Background: Juvenile rheumatoid arthritis (JRA) is not a

single disease. Rather, it is a group of diseases of

unknown etiology, which are manifested by chronic joint
inflammation.
Advances in treatment during the last 30 years have
changed the prognosis for the more severe forms of this
disease. Initial treatment limited to the use of salicylates
and then other nonsteroidal anti-inflammatory drugs
(NSAIDs) resulted in many patients becoming wheelchair
bound. Other patients underwent synovectomies to
remove excess tissue resulting from uncontrolled arthritis.
The addition of second-line drugs, starting with gold salt
injections and then replaced by the much more effective
methotrexate (MTX), improved the outlook for these
patients. These medications are administered in the
context of a team approach in pediatric rheumatology
centers, where physical and occupational therapy have
permitted greatly improved physical function.
The approval of etanercept, a biologic antagonist to tumor
necrosis factor (TNF), has ushered in a new era of
treatment more closely tailored to the pathophysiology of
the disease. Other biologic agents, such as anakinra, an
interluekin-1 (IL-1) receptor antagonist, may play a role in
selected patients who are unresponsive to second-line
drugs. In the future, inhibition of IL-6 may prove to be
effective in systemic patients with JRA who have elevated
levels.
Pathophysiology: The etiology of JRA is unknown.
Chronic inflammation of synovium is characterized by B
lymphocyte infiltration and expansion. Macrophages and
T-cell invasion are associated with the release of
cytokines, which evoke synoviocyte proliferation. A 2001
study by Scola et al found synovium to contain
messenger RNA for vascular endothelial growth factor,
angiopoietin 1, and their respective receptors, suggesting
that induction of angiogenesis by products of lymphocytic
infiltration may be involved in persistence of disease. The
resulting thickened pannus causes joint destruction. In
many patients, predominance of cytokines associated

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with tissue destruction, including interleukin-6 and TNF,

suggests the possibility of improved responsiveness to
specific biologic agents targeting these factors.
Frequency:

In the US: Prevalence of JRA has been estimated

to be 10-20 cases per 100,000 children.
Prevalence data vary (11-83 cases per 100,000),
depending upon the location of the study.
Pauciarticular and polyarticular disease occur
more frequently in girls, while both sexes are
affected with equal frequency in systemic-onset
disease.
Internationally: JRA appears to occur more
frequently in certain populations (eg, Native
Americans) from such disparate areas as British
Columbia and Norway. A study in Sweden found
prevalence similar to that in Minnesota,
approximately 85 cases per 100,000 population.

Mortality/Morbidity:

Endocarditis,
Bacterial
Fever in the
Toddler
Kawasaki Disease
Osteomyelitis
Pericarditis, Viral
Sarcoidosis
Somatoform
Disorder: Pain
Systemic Lupus
Erythematosus
Ulcerative Colitis

Continuing
Education

No recent studies have quantitated mortality in

JRA. However, the mortality rate is less than 1%
and is often associated with the evolution of
disease to manifestations of other rheumatic
diseases, such as systemic lupus erythematosus
(SLE) or scleroderma. Such progression has been
reported to be associated with high titer antinuclear
antibodies (ANA) at presentation in some children.

CME available for

this topic. Click
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CME.

Patients with JRA may experience complications

specific to their disease subset (see Clinical). The
most typical type of morbidity in patients with JRA
relates to adverse effects of medications,
particularly NSAIDs. Abdominal pain related to
gastritis or ulcer disease, hepatotoxicity, and
occasionally, renal toxicity are sufficiently frequent
to warrant routine laboratory screening.

Juvenile
Rheumatoid
Arthritis Overview

Patient Education

Arthritis Center

Juvenile
Rheumatoid
Arthritis Causes
Juvenile

Significant psychologic morbidity (eg, situational

depression, anxiety, problems functioning in
school) can occur in all subtypes. Morbidity
experienced in problems with quality of life is being
actively investigated. Such problems may occur in
children with all subtypes and may be the result of
additional factors, such as socioeconomic status
and family problems.

Race: Few studies documenting racial differences exist.

However, in 1997, Schwartz and colleagues found that,
compared to whites, blacks with JRA were older and less
likely to test positive for ANA or to have uveitis; however,
blacks were more likely to test positive for
immunoglobulin M rheumatoid factor.
Sex: Pauciarticular and polyarticular JRA tend to affect
girls more often than boys. Systemic-onset disease
occurs with equal frequency in boys and girls.
Age: Pauciarticular JRA tends to affect children in early
childhood. Systemic-onset disease can also occur in early
childhood; however, it is sometimes observed in late
childhood or early adolescence. Polyarticular JRA can
occur throughout childhood and adolescence.
Rheumatoid factorpositive disease, similar to
rheumatoid arthritis in adults, is more often found in
adolescents.

CLINICAL

Section 3 of 11

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History: Juvenile rheumatoid arthritis (JRA) is classified

as systemic, pauciarticular, or polyarticular disease
according to onset within the first 6 months.

General history of JRA includes the following:

Rheumatoid
Arthritis Symptoms
Juvenile
Rheumatoid
Arthritis Treatment
Rheumatoid
Arthritis Overview
Understanding
Rheumatoid
Arthritis
Medications

Disease onset is either insidious or abrupt,

with morning stiffness and arthralgia during
the day.

Individuals with JRA may have a school

history of absences, and their abilities to
participate in physical education classes
may reflect severity of the disease.
Typically, patients with JRA and their
parents and/or caregivers are concerned
about missing school; in contrast, when
psychogenic factors predominate (eg, pain
syndromes), patients and their parents
and/or caregivers are more worried about
returning to school than about missing
school.

