Juvenile idiopathic arthritis classification

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Dheeraj Makkar, M.D.[2] Nehal Eid, M.D.[3]

Overview

• Juvenile idiopathic arthritis (JIA) is a heterogeneous group of chronic inflammatory arthritides beginning before 16 years of age.
• A classification system was developed 20 years ago by the International League of Associations for Rheumatology (ILAR), which categorized patients into groups to facilitate trial enrollment.
• Novel molecular/pathobiologic views have helped in developing a revised classification system, which is still to be finalized.
• Major subtypes include oligoarticular JIA, polyarticular JIA, and systemic JIA (Still’s disease), with additional categories such as enthesitis-related arthritis and psoriatic JIA. These subtypes differ in clinical presentation, immunopathogenesis, complications, and long-term outcomes.
• Most JIA categories lie on a disease continuum that includes corresponding adult inflammatory arthritides.
• Hallmarks of JIA are asymptomatic chronic anterior uveitis and skeletal deformities (including temporomandibular joint deformity).
• Systemic JIA differs from other categories biologically and phenotypically and is associated with a risk of life-threatening complications.
• Outcomes have been profoundly improved with newer targeted treatments however treatment-free remission is still uncommon, and many need continued care in adulthood.
• Classification

JIA consists of at least five clinically and biologically distinct categories:

Most categories lie on a continuum with adult inflammatory arthritides.

• Oligoarticular JIA

• Polyarticular JIA (RF-negative and RF-positive)

• Systemic JIA

• Enthesitis-related arthritis

• Psoriatic JIA

JIA

Oligoarticular JIA

Polyarticular JIA

Systemic JIA

Enthesitis-related arthritis

Psoriatic JIA

Oligoarticular (pauciarticular) JIA

Oligoarticular (or pauciarticular) JIA affects 4 or fewer joints. Oligo means few. It was previously known as pauciarticular JIA. Patients with oligoarticular JIA are more often ANA positive, when compared to other types of JIA.

• Epidemiology: Most common subtype (≈40–50%), predominantly affects girls aged 1–5 years who often have positive antinuclear antibodies (ANA).

• Joint pattern: Knee most commonly involved; ~50% present with monoarthritis, most often of the knee

• ~50% remain persistent oligoarticular with involvement of 4 or fewer joints and a high likelihood of medication-free remission.

• ~50% progress to extended oligoarticular disease (>4 joints after 6 months) with less likelihood of remission.
• Early wrist or ankle involvement and an elevated ESR predict extension.

• No adult-onset counterpart for early-onset ANA-positive subtype.
• Major complication:

• • Chronic anterior uveitis occurs in up to 30%, often asymptomatic
  • Treatment:
  • Intraarticular glucocorticoid injections may prevent inflammation and prevent further damage
  • In case of inadequate management, complications or extended oligoarticular JIA conventional DMARDs such as methotrexate with or without biologic DMARDs such as TNF inhibitors are administered

Polyarticular JIA

Polyarticular JIA is defined by arthritis affecting five or more joints during the first 6 months of disease. It may involve both large and small joints, including the cervical spine and temporomandibular joints.

• RF-Negative Polyarticular JIA
  • More common than RF-positive disease with prevalence of 15-20% of JIA cases with peak incidence between 1-3 years, and >8 years.
  • It lies on a continuum with extended oligoarticular JIA and adult seronegative RA.
  • Predominantly affects girls
  • ANA positivity may be present in up to 50% of patient population
  • Clinical course overlaps with extended oligoarticular JIA with relapsing or chronic course in many patients
  • Complications:
  • Children < 6 years are at high risk of developing anterior uveitis.
  • Treatment:
  • Initiate treatment with synthetic DMARDs such as methotrexate soon after diagnosis. In case of insufficient response within 2-3 months, biologic DMARD usually TNF inhibitor should be administered. After 3 to 6 months of inadequate disease control, the biologic DMARD should be substituted with a different biologic DMARD or a targeted synthetic DMARD along with the original synthetic DMARD.

Pathophysiology of oligoarticular and RF-negative polyarticular arthritis

Activated Th1 and Th17 lymphocytes lead to macrophage activation and fibroblast-like synoviocytes resulting in production of TNF and IL-6.

• RF-Positive Polyarticular JIA
  • Less common, with only 5% prevalence among JIA cases
  • Occurs more often in older children and adolescents, uncommon under 9 years of age.
  • Rheumatoid factor positive test is required for diagnosis. Anti-citrullinated protein antibodies may be present; ANA may also be positive.
  • It may represent the same disease as adult seropositive RA genetically and clinically.
  • Shares clinical and genetic features with adult seropositive rheumatoid arthritis with prominent B-cell and plasma cell activation along with autoantibody generation.
  • It has a more aggressive and erosive especially without treatment.
  • Treatment:
  • Similar therapeutic approach to RF-negative polyarticular arthritis, however earlier treatment is often initiated due to poor prognosis.

