Current Treatment of Juvenile Rheumatoid Arthritis

DOI: 10.1542/peds.109.1.109

2002;109;109-115 Pediatrics

Norman T. Ilowite

Current Treatment of Juvenile Rheumatoid Arthritis

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SPECIAL ARTICLE

Current Treatment of Juvenile Rheumatoid Arthritis

Norman T. Ilowite, MD

ABSTRACT. Prognostic factors in juvenile rheumatoid

arthritis (JRA) include polyarticular onset, polyarticular

disease course, and rheumatoid factor positivity; in the

systemic onset subtype, persistence of systemic features

at 6 months after onset confers a worse prognosis. Timely

diagnosis and appropriate aggressive treatment of patients

with poor prognostic features improve quality of

life and outcome. After nonsteroidal anti-inflammatory

drugs, methotrexate is the most commonly used secondline

agent. However, approximately one third of patients

do not respond to methotrexate adequately. Randomized,

placebo-controlled, clinical trials in patients with JRA are

few, but one such trial with the tumor necrosis factor

inhibitor etanercept shows that this drug is effective and

well-tolerated. Other recently approved agents for rheumatoid

arthritis, including infliximab, leflunomide, celecoxib,

and rofecoxib, have not been adequately studied

in pediatric patients, and the role of these agents in

children with JRA remains to be determined. Pediatrics

2002;109:109 –115; antirheumatic agents, disease-modifying

antirheumatic drugs, tumor necrosis factor.

ABBREVIATIONS. JRA, juvenile rheumatoid arthritis; RA, rheumatoid

arthritis; NSAID, nonsteroidal antiinflammatory drug;

FDA, Food and Drug Administration; COX, cyclooxygenase;

DMARD, disease-modifying antirheumatic drug; JCA, juvenile

chronic arthritis; TNF, tumor necrosis factor; LT-_, lymphotoxin-

Juvenile rheumatoid arthritis (JRA) is the most

common rheumatic condition in children. Between

5 and 18 of every 100 000 children develop

JRA each year; the overall prevalence is approximately

30 to 150 per 100 000.1The course of JRA can

be highly variable: some patients recover fully,

whereas others experience lifelong symptoms and

significant disability.

The variability in disease course may partly explain

the misconception that JRA is usually a benign

disease. Although an 80% remission rate by the time

the child reaches adulthood has been cited frequently,

2 this figure is not supported by available data. A

cohort study in which 506 JRA cases were followed

from 1970 to 1999 (mean follow-up of 10 years) found

that only approximately one third of JRA patients

achieved disease remission; for some disease subtypes,

this figure was as low as 20%.3 The visual

complications of iritis are also important in determining

outcome. In 1 study, 17% of patients with

JRA developed chronic iritis; 20% of these children

were left with impaired vision.4 Functional disability

is common and can be long lasting. In patients with

a median disease duration of 7.1 years, 60% reported

some difficulty in activities of daily living, and almost

half still required medication.5,6 Overall, approximately

30% of patients who have been followed

for 10 or more years have severe functional limitations.

2 Even more than 20 years after disease onset,

JRA patients report significantly greater pain and

lower physical functioning, health perception, and

vitality than case control subjects.7 These data indicate

that JRA is often associated with severe, longlasting

effects.

Several new antirheumatic treatments have become

available within the past 2 years. This review

summarizes clinical data available on currently used

agents for JRA and discusses the potential of new

adult rheumatoid arthritis (RA) agents in the treatment

of JRA.

DEFINITION OF JRA

JRA is defined as persistent arthritis in 1 or more

joints for at least 6 weeks if certain exclusionary

conditions have been eliminated; disease onset subtype

is defined by clinical symptoms in the first 6

months of disease.8 The course of JRA is defined by

what happens after the first 6 months.

SUBTYPES OF JRA

The 3 major subtypes of JRA are based on the

symptoms at disease onset and are designated systemic

onset, pauciarticular onset, and polyarticular

onset (Table 1). Pauciarticular-onset and polyarticular-

onset JRA are further divided into 2 subsets each

by some investigators (Table 1).9

Although the major JRA classifications are based

on onset type, the course of the disease is also critical

to patient prognosis. For instance, systemic-onset

JRA can eventually become indistinguishable from

polyarticular JRA.10 Patients with this pattern of onset

and disease course may be particularly difficult to

treat. JRA that begins as pauciarticular-onset disease,

with more extensive joint involvement over time, is

frequently referred to as “extended pauciarticular”

or “extended oligoarticular” disease.

