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RHEUMATIC FEVER
Acute rheumatic fever is a noninfectious delayed complication of
streptococcal sore throat due to
Group A Beta hemolytic
streptococcus (GABHS)
HISTORY
 Historical evidence is clouded probably because
of multisystemic disease
 RF is relatively recent
 Crowded and poor working conditions fostered
by Industrial revolution contributed to spread of
RF
 World War II was associated with ravaging
epidemics
EPIDEMIOLOGY
 Incidence of rheumatic fever and RHD (
rheumatic heart disease) has decreased in
the United States and other industrialized
countries during the past 80 years.
Prevalence of RHD in the United States is
now less than 0.05 per 1000 population
 Worldwide, an estimated 5-30 million
children and young adults have chronic
RHD, and 90,000 patients die from this
disease each year.
Incidence
 The incidence of RF in
Developing countries is 27100/1 mil /yr
 In developed countries is <5/
1mil/yr
(G.S.Sainani Japi 2006)
 US
 Japan
Area
 India
Prevalence/1000
 Africa
 South America
0.3
0.3
2.2
5.7
1.3
Pathogenesis
RF occurs 1-5wks after
streptococcal throat infection avg
is 3 wks
 Streptococci- GABHS ( group A beta haemolitic
streptococcus)
 Gram positive cocci occuring in chains
 Capsulated with fimbria
STREPTOCOCCI
 Streptococci pyogenes
 Beta Haemolytic-Complete haemolysis on
blood agar
 Lancefield groups 19 –according to
carbohydrate antigen ( A to U except I,J)
 Surface M protein -80 serotypes
 T,R proteins.
GABHS Rheumatogenic serotypes
1,3,5,6,14,12,18,19,24,27,29
Nephritogenic serotypes 12 , 49
structure
 Capsule hyaluronic acid
 Cellwall
 Outer –fimbria+lipoteichoic
acid+M protein
 Middle-carbohydrate
 Inner-peptidoglycan layer
 Cytoplasmic membrane
Autoimmune disease; Antigenic mimicry
Antibodies against these antigens result in a
hyperactive immune response
 M protein helical protein-constant ,variable and highly





variable region; M protein of GABHS virulence factor ->
ability to resist phagocytosis
Crossreactivity- cytoskeleton, tropomyosin and myosin.
Group specific polysaccharide wall -> glycoprotein of
cardiac valves
Antibodies to the streptococcal peptidoglycan complexes
have been implicated in rheumatic arthritis
Somatic antigens of the cell wall & cell membrane ->
myocardial sarcolemma ,vascular initima and skin
In Sydenham chorea, antibodies directed against the cell
membrane cross react with tissues in the caudate nucleus
of the brain
TOXINS
 Streptolysin (Hemolysin) O and S
 Erythrogenic toxin
 Streptokinase
 DNAase
 NADase
 Hyaluronidase
 Proteinase
STREPTOCOCCI
 Throat, skin, URTI ( upper respiratory tract
infections)
 Isolated from 10-50% throat culture of healthy
school children
PATHOLOGY
 RF is a multisystem connective tissue disease
 Inflammatory lesions in the heart, joints &
subcutaneous tissue
Microscopy
 Aschoff granuloma is the pathological hallmark of
RF. It consists of central fibrinoid necrosis
surrounded by histiocytes (Anitschkow cells) with a
typical “owl-eye” nucleus.
Aschoff nodule and Anitschkow cell
Gross appearance
 Valves appear dull & thickened
 Verucous vegetations on the atrial surface of the
mitral valve, chords, ventricular surface of aortic
valve with edema or hemorrhage in the leaflet
tissue
 Vegetations are composed of fibrin
MITRAL VALVE ENDOCARDITIS
Characteristics of Juvenile
Rheumatic Mitral Stenosis
 Fusion of cusps
 severe Subvalvular fusion
 Fixed fibrotic valve, no calcification
 Mobile cusps with commissural fusion
 Associated mild Mitral Regurgitation
 Early & Severe pulmonary hypertension
Positive diagnosis
of rheumatic fever
 Sir T .Duckett Jones 1944
 Modified in 1956,1965,1984 and 1992
JONES CRITERIA 1992
MAJOR MANIFESTATIONS
 Carditis
 Polyarthritis
 Chorea
 Erythema marginatum
 Subcutaneous nodules
MINOR MANIFESTATIONS
Previous RF or RHD ( rheumatoid heart disease)
Clinical findings
Athralgia
Fever
Lab findings
Raised ESR
Elevated C-reactive protein
Prolonged PR interval
Supporting evidence of
antecedent GABHS infection
 Positive throat culture or Rapid streptococcal
antigen test
 Elevated or rising streptococcal antibody titer
Diagnosis of Rheumatic Fever
 Two major manifestations OR
One major & Two minor manifestations if
supported by evidence of preceding GABHS
infection indicate a high probability of Acute RF
 Sensitivity 77%, Specificity 97%
Jones Criteria (Revised) for Guidance in the
Diagnosis of Rheumatic Fever*
Major Manifestation
Carditis
Polyarthritis
Chorea
Erythema Marginatum
Subcutaneous Nodules
Minor
Manifestations
Clinical
Previous
rheumatic
fever or
rheumatic
heart disease
Arthralgia
Fever
Laboratory
Acute phase
reactants:
Erythrocyte
sedimentation
rate,
C-reactive
protein,
leukocytosis
Prolonged PR interval
Supporting Evidence
of Streptococal Infection
Increased Titer of AntiStreptococcal Antibodies ASO
(anti-streptolysin O),
others
Positive Throat Culture
for Group A Streptococcus
Recent Scarlet Fever
*The presence of two major criteria, or of one major and two minor criteria,
indicates a high probability of acute rheumatic fever, if supported by evidence of
Group A streptococcal nfection.
Recommendations of the American Heart Association
Carditis
 Seen in 42% of patients with acute RF
 80% of patients who develop carditis within the
first 2 wks of onset of RF
 Rheumatic carditis is a pancarditis affecting the
endocardium, myocardium & pericardium to
various degrees
 Predominant effect is scarring of the heart valves
Endocarditis
 Most commonly effects mitral & aortic valves
 Mitral valve disease 70-75% pts of RHD
 Mitral + Aortic valve disease 20-25%
 Isolated Aortic valve disease 5-8%
 Isolated Aortic stenosis is rare 3-4%
(Kinare S G AIAMS 1972)
 Isolated tricuspid & Pulmonary valve is never
involved
 Tricuspid valve along with Mitral & Aortic valve is
involved in 11.8% of RHD patients
 Rheumatic Pulmonary valve is very rare , if
present it is quadrivalve
POLYARTHRITIS
 Incidence > 2/3 rd of patients
 Asymmetric, migratory involving large joints-
knees, ankles, elbows & wrists
 Axial joints are rarely involved
 Swelling, redness ,hot, severe pain, limitation
of joint movements are the main symptoms
 Physical findings disproptionate to symptoms
 Joints are involved at various intervals lasts for
4-5 days
 Arthritis resolves by 3 to 4 wks without any
permanent damage
 Joint aspirate >10000 WBCs/cu.mm
 Dramatic response to aspirin –improves within
48hrs
Differential diagnosis
 Post streptococcal reactive arthritis
 Septic arthritis
 Gonococcal arthritis
 Juvenile rheumatoid arthritis
 Tuberculosis arthritis
 Hepatitis B
 Henoch-Scholein purpura
 Serum sickness
CHOREA (St.Vitus dance)
 It is a series of jerky, nonrepeatative, involuntary
movements involving the face & extremities with
emotional lability.
 Movements disappear during sleep
 Due rheumatic inflammation of basal ganglia &
caudate nucleus
 Late manifestation after several weeks (3mths or
longer) after RF
SKIN MANIFESTATIONS





