ARTHRITIS, JUVENILE IDIOPATHIC

Donna-Marie McMahon, DO, FAAP • Kathleen M.

Vazzana, DO, MS
BASICS
DESCRIPTION
• Juvenile idiopathic arthritis (JIA) is the most common
chronic pediatric
rheumatologic disease.
• JIA is associated with significant disability.
– Age of onset: <16 years
– Common symptoms: joint swelling, restricted range of
motion, warmth,
redness, pain
– Often =6 weeks of symptoms prior to diagnosis
• Seven (International League of Associations for Rheumatology
[ILAR])
subtypes, determined by clinical characteristics in the first 6 months of
illness
(1):
– Systemic (Still disease): 10%; preceded by febrile onset of
=2 weeks with
rash, serositis, hepatosplenomegaly or lymphadenopathy (1)
– Polyarticular rheumatoid factor (RF) (+): 5–10%; =5 joints
involvement
(1); large and small joints; RF positive on two tests =3 months apart
(2)
– Polyarticular RF (-): 10–30%; =5 (large and small) joints
involved (1); RF
negative (2)
– Oligoarticular: 30–60%; involvement of 1 to 4 joints; risk
for chronic
uveitis in antinuclear antibodies (ANA) (+) females (1) and axial
skeletal
involvement in older boys (2). Types: (i) monoarthritis (50%): knee,
ankle,
elbow; (ii) extended type: >4 joints after first 6 months
– Psoriatic arthritis: (5%); arthritis with psoriasis or arthritis
with >2 of:
dactylitis, nail changes (pitting), psoriasis in first-degree relative (1)
– Enthesitis arthritis: (1–7%); oligo-polyarthritis in small or
large joints and
enthesis plus two of: sacroiliac or lumbosacral pain, Reiter
syndrome
family history or presence of acute anterior uveitis, HLA-B27 (+),
ankylosing spondylitis, inflammatory bowel disease (1)[C]
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– Undifferentiated arthritis: presents with overlapping
symptoms in = 2
categories or arthritis that does not fulfill above categories (2)
• System(s) affected: musculoskeletal, hematologic, lymphatic,
immunologic,
dermatologic, ophthalmologic, gastrointestinal
• Synonyms: juvenile chronic arthritis; juvenile arthritis; juvenile
rheumatoid
arthritis (JRA); Still disease (2)
EPIDEMIOLOGY
• Male = female (1); onset: throughout childhood; 54% of cases
occur in
children 0 to 5 years.
• Polyarticular RF (+): female > male, 3:1 (2); onset: late childhood
or
adolescence (1)
• Polyarticular RF (-): female > male, 3:1; onset: early peak, 2
to 4 years; late
peak, 6 to 12 years (2)
• Oligoarticular: female > male, 5:1; onset: 2 to 4 years (2)
• Psoriatic: female > male, 1:0.95 (2); onset: early peak, 2 to
3 years; late peak,
10 to 12 years (1)
• Enthesitis: female > male, 1:7; onset: early peak, 2 to 4
years; late peak, 6 to
12 years (2)
• Affected patients have an increased risk of developing
cancer, although shortterm risk is low.
Incidence
2 to 20/100,000 children <16 years in developed nations
Prevalence
16 to 150/100,000 children <16 years in developed nations (1)
ETIOLOGY AND PATHOPHYSIOLOGY
• Humoral and cellular immunodysregulation. T lymphocytes play
a key role.
• Genetic predisposition. IL2RA/CD25 and VTCN1 implicated as
genetic loci.
• Environmental triggers, possibly infectious
– Rubella or parvovirus B19 (3)
– Heat shock proteins (3)
• Immunoglobulin or complement deficiency
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Genetics
• Human leukocyte antigen (HLA) class I and II alleles
• HLA-A2 = early onset oligoarthritis in females
• HLA-DRB1*11 increases risk of systemic and oligo-JIA.
• HLA-B27 increases risk of enthesitis-related arthritis.
