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Juvenile Rheumatoid Arthritis

Arthritis Advisory Committee


Meeting
Division of Anesthesia, Analgesia and
Rheumatology Products
Carolyn L. Yancey, MD
Medical Officer, DAARP
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AGENDA
Juvenile Rheumatoid Arthritis

Epidemiology, Pathogenesis and Etiology


Classification of Juvenile Rheumatoid
Arthritis
American College of Rheumatology (ACR)
Criteria
Clinical Manifestations
Disease Course and Prognosis
Treatment of JRA and the State-of-the-Art
Treatment Armamentarium
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BACKGROUND
Chronic Arthritis in Childhood
characterized as
Juvenile Rheumatoid Arthritis
JRA
Age of onset < 16 years of age.

BACKGROUND

Epidemiology
Overall prevalence of juvenile rheumatoid
arthritis is estimated to be from 30 - 150 per
100,000 children.
In the United States and Canada there are an
estimated 30,000 to 60,000 children and
adolescents with juvenile rheumatoid arthritis.

BACKGROUND

Pathogenesis and Etiology of JRA: Multi-factorial


Genetic, Hormonal, Immunologic
Pathogenesis
Characterized by chronic inflammation of the
synovium;
Presence of articular cartilage damage;
Accompanied by extra-articular systemic
manifestations.
Heterogeneity of JRA
At least 3 primary types of onset of JRA:
Pauciarticular (Oligoarticular)
Polyarticular and
Systemic

BACKGROUND

Pathogenesis (Continued)
Genetic
Basis of immune distinction between self
and non-self is the major histocompatibility
complex (MHC) that in humans is called the
human leukocyte antigen (HLA).
HLA system comprises a family of
polymorphic genes located on the short arm
of chromosome 6.
Polymorphisms of JRA suggest a nonmendelian inheritance.
Hormonal Factors
Differences in the sex ratio of JRA subtype
onset
Pre-adolescent or post-adolescent peaks

BACKGROUND

Immune Mechanisms
Disease process involves loss of tolerance
towards auto-antigens chronic synovitis;
Production of auto-antibodies:
Anti-nuclear antibodies (ANA): associated
with increased risk of iridocyclitis (eye
inflammation);
Rheumatoid factors (RF): auto-antibodies
directed against the Fc fragment of IgG
(associated with ~10% of polyarticular JRA);
Complement activation by circulating immune
complexes may also contribute to the disease
process.
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BACKGROUND

Immune Mechanisms (Continued)


Cytokines: act on the immune system and
other cells to initiate and sustain inflammation:
Intercellular mediators: Interleukin-1 (IL1), IL-6, and tumor necrosis factor-alpha
(TNF-);
Immunomodulatory cytokines produced
by T-cells Interferon gamma (IFN-),
IL-4, IL-2.

CLASSIFICATION OF
JUVENILE RHEUMATOID ARTHRITIS

American College of Rheumatology (ACR)


pediatric criterion for juvenile
rheumatoid arthritis was established in
1977.

CLASSIFICATION OF JRA

ACR Criteria
Age at onset: < 16 years of age;
Arthritis - swelling or effusion or the presence of 2
or more of the following signs:
Limitation of range of motion,
Tenderness or pain on motion and
Increased heat in one or more joints;
Duration of disease > 6 weeks;
Onset type is defined by the type of disease in the
first 6 months:

Oligoarticular (Pauciarticular) < 5 inflamed joints;


Polyarticular: > 5 inflamed joints;
Systemic onset: arthritis with characteristic fever.

Exclusion of other forms of childhood arthritis.

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Modified from JT Cassidy, JT Levinson, RM Laxer, CB Lindsley. Textbook of Pediatric Rheum. 2005

CLINICAL MANIFESTATIONS of JRA

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JRA by the Type-of-Onset


Characteristic

Pauciarticular

Polyarticular

Systemic

% Cases (F:M)

60 (5:1)

30 (3:1)

10 (1:1)

<4

>5

Variable

Early
childhood,
peak 1-2 yr

Thru
childhood,
peak 1-3 yr

Thru
childhood,
no peak

Mild;
unremitting
articular
involvement

Systemic selflimited; chronic


destructive
arthritis ~50%

5%

Rare

10%/40-50%

Rare/10%

# Joints
Age at onset

Systemic
involvement

Chronic Uveitis
RF/ANA

None;
uveitis (++)

5-15%
Rare/75-85%

Guarded to
moderately
good

Excellent
except for
JT Cassidy, RE Petty, RM Laxer, CB eyesight
Lindsley. Textbook of Pediatric Rheumatology, 2005
Prognosis

