Juvenile Idiopathic Arthritis: Classification and Basic Concepts

Historical Aspects

Pediatric rheumatology, the study and treatment of acute and chronic diseases of the musculoskeletal system, blood vessels, and other tissues, originated in the first half of the 20th century, principally as a study of chronic inflammatory arthritis, the most common of the childhood rheumatic diseases. Archaeological evidence supports the existence of chronic arthritis in children dating back to 900 AD. ^, Thomas Phaire in 1545 described “stifnes or starckenes of the limmes” resulting from exposure of the child to cold, a symptom of uncertain etiology. Three centuries later, Cornil described a woman who had onset of polyarthritis at 12 years of age. An autopsy at age 28 revealed ankylosis, synovial proliferation, and cartilage destruction involving many joints. Several small case series of childhood arthritis were published in the last half of the 19th century, but the disease was believed to be rare. In 1891 Diamant-Berger published the first detailed account of chronic arthritis in 38 children whom he had seen or whose cases had been documented in the literature. In 1896 George Frederic Still described 22 cases of acute and chronic arthritis in children. This treatise documented the clinical characteristics and the differing modes of disease onset in these children. It pointed out that the disease usually had an insidious onset before the eruption of the permanent teeth, and that it was more frequent in girls. He noted that there was often no articular pain, that contractures and muscle wasting occurred early, and that the cervical spine was affected in the majority of cases. Still notably described a subgroup with lymphadenopathy, splenomegaly, fever, pleuritis, and pericarditis, which for many years bore his name: Still disease. In the same year, Koplick described the first American child with chronic arthritis. Knowledge of childhood arthritis has emerged principally in the last half of the 20th century and in the 21st century. Professor Eric Bywaters and Dr. Barbara Ansell at the Canadian Red Cross Hospital, Taplow, England, and Dr. Elizabeth Stoeber at Garmisch-Partenkirchen in Germany were among the first clinician-investigators to focus on childhood arthritis. A summary of the history of arthritis in children has been published by Hayem.

Classifications of Chronic Childhood Arthritis

In the 1970s two similar, but not identical, sets of criteria were proposed to classify chronic childhood arthritis. ^, Differences between them made it difficult to compare studies that used one or another of these criteria. As a result, in 1994, the International League of Associations for Rheumatology (ILAR) sought to provide an internationally agreed system of definitions and a classification to further the study of childhood arthritis. The three classifications are discussed briefly in the following sections.

American College of Rheumatology Classification of Juvenile Rheumatoid Arthritis

The American College of Rheumatology (ACR) criteria ( Box 16.1 ) defined an age limit for disease onset, the duration of disease necessary for a diagnosis, and the characteristics of the arthritis and extraarticular manifestations. The requirement that age at disease onset be less than 16 years reflected practice patterns rather than specific age-related biological variation in disease. Furthermore, although persistent objective arthritis in one or more joints for at least 6 weeks is sufficient for diagnosis, a disease duration of at least 6 months was required before onset type could be confirmed (unless characteristic systemic features are present). Three types of disease were defined: oligoarticular arthritis, also known as pauciarticular arthritis (four or fewer affected joints); polyarticular arthritis (five or more affected joints); and systemic arthritis (arthritis and characteristic fever). An affected joint was defined as one with swelling or effusion, or with two of the following three signs: (1) limitation of range of motion, (2) warmth, and (3) pain on motion or tenderness. When classification depends on the number of inflamed joints, each joint is counted separately except for joints of the cervical spine, carpus, and tarsus, each of which is counted as one joint.

BOX 16.1

Criteria for the Classification of Juvenile Rheumatoid Arthritis

Adapted from J.T. Cassidy, J.E. Levinson, J.C. Bass, et al., A study of classification criteria for a diagnosis of juvenile rheumatoid arthritis, Arthritis Rheum. 29 (1986) 274–281.

1.
Age at onset <16 years
2.
Arthritis (swelling or effusion, or presence of two or more of the following signs: limitation of range of motion, tenderness or pain on motion, and increased heat) in one or more joints
3.
Duration of disease: 6 weeks or longer
4.
Onset type defined by type of disease in first 6 months:
- a.
  Polyarthritis: ≥5 inflamed joints
- b.
  Oligoarthritis (pauciarticular disease): <5 inflamed joints
- c.
  Systemic onset: arthritis with characteristic fever
5.
Exclusion of other forms of juvenile arthritis

European League Against Rheumatism Classification of Juvenile Chronic Arthritis

The term juvenile chronic arthritis (JCA) of the European League Against Rheumatism (EULAR) criteria ( Box 16.2 ) encompassed six disease categories, and differed from the ACR criteria in other ways: the duration of arthritis is 3 months (rather than 6 weeks) and polyarticular arthritis is divided into two categories depending on presence or absence of rheumatoid factor. Those with rheumatoid factor were termed juvenile rheumatoid arthritis (JRA) (a source of confusion when comparing studies using ACR and EULAR criteria). Juvenile psoriatic arthritis and juvenile ankylosing spondylitis were included as distinct categories of JCA, but without specific criteria to define them.