Limping may be observed in individuals with

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

Injury suggests the possibility of trauma to a

joint (eg, meniscal tear).

A preceding illness raises the possibility of

infectious trigger of JRA or postinfectious
arthritis.

Illness in pets with a history of enteritis

raises the possibility of reactive arthritis.

History of travel with exposure to ticks

raises the possibility of arthritis caused by
Lyme disease.

Gastrointestinal symptoms raise the

possibility of inflammatory bowel disease.

Very severe joint pain raises the possibility

of acute rheumatic fever (also suggested by
migratory but not additive arthritis, with

fevers), acute lymphocytic leukemia (with

metaphyseal pain on examination, decrease
in 2 or more cell lines), septic arthritis, or
osteomyelitis.
o

o
o
o

Systemic-onset JRA is characterized by spiking

fevers, typically occurring several times each day,
with temperature returning to the reference range
or below the reference range.
o

o
o

Weight loss without diarrhea may be

observed in individuals with active JRA and
is sometimes associated with anorexia. This
symptom is also observed in individuals with
acute lymphocytic leukemia with other
obvious findings (eg, decrease in at least 2
cell lines, severe bone pain).
Weight loss with diarrhea may be observed
in persons with inflammatory bowel disease.
Photophobia may be observed in persons
with usually asymptomatic uveitis.
Orthopnea suggests pericarditis in children
with systemic JRA; the differential diagnosis
includes SLE and viral pericarditis.

Systemic-onset JRA may be accompanied

by an evanescent rash, which is typically
linear, affecting the trunk and extremities.
Arthralgia is often present. Frank joint
swelling is atypical; arthritis may not occur
for months following onset, making
diagnosis difficult.
Some children may have a generalized
myalgia.
Localization to proximal muscles raises the
possibility of a myositis.

Pauciarticular disease is characterized by arthritis

affecting 4 or fewer joints.
o

Typically, larger joints (eg, knees, ankles,

wrists) are affected.

Monoarticular arthritis in a hip is highly

unusual.

Consider Legg-Calv-Perthes disease; toxic

synovitis of the hip; septic arthritis;
osteomyelitis; or, in an older child, slipped
capital femoral epiphysis or chondrolysis of
the hip.

When the knee is affected, limping may be

noted, particularly in the mornings.
Chronic involvement can result in atrophy of
extensor muscles in the thigh, tight
hamstring ligaments, and knee flexion
contractures.

Polyarticular disease affects at least 5 joints.

o

Both large and small joints can be involved,

often in symmetric bilateral distribution.

Severe limitations in motion are usually

accompanied by weakness and decreased
physical function.

Physical: A detailed physical examination is a critical tool

in diagnosing JRA. Physical findings are important to
provide criteria for diagnosis and to detect abnormalities
suggestive of other possible diagnoses. The diagnosis of
JRA is based on the physical finding of arthritis (or
synovitis) in at least one joint that persists for at least 6
weeks, with other causes being excluded and with onset
when the individual is younger than 16 years. Arthritis on
examination is defined as either joint swelling (although
trauma can also cause swelling and may need to be
excluded) or the combination of limited motion with pain
(on motion or to palpation). The hips and small joints in
the spine, when affected by synovitis, do not demonstrate
swelling but demonstrate the combination of loss of
motion and pain.

A definite diagnosis of systemic-onset JRA must

await the eventual development of arthritis, which

may not occur for months.

Evanescent salmon-pink rash, often linear,

is found on the trunk and the extremities;
this rash is worse with fever.

Hepatosplenomegaly is often present.

Lymphadenopathy is sometimes present.

Muscle tenderness to palpation may be

observed.

Rarely, serositis, which raises the possibility

of SLE, is found.

In individuals with pauciarticular JRA, 4 or fewer

joints are affected; often, only a single joint is
affected (see Image 1).
o

Typically, large weight-bearing joints, knees,

and ankles are affected.

Involvement of a few small joints in the

hands is atypical and suggests eventual
development of polyarticular JRA or,
occasionally, psoriasis years later, with
retrospective diagnosis of psoriatic arthritis.

Muscle atrophy, often of extensor muscles

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

Flexion contractures in the knees and, less

commonly, the wrists are found.

In persons with polyarticular JRA, 5 or more joints

are affected (see Image 2).
o

Weight-bearing joints are affected, and

symmetric involvement of small joints in the

hands is found (see Image 4).

Pain with decreased range of motion in the
cervical spine is sometimes found.

Other findings in persons with JRA are as follows:

o

Ocular: Photophobia, in uveitis (usually

asymptomatic on onset), and synechiae (ie,
irregular iris perimeter resulting from
postinflammatory adhesions of iris to lens)
may be found (see Image 7).

Cardiovascular: Orthopnea and rub suggest

pericarditis (rub may be absent with large
pericardial effusion). S3, basilar rales, and
hepatomegaly suggestive of heart failure
may rarely be observed, when myocarditis
occurs in individuals with systemic JRA.

Causes: The specific causes of JRA remain undefined.