Enthesitis-Related Arthritis:

• It is defined by inflammation at the entheses, where tendons and ligaments attach to bone. Enthesitis often coexists with synovitis of periphral joints ( upper and lower extremities) with frequent affection of peripatellar and calcaneal entheses.
• Its prevalence ranges between 9–19%; 33% in parts of Eastern and Southeastern Asia. It is more common in boys and uncommon before 6 years of age.
• Acute anterior uveitis 11–13%.
• It is on diseases spectrum that includes juvenile spondyloarthritis and juvenile ankylosing spondylitis.
• Clinical manifestations depend on patient's age at disease onset.
• Symptomatic axial involvement such as sacroillitis or inflammatory spine disease develops in 40 to 60% of patients with enthesitis-related arthritis, usually during adolescence, although one study identified asymptomatic sacroillitis in 30% of patients at time of disease onset on magnetic resonance imaging (MRI).
• Positive HLA-B27 is associated with more severe presentation, sacroillitis, juvenile ankylosing spondylitis and acute anterior uveitis.

Pathophysiology of Enthesitis-Related Arthritis:

• HLA-B27 molecule probably presents arthritogenic antigens to CD8+ T cells, 32 resulting in production of interleukin-17 and TNF-α, leading to tendonal, fibrocartligenous, subchondral bone marrow and synovial inflammation. These inflammatory processes lead to pathologic bone alterations combined with mechanical stress.

Treatment: NSAIDs are used for symptomatic relief. They are often combined with sulfasalazine or a TNF inhibitor in case of uncontrolled enthesitis. If sacroillitis is present, biologic DMARDs (commonly TNF inhibitor) should be administered. In case of unresponsiveness to TNF inhibitor, IL-17 inhibitors may be useful.

Psoriatic JIA:

• Bimodal peak incidence at 2-4 years of age and >10 years of age.
• Younger patients have a similar presentation to early-onset oligoarticular and RF-negative polyarticular JIA in terms of female predominance, ANA positivity and risk of chronic anterior uveitis.
• Psoriasis affects 50% of the patients but may appear later in disease course
• Psoriasis familial history, dactylitis or nail pits may support earlier diagnosis.
• Older children may have similar manifestations to adults' psoriatic arthritis such as enthesitis, peripheral polyarthritis and sacroiliitis. HLA-B27 is positive in 10 to 12% of patients.

Treatment: Early onset disease is treated similarly to oligoarticular or polyarticular arthritis depending on number of joints affected. Older children with enthesitis and sacroiliitis receive similar treatment to patients with enthesitis-related psoriasis. Biologic medications targeting psoriatic arthritis such as IL-17, IL-12 and IL-23 inhibitors are approved for use in psoriatic JIA.

Systemic JIA (Still's Disease)

Is characterized by arthritis, fever and a salmon pink rash. Systemic JIA can be challenging to diagnose because the fever and rash come and go. It affects males and females equally, unlike the other two subtypes of JIA.

Systemic JIA may have internal organ involvement and lead to serositis (e.g. pericarditis).

Systemic Juvenile Idiopathic Arthritis (Still's Disease)

Systemic juvenile idiopathic arthritis (systemic JIA), also known as Still's disease, is a distinct subtype of juvenile idiopathic arthritis characterized by arthritis in combination with prominent systemic inflammatory features. Unlike other subtypes of JIA, systemic JIA is considered an autoinflammatory disorder rather than a primarily autoimmune disease.

Epidemiology

• Affects males and females equally
• Can occur at any pediatric age
• Accounts for approximately 10–15% of all cases of juvenile idiopathic arthritis
• Systemic JIA and adult-onset Still’s disease probably represent the same disease entity.
• Recent guidelines from an expert joint task force of the European Alliance of As sociations for Rheumatology and the Pediatric Rheumatology European Society propose using the term “Still’s disease” to denote this apparent continuum.

Clinical Features

Systemic JIA is characterized by quotidian systemic symptoms that may precede the onset of arthritis.

• Daily spiking (quotidian) fevers, often occurring in the evening
• Evanescent, salmon-pink macular rash, typically coinciding with fever spikes
• Arthritis, which may be absent at disease onset and develop later
• Generalized lymphadenopathy
• Hepatosplenomegaly
• Serositis, including pericarditis and pleuritis

Laboratory Findings

• Markedly elevated inflammatory markers (erythrocyte sedimentation rate and C-reactive protein)
• Leukocytosis with neutrophil predominance
• Thrombocytosis
• Elevated ferritin levels
• Absence of antinuclear antibodies and rheumatoid factor in most patients

Complications

• Macrophage activation syndrome, a potentially life-threatening hyperinflammatory condition
• Chronic destructive arthritis in a subset of patients
• Interstitial lung disease and pulmonary hypertension (emerging recognized complications)

Pathophysiology

Earlier in the disease course, activation of the innate immune system occurs, with high levels of proinflammatory cytokines; treatment with interleukin-1 and interleukin-6 inhibitors at this time may produce a remarkable clinical response and even remission. However, chronic arthritis later in the disease course suggests the involvement of adaptive immunity, with specific lymphocyte activation, along with a strong association with HLA-DRB1*11, a major histocompatibility complex (MHC) class II allele.

