Modified from Cassidy JT, Levison JE, Bass JC, et al: A study of classification criteria for a diagnosis of juvenile rheumatoid arthritis, Arthritis Rheum 29;174–181, 1986.

Table 149-2 CHARACTERISTICS OF THE AMERICAN COLLEGE OF RHEUMATOLOGY (ACR) AND INTERNATIONAL LEAGUE OF ASSOCIATIONS FOR RHEUMATOLOGY (ILAR) CLASSIFICATIONS OF CHILDHOOD CHRONIC ARTHRITIS

PARAMETER	ACR (1977)	ILAR (1997)
Term	Juvenile rheumatoid arthritis (JRA)	Juvenile idiopathic arthritis (JIA)
Minimum duration	≥6 wk	≥6 wk
Age at onset	<16 yr	<16 yr
≤4 joints in 1st 6 mo after presentation	• Pauciarticular	• Oligoarthritis: A Persistent: <4 joints for course of disease B Extended: >4 joints after 6 mo
>4 joints in 1st 6 mo after presentation	• Polyarticular	• Polyarticular rheumatoid factor–negative • Polyarticular rheumatoid factor–positive
Fever, rash, arthritis	• Systemic	• Systemic
Other categories included	Exclusion of other forms	• Psoriatic arthritis • Enthesitis-related arthritis • Undifferentiated: A Fits no other category B Fits more than one category
Inclusion of psoriatic arthritis, inflammatory bowel disease, ankylosing spondylitis	No (Chapter 150)	Yes

Table 149-3 INTERNATIONAL LEAGUE OF ASSOCIATIONS FOR RHEUMATOLOGY CLASSIFICATION OF JUVENILE IDIOPATHIC ARTHRITIS (JIA)

CATEGORY	DEFINITION	EXCLUSIONS
Systemic-onset JIA	Arthritis in ≥1 joints with, or preceded by, fever of at least 2 wk in duration that is documented to be daily (“quotidian”*) for at least 3 days and accompanied by ≥1 of the following: 1 Evanescent (nonfixed) erythematous rash. 2 Generalized lymph node enlargement. 3 Hepatomegaly or splenomegaly or both. 4 Serositis.^†	a Psoriasis or a history of psoriasis in the patient or a 1st-degree relative. b Arthritis in an HLA-B27–positive boy beginning after the 6th birthday. c Ankylosing spondylitis, enthesitis-related arthritis, sacroiliitis with inflammatory bowel disease, Reiter syndrome, or acute anterior uveitis, or a history of one of these disorders in a 1st-degree relative. d Presence of immunoglobulin M RF on at least 2 occasions at least 3 mo apart.
Oligoarticular JIA	Arthritis affecting 1-4 joints during the 1st 6 mo of disease. Two subcategories are recognized: 1 Persistent oligoarthritis—affecting ≤4 joints throughout the disease course. 2 Extended oligoarthritis—affecting >4 joints after the 1st 6 mo of disease.	a, b, c, d (above) plus e. Presence of systemic JIA in the patient.
Polyarthritis (RF-negative)	Arthritis affecting ≥5 joints during the 1st 6 mo of disease; a test for RF is negative.	a, b, c, d, e
Polyarthritis (RF-positive)	Arthritis affecting ≥5 joints during the 1st 6 mo of disease; ≥2 tests for RF at least 3 mo apart during the 1st 6 mo of disease are positive.	a, b, c ,e
Psoriatic arthritis	Arthritis and psoriasis, or arthritis and at least 2 of the following:	b, c, d, e
	1. Dactylitis.^‡
	2. Nail pitting^§ and onycholysis.
	3. Psoriasis in a 1st-degree relative.
Enthesitis-related arthritis	Arthritis and enthesitis,^\| or arthritis or enthesitis with at least 2 of the following:	a, d, e
	1 Presence of or a history of sacroiliac joint tenderness or inflammatory lumbosacral pain or both.^¶ 2 Presence of HLA-B27 antigen. 3 Onset of arthritis in a male > 6 yr old. 4 Acute (symptomatic) anterior uveitis. 5 History of ankylosing spondylitis, enthesitis-related arthritis, sacroiliitis with inflammatory bowel disease, Reiter syndrome, or acute anterior uveitis in a 1st-degree relative.
Undifferentiated arthritis	Arthritis that fulfills criteria in no category or in ≥2 of the above categories.

RF, rheumatoid factor.

* Quotidian fever is defined as a fever that rises to 39°C once a day and returns to 37°C between fever peaks.

^† Serositis refers to pericarditis, pleuritis, or peritonitis, or some combination of the three.

^‡ Dactylitis is swelling of ≥1 digits, usually in an asymmetric distribution, that extends beyond the joint margin.

^§ A minimum of 2 pits on any one or more nails at any time.

^| Enthesitis is defined as tenderness at the insertion of a tendon, ligament, joint capsule, or fascia to bone.

^¶ Inflammatory lumbosacral pain refers to lumbosacral pain at rest with morning stiffness that improves on movement.

From Firestein GS, Budd RC, Harris ED Jr, et al, editors: Kelley’s textbook of rheumatology, ed 8, Philadelphia, 2009, Saunders/Elsevier.