• HLA-DR4 is associated with polyarthritis RF (+) (3).
RISK FACTORS
Female gender 3:1
GENERAL PREVENTION
None identified
COMMONLY ASSOCIATED CONDITIONS
Other autoimmune disorders, chronic anterior uveitis (iridocyclitis),
nutritional
impairment,growth issues (3)
DIAGNOSIS
Clinical criteria: age of onset <16 years and >6 weeks duration of
objective
arthritis (swelling or restricted range of motion of a joint
accompanied by heat,
pain, or tenderness with no other form of childhood arthritis) in
=1 joints
HISTORY
• Arthralgias, fever, fatigue, malaise, myalgias, weight loss,
morning stiffness,
rash
• Limp, if lower extremity involvement
• Arthritis for =6 weeks
PHYSICAL EXAM
• Arthritis: swelling, effusion, loss of musculoskeletal
landmarks, limited range
of motion, tenderness,pain with motion, warmth
• Rash, rheumatoid nodules, lymphadenopathy, hepato- or
splenomegaly,
enthesitis, dactylitis
DIFFERENTIAL DIAGNOSIS
• Legg-Calvé-Perthes, toxic synovitis, growing pains, Perthes
disease
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• Septic arthritis, osteomyelitis, viral infection, mycoplasmal
infection, Lyme
disease
• Reactive arthritis: postinfectious, rheumatic fever, Reiter
syndrome
• Inflammatory bowel disease
• Hemoglobinopathies, hemarthrosis, rickets
• Leukemia (particularly acute lymphocytic leukemia), bone tumors
(osteoid
osteoma), neuroblastoma
• Vasculitis, Henoch-Schönlein purpura, Kawasaki disease
• Systemic lupus erythematosus, dermatomyositis, mixed
connective tissue
disease, sarcoidosis, systemic sclerosis, collagen disorders
• Farber disease
• Accidental or nonaccidental trauma
DIAGNOSTIC TESTS & INTERPRETATION
Initial Tests (lab, imaging)
• CBC: leukocyte count is normal or elevated (systemic),
lymphopenia, reactive
thrombocytosis, anemia. Liver function test (LFT) (evidence of
hepatitis) and
renal function studies (prior to therapy with nephrotoxic drugs)
• Joint-fluid aspiration/analysis: Exclude infection.
• ESR and C-reactive protein typically elevated. CRP often
disproportionately
high.
• Myeloid-related proteins (MRP 8/14) associated with flares
• ANA-positive patients have increased risk of uveitis; ANA
positive in up to
70% with oligoarticular JIA
• RF (+): 2–10% (usually polyarticular); poor prognosis
• HLA-B27 positive: enthesitis-related arthritis
• Diagnostic radiography, MRI, US, and CT; no one modality has
superior
diagnostic value (4)[A].
• Radiograph of affected joint(s): early radiographic changes:
soft tissue
swelling, periosteal reaction, juxta-articular demineralization; later
changes:
joint space loss, articular surface erosions, subchondral cyst
formation,
sclerosis, joint fusion
• If orthopnea, obtain ECG to rule out pericarditis.
• Radionuclide scans: for infection/malignancy
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• CT is best for bony abnormalities. MRI can assess synovial
hypertrophy and
cartilage degeneration. MRI more sensitive to monitor disease
activity and
clinical responsiveness to treatment in peripheral joints
Follow-Up Tests & Special Considerations
• RF and ANA present in mixed connective tissue disease (5)[B]
• Use pediatric (notadult) controls when interpreting results of
dual energy xray photon absorptiometry.
Diagnostic Procedures/Other
Ultrasound: Assess for inflammation (6)[A].
