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- .

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

uvenile 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 100 000.1 The 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

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

From the Division of Rheumatology, Schneider Childrens Hospital, New Hyde Park, New York, and Department of Pediatrics, Albert Einstein College of Medicine, Bronx, New York. Received for publication Apr 20, 2001; accepted Jun 26, 2001. Reprint requests to (N.T.I.) Schneider Childrens Hospital, 269-01 76th Ave, Rm 197, New Hyde Park, NY 11040. E-mail: ilowite@lij.edu PEDIATRICS (ISSN 0031 4005). Copyright 2002 by the American Academy of Pediatrics.

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.
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TABLE 1.

Key Clinical Characteristics of JRA Onset Types Clinical Symptoms Fever, light salmon-colored rash, extra-articular manifestations Fewer than 5 joints involved during the first 6 mo of illness Subtypes Not applicable Early childhood onset Late childhood onset Associated Characteristics Organomegaly and lymphadenopathy sometimes present Usually young females; high incidence of chronic uveitis; antinuclear antibodypositive Usually males older than 8 years; high incidence of sacroiliitis; HLA B27-positive Onset later in childhood Onset later in childhood; similar to adult RA

Onset Type Systemic Pauciarticular

Polyarticular

Five or more joints involved during the first 6 mo of illness

RF-negative RF-positive

PROGNOSTIC INDICATORS

TABLE 2.

Poor Prognostic Indicators for Patients With JRA

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

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 Gare and Fasthr,5 Takei et al,12 and Cassidy and Petty.13

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.1520 Cognitive-behavioral pain management techniques have also been successful in reducing pain intensity in pediatric patients.21 Physical ther-

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

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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

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

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

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

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

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, consolidaSPECIAL ARTICLE 111

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
TABLE 3. Proinflammatory Effects of TNF Leading to Inflammation, Pannus Development, and Joint Destruction* Inflammatory cells Proinflammatory cytokine release (through autocrine and paracrine stimulation) Neutrophil degranulation Endothelial cells Adhesion molecule expression Angiogenesis mediated by vascular endothelial growth factor Synovial fibroblasts Increased production of neutral metalloproteases, prostaglandin E2, nitric oxide, and superoxide Decreased production of tissue inhibitor of metalloproteases Proliferation * Adapted from Jarvis and Faulds.70

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 was more rigorously assessed. Patients who responded in part 1 were randomized to receive blinded treatment with placebo or etanercept 0.4 mg/kg subcutaneously (maximum 25 mg subcutaneously twice weekly) twice weekly for 4 months or until disease flare. Significantly fewer etanercepttreated patients experienced a disease flare compared with patients who received placebo (28% vs 81%; P .003), and the median time to disease flare was much longer ( 116 days vs 28 days; P .001) for those in the etanercept group.51 A subsequent open-label extension trial demonstrated that, with continued treatment, the clinical effect of etanercept is maintained for at least 16 months.54 Etanercept was generally well-tolerated in pediatric patients. The most common adverse events were injection site reactions, headaches, and upper respiratory infections of mild to moderate severity.51,54 Although not observed in the placebo-controlled phase of the study, concern exists regarding increased susceptibility to infection. However, in long-term, controlled trials of etanercept versus placebo, no increased rate of infection was observed.49 It is recommended that pediatric patients be brought up to date with all immunizations before receiving etanercept. Because of cases of aseptic meningitis with varicella zoster infection, immunization with varicella in susceptible children and administration of varicella zoster immune globulin in exposed individuals have been recommended. However, live vaccines should not be given concurrently with etanercept.49,51,54 Ideally, approximately 3 months should be allowed to elapse between live virus vaccination and initiation of etanercept therapy. Pediatric patients with significant exposure to varicella should temporarily discontinue etanercept. In patients with adult RA, etanercept effectively controls disease symptoms.5557 More significantly, etanercept retards radiographic progression in adults with early RA; patients who receive etanercept have been found to have less radiographic disease progression than those who receive methotrex-

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Fig 2. Percentage improvement from baseline at day 90 in the open-label, part I study of etanercept in patients with polyarticular-course JRA according to disease onset type. LOM, loss of motion. Data are from Lovell et al.53

ate, as assessed by total Sharp score (scores based on radiographic evidence of joint erosion) and magnetic resonance imaging.58,59 Although no radiographic studies have been performed in patients with JRA, the available data indicate that etanercept is likely to be a valuable agent in the control of this disease.
Infliximab