• It shares pathogenic and clinical features with adult-onset Still's disease, representing a disease continuum

Prognosis

• Disease course is variable, ranging from monophasic self-limited illness to persistent chronic arthritis
• Early control of systemic inflammation is associated with improved long-term outcomes

Diagnosis:

Infections and neoplasms must be considered and ruled out before treatment initiation especially if arthritis is absent at presentation.

It may resemble monogenic autoinflammatory syndromes such as Familial Mediterranean fever.

Treatment:

• Nonsteroidal anti-inflammatory drugs may be used for mild disease
• Systemic glucocorticoids are effective for severe systemic inflammation or macrophage activation syndrome.
• Biologic therapies targeting interleukin-1 or interleukin-6 may produce remarkable clinical improvement and remission early in disease course. They are central to therapeutic management.
• Early biologic intervention may prevent progression to chronic arthritis
• Targeted synthetic DMARDs are emerging therapies for refractory systemic JIA.
• DMARDs such as methotrexate and TNF inhibitors are generally not effective in early systemic JIA, although may be effective if chronic disease develops.

Classification of Juvenile Idiopathic Arthritis

Subtype	Key Features	Most Common Age at Onset	Female:Male Ratio	Proportion of JIA Cases	Immunopathogenesis	Common Complications	Adult Correlate	Treatment
Oligoarticular JIA	≤4 joints in first 6 months; commonly knees; early childhood onset	1-3 yr	3:1	40–50%; highest among patients of European ancestry	Autoimmune; ANA positivity common	Chronic anterior uveitis; limb-length discrepancy	None for early-onset, ANA positive oligoarthritis with uveitis	Treatment: Intraarticular glucocorticoid injections In case of inadequate management, conventional DMARDs such as methotrexate with or without biologic DMARDs such as TNF inhibitors are administered
Polyarticular JIA (RF-negative)	≥5 joints; symmetric small and large joint involvement	Bimodal 1-3 yr and >8 yr	2-4:1	15–20%	Autoimmune; adaptive immune dysregulation	Uveitis; chronic synovitis	Seronegative rheumatoid arthritis	Synthetic DMARDs such as Methotrexate Biologic DMARDs such as TNF inhibitor Targeted biologic DMARDs in case of inadequate control on commonly used biologic ones
Polyarticular JIA (RF-positive)	≥5 joints; resembles adult rheumatoid arthritis	>8 yr	4-13:1	5% among White patients with European ancestry, higher in non-White cohorts	Autoimmune; RF and ACPA positive	Erosive arthritis; functional disability	Seropositive rheumatoid arthritis	Same as RF-negative polyarticular polyarthritis but earlier treatment is recommended
Enthesitis-related arthritis, including juvenile spondyloarthritis and juvenile ankylosing spondylitis	Arthritis with enthesitis	>9 yr	Depends on cohort but approximately 1:1.4–9	9–19%; 33% in parts of eastern and southeastern Asia	Mixed autoimmune and autoinflammatory mechanisms	Sacroiliitis; axial disease; chronic pain	Spondyloarthritis, including ankylosing spondylitis	NSAIDS for symptom control Add sulfasalazine or a TNF inhibitor in case of uncontrolled enthesitis. If sacroillitis is present, biologic DMARDs (commonly TNF inhibitor) should be administered. IL-17 inhibitors may be useful in case of unsuccessful treatment with TNF inhibitor
Psoriatic JIA	Arthritis with psoriasis features	Bimodal: 2–4 yr and >9 yr	3:1 for onset at younger age, 1:1 for onset at older age	2–5%	Mixed autoimmune and autoinflammatory mechanisms		Psoriatic arthritis	Early onset disease is treated similarly to oligoarticular or polyarticular arthritis Older children with enthesitis and sacroiliitis receive similar treatment to patients with enthesitis-related arthritis. Biologic medications targeting psoriatic arthritis inhibitors are approved for use in psoriatic JIA
Systemic JIA (Still’s disease)	Arthritis with quotidian fever and evanescent rash	Any age, but somewhat more frequent at 1–5 yr	1:1	10–20% in Europe, United States, and Canada; higher in Asia, Latin America, Africa, and the Middle East	Autoinflammatory; innate immune activation (IL-1, IL-6)	Macrophage activation syndrome; serositis; lung disease	Adult-onset Still’s disease	Systemic glucocorticoids are effective for severe systemic IL-1 or IL-6 inhibitors may produce remarkable clinical improvement and remission early in disease course. TNF inhibitors and methotrexate may be effective in chronic disease. Targeted synthetic DMARDs are emerging therapies for refractory systemic JIA.