Background

Juvenile idiopathic arthritis (JIA) is the most common rheumatologic disease in childhood, with an overall prevalence of 7 to 400 per 100,000 children.^1,2 JIA is an important cause of chronic disease in childhood, with prevalence similar to type I diabetes mellitus.³ Several classification systems have been used over time to categorize the various categories of juvenile arthritis, including juvenile rheumatoid arthritis (JRA) and juvenile chronic arthritis (JCA), based upon clinical presentation and disease course. In 1995, the International League of Associations for Rheumatology (ILAR) proposed a new classification system, JIA, which consists of seven main categories. These categories are useful in examining potential differences in treatment response and prognosis. The main categories of JIA are:⁴

• Systemic arthritis: Initial presentation includes spiking fever, rash, and arthritis; one-quarter of children may have severe destructive disease.
• Oligoarthritis: Affects up to four joints within the first 6 months of illness; may be persistent (i.e., involving no more than four joints) or extended (i.e., involving more than four joints after the first 6 months of illness), and may be associated with uveitis.
• Polyarthritis Rheumatoid Factor-Negative: Affects five or more joints during the first 6 months of disease. May be associated with uveitis.
• Polyarticular Rheumatoid Factor-Positive: Affects five or more joints during the first 6 months of disease, and is more likely to result in destructive joint disease. May be associated with uveitis.
• Enthesitis-related arthritis: May be associated with uveitis.
• Psoriatic arthritis: May be associated with uveitis.
• Undifferentiated: Arthritis lasting more than 6 weeks that does not meet the criteria for any of the above categories, or that meets the criteria for more than one category.

It is important to note, however, that the previous definitions of JCA and JRA will be used when reviewing literature published prior to the acceptance of the JIA categorization system.

JIA can place a severe physical and psychological burden on affected children and be a major stressor to their families. As is true for all chronic conditions in childhood, treatment of JIA may be enhanced through the use of a multidisciplinary team to address these issues. There is no cure for JIA, but over the past 25 years new therapies have provided great advances in treatment and symptom control. Previous treatments with non-steroidal anti-inflammatory drugs (NSAIDs; e.g., ibuprofen) and corticosteroids (systemic or intra-articular) were only partially effective in treating the symptoms of arthritis and reducing long-term complications (e.g., growth delay, erosive joint disease, persistently active disease, mortality). Treatment with the class of agents known as disease-modifying antirheumatic drugs (DMARDs) has become an increasingly important component of care because these drugs appear to lead to better disease control, with higher numbers of children achieving remission, and fewer children suffering long-term joint damage. DMARDs interfere with the making or working of immune cells that cause joint inflammation and are typically classified as either biologic drugs, which are created by biologic processes, or non-biologic drugs, which are manufactured chemically. In general, the non-biologic DMARDs are older. Most biologic DMARDs target specific components of the immune system (e.g., signaling or cell-surface molecules). One of these non-biologic DMARDs, methotrexate, whose exact mechanism is unknown, has been used for so long in the treatment of JIA that it is often considered part of conventional treatment, along with NSAIDs and intra-articular corticosteroids.

Although there is significant optimism that treatment with the newer biologic DMARDs may increasingly lead to long-term disease remission, there are many unanswered questions about the safety of these drugs, especially for long-term use in children. For example, the U.S. Food and Drug Administration (FDA) recently placed a box warning on the entire class of biologic DMARDs targeting tumor necrosis factor (TNF) alpha, including etanercept, infliximab, and adalimumab, due to concerns about potential increased risk of malignancy, in particular lymphoma. There are also important questions about effectiveness, including the comparative effectiveness of DMARDs versus conventional treatment and the comparative effectiveness of the various DMARDs versus one another. Furthermore, it is possible that the effectiveness of these drugs varies by category of JIA. Understanding the circumstances in which a DMARD should be used, and which DMARD(s) should be selected, is challenging because JIA is heterogeneous across the various categories. A clear synthesis of the available evidence is needed to help clinicians provide care for children with JIA and to identify the important gaps in the scientific literature.

Juvenile arthritis has a broad impact on a child's physical and mental health. Developing instruments that accurately assess the effect of JIA on health and well-being is critical to enable us to asses the overall impact of the disease and to quantify the efficacy of treatments. The heterogeneity of disease severity, the broad age range of affected individuals, and fluctuations in the natural history of the disease complicate the measurement of disease activity and treatment effects in children with JIA. To provide the most accurate assessment of treatment effects we depend on the performance characteristics (e.g., sensitivity, specificity, responsiveness to change) of the outcomes measures reported in the scientific literature. Multiple instruments have been developed or adapted to assess severity of disease, disability, and quality of life in JIA. Understanding the reliability, validity, and responsiveness of these instruments will facilitate interpretation of clinical trial data.