Another TNF-neutralizing agent, infliximab (also known as cA2), is a chimeric human-mouse monoclonal antibody to TNF.60 Available data regarding efficacy are limited; indeed, dosing and pharmacokinetic data in pediatric patients are lacking. A case study discusses the use of this agent to treat a patient who had severe systemic-onset JCA resistant to conventional therapies.61 The patient received 2 intravenous infusions of infliximab 10 mg/kg separated by 1 week. Treatment was well-tolerated and resulted in rapid control of fever, anorexia, and serositis.61 However, there was no significant improvement in joint pain or tenderness.61 The role of infliximab in the treatment of juvenile arthritis awaits large-scale studies.
COX-2 Inhibitors

activity, and disability index score in RA patients compared with placebo.64 Although COX-2 inhibitors may be a valuable addition to the treatment of adult RA, their contribution to JRA is likely to be less significant. Pediatric patients do not typically experience significant gastrointestinal problems with NSAIDs as often as adults. For instance, in a database study of 702 patients with JRA, only 5 patients were found to have had a gastropathic event attributable to NSAID therapy.65 However, in selected populations (eg, patients with abdominal pain and anemia), the incidence of gastroduodenal lesions is much higher.66,67 In any case, COX-2 inhibitors may be helpful in pediatric patients who do experience gastrointestinal adverse events and may also be helpful in cases of other NSAID-associated adverse effects, such as naproxeninduced pseudoporphyria.26
REMAINING CHALLENGES IN THE MANAGEMENT OF JRA

A new class of therapeutic NSAID agents has been designed to inhibit selectively the COX-2 enzyme, thus allowing the continued production of COX-1, an essential enzyme involved in cytoprotective and regulatory functions in gastrointestinal mucosa, platelets, and renal cells. Studies in adults with RA suggest that celecoxib is associated with a lower incidence of ulcers than conventional pain relief agents, such as naproxen and diclofenac.62,63 Another COX-2 inhibitor, rofecoxib, has been shown to improve ACR 20 response, patient assessment of pain, patient and physician assessment of disease

Our knowledge of JRA remains incomplete. An improved understanding of disease cause and pathogenesis could provide insights into the possible relationships among different disease subtypes and may also reveal new therapeutic options. Among the current crop of new adult RA agents, only 1, etanercept, has been adequately tested in patients with JRA. For the foreseeable future, the optimal treatment of JRA will continue to pose a challenge to clinicians. Our inability to predict patient outcome accurately remains a barrier to optimal management. Additional studies on factors associated with favorable and unfavorable prognoses would be invaluable in guiding therapy. We must learn to optimize JRA therapy in the context of new options. Studies of combination regimens, such as etanercept plus methotrexate, may
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provide more effective options for first- and secondline treatment of patients with JRA. In addition, the optimal agent or combination of agents for resistant and severe chronic uveitis has yet to be identified. For most patients with a poor prognosis, methotrexate will continue to be the first-line DMARD. Until more clinical experience is gained, etanercept should be reserved until after methotrexate failure in JRA because long-term study data of etanercept therapy in JRA are not yet available. Nevertheless, the significant proportion of incomplete responders or nonresponders to methotrexate suggests that etanercept will be a valuable addition to JRA treatment options. This agent is well-tolerated by both adults and children, and data from long-term studies have not revealed any cumulative toxicities. However, infections, neoplastic complications, hematologic complications, and multiple sclerosis-like neurologic disease have been identified in small numbers of patients during postmarketing surveillance, and concerns regarding these events exist because long-term experience is still limited.54,68 Options for etanercept nonresponders include cyclosporin A, azathioprine, and sulfasalazine, or parenteral gold. Other biologics including inhibitors of interleukin-1 (r-metHuIl1ra), and antibodies that bind to Bcell surface antigens (rituximab) are being evaluated in the treatment of arthritis. For patients who have severe systemic JRA and have failed proven therapies, monthly intravenous cyclophosphamide has been studied.45 For patients with severe, recalcitrant disease, autologous stem cell transplantation has been considered. There is some encouraging preliminary efficacy data regarding this procedure; however, there is significant associated morbidity and mortality, including the life-threatening complication of macrophage activation syndrome.69 At present, these treatments should be considered experimental and should be reserved for only those patients who have the most severe disease, and be performed in experienced centers. The Pediatric Rule of the FDA is encouraging study of dosing, pharmacokinetics, safety, and efficacy of new agents for JRA, and new data thus obtained are likely to improve our future understanding regarding optimal treatment of this disease.
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