DIFFERENTIALS

Section 4 of 11

Author Information Introduction Clinical Differentials Workup Treatment Medication

Follow-up Miscellaneous Pictures Bibliography

Acute Lymphoblastic Leukemia

Autoimmune Chronic Active Hepatitis
Crohn Disease
Endocarditis, Bacterial
Fever in the Toddler
Kawasaki Disease
Osteomyelitis
Pericarditis, Viral
Sarcoidosis
Somatoform Disorder: Pain
Systemic Lupus Erythematosus
Ulcerative Colitis
Other Problems to be Considered:

Many conditions may manifest with arthritis of brief

duration. Postinfectious arthritis typically affects large
joints. This syndrome is clinically indistinguishable from
the early phase of juvenile rheumatoid arthritis (JRA),
particularly because JRA can be triggered by viral
infections. Patients with acute lymphocytic leukemia can
present with joint pain and even the physical findings of
arthritis. Expansion of lymphoblasts in bone metaphyses
can result in pain, which is typically severe.
Thrombocytopenia is rare in persons with JRA; its
presence, although it raises the possibility of SLE, also
suggests the possibility of leukemia. The differential count
in JRA often demonstrates a relative lymphopenia,
presumably because of egress of activated lymphocytes
from circulation into synovium. Lymphocytosis is
uncharacteristic of JRA and raises the possibility of
leukemia, particularly when a neutropenia is present.
Spondyloarthropathy is a chronic disease characterized
by periods of inflammation of tendons and ligaments,
particularly at the area of insertion into bone (entheses).
Often, children and adolescents with spondyloarthropathy
present with arthritis, making the distinction from JRA
difficult. Furthermore, some children occasionally develop
a disease that appears to be a combination of the 2
diseases. Nevertheless, although enthesitis can be
observed in persons with pauciarticular and polyarticular
JRA, the eventual evolution of arthritis to a predominant
enthesitis is more characteristic of spondyloarthropathy.
The presence of the human leukocyte antigen (HLA) B27
is helpful in suggesting the diagnosis. However,
radiographic changes observed in adults (eg, sclerosis of
the sacroiliac joints, bamboo spine) are rare in childhood
and adolescence.

WORKUP

Section 5 of 11

Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Pictures
Bibliography

Lab Studies:

Laboratory studies support the diagnosis of juvenile rheumatoid arthritis

(JRA) and, in many patients, are a helpful means of monitoring success
of medical treatment. Initial evaluation should include the following:
o

Erythrocyte sedimentation rate (ESR)

ESR is always elevated in children with systemic JRA, is
usually elevated in those with polyarticular disease, but is
often within the reference range in those with pauciarticular
disease.
When elevated, ESR may be used to monitor success of
medical treatment.

CBC with differential and platelet count

Lymphopenia is not uncommon because of emigration of
activated lymphocytes out of the circulation into synovium.
Neutropenia is uncommon and, particularly with
lymphocytosis or thrombocytopenia, raises the possibility of
acute lymphocytic leukemia.
Thrombocytopenia may also be observed in persons with
SLE presenting with arthritis.
Anemia may result from chronic active JRA; often
microcytic, anemia is usually refractive to treatment with
iron.

Alanine aminotransferase (ALT) test: Obtain ALT levels to exclude

the possibility of hepatitis (viral or autoimmune) prior to initiating
treatment with NSAIDs, which can cause hepatotoxicity.

Urinalysis with microscopic examination: Perform a urinalysis to

exclude the possibility of infection (as a trigger of JRA or transient
postinfectious arthritis) and nephritis (observed in individuals with
SLE).

Antinuclear antibody
ANA is observed in as many as 25% of children with JRA,

particularly in patients with pauciarticular disease.

Titers of 1:80 or higher are positive; a 1:40 titer or lower is
negative.
When found in young girls, a positive ANA is a marker of
increased risk of uveitis.
Very high titers may sometimes be associated with
evolution to other rheumatic disease (eg, SLE).
Titers otherwise do not correlate with disease activity.

Rheumatoid factor: Rare in persons with systemic JRA,

rheumatoid factor is considered a marker for persistence of
polyarticular JRA into adulthood.

Other laboratory tests for systemic JRA include the following:

o

Total protein and albumin: Levels are often decreased during

active disease.

Fibrinogen and D-dimer: Levels are often elevated in individuals

with active disease.

Imaging Studies:

Radiography of affected joints (see Image 3 and Image 6): When only a
single joint is affected, radiography is important to exclude other
diseases, such as osteomyelitis or septic arthritis.

Bone scanning: When physical findings do not document definite

arthritis, consider bone scanning as a means of identifying a potential
focus of osteomyelitis or other abnormality.

MRI

Perform MRI of the affected joint, with gadolinium injection to

enhance inflamed synovium.

MRI is helpful when considering trauma in the differential

diagnosis.

CT scanning of long bones: Perform when considering osteoid osteoma

in a child with lower extremity pain (often at night) and unremarkable

findings on physical examination.

Echocardiography
o

This is performed in a child with possible systemic JRA and with

fevers.

Perform echocardiography in an individual who has orthopnea by

history or a rub to exclude pericarditis.
In a person who has nonspecific rash, adenopathy, and
possible mucocutaneous changes, perform
echocardiography to exclude coronary arterial dilation
resulting from (possibly atypical) Kawasaki disease.
In an individual who has findings suggestive of SLE (eg,
nephritis, pleuritic chest pain, thrombocytopenia), perform
echocardiography to exclude valvular disease, although
mild dilation may be seen in some patients with systemic
JRA.

Other Tests:

Dual-energy radiograph absorptiometry (DXA) scanning: Perform DXA

scanning to document osteopenia in children with polyarticular JRA.

Procedures:

Arthrocentesis: Perform arthrocentesis to exclude septic arthritis in a

child with monoarticular swelling.

Synovial biopsy: This procedure may be helpful to exclude other

diagnoses, particularly when the knee is affected (eg, villonodular
synovitis, granulomatous arthritis).

Pericardiocentesis: Perform this in an ICU setting to treat severe

pericarditis.