Synovial biopsy: if synovial fluid cannot be aspirated or if
infection is suspected
in spite of negative synovial fluid culture
Test Interpretation
Synovial biopsy → synovial cells hyperplasia, hyperemia, infiltration
of small
lymphocytes, and mononuclear cells
TREATMENT
GENERAL MEASURES
• Goal is to control active disease, extraarticular
manifestations, and achieve
clinical remission
• All patients require regular (every 3 to 4 months for oligo-JIA
and in ANApositive patients) ophthalmic exams to uncover
asymptomatic eye disease,
particularly for the first 3 years following diagnosis.
• Moist heat or electric blanket for morning stiffness
• Splints for contractures
• Aerobic exercise: weight-bearing or aquatic therapy to improve
functional
capacity
MEDICATION
First Line
• =4 joints
• NSAIDs: adequate in ~50%, symptoms often improve within
days, full
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efficacy 2 to 3 months
• Drugs for children include the following:
– Ibuprofen: 30 to 50 mg/kg/day, divided QID; max dose 2,400
mg/day
– Naproxen: 10 mg/kg/day, divided BID; max dose 1,250
mg/day
– Tolmetin sodium: 20 mg/kg/day, TID or QID; max dose
30 mg/kg/day
– Diclofenac: 2 to 3 mg/kg, divided TID; max dose 50 mg
TID
– Indomethacin: 1 to 2 mg/kg/day, divided BID to QID; max
dose of 4
mg/kg/day
– NSAIDs are contraindicated if known allergy.
– Precautions: may worsen bleeding diatheses; use caution in
renal
insufficiency and hypovolemic states; take with food.
– Significant drug interactions: may lower serum levels of
anticonvulsants
and blunt the effect of loop diuretics. NSAIDs may increase
serum
methotrexate levels.
• Intra-articular long-acting corticosteroids: immediately effective;
improve
synovitis, joint damage, and contractures and prevent leg length
discrepancy
(4)[B]
– Indication: patients with oligoarthritis who have failed a
2-month NSAID
trial or with poor prognosis factors (6)[C]
– Example: triamcinolone hexacetonide
• =5 joints
– If high disease activity or a failed 1 to 2 months NSAID
trial →
methotrexate (6)[C]
Second Line
• 30–40% of patients require addition of disease-modifying
antirheumatic drugs
(DMARDs): methotrexate, sulfasalazine, leflunomide, and tumor necrosis
factor (TNF) antagonists (etanercept, infliximab, adalimumab); newer
biologic therapies, including IL-1and IL-6receptor antagonists, are
currently
under investigation
• Methotrexate: 10 mg/m
/wk PO or SC (5)[B]
– Plateau of efficacy reached with 15 mg/m
2
/wk; further increase in dosage is
not associated with therapeutic benefit.
2
• Sulfasalazine: oligoarticular and HLA-B27 spondyloarthritis (5)[B]
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• Etanercept: 0.8 mg/kg (max of 50 mg/dose) given SC q1wk or
0.4 mg/kg SC
twice a week (max of 25 mg/dose)
• Infliximab: 5 mg/kg q6–8wk
• Adalimumab: if weight 15 kg to <30 kg, 20 mg SC q2wk; if
weight =30 kg,
40 mg SC q2wk
• Tocilizumab: IL-6antibody demonstrating efficacy in phase III
open label
trials; ongoing studies to evaluate efficacy and appropriate dosing (5)[B]
• Anakinra: IL-1receptor antibody under investigation with
phase II and III
clinical trials for systemic JIA (5)[B]
• Begin treatment with TNF-a inhibitors in children with a
history of arthritis in
=4 joints and significant active arthritis despite treatment with
methotrexate or
arthritis in =5 joints and any active arthritis following an adequate trial of
methotrexate (6)[C].
• Begin treatment with anakinra in children with systemic
arthritis and active
fever whose treatment requires a second medication, in addition to
systemic
glucocorticoids (5)[C].