BOX 16.2

Criteria for a Diagnosis of Juvenile Chronic Arthritis

From EULAR Bulletin 4, Nomenclature and classification of arthritis in children, National Zeitung AG, Basel, 1977.

1.
Age at onset <16 years
2.
Arthritis in one or more joints
3.
Duration of disease 3 months or longer
4.
Type defined by characteristics at onset:
- a.
  Pauciarticular: <5 joints
- b.
  Polyarticular: >4 joints, rheumatoid factor negative
- c.
  Systemic: arthritis with characteristic fever
- d.
  Juvenile rheumatoid arthritis: >4 joints, rheumatoid factor positive
- e.
  Juvenile ankylosing spondylitis
- f.
  Juvenile psoriatic arthritis

International League of Associations for Rheumatism Classification of Juvenile Idiopathic Arthritis

In 1995, the Classification Taskforce of the Pediatric Standing Committee of ILAR proposed a classification of the idiopathic arthritides of childhood ( Box 16.3 ). This classification and its revisions ^, were developed by consensus with the aim of achieving homogeneity within disease categories to better facilitate clinical and basic research, and to eliminate inconsistencies resulting from the differences between the ACR and EULAR classifications. Like its predecessors, the ILAR classification applies to children with disease onset before 16 years of age and is based on disease expression during the first 6 months of the disease. It differs, however, in the application of exclusion criteria to minimize overlap and improve homogeneity within the six subtype categories. It resembles the EULAR classification in that polyarthritis is categorized as either rheumatoid factor negative or positive, and it includes psoriatic arthritis and enthesitis-related arthritis (representing diseases similar to psoriatic arthritis and juvenile ankylosing spondylitis of the EULAR criteria). It anticipates that the number of affected joints may not be a useful classification criterion by subdividing oligoarthritis into persistent and extended types. Extended oligoarthritis has been recognized as being similar, at the genetic level, to polyarticular rheumatoid factor negative arthritis, an observation that may influence the development of future classifications.

BOX 16.3

Classification Criteria for Juvenile Idiopathic Arthritis: Edmonton, 2001

Reprinted with permission from The Journal of Rheumatology, Petty RE, et al. International League of Associations for Rheumatology classification of juvenile idiopathic arthritis: second revision, Edmonton, 2001. J Rheumatol 2004;31(2):390–92. All rights reserved.

Systemic Arthritis
Oligoarthritis
- a.
  Persistent
- b.
  Extended
Polyarthritis (rheumatoid factor negative)
Polyarthritis (rheumatoid factor positive)
Psoriatic arthritis
Enthesitis-related arthritis
Undifferentiated arthritis
- a.
  Fits no other category
- b.
  Fits more than one category

The ILAR classification includes undifferentiated arthritis as a seventh category, to accommodate the classification of children who do not meet criteria for any of the six categories or who fulfill criteria for more than one category.

Other Classifications

Although there have been numerous variations on these classification criteria, and on the EULAR criteria in particular, none have been widely used. Classification criteria for three categories of chronic arthritis occurring in childhood merit particular attention, however.

Yamaguchi Criteria for the Diagnosis of Adult-Onset Still Disease

The question arises as to whether systemic juvenile idiopathic arthritis (JIA) should be considered a type of JIA, or whether it should be reclassified as an autoinflammatory disease. One of the principal reasons for this is the occurrence of the disease, which for all intents and purposes is systemic JIA, except that arthritis is absent or has been present for less than the mandatory 2 weeks required by the ILAR classification. The diagnostic criteria proposed by Yamaguchi et al ( Box 16.4 ) for adult-onset Still disease, which is thought to be the adult equivalent of systemic JIA, do not require the presence of arthritis. Kumar et al. studied 13 children who did not have arthritis at disease onset but who developed arthritis from 15 days to 1 year after onset of symptoms. Arthritis developed in many of the children before the sixth month of disease, and these children would therefore have fulfilled ILAR criteria for classification of systemic JIA.

BOX 16.4

The Yamaguchi Criteria for Diagnosis of Adult-Onset Still Disease

Diagnosis requires presence of at least 5 criteria, at least 2 of which are major criteria.