Histologic Findings: Synovial biopsy may demonstrate synovial infiltration with

plasma cells, mature B lymphocytes, and T lymphocytes, with areas of synovial
thickening and fibrosis.
Section 6 of 11
TREATMENT
Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Pictures
Bibliography

Medical Care: Medical care of children with juvenile rheumatoid arthritis (JRA)
must be provided in the context of a team-based approach, considering all
aspects of their illness (eg, physical functioning in school, psychological
adjustment to disease). Using medications in the absence of an appropriate
physical therapy program and attention to problematic social issues of the
family is not successful. Success of medications is monitored best with
repeated physical examinations and history. Both the number of joints involved
and the duration of morning stiffness should demonstrate continued decrease,
with elimination reflecting success.
Surgical Care: Surgery is not usually needed; however, some children with
persisting pauciarticular JRA, despite medical treatment, may benefit from intraarticular steroid injection. Such injections may also be effective in treating
temporomandibular arthritis in children with polyarticular JRA. Usually, delay
joint replacement (often of the hips, in patients with polyarticular JRA) until bone
growth has completed, which is reflected by epiphyseal closure. The consistent
effective use of medical treatment has consigned synovectomy to a rarely used
intervention.
Consultations:

The subspecialty team includes the following:

o
o
o

Pediatric rheumatologist (when available)

Nurses (who help with education)
Physical and occupational therapists: Nonmedical approaches
(eg, physical and occupational therapy) are an important part of
treatment. At presentation, arthritis may be so active as to
preclude the use of an aggressive program of muscle
strengthening. Nevertheless, the use of pain modalities during this
period may permit the gradual introduction of an active program of
exercises and stretching.

Social workers: Social work evaluation helps to determine how

well each family is coping with their child's disease in terms of
emotional and financial resources. Social workers can offer
invaluable guidance for helping children to maintain healthy
relationships both within their families and at school. Transition
programs for adolescents with arthritis can help prepare them for
higher education and future vocations.

Pediatric ophthalmologists help provide slit-lamp examinations to exclude

uveitis.
Pediatric orthopedic surgeons can offer consultation when orthopedic
diagnoses are being considered.

The development of profound anemia or a drop in 2 or more cell lines

may require the help of a pediatric hematologist.

A pediatric gastroenterologist may help with hepatic abnormalities or

symptoms suggesting inflammatory bowel disease.

Diet: No specific diet helps in the treatment of JRA. However, because active
JRA has been associated with decreased osteoblastic activity and a risk of
osteopenia, encourage the inclusion of at least 3 servings of calcium-rich foods
each day. Consider behavioral intervention when poor calcium intake persists.
Activity: Encourage patients with JRA to be as active as possible. Except in
individuals with severe systemic disease, bed rest is not a part of the treatment.
In fact, the more active the patient the better the long-term prognosis is.
Children may experience increased pain during routine physical activities. As a
result, these children must be allowed to self-limit their activities, particularly
during physical education classes. A consistent physical therapy program, with
attention to stretching exercises, pain modalities, joint protection, and home
exercises, can help ensure that patients with JRA are as active as possible.

MEDICATION

Section 7 of 11

Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Pictures
Bibliography

Classes of medications are suggested below, and specific drugs are covered in
detail by category. See the therapeutic algorithm in Image 8.
NSAIDs are used to treat all subtypes of juvenile rheumatoid arthritis (JRA).
These medications are effective because of inhibition of prostaglandin
synthesis. Naproxen is listed below as an example of an NSAID used in
treatment; other NSAIDs commonly used include ibuprofen, tolmetin,
diclofenac, and indomethacin. In addition, sulfasalazine is sometimes used as a
second anti-inflammatory drug in some children with persisting pauciarticular
and polyarticular disease. Its use may be considered as an intermediate step
prior to adding a second-line drug such as MTX.

Aspirin is no longer the drug of first choice because of the increased frequency
of gastric toxicity and hepatotoxicity when compared to other NSAID
medications. Recently, the discovery that cyclooxygenase (COX) in gastric and
intestinal endothelium (ie, COX-1) is different in structure from that in leukocytes
(ie, COX-2) has led to the development of anti-inflammatory drugs specific for
COX-2. COX-2 inhibitors have been found to be effective in treatment of adults
with rheumatoid arthritis. Studies of COX-2 inhibitors in persons with JRA are
being planned. Besides the benefit of greatly reducing gastric toxicity (although
hepatotoxicity remains a possible adverse event), COX-2 inhibitors do not
inhibit platelet aggregation. Thus, these agents may find a role in the treatment
of inflammatory conditions in which a bleeding diathesis is a potential problem,
such as in the postoperative setting.
NSAIDs alone are usually adequate for treatment of pauciarticular disease.
However, an aggressive arthritis sometimes develops in this subtype, requiring
the need to add a second-line drug. Various second-line drugs have been used
in addition to first-line NSAIDs. Gold salt injections were used until
approximately 15 years ago, when studies by the Pediatric Rheumatology
Collaborative Study Group demonstrated the efficacy of PO MTX. Subsequent
studies have demonstrated that some children with polyarticular arthritis
unresponsive to PO MTX benefit from SC or IM administration. The use of highdose IV steroids in selected patients has been beneficial in some patients,
particularly during an early period before MTX may have a full therapeutic
effect.
Recently, etanercept, a biologic agent administered SC twice weekly and
containing a receptor to TNF ligated to an Fc portion of immunoglobulin, has
been found to be effective in controlling polyarticular arthritis not controlled by
conventional medical treatment. Prescribe this medication for those children
treated by pediatric rheumatology centers who are unresponsive to treatment
including conventional second-line drugs.
Finally, the treatment of systemic JRA may require, in addition to treatment with
NSAIDs, the careful use of either PO or high-dose pulse IV corticosteroids.
Such treatment is best reserved for patients in whom definite arthritis has
developed to avoid premature treatment in a patient who may prove to have a
disease other than JRA. Medication alone is not sufficient for most children with
arthritis, who benefit from a team approach (see Consultations).

