45953032 Juvenile Rheumatoid Arthritis JRA

7/31/2019 45953032 Juvenile Rheumatoid Arthritis JRA

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Juvenile rheumatoidarthritis (JRA)


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BACKGROUND

Chronic Arthritis in Childhood ischaracterized as

Juvenile Rheumatoid Arthritis

(JRA)Age of onset < 16 years of age.


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BACKGROUND

Pathogenesis and Etiology of JRA: Multi-factorial

Genetic, Hormonal, Immunologic Pathogenesis

Characterized by chronic inflammation of thesynovium;

Presence of articular cartilage damage;

Accompanied by extra-articular systemicmanifestations.

Heterogeneity of JRA

At least 3 primary types of onset of JRA:

Pauciarticular (Oligoarticular)

Polyarticular and

Systemic


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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 leukocyteantigen (HLA).

HLA system comprises a family of polymorphicgenes located on the short arm of chromosome 6.

Polymorphisms of JRA suggest a non-mendelianinheritance.

Hormonal Factors Differences in the sex ratio of JRA subtype onset Pre-adolescent or post-adolescent peaks


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BACKGROUND Immune Mechanisms

Disease process involves loss of tolerance towardsauto-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 immunecomplexes may also contribute to the diseaseprocess.


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BACKGROUND

Immune Mechanisms (Continued)

Cytokines: act on the immune system and other cellsto initiate and sustain inflammation:

Intercellular mediators: Interleukin-1 (IL-1), IL-6,and tumor necrosis factor-alpha (TNF-);

Immunomodulatory cytokines produced by T-cells Interferon gamma (IFN-), IL-4, IL-2.


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CLASSIFICATION OF JRA

ACR (American College of Rheumatology)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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General history of JRA includes the following: Disease onset is either insidious or abrupt, with morning

stiffness and arthralgia during the day. Their abilities to participate in physical education classes

may reflect severity of the disease.

Limping may be observed in individuals with more severe

JRA; however, the presence of limping also raises thepossibility of trauma or another orthopedic problem.

A preceding illness raises the possibility of infectious triggerof JRA or postinfectious arthritis.

Very severe joint pain raises isnt typical for JRA and showsthe possibility of acute rheumatic fever (also suggested bymigratory but not additive arthritis, with fevers).

Weight loss without diarrhea may be observed in individuals

with active JRA and sometimes associated with anorexia.


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CLINICAL MANIFESTATIONS of JRA


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Characteristic

% Cases (F:M)

# Joints

Age at onset

Systemicinvolvement

Chronic Uveitis

RF/ANA

Prognosis

Polyarticular

30 (3:1)

> 5

Thruchildhood,peak 1-3 yr

Mild;unremitting

articularinvolvement

5%

10%/40-50%

Guarded tomoderately

good

Pauciarticular

60 (5:1)

< 4

Earlychildhood,peak 1-2 yr

None;uveitis (++)

5-15%

Rare/75-85%

Excellentexcept for

eyesight

Systemic

10 (1:1)

Variable

Thruchildhood,

no peak

Systemic self-limited; chronic

destructivearthritis ~50%

Rare

Rare/10%

Moderate topoor

JRA by the Type-of-Onset


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Extra-Articular Manifestations of JRA

FeverRheumatoid rash

Rheumatoid nodulesHepatosplenomegalyLymphadenopathyChronic uveitisPericarditisPleuritisAbdominal pain

Polyarticular

30%2

101055511

Pauciarticular

0%0

000

20000

Systemic

100%95

585701

352010


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Systemic-onset JRAis characterizedby spiking fevers, typically occurring severaltimes each day

Evanescent salmon-pink rash, often linear, is foundon the trunk and the extremities; this rash is worsewith fever.

Hepatosplenomegaly. Lymphadenopathy.

Muscle tenderness to palpation.

Ocular: Photophobia, in uveitis (usually

asymptomatic on onset), and synechiae (irregulariris perimeter resulting from postinflammatoryadhesions of iris to lens) may be found

Cardiovascular: myocarditis occurs in individuals

with systemic JRA.


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Pauciarticular formis characterized by arthritisaffecting 4 or fewer joints.

Typically, large weight-bearing joints, knees, and

ankles are affected.

Involvement of a few small joints in the hands isatypical and suggests eventual development of

polyarticular JRA. Muscle atrophy, often of extensor muscles

(vastus lateralis, quadriceps when knee affected)is found.

Flexion contractures in the knees and, lesscommonly, the wrists are found.


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Picture 1. Patient with active pauciarticular disease. (significantsuprapatellar swelling (effusion), loss of natural contour medial tothe patella).
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Polyarticular formaffects at least 5 joints

Both large and small joints can be involved,often in symmetric bilateral distribution.