Moderate to
poor
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Extra-Articular Manifestations of JRA


Pauciarticular
Fever
Rheumatoid rash
Rheumatoid nodules
Hepatosplenomegaly
Lymphadenopathy
Chronic uveitis
Pericarditis
Pleuritis
Abdominal pain

0%
0
0
0
0
20
0
0
0

JT Cassidy, RE Petty. Textbook of Pediatric Rheumatology, 2001

Polyarticular
30%
2
10
10
5
5
5
1
1

Systemic
100%
95
5
85
70
1
35
20
10

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PROGNOSIS OF JRA

Pauciarticular JRA
Boys may be affected in older childhood or
adolescence; this may represent an early
manifestation of a spondyloarthropathy.
Leg length discrepancy from asymmetric knee
synovitis and bone growth may cause flexion
contractures, gait abnormalities and long-term
growth abnormalities.
Eye involvement as anterior uveitis, may lead
to scarring or blindness in ~ 15-20% of
children.
Active arthritis into adulthood in 40% to 50%
of patients.
Radiographic joint damage within 5 years.
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PROGNOSIS OF JRA

Polyarticular JRA and Systemic JRA


Active arthritis into adulthood: 50% to 70% of
polyarticular or systemic onset JRA;
Long-term disabilities: 30% to 40% of children
Unemployment: 25% to 50% of adult JRA
patients;
May need major surgery (joint replacement).
Radiographic joint damage within 2 years;
Mortality rate: 0.4% to 2% (greater risk with
systemic JRA than with polyarticular JRA).
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Traditional Approach to the


Treatment of JRA
Before the 1990s
Pyramid Approach

Cytotoxic Drugs
Disease Modifying
Anti-Rheumatic Drugs
(DMARDs)
Intra-Articular/Oral Corticosteroids
Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)
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Evolving Treatment of JRA


Since the 1990s and
into the 2000s

Paradigm shift.
The trend in managing JRA is much more
aggressive treatment earlier in the disease course
with the goal of preventing joint damage and
slowing progressive articular damage.

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Treatments with Indications for JRA

Non-Selective NSAIDs
Aspirin, tolmetin sodium, ibuprofen, naproxen
Naproxen [Tablets and Suspension]
Indicated for patients 2 years and older with
juvenile arthritis.
Daily dose: approximately 10 mg/kg/day as a
BID dose (5 mg/kg given twice-a-day). Total
daily dose is not to exceed 15 mg/kg/day.
Adverse events: gastrointestinal, central
nervous system (headache, dizziness,
drowsiness, vertigo), rash (ecchymoses,
purpura), pruritus, sweating, special senses
(tinnitus, visual disturbances, hearing
disturbances), cardiovascular (edema,
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palpitations) prolonged bleeding times.

Treatments with Indications for JRA

Non-Selective NSAIDs/COX-2 Selective Inhibitors


MOBIC (meloxicam) [Tablets and Suspension]

Indicated for the relief of the signs and symptoms of


pauciarticular and polyarticular course JRA in patients
2 yrs and older.
0.125 mg/kg once daily up to a maximum of 7.5 mg.
Adverse events: abdominal pain/upper, vomiting,
diarrhea, headache, infection (rhinitis), cough,
pyrexia, rash. urticaria, slight increases in systolic
blood pressure.

VIOXX (rofecoxib) [Tablets and Suspension]

Withdrawn from the global market September 2004.


Indicated for the relief of the signs and symptoms of
juvenile rheumatoid arthritis in patients 2 years and
older.
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Treatment of JRA

Corticosteroids
Used for uncontrolled or life-threatening
systemic disease;
Treatment of chronic uveitis as local
ophthalmic drops; or
Intra-articular agents (Pauci- and polyarticular
JRA)
Intermediate-acting corticosteroids:
Prednisone; methyl-prednisolone (Intravenous
pulse therapy for severely active JRA).
Prednisone low-dose as 0.1 to 0.2 mg/kg;
higher-dose 0.25 to 1.0 mg/kg/day
(maximum single dose 40 mg)
Adverse events: hypertension, iatrogenic
Cushings syndrome, growth suppression,
fractures, cataracts, increased susceptibility
to infection.
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Treatment of JRA

DMARDs and Biologic DMARDs


Methotrexate (MTX): used when NSAIDs fail to
bring relief.
Indicated for polyarticular JRA. MTX is the
most widely used DMARD for JRA treatment.
Starting dose 7.5 mg/m2 per week; maximum
dose of 15 mg/m2 per week.
Methotrexate compared to leflunomide (Lef):
240 JRA pts, 16-week DB + 6 mo Ext +
optional 30 mo Ext in JRA; JRA Definition of
Improvement > 30% (JRA DOI > 30):
89% MTX compared to 68% Lef.
Adverse events: stomatitis, leukopenia,
nausea/ abdominal pain, gastrointestinal
bleeding, anorexia, malaise, fatigue, chills and
fever, headache, alopecia, rash, decreased
resistance to infection, elevated hepatic
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enzymes.