Drug Category: Nonsteroidal anti-inflammatory drugs (NSAIDs) -- These

agents are used in all children with JRA as the medication of first choice.

Predicting which individual patient will respond to a particular NSAID is not

possible; sometimes, after 1-2 months of treatment, those persons who do not
respond may benefit from changing to a different NSAID. Most children with
pauciarticular JRA and only a few with polyarticular JRA respond to NSAID
treatment without needing the addition of second-line drugs (eg, MTX).
Administer NSAIDs with caution in any patient with renal or liver disease and
avoid administering NSAIDs during pregnancy. NSAIDs have a variety of
adverse effects (eg, gastritis, bone marrow suppression, hepatitis, interstitial
nephritis, CNS changes), which should be monitored.

Drug Name

Naproxen (Aleve, Naprelan,

Naprosyn) -- Used for analgesic and
anti-inflammatory properties, treating
arthralgia and arthritis. Each brand is
marketed with slightly different safety
and efficacy profiles. Inhibits
inflammatory reactions and pain by
decreasing activity of COX, which is
responsible for prostaglandin
synthesis.

Adult Dose

500-1000 mg/d PO divided bid;

available in SR formulation (ie,
Naprelan) that is administered qd

Pediatric Dose

7-20 mg/kg/d PO divided bid/tid; not

to exceed 1 g/d

Documented hypersensitivity; peptic

Contraindications ulcer disease; recent GI bleeding or
perforation; renal insufficiency
Interactions

Coadministration with aspirin

increases risk of inducing serious
NSAID-related adverse effects;
probenecid may increase
concentrations and, possibly, toxicity
of NSAIDs; may decrease effect of
hydralazine, captopril, and betablockers; may decrease diuretic
effects of furosemide and thiazides;
may increase PT when taking
anticoagulants (instruct patients to

watch for signs of bleeding); may

increase risk of MTX toxicity;
phenytoin levels may be increased
when administered concurrently
Compared with other NSAIDs,
increased likelihood of causing
pseudoporphyria cutanea tarda, a
photosensitive eruption that causes
scarring, especially in fair-skinned
young individuals; contraindicated in
patients who have pseudoporphyria
from this drug
Pregnancy

B - Usually safe but benefits must

outweigh the risks.

Precautions

Category D in third trimester of

pregnancy; acute renal insufficiency,
interstitial nephritis, hyperkalemia,
hyponatremia, and renal papillary
necrosis may occur; patients with
preexisting renal disease or
compromised renal perfusion risk
acute renal failure; leukopenia occurs
rarely, is transient, and usually
returns to normal during therapy;
persistent leukopenia,
granulocytopenia, or
thrombocytopenia warrants further
evaluation and may require
discontinuation of drug

Drug Name

Ibuprofen (Motrin, Ibuprin) -- Inhibits

inflammatory reactions and pain by
decreasing prostaglandin synthesis.

Adult Dose

400 mg PO q4-6h, 600 mg q6h, or

800 mg q8h while symptoms persist;
not to exceed 3.2 g/d

Pediatric Dose

30-50 mg/kg/d PO divided qid; not to

exceed 2.4 g/d

Contraindications Documented hypersensitivity; peptic

ulcer disease; recent GI bleeding or
perforation; renal insufficiency; high

risk of bleeding

Interactions

Coadministration with aspirin

increases risk of inducing serious
NSAID-related side effects;
probenecid may increase
concentrations and, possibly, toxicity
of NSAIDs; may decrease effect of
hydralazine, captopril, and betablockers; may decrease diuretic
effects of furosemide and thiazides;
may increase PT when taking
anticoagulants (instruct patients to
watch for signs of bleeding); may
increase risk of MTX toxicity;
phenytoin levels may be increased
when administered concurrently

Pregnancy

B - Usually safe but benefits must

outweigh the risks.

Precautions

Category D in third trimester of

pregnancy; caution in congestive
heart failure, hypertension, and
decreased renal and hepatic function;
caution in coagulation abnormalities
or during anticoagulant therapy

Drug Name

Diclofenac (Voltaren, Cataflam) -Inhibits prostaglandin synthesis by

decreasing activity of enzyme COX,
which in turn decreases formation of
prostaglandin precursors.

Adult Dose

100-200 mg/d PO divided bid/qid; not

to exceed 225 mg/d

Pediatric Dose

<12 years: 2-3 mg/kg/d PO divided

bid/qid
>12 years: Administer as in adults

Documented hypersensitivity;
administration into CNS; peptic ulcer
Contraindications disease; recent GI bleeding or
perforation; renal insufficiency; high
risk of bleeding

Interactions

Coadministration with aspirin

increases risk of inducing serious
NSAID-related side effects;
probenecid may increase
concentrations and, possibly, toxicity
of NSAIDs; may decrease effect of
hydralazine, captopril, and betablockers; may decrease diuretic
effects of furosemide and thiazides;
may increase PT when taking
anticoagulants (instruct patients to
watch for signs of bleeding); may
increase risk of MTX toxicity;
phenytoin levels may be increased
when administered concurrently

Pregnancy

B - Usually safe but benefits must

outweigh the risks.