Subcutaneous nodules(1 to 21%)
Late manifestation of RF
Indicate presence of underlying carditis
Firm, painless, moveable 0.5 to 3cm in size
On bony prominence, extensor tendons (elbows,
knees , wrists, ankles), vertebral spinous
process,suboccipital region,medial border of
scapulae
 Appear in crops, disappear in 8 to 12wks
SUBCUTANEOUS NODULES
Erythema Marginatum
 Early or late manifestation
 Incidence 10-15 %
 Indicate presence of underlying carditis
 On trunk & proximal extremities
 Serpigenious erythrematous macular/papular
nonpuritic rash
 Rash extends outwards with central clearing
 No residual scarring
 May appear or disappear in mins-hrs
Erythema Marginatum
Laboratory Diagnosis
Throat Culture
 Positive in only 11% cases of ARF
Streptococcal Antibody Tests
ASLO Titer
 Slide agglutination test
 Elevated in 80% patients with ARF
 Reach a maximum level 2-3wks after infection,
plateau for 3-6mths & disappear in the next 612mths
 Adults /preschool children < 85 todd units
 School age = 170 todd units
 Titers alter with age, geographical area
 ASO titer >250 Todd units in adults >333 Todd
units in children is used for diagnosis,
AntiDNAse B/Antihyaluronidase test
 Done when ASO is nondiagnostic
 Levels remain elevated for several mths
 Less affected by antibiotics and steriods.
 DNA ase 6-12 mths
 Titre > 300 IU/dl
 normal values Anti DNase B titer 1:60 unit in
preschool,
 1:480 units in – school children & 1:340 in adults)
 Antihyaluronidase > 200 IU/dl
 Streptozyme test – 5 antigens
 Rapid slide agglutination test
Acute phase reactants
 Raised ESR
 Elevated CRP
ECG
 Prolonged PR interval
 Tachycardia
 AV block
 QRS-T changes s/o Myocarditis
Echocardiography
 Helpful to diagnose silent carditis
 More sensitive than clinical examination
 30% cardiac involvement in patients without
clinical carditis
TREATMENT
Acute Rheumatic fever
 Inj. Benzathine Penicillin 12 lac units i.m
single dose
 OR Erythromycin 40mg/kg/day in 2-4 divided
doses for 10 days
 Aspirin 100mg/kg/day in 4-5 divided doses for
3-4 wks, dose is gradually tapered depending
upon ESR & CRP levels.
Treatment of Rheumatic
Carditis
 Without Failure
 Same as ARF
 If no response to aspirin ,start Corticosteroids
 With Failure/severe carditis
 Prednisone 1-2mg/kg/day for minimum of 2
wks & then tapered for next 2 wks
 Aspirin is started during the tapering course of
Corticosteroids and is continued for 4 wks or
until there is sufficient clinical &laboratory
evidence of reduced rheumatic activity
 Aspirin for minimum 12 wks
 It is given to reduce the rebound activity after
stopping of steroids.
 5% of patients of ARF continue to have
rheumatic activity for >6mths
SEVERE CASES
 Anti failure therapy
 SURGICAL THERAPY
 Mitral valve repair
 Mitral valve replacement
Prevention of RF
PRIMODIAL PREVENTION
 Involves measures to prevent the occurrence of




a GABHS sore throat
Clean & Healthy environment.
Mass chemoprophylaxis can work in some high
risk situations
Vaccines are in experimental phase
Not feasible in all situations
Primary prophylaxis
 Benzathine penicillin G
<27kg 0.6 MU
IM Once
>27kg 1.2 MU
 PenicillinV
Children
250 mg bd/tid PO 10days
Adults
500 mg bd/tid
 Penicillin allergy
Erythromycin 250mg qid PO 10days
Azithromycin 500mg
PO 1 day
250mg OD
4 days
 Others – nafcillin, ampicillin,
amoxycillin, clindamycin, cephalexin
SECONDARY PREVENTION
 Involves prevention of streptococcal sore
throat in patients with previous episodes of
RF & thereby prevent recurrent cardiac
damage
 RF is a recurrent disease
 Recurrence per infection 40-60%
 Permanent cardiac damage increases with
Recurrences
Secondary prophylaxis
 Benzathine penicillin G 1.2 MU IM
 Penicillin V
250mg BD PO
 Sulfadiazine
<27kg
500mg OD PO
>27kg
1000mg
 Penicillin/ sulfa allergy
Erythromycin 250mg BD PO
Duration of secondary
prophylaxis
Category
 RF with carditis &
residual valvular
Duration
 RF with carditis
but no residual
valvular disease
10yrs or well into
adulthood
 RF without
5yrs or until age 21
carditis
lifelong
Juvenile
Rheumatoid
Arthritis
 Juvenile Rheumatoid Arthritis
is an inflammatory arthritis in which joints,
usually including those of the hands and feet,
are inflamed, resulting in swelling, pain,
and often destruction of joints.
 Juvenile rheumatoid arthritis is now called by
several different names : juvenile chronic
arthritis (JCA) or juvenile idiopathic arthritis
(JIA). No matter which of these names you
use , JRA is not a single disease.;
EPIDEMIOLOGY
 1. Juvenile arthritis (JRA) most frequent
connective tissue disease of childhood
 2. Incidence
 Mayo Clinic, 1966, 13.9 cases per 100,000.
 3. Prevalence
 a. Mayo Clinic Survey, 113.4 cases per
100,000 children.
 b. English schoolchildren, Bywaters, 65 cases
per 100,000.
AGE OF ONSET
Onset usually after 6 months of age
The highest frequency occurs at 1 to
3 years of age.
Largely children with pauciarticular arthritis
Another peak occurs at 9 years of age.
This peak has an equal contribution between
boys and girls and is a much broader peak.
JUVENILE RHEUMATOID ARTHRITIS
Etiology and Pathogenesis
 unknown
 combination of factors
 environment (infection, trauma, stress)
 autoimmunity
 immunogenetic
Synovium
 Synovium becomes
hyperplastic and locally
invasive at the synovial
interface with cartilage and
bone.
 • The destructive tongue of
tissue is called pannus and is
responsible for marginal
erosions observed on X-rays.
 • The pannus is comprised
primarily of invasive lining
cellsmetalloproteinases)
Patholog
y
CRITERIA FOR THE CLASSIFICATION OF JA
 1. Age of onset < 16 years.
 2. Arthritis in one or more joints
defined as swelling or effusion, or
presence of two or more of the
following signs: limitation of range
of motion, tenderness, or pain on
motion, and increased heat.
 3. Duration of disease ≥ 6 weeks.
 4. Exclusion of other forms of
juvenile arthritis.
ANCILLARY
MANIFESTATIONS OF JA
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1. Morning Stiffness
2. Rheumatoid rash
3. Intermittent fever
4. Pericarditis
5. Chronic uveitis
6. Cervical spondylitis
7. Rheumatoid nodules
8. Tenosynovitis
9. Antinuclear antibodies
10. Rheumatoid factors
CLASSIFICATION OF THE
TYPES OF ONSET OF JA
 1. Polyarticular arthritis (5 or more joints)
a. Rheumatoid factor negative
b. Rheumatoid factor positive
 2. Pauciarticular arthritis (4 or fewer joints)
a. Early childhood onset
b. Late onset
 3. Systemic disease (arthritis with intermittent
fever)
IMPORTANT !
ILAR Classification Criteria
(International League of Associations for
Rheumatology)
Juvenile Idiopathic Arthritis (JIA)
Systemic
Polyarticular RF+
Polyarticular RFOligoarticular
persistent
extended
Psoriatic arthritis
Enthesitis-related arthritis
Other arthritis
JUVENILE RHEUMATOID ARTHRITIS
Clinical features: systemic disease
 10-20% of patients with JRA
 prominent systemic symptoms: fever, rash,
lymphadenopathy, hepatosplenomegaly,
pericarditis, pleuritis
 arthritis may be absent for months to years
 uveitis uncommon
 In systemic disease (Still's disease), inflammation
occurs at sites other than the joints (which also may be
affected)
 high fever and rash that frequently appear before joint
pain and swelling. The fever comes and goes, usually for
at least 2 weeks. The temperature is usually highest in
the afternoon or evening (often 103° F [39° C] or higher)
and then returns rapidly to normal.
 A child -tired and irritable. The rash is made up of flat,
pink-colored or salmon-colored patches—on the trunk
and the upper part of the legs or arms. It appears for
hours at a time (often in the evening with the fever) and
does not always appear in the same spot.
 The liver, spleen, and lymph nodes may enlarge.
Sometimes -pericarditis,pleuritis causing chest pain.
JUVENILE RHEUMATOID ARTHRITIS
Laboratory studies: systemic disease
 WBC   , Hgb , platelets  to  ,
 ESR   to   
 ANA and RF usually negative
 x-rays : soft tissue swelling
JUVENILE RHEUMATOID ARTHRITIS
Clinical features: pauciarticular
disease
 40-60% of patients with JRA
 insidious onset
 morning irritability/stiffness subtle
 systemic symptoms: usually absent
 large joints (rarely hip), asymmetric
involvement
 uveitis 20%
 subtypes
 In pauciarticular juvenile idiopathic arthritis,
four or fewer joints, usually those of the leg
(and often the jaw), are affected by pain and
swelling. The knee is the most common joint
affected. The hip and shoulder are usually
spared. Occasionally, a single toe, a finger, or a
wrist becomes stiff and swollen.
JUVENILE RHEUMATOID ARTHRITIS
Laboratory Studies: Pauciarticular Disease