Severe limitations in motion are usuallyaccompanied by weakness and decreased

physical function.
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Picture 2. Patient with active polyarticular arthritis. (swelling of allproximal interphalangeal joints, boney overgrowth, lack of distalinterphalangeal joint involvement. The patient has interosseusmuscle wasting and subluxation and ulnar deviation of the wrists

are present).
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Laboratory studies should include the following:

o Erythrocyte sedimentation rate (ESR)

o

CBC with differential and platelet counto Alanine aminotransferase (ALT) test

o Urinalysis with microscopic examination

o Antinuclear antibody

o Rheumatoid factor

o Total protein, albumin, fibrinogen, D-dimer (forsystemic JRA)

o

Imaging Studies: radiography of affectedjoints, bone scanning, MRI, CT scanning oflong bones, echocardiography
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Picture 3. Wrist radiographs of the patient with active polyarticular arthritis shownin Image 2. (severe loss of cartilage in the intercarpal spaces and the radiocarpalspace of the right wrist, large erosion is present in the articular surface of theulnar epiphysis. The view of the left wrist shows boney ankylosis involving the

lateral 4 carpal bones with sparing of the pisiform. Erosions are present in thedistal radius and ulna.
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PROGNOSIS OF JRA

Pauciarticular JRA

Boys may be affected in older childhood oradolescence; this may represent an earlymanifestation of a spondyloarthropathy.

Leg length discrepancy from asymmetric knee

synovitis and bone growth may cause flexioncontractures, gait abnormalities and long-term growthabnormalities.

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 JRAthan with polyarticular JRA).
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Traditional Approach to theTreatment of JRA

Cytotoxic Drugs

Disease Modifying

Anti-Rheumatic Drugs(DMARDs)

Intra-Articular/Oral Corticosteroids

Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)

Before the 1990s Pyramid Approach
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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 juvenilearthritis.

Daily dose: approximately 10 mg/kg/day as a BIDdose (5 mg/kg given twice-a-day). Total daily dose isnot 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, hearingdisturbances), cardiovascular (edema, palpitations)prolonged bleeding times.
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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 yrsand 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 systemicdisease; 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 forseverely 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, iatrogenicCushings syndrome, growth suppression,fractures, cataracts, increased susceptibility toinfection.
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Treatment of JRA DMARDs and Biologic DMARDs

Methotrexate (MTX): used when NSAIDs fail to bringrelief. Indicated for polyarticular JRA. MTX is the most

widelyused 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 inJRA; 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, elevatedhepatic enzymes.
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Treatment of JRA

DMARDs and Biologic DMARDs (Continued)

Sulfasalazine Indicated for polyarticular JRA who have responded

inadequately to salicylates or other non-steroidalanti-inflammatory drugs.

Children 6 yrs and older: 40 - 60 mg/kg/day dividedinto 3 to 6 doses.

Maintenance dose: 30 mg/kg/day divided into 4doses.

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 JRApatients 4 to 17 years of age who had an inadequate responseto 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, andvomiting. Infection was reported in 43 of 69 (62%) of JRApatients 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 tissueand post-operative wound infection.
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Treatment in JRA

DMARDs indicated for RA without an indication for JRA

Hydroxychloroquine, injectable gold, leflunomide andd-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 2008

Pauciarticular 25% to 33% will respond to NSAIDs;

Patients not responsive to NSAIDS after 4 - 6 weekswith flexion contractures or leg length discrepancy

intra-articular corticosteroids. Patients with extended pauciarticular JRA or small

joint involvement treat as polyarticular JRA.
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Polyarticular

RF (-) or (+), NSAID (symptom control) alone is usuallynot 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.


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Systemic

NSAIDs 2 to 3 weeks with caution risk ofDisseminated Intravascular Coagulation (DIC),(macrophage activation syndrome);

Intravenous pulse methylprednisolone;

Oral corticosteroids

Lowest effective dose;

Steroid sparing immunomodulatory approach isunder evaluation for steroid sparing effects.

omp cat ons:


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omp cat ons: Systemic-onset JRA

Pericarditis Hemolytic anemia Disseminated intravascular coagulopathy. Macrophage activation syndrome Endarteritis resulting in circulatory compromise of the digits

with threatened autoamputation

Pauciarticular JRA Knee flexion contractures: Uveitis (Picture 7). Leg length discrepancy (can result from neovascularization

of growth plates of an affected knee)

Polyarticular JRA Skeletal abnormalities - (Picture 5-6). Cervical spine involvement
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Picture 5. Patient with inactive polyarticular arthritis. Long-term sequelae ofpolyarticular disease includes joint subluxation (note both wrists and thumbs),

joint contractures (at proximal interphalangeal joints and distal interphalangealjoints), boney overgrowth), and finger deformities (swan-neck or boutonniere

deformities).
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Picture 6. Hand and wrist radiographs of the patient with inactive polyarticulararthritis shown in Image 5. Long-term sequelae of polyarticular disease includesperiarticular osteopenia, generalized increase in the size of epiphyses,accelerated bone age, narrowed joint space, boutonniere deformities (at left third

and fourth interphalangeal joints), and medial subluxation of the firstmetacarpophalangeal joints bilaterally.

Pi t 7 S l f h i t i iti N t th t i hi
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Picture 7. Sequelae of chronic anterior uveitis. Note the posterior synechiae(weblike attachments of the pupillary margin to the anterior lens capsule) of theright eye secondary to chronic anterior uveitis. This patient has a positiveantinuclear antibodies and initially had a pauciarticular course of her arthritis.
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Documents

45953032 Juvenile Rheumatoid Arthritis JRA