Precautions

Category D in third trimester of

pregnancy; acute renal insufficiency,
hyperkalemia, hyponatremia,
interstitial nephritis, and renal
papillary necrosis may occur;
increases risk of acute renal failure in
patients with preexisting renal
disease or compromised renal
perfusion; low white blood cell counts
occur rarely and usually return to the
reference range in ongoing therapy;
discontinuation of therapy may be
necessary if persistent leukopenia,
granulocytopenia, or
thrombocytopenia occurs

Drug Name

Tolmetin (Tolectin) -- Inhibits

prostaglandin synthesis by
decreasing activity of enzyme COX,
which in turn decreases formation of
prostaglandin precursors.

Adult Dose

400 mg PO tid; typical dosage range

is 600 mg/d to 1.8 g/d; not to exceed
2 g/d

Drug Name

Indomethacin (Indocin) -- Rapidly

absorbed. Metabolism occurs in liver
by demethylation, deacetylation, and
glucuronide conjugation. Inhibits
prostaglandin synthesis.

Adult Dose

25-50 mg PO bid/tid; not to exceed

200 mg/d
ER product may be administered qd
or bid

Pediatric Dose
Contraindications

1-2 mg/kg/d PO divided bid/qid; not to

exceed 4 mg/kg/d or 150-200 mg/d
Documented hypersensitivity; GI
bleeding; renal insufficiency

Interactions

Coadministration with aspirin

increases risk of inducing serious
NSAID-related side effects;
probenecid may increase
concentrations and, possibly, toxicity
of NSAIDs; may decrease effect of
hydralazine, captopril, and betablockers; may decrease diuretic
effects of furosemide and thiazides;
may increase PT when taking
anticoagulants (instruct patients to
watch for signs of bleeding); may
increase risk of MTX toxicity;
phenytoin levels may be increased
when administered concurrently

Pregnancy

B - Usually safe but benefits must

outweigh the risks.

Precautions

Category D in third trimester of

pregnancy; acute renal insufficiency,
hyperkalemia, hyponatremia,
interstitial nephritis, and renal
papillary necrosis may occur;
increases risk of acute renal failure in
patients with preexisting renal
disease or compromised renal
perfusion; reversible leukopenia may
occur (discontinue if persistent

leukopenia, granulocytopenia, or
thrombocytopenia occurs)

Drug Category: Immunosuppressive agents -- Most children with

polyarticular JRA and some with aggressive pauciarticular disease benefit from
additional immunosuppressive agents (ie, in particular, MTX).

Drug Name

Methotrexate (Rheumatrex) -Unknown mechanism of action in

treatment of inflammatory reactions;
may affect immune function. The antiinflammatory effects do not appear to
be mediated by inhibition of
dihydrofolate reductase. Ameliorates
symptoms of inflammation (eg, pain,
swelling, stiffness). Adjust dose
gradually to attain satisfactory
response. Consider SC route for
patients who do not respond to PO
methotrexate

Adult Dose

7.5 mg/wk PO/SC or 2.5 mg PO/SC

q12h for 3 doses administered qwk

Pediatric Dose

10-25 mg/m2/wk PO/IM/SC as a

single dose or divided into 2 doses
qwk; many pediatric rheumatologists
increase dose (not to exceed 30
mg/m2, approximately equivalent to 1
mg/kg); administer with folic acid 1-2
mg PO qd or folinic acid 2.5-5 mg PO
qwk

Documented hypersensitivity;
alcoholism; hepatic insufficiency;
documented immunodeficiency
syndromes; preexisting blood
Contraindications
dyscrasias (eg, bone marrow
hypoplasia, leukopenia,
thrombocytopenia, significant
anemia); renal insufficiency
Interactions

Coadministration with etretinate may

increase hepatotoxicity of MTX;

indomethacin and phenylbutazone

can increase MTX plasma levels;
may decrease phenytoin serum
levels; probenecid, salicylates,
procarbazine, and sulfonamides,
including TMP-SMZ, may increase
effects and toxicity of MTX; may
increase plasma levels of thiopurines
Pregnancy

X - Contraindicated in pregnancy

Precautions

Monitor CBCs q1-2mo and liver and

renal function q1-3mo during therapy
(monitor more frequently during initial
dosing, dose adjustments, or when
risk of elevated MTX levels, such as
dehydration); MTX has toxic effects
on hematologic, renal, GI, pulmonary,
and neurologic systems; discontinue
if significant drop in blood counts
occurs; aspirin, NSAIDs, or low-dose
steroids may be administered
concomitantly with MTX (possibility of
increased toxicity with NSAIDs,
including salicylates, has not been
tested); supplement folic acid to
prevent deficiency; add daily folic acid
or weekly folinic acid to ameliorate
adverse effects

Drug Name

Sulfasalazine (Azulfidine, EN-tabs) -Decreases the inflammatory

response and systemically inhibits
prostaglandin synthesis.

Adult Dose

500 mg PO qd initially; gradually

increase by 500 mg/wk to 2-3 g/d PO
divided bid

Pediatric Dose

<6 years: Not established

>6 years: 10 mg/kg/d PO divided bid
initially; increase by 10 mg/kg/d qwk;
typical dose range is 30-50 mg/kg/d;
not to exceed 2 g/d

Contraindications Documented hypersensitivity;

coadministration of sulfa drugs or any

component; GI or GU obstruction
Interactions

Decreases effects of iron, digoxin,

and folic acid; conversely, increases
effect of PO anticoagulants, PO
hypoglycemic agents, and MTX

Pregnancy

B - Usually safe but benefits must

outweigh the risks.

Precautions

Do not use in pregnancy when near

term; caution in patients with renal or
hepatic impairment, blood dyscrasias,
or urinary obstruction

Drug Name

Methylprednisolone (Solu-Medrol) -Decreases inflammation by

suppressing migration of
polymorphonuclear leukocytes and
reversing increased capillary
permeability. Used temporarily for
JRA until longer-term treatment
provides effective relief.