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CBC: normal
ESR: usually normal
ANA: frequently positive
RF: usually negative
synovial fluid: class II (inflammatory)
x-ray findings: soft tissue swelling,
periarticular osteoporosis, growth
disturbance, loss of joint space
Inflammation of the iris in the eye (iridocyclitis)
can develop with any type of juvenile idiopathic
arthritis, but most often iridocyclitis develops
with pauciarticular juvenile idiopathic arthritis or
polyarthritis. Iridocyclitis in juvenile idiopathic
arthritis is asymptomatic (there is no pain or
redness), but it can lead to permanent loss of
vision if untreated.
FACTORS DETERMINING HIGH
RISK OF UVEITIS
(iridocyclitis)




•Female
•< 6 years of age
•Pauciarticular
•< 2 years duration of
arthritis
 •ANA present
JUVENILE RHEUMATOID ARTHRITIS
Clinical features: polyarticular
disease
 30-40% of patients with JRA
 morning irritability/stiffness more prominent
 systemic symptoms: mild to moderate
 large and small joints including cervical spine,
symmetric involvement
 uveitis 5%
 subtypes
polyarthritis

five or more (sometimes as many as 20 to 40)
joints are affected. The inflammation usually
affects the same joint on both sides of the body—
for example, both knees or both hips. The jaw, neck
joints, and wrists may be affected.
 Inflammation may develop in the tendons and
connective tissues around joints (tenosynovitis),
causing pain, swelling, and warmth.
 Rarely, generally in adolescents, small lumps
(rheumatoid nodules) may form over the elbows,
fingers, or toes
 joints may be stiff when the child awakens.
 joints often become swollen and warm, joints may
become painful, but the pain may be milder than
expected from the amount of swelling. Pain may
become worse when the joint is moved. A child
may be reluctant to walk or may limp. Joint pain
persists for years if untreated.
 any type of juvenile idiopathic arthritis can interfere
with physical growth. Joint deformities may
develop if untreated. When juvenile idiopathic
arthritis interferes with growth of the jaw, a small
chin (micrognathia) can result.
 long-standing (chronic) joint inflammation can
eventually cause deformities or permanent damage
of the affected joint.
JUVENILE RHEUMATOID ARTHRITIS
Laboratory features: polyarticular disease



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WBC , Hgb , platelets WNL to 
ESR  to  
ANA may be positive
RF may be positive
Synovial fluid: class II (inflammatory)
X-ray findings: soft tissue swelling,
periarticular osteoporosis, joint space
narrowing, erosions
JUVENILE RHEUMATOID ARTHRITIS
Extra-articular Manifestations
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generalized or local growth disturbances
delayed puberty
pericarditis, myocarditis, rarely endocarditis
plural effusion, rarely
pneumonitis, pulmonary fibrosis
hepatitis
hematuria
Laboratory test for juvenile idiopathic
arthritis.
 The erythrocyte sedimentation rate is usually very high in the systemic




form, less so in the polyarticular form, and usually normal in the
pauciarticular form.
Rheumatoid factor and antinuclear antibodies, which are present in some
people with rheumatoid arthritis and related diseases (for example,
autoimmune diseases, such as lupus, polymyositis, or scleroderma).
Some children with juvenile idiopathic arthritis do not have rheumatoid
factor or antinuclear antibodies in their blood. An adolescent with
polyarticular juvenile arthritis and a positive test result for rheumatoid
factor has a form of arthritis that is very similar to rheumatoid arthritis in
adults.
Children with juvenile idiopathic arthritis who have antinuclear antibodies
in their blood are at a higher risk of developing iridocyclitis. X-ray studies
eventually may show characteristic changes in the bones or joints.
Children must be examined several times a year by an ophthalmologist for
iridocyclitis regardless of whether symptoms are present. If the children
have systemic juvenile idiopathic arthritis, then an annual eye exam
suffices.
Synovial Fluid Analysis in JA
•Cloudy
•Poor mucin clot, due to partial
degradation of hyaluronic acid
•Leukocyte count > 2,000/cmm
(2,000-50,000)
> 50% neutrophils
 1. Pauciarticular JA and Polyarticular
(Factor negative)




– a. DR 8 (DRB1*0801)
– b. DR 5 (DRB1*1101 and *1104)
– c. DR 6 (DRB1*1301)
– d. DP w2.1 (DPB1*0201)