In this comparative effectiveness review, we examine the scientific literature on DMARDs for JIA in childhood. Moreover, we review evidence regarding the usefulness of available outcomes measures for JIA that are commonly used in clinical trials and within the clinical practice setting.

Scope and Key Questions

This review summarizes the evidence on the benefits and harms of DMARDs compared to conventional treatment (NSAIDs and/or intra-articular corticosteroids) with or without methotrexate, and of the various DMARDs compared to one another, in children with JIA. In addition, this review summarizes the usefulness of selected tools commonly used to measure clinical outcomes associated with JIA.

Key questions addressed are:

Key Question 1.

In children^a with JIA,^b does treatment with DMARDs,^c compared to conventional treatment (i.e., NSAIDs or corticosteroids) with or without methotrexate,^d improve laboratory measures of inflammation or radiological progression, symptoms (e.g., pain, symptom scores), or health status (e.g., functional ability, mortality)?

Key Question 2.

In children with JIA, what are the comparative effects of DMARDs^e on laboratory markers of inflammation or radiological progression, symptoms (e.g., pain, symptom scores), or health status (e.g., functional ability, mortality)?

Key Question 3.

In children with JIA, does the rate and type of adverse events^f differ between the various DMARDs or between DMARDs and conventional treatment with or without methotrexate?

Key Question 4.

How do the efficacy, effectiveness, safety, and adverse effects of treatment with DMARDs differ among the various categories^g of JIA?

Key Question 5.

What are the validity, reliability, responsiveness, and feasibility of the clinical outcomes measures^h for childhood JIA that are commonly used in clinical trials or within the clinical practice setting?

These instruments were assessed for test-retest reliability, inter- and intra-rater reliability, internal reliability, construct validity, responsiveness (standardized response mean and responsiveness index), and feasibility metrics such as time to administer.

Footnotes

a

“Children” are defined as individuals aged 18 years or younger.

b

“JIA” includes any category of any severity of the following:

• JIA according to the International League of Associations for Rheumatology (ILAR) criteria;
• Juvenile rheumatoid arthritis (JRA) according to the American College of Rheumatology (ACR) definition; or
• Juvenile chronic arthritis (JCA) according to the European League Against Rheumatism (EULAR) criteria.

c

DMARDs evaluated are: abatacept, adalimumab, anakinra, canakinumab, etanercept, infliximab, intravenous immunoglobulin (IVIG), rilonacept, rituximab, and tocilizumab (biologic DMARDs); and azathioprine, cyclosporine A, penicillamine, hydroxychloroquine, leflunomide, methotrexate, mycophenolate mofetil, sulfasalazine, tacrolimus (FK506), and thalidomide (non-biologic DMARDs).

d

Conventional treatments evaluated are: betamethasone, triamcinolone acetonide, triamcinolone hexacetonide, celecoxib, etodolac, ibuprofen, indomethacin, meloxicam, naproxen, oxaprozin, and tolmetin.

e

This question is identical to Key Question 1, but focuses on comparisons of one DMARD versus another, rather than on comparisons of DMARDs versus conventional treatments.

f

Because of the known risks associated with DMARDs, we focused primarily on serious infections and the development of cancer when assessing adverse events. Other adverse events considered included mortality, hepatitis, bone marrow suppression, nausea or vomiting, and risks to fetus or pregnant mother.

g

Categories of JIA include:

• Systemic arthritis
• Oligoarthritis
• Rheumatoid-factor positive (RF+) polyarthritis
• Rheumatoid-factor negative (RF-) polyarthritis
• Enthesitis-related arthritis
• Psoriatic arthritis
• Other (arthritis of unknown cause with symptoms lasting more than 6 weeks).

h

The outcomes measures assessed were those most commonly used in clinical trials and practice, as well as newer instruments of particular interest that were selected in consultation with the project's technical expert panel (TEP). The outcome measures assessed were:

• Measures of disease activity:

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  Active joint count (AJC)

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  Physician global assessment of disease activity (PGA)

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  Parent/patient global assessment of well-being (PGW)

• Measure of functional status/disability:

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  Childhood Health Assessment Questionnaire (CHAQ)

• Measures of health-related quality of life:

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  Child Health Questionnaire (CHQ)

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  Pediatric Quality of Life Inventory (PedsQL) 4.0

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  Pediatric Quality of Life Inventory Rheumatology Module (PedsQL-RM)

• Composite measures of response to therapy and developing definitions of disease status:

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  American College of Rheumatology Pediatric Response Criteria (ACR Pediatric 30)

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  Juvenile Arthritis Disease Activity Score (JADAS)

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  A consensus-based definition of remission

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  Flare

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  Minimal disease activity (MDA)