Adult Dose

30 mg/kg/dose IV administered over

30 min q4-6h prn; administer high
dose only for 2-3 d

Pediatric Dose

15-30 mg/kg IV qd administered over

30 min for 2-3 d

Contraindications

Documented hypersensitivity; viral,

fungal, or tubercular skin infections

Interactions

Coadministration with digoxin may

increase digitalis toxicity secondary to
hypokalemia; estrogens may increase
levels of methylprednisolone;
phenobarbital, phenytoin, and
rifampin may decrease levels of
methylprednisolone (adjust dose);
monitor patients for hypokalemia
when taking medication concurrently
with diuretics

Pregnancy

C - Safety for use during pregnancy

has not been established.

Precautions

Hyperglycemia, edema,
osteonecrosis, peptic ulcer disease,
hypokalemia, osteoporosis, euphoria,
psychosis, growth suppression,
myopathy, and infections are possible
complications of glucocorticoid use

Drug Name

Prednisone (Deltasone, Meticorten,

Orasone, Sterapred) -Immunosuppressant for treatment of
JRA. May decrease inflammation by
reversing increased capillary
permeability and suppressing PMN
activity. Stabilizes lysosomal
membranes and also suppresses
lymphocytes and antibody production.

Adult Dose

7.5 mg PO qd for short-term

treatment while waiting for efficacy of
other antirheumatic drugs

Pediatric Dose

4-5 mg/m2/d PO; alternatively, 0.05-2

mg/kg PO divided bid/qid; taper over
2 wk, as symptoms resolve and other
antirheumatic drugs take effect

Documented hypersensitivity; viral

infection; peptic ulcer disease;
Contraindications hepatic dysfunction; connective tissue
infections; fungal or tubercular skin
infections; GI disease

Interactions

Coadministration with estrogens may

decrease prednisone clearance;
concurrent use with digoxin may
cause digitalis toxicity secondary to
hypokalemia; phenobarbital,
phenytoin, and rifampin may increase
metabolism of glucocorticoids
(consider increasing maintenance
dose); monitor for hypokalemia with
coadministration of diuretics

Pregnancy

C - Safety for use during pregnancy

has not been established.

Precautions

Abrupt discontinuation of
glucocorticoids may cause adrenal
crisis; hyperglycemia, edema,
osteonecrosis, myopathy, peptic ulcer
disease, hypokalemia, osteoporosis,
euphoria, psychosis, myasthenia
gravis, growth suppression, and
infections may occur with
glucocorticoid use

Drug Category: Tumor necrosis factor (TNF) inhibitors -- TNF is a

cytokine of which 2 forms have been identified with similar biological properties.
TNF-alpha or cachectin is produced predominantly by macrophages, and TNFbeta or lymphotoxin is produced by lymphocytes. TNF is but one of many
cytokines involved in the inflammatory cascade that contributes to symptoms.

Drug Name

Etanercept (Enbrel) -- Acts by binding

and inhibiting TNF, a cytokine that
contributes to inflammatory and
immune response.

Adult Dose

25 mg SC 2 times qwk

Pediatric Dose

<4 years: Not established

4-17 years: 0.4 mg/kg SC 2 times
qwk (administered at least 72-96 h
apart); not to exceed 25 mg/dose
>17 years: Administer as in adults

Contraindications Documented hypersensitivity; sepsis

Interactions

Do not administer within 3 mo of live

virus vaccines (eg, MMR)

Pregnancy

B - Usually safe but benefits must

outweigh the risks.

Precautions

Caution in impaired renal function

and asthma; discontinue
administration if a serious infection
develops; adverse effects may
include injection site pain, localized
erythema, rash, URI symptomatology,
GI upset, nausea, vomiting, rhinitis,
and cough; adverse events in

children and adults are similar in

frequency and type, those reported
more commonly include headache
(19%), nausea (9%), abdominal pain
(19%), and vomiting (13%);
immunizations should be brought upto-date prior to initiating; rare cases of
lupuslike symptoms and heart failure
have been reported (discontinue
treatment if symptoms develop)
FOLLOW-UP

Section 8 of 11

Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Pictures
Bibliography

Further Inpatient Care:

Further inpatient care is required for persisting fevers of unknown origin

or when children with known juvenile rheumatoid arthritis (JRA) have
severe exacerbation of disease.

Admit for evaluation any child who loses the ability to walk for unknown
reasons.

Development of pericarditis in children with systemic JRA is usually an

indication for admission.

Further Outpatient Care:

Patients with JRA may have a gradually responsive disease (particularly

those with pauciarticular JRA).

A small number of patients with pauciarticular JRA develop aggressive

arthritis confined to a single joint; such patients may require more
intensive medical treatment and physical therapy.

Some patients with polyarticular JRA demonstrate rapid response to

treatment; however, most have prolonged courses, requiring frequent
adjustments in medical and nonmedical therapy. Some have sufficient
problems with activities of daily living, and they may benefit from courses
of outpatient (and sometimes inpatient) rehabilitation.

In/Out Patient Meds:

See Medication.

Transfer:

Consider outpatient evaluation in a pediatric rheumatology center for all

patients with known and suspected disease. Inpatient care for individuals
with intercurrent illnesses may best be carried out at local hospitals;
complications from JRA usually indicate transfer to a hospital with a
pediatric rheumatology center.