2. Polyarticular Erosive Disease
– a. DQA1*0101
– b. DRB1*0101
– c. DPw3
 3. Polyarthritis RF+
 a. DR 4, Dw4 (DRB1*0401)
 b. DR4, Dw14 (DRB1*0404)
JUVENILE RHEUMATOID ARTHRITIS
Treatment
 supportive not curative
 involves multidisciplinary team approach
 goals:
 to suppress articular and/or systemic inflammation with as
little risk as possible
 to maintain function/prevent disabilities
 to foster normal psychological and social development
 heterogenity of disease mandates individualization
Medications in the Treatment of
JRA
NSAID

intra-articular steroids
sulfasalazine
hydroxychloroquine
(auranofin)

methotrexate
(IM gold)
(D-penicillamine)

etanercept
azathioprine
cyclophosphamide
cyclosporin
Pauci Articular
 NSAID
2-4 weeks
No response
Change NSAID (2-4 weeks)
No response
Methotrexate
no response
Intra Articular Steroid
Poly Articular

NSAID (2-4 weeks)
no response
Change NSAID
(2-4 weeks)
no response
2
Methotrexate (10-15 mg/m/ week
Steroid ( Bridge therapy)
Newer drugs
Systemic Onset
Less severe disease
Life threatening/ severe
features
NSAIDs for 2 weeks.
Acute onset flare
Pulse steroid
MP( 30 mg/kg/day) x 3 days.
Oral steroid
No response
Change NSAIDs( 2 weeks)
Oral steroids and taper
slowly
 Typically, nonsteroidal anti-inflammatory drugs
(NSAIDs) are used, but children with severe
systemic disease may require given by mouth or
intravenously.
 When corticosteroids ( 1.5 -2 mg/kg) are
necessary, the lowest possible dose is used to
decrease the chance of long-term complications
such as slowed growth, osteoporosis, and
osteonecrosis (death of bone tissue). If just a few
joints are inflamed, doctors may inject
corticosteroids directly into the joint.
NSAIDs
 Salicyclic acids ( aspirin )
 Phenylacetic acid ( diclofenac)
 Carbo- and Heterocyclic Acid: *Etodolac
Indomethacin, Sulindac, Tolmetic, Ketorolac
 Propionic acids: Flurbiprofen, Ketoprofen,
Oxaprozin, *Ibuprofen, Naproxen, Fenoprofen
 Fenamic acids: **Mefanamic
 Pyrazolones : *Phenylbutazone
 Oxicams : piroxicam, metoxicam
 Nabumetone
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
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COX-2-selective inhibitors (Coxibs)
Meloxicam
Nimesulide
*Celecoxib
Rofecoxib
Meloxicam
Nimesulide
Paracoxib
Valdecoxib
Deracoxib
Etodolac
Lumiracoxib
Valdecoxib
Deracoxib
Etoricoxib
 Sometimes, stronger drugs, such as methotrexate are
used for pauciarticular juvenile idiopathic arthritis and are
usually needed to treat polyarticular and systemic juvenile
idiopathic arthritis. Side effects include bone marrow
depression and liver toxicity, so children taking these
drugs require regular blood tests.
 Etanercept Some Trade Names ENBREL
and infliximab Some Trade Names REMICADE
drugs that block tumor necrosis factor (a protein involved
in inflammation), are effective and have improved the
outcome for children with juvenile idiopathic arthritis
significantly. Systemic juvenile arthritis is often treated
with anakinra, a drug that blocks the inflammatory
protein interleukin 1.
 Iridocyclitis is treated with corticosteroid eye drops or
ointments, which suppress inflammation. If this treatment
is not enough, methotrexate
 Used in Treatment of JRA

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
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
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• Methotrexate
• Arava (leflunomide)
• Anti-malarial drugs
– chloroquine
– OH-chloroquine (Plaquenil)
• Immunosuppressive drugs
– cyclophosphamide
– azathiaprine
– Chlorambucil
– Cyclosporin A
• Gold salts oral or injectable
• D-penicillamine
Role of TNFα in JA
 Etanercept
ENBREL
infliximab
REMICADE
and adalimumab are TNF inhibitors and can be dramatically
effective for people who do not respond sufficiently to methotrexate
ENBREL
is given once or twice weekly by injection under the skin,
REMICADE
is given by vein every 8 weeks after loading doses.
 Adalimumab is injected under the skin once every 1 or 2 weeks. TNF is
part of the body's immune system, so inhibition of TNF can impair the
body's ability to fight infections. These drugs should be avoided in
people who have active infections. Etanercept Some Trade Names
ENBREL
 infliximab Some Trade Names
REMICADE
, and adalimumab can be used with methotrexate
.
IL-1 Receptor Antagonist
(Anakinra, Kineret)
 • Patients with RA were given IL-1ra sq daily
in varying doses ranging from 30mg to 115
mg/dose.
 • By 24 weeks after onset, significant
reductions in radiologic progression were
noted (using hand radiographs).
 • IL1ra was felt to be safe, and effective.

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
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
Newer Therapies
• Anti-T cell therapy
– Abatacept (Monoclonal antibodies to
CTLA4Ig (Cytotoxic T-Lymphocyte Antigen 4)
• Anti B cell therapy
– Rituximab (antibodies directed against CD20)
• Therapy directed against innate immunity
 – Leukotrienes and other inflammatory
mediators • Antigen-specific
immunosuppression
 – Induction of tolerance
 – Analog peptide therapy
 Along with drugs to reduce joint inflammation, a
treatment plan for rheumatoid arthritis should
include nondrug therapies, such as exercise,
physical or occupational therapy, and
sometimes surgical treatment. Inflamed joints
should be gently stretched so they do not freeze
in one position. As the inflammation subsides,
regular, active exercises can help, although a
person should not exercise to the point of
excessive tiredness (fatigue; exercise in water
may be easier.
JUVENILE RHEUMATOID ARTHRITIS
Treatment: physical measures
heat:
splinting:
exercise:
rest
analgesia
muscle relaxation
provide joint rest
maintain functional position
correct deformities
passive, active assisted and
active range of motion
general conditioning
JUVENILE RHEUMATOID ARTHRITIS
Treatment: education and supportive counseling
 understand disease process, treatment and
prognosis
 understand roles in care
 as normal possible:
 discipline/family life
 school
 peer relationships
 counseling
JUVENILE RHEUMATOID ARTHRITIS
Poor Prognostic Signs
 pauciarticular
 long duration of active disease
 conversion to polyarticular disease (30%)
 chronic uveitis
 polyarticular
 long duration of active disease
 articular erosions
 RF positivity/rheumatoid nodules
 systemic
 conversion to polyarticular disease (25-50%)
Pediatric
Systemic
Lupus
Erythematosus
 Systemic lupus erythematosus (disseminated
lupus erythematosus, lupus) is a chronic
inflammatory connective tissue disorder that
can involve joints, kidneys, mucous
membranes, blood, heart, lungs, CNS and
blood vessel walls.
 Systemic lupus erythematosus (SLE) is a
chronic autoimmune disease affecting
multiple organ systems with protean
manifestations.
 Systemic lupus erythematosus (SLE) is an
autoimmune disease characterized by
antinuclear antibody (ANA) production with
widespread immune dysregulation, often
resulting in multiorgan system inflammation.
15% of all lupus cases have onset in childhood
 Incidence rates among children younger than
age 15 years have been reported to be 0.5-0.6
case per 100,000 persons. Prevalence rates of
4-250 cases per 100,000 persons
ETIOPATHOGENY
The American Rheumatism Association (ARA) criteria were called
“criteria for classification” as they were not meant to be exclusive or
restrictive. The ACR’s ( American College of Rheumathology) diagnostic
criteria for SLE include the following:
 Malar rash
 Naso-oral ulcers
 Photosensitive rash
 Discoid rash
 Arthritis
 Pleuritis or pericarditis
 Proteinuria (>500 mg/d) or evidence of nephritis in urinalysis
 Hemolytic anemia, thrombocytopenia, leukopenia, or lymphopenia
 Seizure or psychosis
 Positive ANA finding
 Positive anti–double-stranded DNA, anti-Smith, or antiphospholipid
antibody/lupus anticoagulant
 The Systemic Lupus International Collaborative Clinics recently published
a modification of the ACR criteria. Lupus patients meet 4 criteria with at
least one clinical and one immunologic criterion or with biopsy-proven
nephritis in association with positive ANA and anti-dsDNA
Symptoms
 may develop gradually over months or years with
episodes of fever, feeling unwell, or any of the
symptoms discussed below alternating with periods
when symptoms are absent or minimal.
 Joint Problems: Joint symptoms, ranging from
intermittent joint pains (arthralgias) to sudden
inflammation of multiple joints (acute polyarthritis),
occur in about 90% of people and may exist for years
before other symptoms appear. In long-standing
disease, marked joint deformity may occur
(Jaccoud's arthropathy) but is rare. However, joint
inflammation is generally intermittent and usually
does not damage the joints.
Mucocutaneous Manifestations
 Frequency: 76%
 Malar rash - butterfly-like redness
 Discoid lupus
 Vasculitis (purpura, petechiae)
 Raynaud’s phenomenon
 Nail involvement
 Alopecia
 Periungual erythema/ Livedo reticularis
 Photosensitivity
 Oral/ nasal ulcers
SYSTEMIC LUPUS
ERYTHEMATOSUS: ACUTE FACIAL
RASH
Acute malar rash
Pulmonary Findings In SLE