Table 149-4 OVERVIEW OF THE MAIN FEATURES OF THE SUBTYPES OF JUVENILE IDIOPATHIC ARTHRITIS

Epidemiology

The worldwide incidence of JIA ranges from 0.8 to 22.6/100,000 children per year, with prevalence ranges from 7 to 401/ 100,000. These wide-ranging numbers are attributable to population differences, particularly environmental exposure and immunogenetic susceptibility, along with difficulty in case ascertainment and lack of population-based data. It is estimated that 300,000 children in the USA have arthritis, including 100,000 with a form of JIA. Pauciarticular JIA (oligoarthritis) is the most common subtype (50-60%), followed by polyarticular (30-35%) and systemic-onset (10-20%). There is no sex predominance in systemic-onset JIA (SoJIA), but more girls than boys are affected in both pauciarticular (3 : 1) and polyarticular (5 : 1) JIA. The peak age at onset is between 2 and 4 yr for pauciarticular disease. Age of onset has a bimodal distribution in polyarthritis, with peaks at 2-4 yr and 10-14 yr. SoJIA occurs throughout childhood without a peak.

Etiology

The etiology and pathogenesis of JIA is not completely understood. At least 2 components are considered necessary: immunogenetic susceptibility and an external trigger. JIA is a complex genetic trait in which multiple genes may affect disease susceptibility. Various major histocompatibility complex regions (HLA) class I and class II alleles have been associated with different JIA subtypes. Several non-HLA candidate loci are also associated with JIA, including polymorphisms in the genes encoding tumor necrosis factor (TNF)-α, macrophage inhibitory factor (MIF), interleukin-6 (IL-6), and IL-1α. Possible nongenetic triggers include bacterial and viral infections (parvovirus B19, rubella, Epstein-Barr virus), enhanced immune responses to bacterial or mycobacterial heat shock proteins, abnormal reproductive hormone levels, and joint trauma.

Pathogenesis

JIA is an autoimmune disease associated with alterations in both humoral and cell-mediated immunity. T lymphocytes have a central role, releasing proinflammatory cytokines (e.g., TNF-α, IL-6, and IL-1). The cytokine profile favors type 1 helper T-lymphocyte response. Studies of T-cell receptor expression confirm recruitment of T lymphocytes specific for synovial non-self antigens. Complement consumption, immune complex formation, and B-cell activation also promote inflammation. Inheritance of specific cytokine alleles may predispose to upregulation of inflammatory networks, resulting in systemic-onset disease or more severe articular disease.

Systemic-onset JIA may be more accurately classified as an autoinflammatory disorder, more like familial Mediterranean fever (FMF), than the other subtypes of JIA. This theory is supported by work demonstrating similar expression patterns of a phagocytic protein (S100A12) in SoJIA and FMF, as well as the same marked responsiveness to IL-1 receptor antagonists.

All these immunologic abnormalities cause inflammatory synovitis, characterized pathologically by villous hypertrophy and hyperplasia with hyperemia and edema of the synovial tissue. Vascular endothelial hyperplasia is prominent and is characterized by infiltration of mononuclear and plasma cells with a predominance of T lymphocytes (Fig. 149-1). Advanced and uncontrolled disease leads to pannus formation and progressive erosion of articular cartilage and contiguous bone (Figs. 149-2 and 149-3).

Figure 149-1 Synovial biopsy specimen from a 10 yr old child with oligoarticular juvenile idiopathic arthritis. There is a dense infiltration of lymphocytes and plasma cells in the synovium.

Figure 149-2 Arthroscopy in the shoulder of a child with juvenile idiopathic arthritis showing pannus formation and cartilage erosions.

(Courtesy of Dr. Alison Toth.)

Figure 149-3 MRI with gadolinium of a 10 yr old child with juvenile rheumatoid arthritis (same patient as in Fig. 149-1). The dense white signal in the synovium near the distal femur, proximal tibia, and patella reflects inflammation. MRI of the knee is useful to exclude ligamentous injury, chondromalacia of the patella, and tumor.

Clinical Manifestations

Arthritis must be present for a diagnosis of any subtype of JIA to be made. Arthritis is defined by intra-articular swelling or the presence of 2 or more of the following signs: limitation in range of motion, tenderness or pain on motion, and increased heat or erythema. Initial symptoms may be subtle or acute and often include morning stiffness with a limp or gelling after inactivity. Easy fatigability and poor sleep quality may be associated. Involved joints are often swollen, warm to touch, and painful on movement or palpation with reduced range of motion but usually are not erythematous. Arthritis in large joints, especially knees, initially accelerates linear growth, causing the affected limb to be longer and resulting in a discrepancy in limb lengths. Continued inflammation stimulates rapid and premature closure of the growth plate, resulting in shortened bones.

Oligoarthritis is defined as involving ≤4 joints within the first 6 mo of disease onset, predominantly affecting the large joints of the lower extremities, such as the knees and ankles (Fig. 149-4). Often only a single joint is involved. Isolated involvement of upper extremity large joints is less common. Those in whom disease never develops in more than 4 joints are regarded as having persistent oligoarticular JIA, whereas evolution of disease in more than 4 joints over time changes the classification to extended oligoarticular JIA. The latter often portends a worse prognosis. Involvement of the hip is almost never a presenting sign and suggests a spondyloarthropathy (Chapter 150) or nonrheumatologic cause. The presence of a positive antinuclear antibody (ANA) test result confers increased risk for asymptomatic anterior uveitis, requiring periodic slit-lamp examination (Table 149-5).