From the Division of Rheumatology, Schneider Children’s Hospital, New

Hyde Park, New York, and Department of Pediatrics, AlbertEinsteinCollege

of Medicine, Bronx, New York.

Received for publication Apr 20, 2001; accepted Jun 26, 2001.

Reprint requests to (N.T.I.) Schneider Children’s Hospital, 269-01 76th Ave,

Rm 197, New Hyde Park, NY11040. E-mail:

of Pediatrics.

PEDIATRICS Vol. 109 No. 1 January 2002 109

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PROGNOSTIC INDICATORS

The course of the disease is highly variable. Figure

1 shows the percentage of patients who had remission

or articular erosions at 5 years by disease onset

subtype and who were followed at tertiary centers in

North America.10 In systemic-onset JRA, active systemic

disease at 6 months (ie, with fever, the need for

corticosteroids, and thrombocytosis) is a strong predictor

of poor functional outcome.11 Only approximately

one quarter of patients with polyarticular

onset are in remission at 5 years after disease onset,

and more than two thirds develop erosions within

the first 5 years of the disease.10 The extended oligoarthritis

phenotype has a similar prognosis.

As might be expected from the high frequency of

erosions in patients with polyarticular disease, polyarticular

onset and polyarticular disease course both

have been identified as significant risk factors for

disability (Table 2).5 Other factors that determine

disability include female gender and the presence of

rheumatoid factor.5 Lower remission rates have been

observed in patients with polyarticular onset, rheumatoid

factor, persistent morning stiffness, tenosynovitis,

subcutaneous nodules, or antinuclear antibody.

12 Poor outcomes are also associated with early

involvement of the small joints of the hands and feet

and rapid appearance of erosions.13

The most challenging patients to treat are those

with poor prognostic indicators (Table 2). These patients

are likely to require more aggressive therapy,

as well as early initiation of treatment. A recent study

of predictive factors that influence the outcome of

patients with JRA or juvenile spondyloarthropathy

found that patients who developed erosions and disability

tended to have received treatment later than

those who did not.14

THERAPY FOR JRA

General Considerations

For all patients, the goals of therapy are to decrease

chronic joint pain and suppress the inflammatory

process. Accomplishing these goals will lead not

only to improved short-term and long-term function

but also to normal growth and development.

First-line therapy includes nonsteroidal antiinflammatory

drugs (NSAIDs). In addition, intra-articular

corticosteroid injections have been shown to be

safe and effective, may have beneficial effects on

growth parameters, and can be administered with

little psychologic trauma, even in young patients.

15–20 Cognitive-behavioral pain management

techniques have also been successful in reducing

pain intensity in pediatric patients.21 Physical ther-

TABLE 1. Key Clinical Characteristics of JRA Onset Types

Onset Type Clinical Symptoms Subtypes Associated Characteristics

Systemic Fever, light salmon-colored rash,

extra-articular manifestations

Not applicable Organomegaly and lymphadenopathy

sometimes present

Pauciarticular Fewer than 5 joints involved

during the first 6 mo of illness

Early childhood onset Usually young females; high incidence of

chronic uveitis; antinuclear antibodypositive

Late childhood onset Usually males older than 8 years; high

incidence of sacroiliitis; HLA B27-positive

Polyarticular Five or more joints involved

during the first 6 mo of illness

RF-negative Onset later in childhood

RF-positive Onset later in childhood; similar to adult RA

Fig 1. Percentage of JRA patients with remission

or articular erosions at 5 years after

disease onset according to disease onset

subtype. Data are from Cassidy et al.10

TABLE 2. Poor Prognostic Indicators for Patients With JRA

Active systemic disease at 6 months

Polyarticular onset or disease course

Female gender

Rheumatoid factor

Persistent morning stiffness

Tenosynovitis

Subcutaneous nodules

Antinuclear antibodies

Early involvement of small joints of hands and feet

Rapid appearance of erosions

Extended pauciarticular disease course

From Ga¨re and Fasthr,5 Takei et al,12 and Cassidy and Petty.13

110 CURRENT TREATMENT OF JUVENILE RHEUMATOID ARTHRITIS

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apy is important not only for reducing pain but also