Incidence: 5-67%
May be subclinical (abnormal PFTs)
Pleuritis
Pleural effusion
Pneumonitis
Pulmonary hemorrhage
Pulmonary hypertension
Restrictive lung disease & diffusion defects most
commonly observed abnormalities on PFTs
Cardiovascular Findings
In SLE
 Pericarditis
 Myocarditis
 Sterile valvular vegetations (rarely clinically
significant except for risk of bacterial
endocarditis)
 Arrhythmias
 Cor pulmonale
 Vasculitis (small vessels)
 Atherosclerosis/ Coronary Heart disease
 Dyslipoproteinemias
Lymph Node and Spleen
 Wide-spread enlargement of the lymph
nodes is common, particularly among
children, young adults, and blacks of all ages.
 Enlargement of the spleen (splenomegaly)
occurs in about 10% of people. People may
experience nausea, diarrhea, and vague
abdominal discomfort
Neuropsychiatric Manifestations
Of SLE
 Frequency: 20-40%
 Difficult to diagnose and treat
 Second to nephritis as most common cause of
morbidity & mortality
 Can occur at any time; even at presentation
 Standard lab examinations have not been helpful
in diagnosing or managing CNS sxs
 Imaging modalities are not specific enough
 SLE patients have imaging abnormalities but are
clinically normal
Neuropsychiatric Manifestations
Of SLE
 COMMON: Depression, organic brain syndrome,
functional psychosis, headaches, seizures,
cognitive impairment, dementia, coma
 OCCASIONAL: Cerebral vascular accidents
(thrombosis or vasculitis), aseptic meningitis,
peripheral neuropathy, cranial nerve palsies
 RARE: Paralysis, transverse myelopathy,
chorea
Diagnosis Of CNS Lupus
 CNS: CSF analysis shows pleocytosis; CT, MRI,



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

MRA all may be normal or nonspecific
Autoantibodies (anti-neuronal, anti-cardiolipin,
anti-ribosomal P) are not helpful
Vasculitis: CT, MRI, MRA may or may not be
positive → conventional angiography
CVA (cerebrovascular accident ): CT, MRI often
positive
Spectamine (PET) scans positive in mild, acute,
or old disease
Neurocognitive testing
Electroencephalography for seizures
Hematologic Findings In SLE
 Leukopenia, especially lymphopenia
 Anemia
 mild to moderate, common, due to chronic disease
and mild hemolysis
 severe, uncommon (5%), due to
immune mediated hemolysis (Coombs +)
 Thrombocytopenia
 mild 100-150K, common due to immune mediated
damage
 severe <20K, uncommon (5-10%),
immune mediated damage
 Bone marrow suppression/arrest--very rare,
due to antibodies against precursors
Coagulopathy In SLE
 Hypocoagulable states:
 Anti-platelet antibodies--decreased numbers of platelets
or decreased function (increased bleeding time)
 Other platelet dysfunction and thrombocytopenia
 Anti-clotting factor antibodies
 Hypercoagulable states:
 Antiphospholipid Antibody Syndrome (APS): more later
 Protein C and S deficiencies
 Thrombotic thrombocytopenic purpura
GI INVOLVEMENT IN SLE