Major Criteria
- Fever of 39°C of higher, lasting 1 week or longer
- Arthralgia lasting 2 weeks or longer
- Typical rash (nonpruritic macular or maculopapular salmon colored over trunk or extremities while febrile)
- Leukocytosis (10,000/mm ³ or greater with 80% or more neutrophils)
Minor Criteria
- Sore throat
- Lymphadenopathy and/or splenomegaly
- Liver dysfunction
- Negative tests for ANA and RF
Exclusions
- Infections, malignancies, and rheumatic diseases

Classification of Spondyloarthropathies

Moll and Wright introduced the concept of seronegative spondyloarthritis, a grouping of chronic arthritides on the basis of seronegativity for rheumatoid factor, absence of rheumatoid nodules, a tendency toward family history of similar diseases, and the frequent involvement of the sacroiliac joints and lumbosacral spine. The later discovery of the association of this spectrum of disorders with the human leukocyte antigen HLA-B27 further strengthened the legitimacy of the association. Originally included in this grouping were ankylosing spondylitis (AS), psoriatic arthritis, reactive arthritis, arthritis with inflammatory bowel disease, JCA, Whipple syndrome, Behçet syndrome, and acute anterior uveitis. As currently used, the spondyloarthritis concept includes AS, psoriatic arthritis, reactive arthritis, and the axial spine arthritis of inflammatory bowel disease. AS is the prototype of the spondyloarthritides, and the other members are quite heterogeneous; some have a strong similarity to AS whereas others do not, especially in childhood. Two major challenges in defining the spondyloarthritides are that they evolve considerably over time, and within any one category (e.g., juvenile psoriatic arthritis and the arthritis of inflammatory bowel disease), there is considerable heterogeneity (see Chapter 21, Chapter 51 ). Some, but not most, children with arthritis and psoriasis do not have axial arthritis or enthesitis. Most children with inflammatory bowel disease and arthritis do not have spondylitis or HLA-B27. Their inclusion in groups as spondyloarthritides is therefore problematic, because many, if not most, do not conform to the ankylosing spondylitis prototype. The problem has been the subject of many publications.

Classification of Psoriatic Arthritis in Childhood

The place of psoriatic arthritis as an identifiable category of chronic arthritis in adults is well established. Criteria for the classification of juvenile psoriatic arthritis have been proposed, ^, and are a component of the ILAR classification of JIA. The identification of a child with juvenile psoriatic arthritis is difficult, however, because psoriasis may be atypical, misdiagnosed, or delayed in its appearance after the onset of arthritis. Furthermore, children with psoriatic arthritis share some characteristics with oligoarticular JIA (chronic uveitis, antinuclear antibodies [ANA] positivity) or enthesitis-related arthritis (occasional presence of axial spine disease or the presence of HLA-B27; see Chapter 21 ).

New Classification Proposals

The ILAR criteria were intended to be modified as new information became available. Numerous suggestions have been collected and proposed changes will be tested in an international cohort . This classification proposes four categories of JIA: (1) rheumatoid factor (RF)-positive arthritis, (2) enthesitis/spondyloarthritis-related JIA, (3) systemic JIA, and (4) ANA-positive arthritis in young girls. It is probable that RF-positive arthritis is the same disease in children and adults, ^, and that systemic JIA is the same disease as adult-onset Still disease. The utility of using the number of inflamed joints as a classification criterion (as in the ACR, EULAR, and ILAR classifications) is based on clinical observation, and imaging with magnetic resonance imaging (MRI) may well detect affected joints that are not apparent clinically. It is theoretically logical, therefore, to exclude the number of affected joints from consideration in classification. The proposed enthesitis/spondyloarthritis category and ANA-positive arthritis in young girls category are more controversial and their validity awaits results of this and other studies. It would be preferable that any future classification take into account the contribution of genetics and biomarkers, some of which will hopefully emerge as attempts are made to validate these criteria. This proposal has been reviewed in an editorial by Beukelman and Nigrovic. These authors suggest, furthermore, that it may be time to discard the differentiation between adult and childhood arthritis and recognize the identity of some disease categories that cross between childhood and adulthood.

Notwithstanding the arguments favoring a change in classification of childhood arthritis, at the time of this writing the revised ILAR classification criteria for JIA remain the predominant classification of chronic childhood arthritis. Almost all published studies of chronic childhood arthritis over the last two decades have used the ILAR classification, enabling comparison between studies and cohorts, and for these reasons it is the classification that is used throughout this textbook.

Epidemiology

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