Deterrence/Prevention:

No prevention of JRA is known. The best means of deterrence is

compliance with recommended treatment. As many as one half of
patients may not comply with every detail of recommended treatment.
Persisting noncompliance is a problem that increases risk of morbidity.
Parents of such patients often admit noncompliance only to the child's
primary care physician, rather than to a pediatric subspecialty team. The
continued monitoring of compliance by the primary care physician,
together with continuing communication between the pediatric
subspecialist and primary physician, is an important part of the treatment
of children with JRA and any chronic illness.

Complications:

Systemic-onset JRA
o

Pericarditis (patients often presenting with orthopnea and

responsive to intravenous corticosteroid treatment)

Hemolytic anemia

Disseminated intravascular coagulopathy (often present at a low

level of activity): Levels of D-dimer and fibrinogen may be
elevated; their return to reference range levels is observed with
successful treatment.

Macrophage activation syndrome

This is a rare, but important, complication, in which

numbers of all 3 bloodlines become rapidly decreased.

Hypofibrinogenemia, thrombocytopenia, and elevated
aspartate aminotransferase levels are hallmarks.
Hypotension, central nervous system disease, and marked
hepatosplenomegaly may be noted as complications of a
release of massive amounts of cytokines.
Bone marrow aspiration finding histiocytic consumption of
bone marrow precursors confirms the diagnosis and
excludes malignancy.
Macrophage activation syndrome often responds to
cyclosporin A.

Endarteritis resulting in circulatory compromise of the digits with

threatened autoamputation
This complication is even more rare than macrophage
activation syndrome.
Central administration of prostaglandin E1 may be of
potential benefit, similar to its use for patients with
scleroderma and endarteritis.

Pauciarticular JRA
o

Knee flexion contractures: This complication requires splinting at

night, in addition to medical treatment, to restore range of motion,
allow recovery of muscle strength, and avoid subluxation of the
joint.
Uveitis
Often asymptomatic, patients are typically young girls who
have positive levels of ANA.
In such patients, evaluation using a slit-lamp examination
by a pediatric ophthalmologist every 4 months can detect
early disease.
Treatment with topical corticosteroid medication and with
mydriatic agents (to prevent closed-angle glaucoma) often
can prevent progression of disease to development of
calcium deposition in the lens (band keratopathy) and
adhesions of the iris to the lens (posterior synechiae), in
which an irregular pupillary margin develops (see Image 7).
Such complications may herald a chronic active disease, in
which vision is threatened; immunosuppressive agents,
such as methotrexate or cyclosporin, may help to control
chronic uveitis. Infliximab can be effective in some patients

who are resistant to immunosuppressive agents.

Leg length discrepancy (can result from neovascularization of
growth plates of an affected knee)
The problem may not be detected in patients with a knee
flexion contracture until the contracture is corrected.
Treatment consists of a shoe lift on the nonaffected side.

Polyarticular JRA
o Skeletal abnormalities - Increased size of epiphyses, accelerated
bone age, narrowed joint spaces, swan-neck and/or boutonniere
deformities, and joint subluxation (see Images 5-6).
o

Cervical spine involvement

Difficulty flexing the spine may create a problem for
intubation prior to surgery; inform anesthesiologists of the
patient's diagnosis. Screening cervical spine radiography
may help screen for potential difficulties during induction of
anesthesia.
High-level subluxation is a potential complication.

Prognosis:

Some studies suggest that many children with JRA can lead productive
lives. However, other studies suggest many patients, particularly those
with polyarticular disease, may have problems with active disease
throughout adulthood, with sustained remission attained in a minority of
patients. Early hip or wrist involvement, symmetric disease (even in
pauciarticular patients), presence of rheumatoid factor, and prolonged
active disease have been associated with poor long-term outcomes.

Children with systemic disease tend to have either complete

responsiveness to medical therapy or development of a polyarticular
course that tends to be refractive to medical treatment, with disease
persisting into adulthood.

Most children with pauciarticular disease demonstrate eventual

permanent remission; a small number progress to persisting polyarticular
disease.

Patient Education:

Educating the patient, family, and school personnel (eg, classroom

teachers, physical education teachers, nurses) about JRA and its

presentation, treatment, and potential effects is continually necessary.
Members of the pediatric rheumatology team in pediatric rheumatology
clinics are the best educators about JRA. Another important source of
information is the American Juvenile Arthritis Organization, a council of
the Arthritis Foundation.

For excellent patient education resources, visit eMedicine's Arthritis

Center. Also, see eMedicine's patient education articles Juvenile
Rheumatoid Arthritis and Understanding Rheumatoid Arthritis
Medications.

MISCELLANEOUS

Section 9 of 11

Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Pictures
Bibliography

Medical/Legal Pitfalls:

The major medicolegal pitfall lies in diagnosing juvenile rheumatoid

arthritis (JRA) when another problem exists (eg, infection, malignancy,
orthopedic problem). Whenever possible, referral to a pediatric
rheumatologist can help address this issue. Careful attention to
presenting history and initial physical examination findings can lower the
likelihood of such a pitfall. However, the chance of such a pitfall can
never be eliminated completely. At the time of diagnosis, inform parents
and/or caregivers of the possible need to revise the diagnosis of JRA
should new symptoms, physical findings, or unusual laboratory results
develop.

Special Concerns:

Chronic illness imposes burdens on families, who may vary in their

abilities to cope. Social workers can help provide assessment and assist
families in finding resources (including counseling). Remind parents
and/or caregivers to bring all questions to the pediatric rheumatology
team, who can often help. Any unusual symptom may signal a new
complication of disease or adverse effect of medication. In the current
health care environment, managed care can result in initial denial of
services (eg, physical therapy), resulting in delays in treatment with
subsequent morbidity. Advocacy by the primary care physician and
pediatric rheumatologist can help point out the need for such services.