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
Mild LFT elevation--not significant clinically-BUT NEED TO EXCLUDE AUTOIMMUNE
HEPATITIS
Colitis
Mesenteric vasculitis
Protein-losing enteropathy
Pancreatitis
Exudative ascites
Renal Findings In SLE
Most common cause of morbidity & mortality
 Glomerulonephritis – at least 75%
 Microscopic or gross hematuria
 Proteinuria, including nephrotic syndrome
 Hypertension
 Decreased GFR
 Renal failure (up to 30-50% of children prior to
1980)
 Renal biopsy predictive of potential for renal
damage
 ISN/ RPS classification with NIH activity and chronicity
indices
Histological Classifications
 • WHO classification:
 – I normal
 – II Mesangiopathic
 – III Focal and segmental proliferation
 – IV Diffuse proliferative
 – V Membranous
 – VI Advanced sclerosing
Laboratory Findings
 Cytopenias (anemia, thrombocytopenia,
leukopenia)
 Elevated ESR, CRP, Immunoglobulins
 Hypoalbuminemia
 Proteinuria; RBCs, casts in urine
 Decreased creatinine clearance
 Low complement levels (C3/ C4)
 Autoantibodies (ANA, APL (Antiphospholipid
antibody), Coombs, anti-platelet Ab, rheumotoid
factor, etc.)
 (Immune complexes)
LABORATORY
 antinuclear antibodies.
 if antinuclear antibodies are detected,
antibodies to double-stranded DNA, other
autoimmune antibodies (autoantibodies,
 anti-smith antibodies.
 antibodies to phospholipids, can help identify
people at risk of recurrent blood clots.
 blood tests can also indicate anemia, a low white
blood cell count, or a low platelet count.
Antinuclear Antibodies (ANA)
 Sensitive but not specific, 95-98% pts positive
 Against nuclear components of the cell
 Titer specific- up to 10% of population have +ANA w/o disease;
also see with infections, medications, malignancy
 Subtypes:
 dsDNA (Double-stranded (ds, native) DNA : high
specificity for lupus (over 80%)
 ENA (extractable nuclear antigen) = RNP/ Smith
ribonucleoprotein/Smith; RNP assoc w/ MCTD (Mixed
connective-tissue disease), Smith specific for SLE
 Ro/ La (SS-a/ SS-b): neonatal lupus, Sjogren’s
 Anti-C1q
 – Increase in anti-C1q correlates with
 proliferative GN
 • Others: Complement levels, ESR, Hgb,
 renal function
SLE - Treatment
 MILD DISEASE: Rashes, arthralgias, leukopenia,
anemia, arthritis, fever, fatigue
 Treatment: NSAIDs, low dose corticosteroids (<60
mg/day), antimalarials (hydroxychloroquine), low dose
methotrexate
 MODERATE DISEASE: Mild disease + mild
organ system involvement such as: mild
pericarditis, pneumonitis, hemolytic anemia,
thrombocytopenia, mild renal disease, mild CNS
disease
SLE - Treatment
 MODERATE DISEASE (cont.):
 Treatment: Prednisone 1-2 mg/kg/day, NSAIDS,
Antimalarials, Low dose methotrexate,
Azathioprine, MMF
 SEVERE DISEASE: Severe, life-threatening
organ system involvement
 Treatment: High dose corticosteroids (2-3
mg/kg/day or pulse), Immunosuppressives (IV
pulse Cyclophosphamide), Plasmapheresis,
Anticoagulation where appropriate
• Serositis is usually treated with a short course of
low-dose steroids and a NSAID. If the serositis
recurs when the steroids are discontinued, a
steroid-sparing agent such as azathioprine or
methotrexate is typically added to the treatment
regimen. Hydroxychloroquine is beneficial in
treating arthritis in SLE but may require several
months before the maximal benefit is seen.
Central nervous system (CNS) inflammation in
childhood lupus requires aggressive therapy,
often requiring high-dose steroids and
cyclophosphamide
• Cytopenia in SLE usually responds to low- to
moderate-dose corticosteroids; however,
occasionally a child will present with acute
hemolytic crisis that may require pulse
intravenous (IV) corticosteroids to gain rapid
control of the hemolytic process. The presence of
antiphospholipid antibodies requires attention.
The primary treatment in these patients is
anticoagulation as antiphospholipid antibody
levels are resistant to immunosuppressive or
cytotoxic agents.
•
•
•
•
•
•
•
•
The treatment of lupus nephritis varies depending on the renal lesion present.
In mesangial disease, low-dose steroids are usually adequate.
Treatment of focal proliferative glomerulonephritis : moderate doses of
corticosteroids plus azathioprine.
The treatment of diffuse proliferative glomerulonephritis is in transition. The current
treatment of this serious renal lesion is sequential therapy designed to induce and
then maintain disease remission with the goal of improving the rate of remission and
at the same time minimizing the long-term toxicity of the treatment.
The most common approach is to induce remission with monthly IV
cyclophosphamide +high-dose corticosteroids (IV pulses followed by high-dose daily
oral glucocorticoids) for 3 to 6 months, followed by a less-toxic treatment regimen to
maintain remission.
Maintenance therapy typically consists of either less-frequent (quarterly) IV
cyclophosphamide or, more commonly, discontinuing cyclophosphamide and
replacing it with either azathioprine or mycophenolate mofetil.
Using this approach, renal outcomes have improved in diffuse proliferative
glomerulonephritis (GN). Yet, despite the improvement in the treatment, many
children with diffuse proliferative glomerulonephritis (DPGN) go on to end-stage renal
disease (ESRD).
Membranous lupus nephritis continues to be difficult to treat. This type of lesion is
less responsive to immunosuppressive therapy and a substantial proportion of
individuals with membranous disease develop nephrotic syndrome and ESRD. Despite
the poor response to treatment, those individuals with membranous disease who
develop nephrotic syndrome are treated with IV pulse cyclophosphamide and
glucocorticoids
Management of Pediatric
Systemic Lupus Erythematosus
•
•
•
•
•
•
•
•
•
General Use high-SPF sunscreen throughout the year.
Encourage good sleep and nutritional patterns.
Address psychological aspects of disease/treatment.
Prescribe calcium and vitamin D supplements (especially
if on corticosteroids).
Immunize against pneumococcus.
Treat with anticoagulant if evidence of antiphospholipid
antibody is present (agent depends on if the child has
had a clot or not).
Perform annual ophthalmologic evaluations (especially if
on hydroxychloroquine).
Treat dyslipoproteinemia when present.
Maintain good blood pressure control in those with
hypertension
• Noncytotoxic Nonsteroidal anti-inflammatory
medications:
– Prescribe for constitutional symptoms (arthralgia, fatigue,
malaise).
– Avoid ibuprofen (associated with aseptic meningitis in
SLE).
• Use hydroxychloroquine (<6.5 mg/kg/day, not to
exceed 400 mg/day) for:
– Arthritis.
– Cutaneous disease.
• Low-dose methotrexate may be useful with mild
disease and when arthritis is a prominent feature.
• Glucocorticoids Use topical steroids for cutaneous
disease.
• Use low-dose oral (< 0.5 mg/kg/day) for:
– Arthritis.
– Serositis.
– Mild cytopenia.
• Use moderate-dose oral (0.5 to 1 mg/kg/day) for mild
nephritis (mesangial, focal proliferative, membranous).
• Use high-dose oral (1 to 2 mg/kg/day) for:
– Diffuse proliferative lupus nephritis and membranous disease
with nephrotic syndrome.
– CNS disease.
– Acute hemolytic anemia.
• Use pulse intravenous for:
– Severe, life-threatening or organ-threatening disease.
– Severe, hematologic abnormalities.
– Catastrophic antiphospholipid syndrome.
•
•
•
Cytotoxic Azathioprine can be used as a steroid-sparing drug for:
– Arthritis.
– Serositis.
– Following induction therapy with cyclophosphamide to maintain
remission.
Mycophenolate mofetil can be used as a steroid-sparing drug, especially
if patient does not tolerate azathioprine, for:
– Following induction therapy with cyclophosphamide to maintain
remission.
– Induction therapy in nephritis for patients who do not want the
toxicity associated with cyclophosphamide.
Cyclophosphamide is used for:
– Major renal involvement, particularly diffuse proliferative
glomerulonephritis.
– CNS lupus.
– Catastrophic antiphospholipid syndrome.
– Other Use plasmapheresis for catastrophic antiphospholipid
syndrome.
– Use IVIG for refractory thrombocytopenia.
– Experimental Therapies* Anti-CD20 B-cell depletion therapy.
– Autologous stem cell transplantation.
– CTLA4Ig.
SPECIAL CONSIDERATIONS IN
CHILDREN AND ADOLESCENTS


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
Life-long burden of renal failure and (multiple)
renal transplant(s)
Steroid toxicity
Immunosuppressive toxicity
Infection risk different in children:
 CMV, EBV
 Bacterial infections, esp. strep
 Fungal infections