for maintaining joint and muscle function.13

Preventing eye damage is another important goal

of JRA therapy. Because of the risk of chronic uveitis

in patients with JRA, careful ophthalmologic surveillance

is essential. Pharmacotherapy of uveitis with

methotrexate and cyclosporin A may be beneficial in

decreasing the severity of this condition.22,23

The toxicities associated with therapeutic agents

pose a significant problem in effective treatment. For

instance, agents that work by general immunosuppression

may be associated with increased susceptibility

to infection, complication of vaccine administration,

or increased oncogenic risk. The distinction

between symptom control and prevention of erosive

disease must also be recognized. Many of the agents

that are most effective at pain and symptom control,

including corticosteroids and NSAIDs, have no effect

on erosive disease. Even methotrexate, which is

known to have disease-modifying activity,24,25 may

relieve symptoms and signs without halting disease

progression in some patients.

Systemic Pharmacologic Therapy

NSAIDs

Conventional NSAIDs inhibit both the cyclooxygenase

(COX)-1 constitutive form of the enzyme,

which releases prostaglandins that protect the stomach

and kidneys, and the COX-2 inducible form,

which produces prostaglandins involved in the inflammatory

process. Only a handful of NSAIDs have

been approved by the US Food and Drug Administration

(FDA) for use in JRA (ibuprofen, naproxen,

tolmetin, and choline magnesium trisalicylate).

However, most of the other NSAIDs are also commonly

used for JRA, including indomethacin and

diclofenac.13

Pseudoporphyria may occur with all of the propionic

acid NSAIDs and may be more common with

naproxen sodium, especially in fair-skinned young

patients.26 Because of the lack of a clear-cut consensus

on the optimal NSAID for patients with JRA,

many clinicians choose an NSAID on the basis of

considerations such as dosing schedule, patient preference,

or medication taste.

Disease-Modifying Antirheumatic Drugs

The term “disease-modifying antirheumatic drugs”

(DMARD) is limited to agents that retard radiologic

progression of disease. Only 3 DMARDs have been

proved to be effective in controlling disease activity

in double-blind, placebo-controlled studies of children

with JRA: methotrexate, sulfasalazine, and,

more recently, etanercept.

