Presumptive pathogenesis: immune complex deposition
 Suggested inciting agents:
 Upper respiratory tract infections
 Drugs
 Food
 Insect bites
 Immunizations
 Treatment:
 Prednisone (1mf/kg/d) – useful in decreasing tissue
edema, arthralgias and abdominal discomfort

VII. BEHCET’S SYNDROME

 Characterized by recurrent episodes of
 oral and genital ulcers
 iritis
 cutaneous lesions
 Underlying pathologic process: leukocytoclastic venulitis
 Vessels of any size can be involved

6 of 6