Developmental age and psychosocial issues
HENOCHSCHÖNLEIN
PURPURA
 Henoch-Schönlein purpura (HSP) is an
immunoglobulin (Ig) A-mediated small-vessel
vasculitis that predominantly affects children but
also is seen in adults. HSP is a subset of
necrotizing vasculitis characterized by fibrinoid
destruction of blood vessels and leukocytoclasis.
 Henoch-Schönlein purpura, an uncommon
disease, affects mainly young children, but it can
affect older children and adults.
 The disease is believed to result from an
autoimmune reaction
 Clinical manifestations primarily include
palpable purpura, arthralgia or arthritis,
abdominal pain, gastrointestinal (GI)
bleeding, and nephritis. The most serious
long-term complication from HSP is
progressive renal failure, which occurs in 12% of patients.
 Small bluish purple spots on their feet, legs,
arms, and buttocks. Over several days, the
purpura may become raised and hard; crops of
new purpura may break out for several weeks
after the first one appears.
 Swollen, achy joints are common, usually
accompanied by fever.
 Bleeding in the digestive tract may cause
abdominal cramps and pain.
 Blood in the urine (hematuria) may develop.
 Most children recover completely within a
month, but symptoms may recur several
times
 The diagnosis is based on the symptoms.
Sometimes a sample of affected skin is
removed and examined under a microscope
(biopsy) to confirm the diagnosis.
Treatment
 A drug that may be causing an allergic reaction is
discontinued immediately.
 Corticosteroids (for example, prednisone ) may
help relieve swelling, joint pain, and abdominal
pain, but they do not prevent or reverse kidney
damage. Drugs that reduce the activity of the
immune system (immunosuppressive drugs),
including azathioprine or cyclophosphamide, are
sometimes used if kidney damage develops, but
it is not known if they are helpful.
KAWASAKI DISEASE
KAWASAKI DISEASE
 Vasculitis of unknown etiology
 Multisystem involvement and inflammation
of small and medium sized arteries with
aneurysm formation
 More common among children of Asian
decent
 Usually children <5 years; peak 2-3 years
Kawasaki Disease
 Mucocutaneous lymph node syndrome
 Disease of children
 Fever, conjuctivitis, red dry lips, erythema of oral
mucosa, polymorphous truncal rash, desquamation
of the fingers and toes, cervical lymphadenopathy
 Oral cavity erythema and cervical adenopathy are
presenting symptoms
 Cardiac abnormalities cause 1-2% mortality rate
KAWASAKI DISEASE
 In children < 3 months of age
 Usually see atypical course leading to rapid and severe
coronary artery damage (CAD)
 ECHO mandatory if considered in this age group; diagnosis
very difficult
 Age is independent risk factor for CAD
 CAD develops in 5% of timely treated patients
 Incomplete/atypical definition
 Fever, at least 2 of the clinical criteria for KD, and
laboratory data showing systemic inflammation; 2D echos
should be performed
KAWASAKI DISEASE
 Prolonged fever is hallmark of the disease
 Lymphadenopathy is least common finding (seen
in 75% of cases compared with 90% for other
signs)
 Coronary lesions are usually not present until 10
days; therefore decision to treat made prior to
knowledge of cardiac outcome
 Other useful signs
 Extreme irritability
 Inflammation of BCG scar
KAWASAKI DISEASE – CLINICAL
PRESENTATION
 Acute phase (1-2 weeks)
 Sudden onset of high fever followed by
conjunctival erythema, mucosal changes, cervical
adenopathy, swelling of hands and feet
 Irritability
 Abdominal pain, hydrops of gall bladder
 Arthritis
 Carditis – tachycardia, CHF, giant coronary artery
aneurysms
KAWASAKI DISEASE – CLINICAL
PRESENTATION
 Subacute phase
 Lasts up to 4th week
 Resolution of fever and other symptoms
 Desquamation of fingers and toes
 Elevation of platelet count
 Coronary artery aneurysms
 Convalescent phase
 Disappearance of clinical symptoms
 6-8 weeks after initial symptoms
CLINICAL DIAGNOSIS
Kawasaki Disease
 A self-limited vasculitis of unknown etiology
that predominantly affects children younger
than 5 years. It is now the most common
cause of acquired heart disease in children in
the United States and Japan
 Idiopathic multisystem disease characterized
by vasculitis of small & medium blood
vessels, including coronary arteries
Epidemiology





Median age of affected children = 2.3 years
80% of cases in children < 4 yrs,
Males:females = 1.5-1.7:1
Recurs in 3%
Positive family history in 1% but 13% risk of
occurrence in twins
 Overall U.S. in-hospital mortality ≈ 0.17%
Etiology






Age-restricted susceptible population
Seasonal variation
Well-defined epidemics
Acute self-limited illness similar to known infections
Bacterial, retroviral, superantigenic bacterial toxin
Immunologic response triggered by one of several
microbial agents
Diagnostic Criteria
•
•
Fever for at least 5 days
At least 4 of the following 5 features:
1. Changes in the extremities