Methotrexate

Methotrexate is currently the most frequently used

DMARD for JRA.27 This agent, demonstrated to be

effective in polyarticular JRA, has been used to treat

juvenile arthritis for more than 10 years.28,29 Data

from uncontrolled studies suggest that methotrexate

slows radiographic progression in JRA.24,25 Overall,

between 60% and 80% of JRA patients who are

treated with methotrexate experience some clinical

improvement.30–32

Some controversy exists concerning whether

methotrexate is more effective in certain JRA subtypes

than in others. Highest response rates to methotrexate

are obtained in children with oligoarticular

onset, particularly those with extended polyarticular

disease33; patients with systemic onset may respond

less frequently.34

The most common adverse events associated with

methotrexate use in children with JRA are gastrointestinal

symptoms, which occur in approximately

13% of patients.29 Liver toxicity does not seem to be

a major concern in pediatric patients. In adults, recommendations

are to follow serum transaminase

and albumin levels every 4 to 8 weeks35; most pediatric

rheumatologists check blood counts and

transaminases similarly. Significant liver damage

seems to be rare, probably in part because comorbid

hepatotoxic risk factors are absent in most pediatric

patients. In a study of 14 JRA patients who were

treated with methotrexate for a mean of 6.3 years,

needle biopsies failed to detect signs of significant

liver fibrosis in any of the patients, although some

histologic abnormalities were noted.36 Despite the

widespread use of methotrexate, data on immunosuppressive,

teratogenic, or oncogenic risks associated

with long-term methotrexate therapy in JRA

patients are lacking.29 Current recommendations are

not to administer live virus vaccines to patients who

are taking methotrexate. For help in minimizing potential

long-term effects, discontinuation of methotrexate

in patients whose disease is completely controlled

for extended periods may be advisable.30,37

Sulfasalazine

In a double-blind, placebo-controlled, multicenter

study of patients with juvenile chronic arthritis

(JCA), sulfasalazine was significantly more effective

than placebo in suppressing disease activity, as indicated

by decreases in overall articular severity scores,

all global assessments, and laboratory parameters.38

However, drug toxicity is a problem: elevated liver

transaminases, leukopenia, hypoimmunoglobulinemia,

and gastrointestinal problems contributed to a

30% withdrawal rate in this trial.38 The manufacturer

recommendations are to check blood counts and

transaminase levels before treatment, every other

week for the first 3 months, monthly for the next 3

months, then every 3 months. In a small trial of

sulfasalazine in systemic JCA, 3 of 4 children had to

withdraw as a result of severe toxic side effects possibly

related to a hypersensitivity reaction, including

high fevers and rash.39 Some data suggest that sulfasalazine

may be most useful for pauciarticularonset

JRA.40,41

Other DMARDs

Double-blind, placebo-controlled studies have

failed to demonstrate efficacy of penicillamine, hydroxychloroquine,

42 or auranofin,43 although the

power of these studies with relatively small numbers

of patients has been questioned. Cyclosporin A has

not been studied in a double-blind, placebo-controlled

manner. Combination chemotherapy early in

RA,44,45 with withdrawal of drug after response, akin

to the oncology paradigm of induction, consolida-

SPECIAL ARTICLE 111

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tion, and maintenance regimes, is less applicable in

JRA for which the prognosis is highly variable.

New Drugs for Adult RA and Their Potential Use in

JRA

Leflunomide

The FDA approval of leflunomide in August 1998

marked the arrival of the first new drug for adult RA

in many years. Leflunomide, an immunosuppressive

agent that acts as a reversible inhibitor of de novo

pyrimidine synthesis, has been shown to be significantly

superior to placebo and comparable to sulfasalazine

and methotrexate in controlling measures

of disease activity in patients with adult RA.46,47 The

ability of these 3 agents to retard radiographic progression

is also similar.48 The most common adverse

effects associated with leflunomide are diarrhea, elevated

liver enzymes, alopecia, and rash.46,47 Although

leflunomide has good efficacy and safety

profiles in adults, it has not been studied in pediatric

patients, possibly because of the cytotoxic nature of

this agent. In particular, the teratogenic potential of

this agent may be a concern when treating pediatric

patients, especially adolescent females. The long

half-life of this agent (2 weeks) may also be a drawback,

although a regimen of thrice-daily cholestyramine

for 8 days can eliminate the drug by 11 days, if

necessary (eg, pregnancy).

Etanercept

Etanercept is a new agent recently approved by the

FDA for use in reducing signs and symptoms and

delaying structural damage in patients with moderately

to severely active adult RA, and for reducing

signs and symptoms of moderately to severely active

polyarticular-course JRA that is refractory to 1 or

more DMARDs.49 This agent consists of 2 soluble p75

tumor necrosis factor (TNF) receptors fused to the Fc

portion of immunoglobulin G. Etanercept is a potent

inhibitor of TNF and lymphotoxin-_ (formerly

known as TNF_). TNF is a key proinflammatory

cytokine that is found in the synovial tissue of patients

with JRA and is believed to play an important

role in proinflammatory signaling (Table 3), whereas

lymphotoxin-_ is a related cytokine that binds to

TNF receptors and is also found specifically in JRA

patients.50

In a 2-part study, etanercept was tested in 69 patients

who had active polyarticular-course JRA and

were refractory or intolerant to methotrexate.51 All of

the 3 major onset types were represented (Fig 2). The

study was designed so that the efficacy of etanercept

could initially be assessed without subjecting a control

group to placebo injections. Accordingly, in the

first part of the study, all patients received open-label

etanercept at 0.4 mg/kg subcutaneously twice

weekly for 90 days. Fifty-one patients (74%) achieved

the JRA definition of improvement.52 To meet these

criteria, a patient must show a 30% or greater improvement

from baseline in at least 3 of the 6 core set

response variables (physician global assessment, parent/

patient global assessment, number of active

joints, number of joints with limited range of motion,

functional ability, and erythrocyte sedimentation

rate), with a 30% or greater worsening in not more

than 1 of these variables. As shown in Fig 2, patients

of all 3 JRA onset subtypes showed improvement

from baseline in response variables after open-label

etanercept treatment.53

The second part of the study was a double-blind,

placebo-controlled trial in which the efficacy of etanercept