• Analgesics, including narcotics for pain control
ISSUES FOR REFERRAL
• Pediatric rheumatologist for management of JIA
• Orthopedics as needed for articular complications
• Ophthalmology: for suspected uveitis
• Physical therapy to maintain range of motion, improve
muscle strength, and
prevent deformities
• Occupational therapy to maintain and improve appropriate
age-related
functional activities
• Behavioral health if difficulty coping with disease
SURGERY/OTHER PROCEDURES
• Total hip and/or knee replacement for severe disease
• Soft tissue release if splinting/traction unsuccessful
• Correct limb length or angular deformities
• Synovectomy is rarely performed.
ADMISSION, INPATIENT, AND NURSING
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CONSIDERATIONS
• Admit if:
– Patient nonambulatory
– Signs/symptoms of pericarditis
– Persistent fever or diagnostic confusion to facilitate
evaluation and workup
– Need for surgery
• Discharge upon resolution of fever and swelling or serositis.
ONGOING CARE
FOLLOW-UP RECOMMENDATIONS
Patient Monitoring
Determined by medication and disease activity
• NSAIDs: periodic CBC, urinalysis, LFTs, renal function
tests
• Aspirin and/or other salicylates: transaminase and salicylate
levels, weekly for
1st month and then every 3 to 4 months
• Methotrexate: monthly LFTs, CBC, BUN, creatinine
DIET
Regular diet. Ensure adequate calcium, iron, protein, and caloric
intake.
PATIENT EDUCATION
• Attend to psychosocial needs; school issues; discuss behavioral
strategies for
dealing with pain and noncompliance; use of health care
resources; support
groups
• Resources available from the American College of
Rheumatology:
http://www.rheumatology.org/I-Am-A/Patient-Caregiver
PROGNOSIS
• 50–60% ultimately remit, functional ability depends on
adequacy of long-term
therapy (disease control, maintaining muscle and joint function)
• Poor prognosis in patients with active disease at 6
months, polyarticular
disease, extended pauciarticular disease course, female gender, RF (+),
ANA
(+), persistent morning stiffness, rapid appearance of erosions,
hip
involvement
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COMPLICATIONS
• Blindness, band keratopathy, glaucoma, short stature,
micrognathia if
temporomandibular joint involvement, debilitating joint disease,
disseminated
intravascular coagulation, hemolytic anemia
• NSAIDs: peptic ulcer, GI hemorrhage, CNS reactions, renal
disease,
leukopenia
• DMARDs: bone marrow suppression, hepatitis, renal disease,
dermatitis,
mouth ulcers, retinal toxicity (antimalarials; rare)
• TNF antagonists: higher risk of infection
• Osteoporosis, avascular necrosis
• Methotrexate: Folate supplementation decreases hepatic/GI
symptoms; may
reduce stomatitis
• Macrophage activation syndrome: decreased blood cell
precursors secondary
to histiocyte degradation of marrow
REFERENCES
1. Restrepo R, Lee EY. Epidemiology, pathogenesis, and imaging of
arthritis in
children. Orthop Clin North Am. 2012;43(2):213–225.
2. Prince FH, Otten MH, van Suijlekom-Smit LW. Diagnosis and
management
of juvenile idiopathic arthritis. BMJ. 2010;341:c6434.
3. Weiss JE, Ilowite NT. Juvenile idiopathic arthritis. Rheum Dis
Clin North Am.
2007;33(3):441–470.
4. Collado P, Vojinvic J, Nieto JC, et al. Toward Standardized
Musculoskeletal
ultrasound in Pediatric Rheumatology: Normal Age Related Ultrasound
Findings. Arthritis Care Res (Hoboken). 2016;68(3):348–356.
5. Kahn P. Juvenile idiopathic arthritis—current and future
therapies. Bull NYU
Hosp Jt Dis. 2009;67(3):291–302.
6. Beukelman T, Patkar NM, Saag KG,et al. 2011 American
College of
Rheumatology recommendations for the treatment of juvenile idiopathic
arthritis: initiation and safety monitoring of therapeutic agents for the
treatment of arthritis and systemic features. Arthritis Care Res
(Hoboken).
2011;63(4):465–482