Edema, erythema, desquamation
2. Polymorphous exanthem, usually truncal
3. Conjunctival injection
4. Erythema&/or fissuring of lips and oral cavity
5. Cervical lymphadenopathy
•
Illness not explained by other known disease
process
DIFFERENTIAL DG
 Infectious
 Measles & Group A beta-hemolytic strep
can closely resemble KD
 Bacterial: severe staph infections w/toxin
release
 Viral: adenovirus, enterovirus, EBV,
roseola
• Infectious
– Spirocheteal: Lyme disease, Leptospirosis
– Parasitic: Toxoplasmosis
– Rickettsial: Rocky Mountain spotted fever, Typhus
• Immunological/Allergic
–
–
–
–
JRA (systemic onset)
Atypical ARF
Hypersensitivity reactions
Stevens-Johnson syndrome
• Toxins
– Mercury
PHASES OF DISEASE
 Acute (1-2 weeks from onset)
 Febrile, irritable, toxic appearing
 Oral changes, rash, edema/erythema of feet
 Subacute (2-8 weeks from onset)
 Desquamation, may have persistent arthritis or
arthralgias
 Gradual improvement even without treatment
 Convalescent (Months to years later)
ANGULAR CHELITIS
STRAWBERRY TONGUE
CONJUNCTIVAL HYPEREMIA
ERYTHEMATOUS MACULAR
ERUPTION - KAWASAKI
SYNDROME
DESQUAMATION OF THE SKIN
• Respiratory
– Rhinorrhea, cough, pulmonary infiltrate
• GI
– Diarrhea, vomiting, abdominal pain, hydrops of
the gallbladder, jaundice
• Neurologic
– Irritability, aseptic meningitis, facial palsy, hearing
loss
• Musculoskeletal
– Myositis, arthralgia, arthritis
Kawasaki Disease: Lab TESTS
Early
Leukocytosis
Left shift
Mild anemia
Thrombocytopenia
/ Thrombocytosis
Elevated ESR
Elevated CRP
Hypoalbuminemia
Elevated
transaminases
Sterile pyuria
Late
Thrombocytosis
Elevated CRP
Cardiovascular Manifestations
of Acute Kawasaki Disease
 EKG changes
 Arrhythmias
 Abnormal Q waves
 Prolonged PR and/or QT intervals
 Low voltage
 ST-T–wave changes.
 CXR–cardiomegaly
 None
 Suggestive of myocarditis (50%)
 Tachycardia, murmur, gallop rhythms
 Disproportionate to degree of fever & anemia
 Suggestive of pericarditis
 Present in 25% although symptoms are rare
 Distant heart tones, pericardial friction rub,
tamponade
Echocardiography
 Myocarditis with dysfunction
 Pericarditis with an effusion
 Valvar insufficiency
 Coronary arterial changes
Coronary Arterial Changes
 15% to 25 % of untreated patients
develop coronary artery changes
 3-7% if treated in first 10 days of fever
with IVIG
 Most commonly proximal, can be
distal
 Left main > LAD > Right
•
Patients most likely to develop
aneurysms
 Younger than 6 months, older than 8
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years
Males
Fevers persist for greater than 14 days
Persistently elevated ESR
Thrombocytosis
Pts who manifest s/s of cardiac
involvement
Cardiovascular Sequelae
 0.3-2% mortality rate due to cardiac disease
 10% from early myocarditis
 Aneurysms may thrombose, cause MI/death
 MI is principal cause of death in KD
 32% mortality
 Most often in the first year
 Majority while at rest/sleeping
 About 1/3 asymptomatic
• IVIG: 2g/kg as one-time dose
– Beneficial effect 1st reported by Japanese
– Mechanism of action is unclear
• Aspirin
– High dose (80-100 mg/kg/day) until afebrile
x 48 hrs &/or decrease in acute phase
reactants
– Decrease to low dose (3-5 mg/kg/day) for 68 weeks or until platelet levels normalize
JUVENILE
DERMATOMYOSITIS
(JDM)
 Juvenile dermatomyositis (JDM) is an
inflammatory disease of the muscle
(myositis), skin and blood vessels that affects
about 3 in 1 million children each year
 idiopathic inflammatory myopathy
PATHOGENESIS
• pathogenetic mechanisms involved in the
myopathy
• recent studies reveal abnormal levels of nitric
oxide, elevation of circulating tumor necrosis
factor (TNF) receptors, elevated soluble CD40
expression, and increased expression of major
histocompatibility complex class I and
interleukin 1a within the muscle.
• the pathogenesis of the cutaneous disease is
poorly understood.
CLINICS
• violet‐colored or dusky red rash, most
commonly on the face, eyelids, and areas
around the nails, knuckles, elbows, knees,
chest and back. The rash, which can be
patchy with bluish‐purple discolorations, is
often the first sign of dermatomyositis
• skin rashes that range from mild redness to
severe ulcers
 Gottron’s papules are found over bony
prominences, particularly the
metacarpophalangeal joints, the proximal
interphalangeal joints, and/or the distal
interphalangeal joints
 They may also be found overlying the
elbows, knees, and/or feet.
 Photosensitivity
• weakness in the large muscles around the neck, shoulders
and hips.
• difficulty in climbing stairs, getting into cars, getting up
from a chair or off the floor, or brushing hair.
• symptoms range from minimal muscle weakness,
including falling when running and having to turn over to
out of bed, to not being able to swallow and changes in
the voice ; dysphagia or dysphonia generally signifies a
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rapidly progressive course and may be associated with
poor prognosis.
fatigue, fever and weight loss
hardened deposits of calcium under the skin
stomach ulcers and intestinal tears
lung problems
occur in children ages 5 ‐10 and adults ages 40‐50. Women
are affected about twice as often as men.
Dermatomyositis is a
multisystem disorder
 .
 Arthralgias and/or arthritis
 The usual picture is one of generalized
arthralgias accompanied by morning
stiffness.
 The small joints of the hands, wrists, and
ankles may be involved with symmetrical
non-deforming arthritisthat is non-erosive.
• Esophageal disease as manifested by
dysphagia is estimated to be present in 15%
to 50% of patients with inflammatory
myopathy. The dysphagia can be of 2 types:
proximal dysphagia or distal dysphagia
• Pulmonary disease occurs in DM and PM in
approximately 15% to 65% of patients.40-43
Interstitial pneumonitis is a primary process
observed in DM
• Calcinosis of the skin or muscle may occur in up to
40% of children or adolescents with DM.
• Calcinosis cutis is manifested by firm, yellow, or
fleshcolored nodules, often over bony prominences.
Occasionally these nodules can extrude through the
surface of the skin, in which case secondary infection
may occur.
• Calcification of the muscles is often asymptomatic
and
• may be seen only on radiologic examination. In
severe
forms, the calcinosis can cause loss of function, and,
rarely bone formation is possible.
 The reported frequency of malignancy
in DM has varied from 6% to 60%
 Increased association of ovarian cancer, but
also noted increases in lung, pancreatic,
stomach, colorectal cancer, and nonHodgkin’s lymphoma.
Laboratory manifestations of
dermatomyositis
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1. Muscle enzyme elevation (CPK, serum aldolase, LDH, ALT, AST,
carbonic anhydrase isoenzyme II)
2. Autoantibodies
i. ANA levels elevated in 60 to 80% of patients with classic
dermatomyositis
ii. Anti-Jo-1 most common antisynthetase found; 20% of patients
with dermatomyositis may have positive result
iii. Anti-EJ may be more associated with typical skin lesions
iv. SRP occurring in 5% patients
v. Mi-2 antibodies (a nuclear protein complex): occurring in 15 to
20% of patients with classic dermatomyositis, associated with a
more treatment-responsive form, shawl sign and prominent
cuticular changes
vi. Anti-PM-Scl antibodies associated
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vii. Anti-Ku antibodies associated with overlap of scleroderma or SLE with dermatomyositis.
3. ESR
It is elevated in approximately 50% patients (does not correlate well with disease activity).
4. Rheumatoid factor
It is seen in 20% patients, mostly in those with overlap syndrome.
5. von Willebrand factor
It is reported to correlate with juvenile dermatomyositis.
6. EMG
There is myopathic pattern, 10% are false-negative.
7. Magnetic resonance imaging
It is useful for assessing the presence of an inflammatory myopathy in patients without weakness.
It is also useful in differentiating steroid myopathy from continued inflammation and may serve as
a guide in selecting a muscle biopsy site.2,3,4,5,6
 Anti–Jo-1 antibody (and the 6 other antisynthetase
autoantibodies) is predictive of pulmonary
involvement and is much more common in patients
with PM than in those with DM. Anti–Mi-2 occurs in
roughly 25% to 30% of patients with DM
 The anti–155-kd antibody may also be associated with
juvenile DM and might predict a chronic course. AntiRo (SS-A) antibody may occur rarely. When other
antibodies such as PM-SCL or U1-RNP are present, an
overlap syndrome is suggested
POSITIVE DIAGNOSIS
 (1)progressive proximal symmetrical
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weakness,
(2) elevated muscles enzymes,
(3) an abnormal electromyogram,
(4) an abnormal muscle biopsy
(5) presence of compatible cutaneous
disease.
DM differed from PM only by the presence of
cutaneous disease
THERAPY
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Different systemic medications used in dermatomyositis
•
Oral corticosteroids
0.5 to 1.5 mg/kg daily until serum CK normalizes, then slowly taper
over 12 months
Consider adjunctive therapy if no improvement in objective muscle strength
after three months of therapy
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Methotrexate
Oral: 7.5 to 10 mg/week, increased by 2.5 mg/week to total of 25 mg/week
Intravenous: 10 mg/week, increased by 2.5 mg/week to total of 0.5 to 0.8 mg/kg First-line
adjuvant therapy in patients unresponsive to steroids
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Azathioprine
2 - 3 mg/kg/day tapered to 1 mg/kg/day once steroid is tapered to 15 mg/day
Screen patients for thiopurine methyltransferase deficiency before therapy
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Cyclophosphamide
Oral: 1 -3 mg/kg/day Intravenous: 2 -4 mg/kg/day, in conjunction
with prednisone In refractory cases only
Hydroxychloroquine
200 mg twice daily in adults; 2-5 mg/kg/day in children
Intravenous immunoglobulin 2 g per kg in divided doses once per month for 3 months
 Diet
 Physical therapy
 Skin protection
 Speech therapy
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Fludarabine
It prevents the development and growth of malignant cells.
Tacrolimus
This transplant rejection drug may work to inhibit immune
system.
Monoclonal antibodies
These are man-made antibodies designed to target and
destroy specific types of cells.
Prognosis
The disease may spontaneously remit in 20% of patients.
5% of patients have fulminant progressive course with
eventual death. Many patients require long-term therapy.2,3
40