Treatment of JRA

DMARDs and Biologic DMARDs (Continued)


Sulfasalazine
Indicated for polyarticular JRA who have
responded inadequately to salicylates or other
non-steroidal anti-inflammatory drugs.
Children 6 yrs and older: 40 - 60 mg/kg/day
divided into 3 to 6 doses.
Maintenance dose: 30 mg/kg/day divided into
4 doses.
Adverse events: anorexia, headache,
vomiting, gastric distress, rash, urticaria,
hemolytic anemia.
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Treatment in JRA

DMARDs and Biologic DMARDs (Continued)


ENBREL (etanercept): a cytokine antagonist

Indicated for moderate to severe polyarticular course


JRA patients 4 to 17 years of age who had an
inadequate response to one or more DMARDs.
Dosage: 0.4 mg/kg/week (maximum 25 mg/ dose given
twice weekly) as subcutaneous injection pre-filled
syringe, 72-96 hrs. apart.
Adverse events: headache, nausea, abdominal pain, and
vomiting. Infection was reported in 43 of 69 (62%) of
JRA patients during the 3-month (open-label phase).
Serious AEs reported in the study: varicella,
gastroenteritis, depression/ personality disorder,
cutaneous ulcer, esophagitis/ gastritis, group A
streptococcal septic shock, Type 1 diabetes, soft tissue
and post-operative wound infection.
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Treatment in JRA

DMARDs indicated for RA without an indication for


JRA
Hydroxychloroquine, injectable gold,
leflunomide and d-penicillamine.
Other Immunomodulatory or Cytotoxic Drugs
Indicated in RA without a JRA indication:
Azathioprine
Cyclosporine A
Without a RA or a JRA indication:
Chlorambucil
Thalidomide
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Treatment of JRA in 2006

Pauciarticular
25% to 33% will respond to NSAIDs;
Patients not responsive to NSAIDS after 4 - 6
weeks with flexion contractures or leg length
discrepancy intra-articular corticosteroids.
Patients with extended pauciarticular JRA or
small joint involvement treat as polyarticular
JRA.

Modified from Laxer R, Hashkes PJ. Medical Treatment of Juvenile Idiopathic


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Arthritis. JAMA, October 5, 2005. Vol 294, No. 13, pp 1671-1684.

Treatment of JRA in 2006

Polyarticular
RF (-) or (+), NSAID (symptom control) alone is
usually not as effective as a NSAID + DMARD.
NSAID trial for several weeks add oral MTX.
If oral MTX is not effective parenteral route
MTX.
If NSAID + MTX (oral or parenteral) is not
effective anti-TNF medication.
No current evidence whether a combination of
MTX + anti-TNF medication are more effective
than only anti-TNF medication.

Modified from Laxer R, Hashkes PJ. Medical Treatment of Juvenile


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Idiopathic Arthritis. JAMA, October 5, 2005. Vol 294, No. 13, pp 1671-1684.

Treatment of JRA in 2006

Systemic
NSAIDs 2 to 3 weeks with caution risk of
Disseminated Intravascular Coagulation (DIC),
(macrophage activation syndrome);
Intravenous pulse methylprednisolone;
Oral corticosteroids
Lowest effective dose;
Steroid sparing immunomodulatory
approach is under evaluation for steroid
sparing effects.

Modified from Laxer R, Hashkes PJ. Medical Treatment of Juvenile


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Idiopathic Arthritis. JAMA, October 5, 2005. Vol 294, No. 13, p1671-1684.

CELEBREX (celecoxib)

Non-Selective NSAID/COX-2 Selective Inhibitor


Proposed Formulation: a capsule (50 mg, option
to use as a sprinkle onto applesauce)
Pivotal Study: 12-wk DB + 12-wk OL Ext (242
pts); celecoxib oral investigational suspension
and naproxen oral suspension (active
comparator)
Proposed Dosing in Patients with JRA
50 mg capsule BID (100 mg/day):
Patient weight 10 - 25 kg.
100 mg capsule BID (200 mg/day):
Patient weight > 25 kg.
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