Juvenile idiopathic arthritis

Authors: Nicole S. Kim, Medical Student, University of Toronto, Canada. Dr Yuliya Velykoredko, Dermatology Resident, University of Toronto, Canada. DermNet NZ Editor-in-Chief: A/Prof Amanda Oakley, Dermatologist, Hamilton, New Zealand. Copy edited by Gus Mitchell. September 2018.


What is juvenile idiopathic arthritis?

Juvenile idiopathic arthritis (sometimes abbreviated as JIA) encompasses all chronic childhood arthropathies beginning before 16 years of age, with persistence of arthritis for at least 6 weeks.

Juvenile idiopathic arthritis is recognised as having seven major subtypes, some of which exhibit clinical and pathological features of other autoimmune disorders:

  • Systemic juvenile idiopathic arthritis (also known as juvenile-onset Still disease)
  • Oligoarthritis
  • Rheumatic factor (RF)-positive polyarthritis
  • RF-negative polyarthritis
  • Psoriatic arthritis
  • Enthesitis-related arthritis
  • Undifferentiated arthritis [2,3].
Juvenile idiopathic arthritis

Who gets juvenile idiopathic arthritis?

Juvenile idiopathic arthritis can occur in anyone from infants to adolescents, with a mean onset age of 6 years of age. Most types of juvenile idiopathic arthritis affect boys and girls equally, although systemic-onset juvenile idiopathic arthritis (juvenile-onset Still disease) is predominantly seen in female children [1].

What causes juvenile idiopathic arthritis?

The exact cause of juvenile idiopathic arthritis is unclear, but a pronounced immune response in a perpetuating loop of both innate and adaptive immunity is believed to contribute to the pathogenesis of juvenile idiopathic arthritis. Aberrant activation of the innate immune system, leading to dysregulated production of inflammatory cytokines. Tumour necrosis factor [TNF]-alpha, interleukin [IL]-1, and IL-6 play a critical inciting role. The effects of the cytokines provide explanations for various clinical features seen in systemic juvenile idiopathic arthritis. These effects include:

  • Bone marrow granulopoiesis (proliferation of granulocytes)
  • Increase in osteoclast activity (cells that absorb bone)
  • Hepatocyte stimulation
  • Activation of thermoregulatory functions [1,5].

Increased recruitment of inflammatory cells in the joint synovial membrane was demonstrated in several studies by significant elevation of proinflammatory cytokines in the synovial fluid of affected children. Inflammatory cytokines in the synovium lead to increased production and accumulation of synovial fluid, and thickening of the synovial lining. This chronic synovial inflammation is apparent and common to all juvenile idiopathic arthritis subtypes. In addition, RANKL cytokine, which is associated with bone resorption and cartilage damage, was reported to be present in large amounts in the synovial membrane of children with juvenile idiopathic arthritis.

Some studies have consistently supported associations between enthesitis-related juvenile idiopathic arthritis and HLA polymorphisms. There appears to be increased associations especially with early-onset disease. A monogenic form of systemic juvenile idiopathic arthritis with an underlying mutation in regulatory protein involved in macrophage metabolism has been described [1,3].

Environmental factors may be contributory to the development of juvenile idiopathic arthritis. Some studies have suggested associations with exposure to antibiotics, bacterial infection in immune-suppressed individuals, and maternal smoking during pregnancy [3,5].

What are the clinical features of juvenile idiopathic arthritis?

Cutaneous involvement is one of the key extra-articular factors in systemic juvenile idiopathic arthritis. The exanthem or rash presents as discrete, salmon-pink macules or oedematous papules that are typically transient and coinciding with fevers. They tend to occur on the trunk, axillae and proximal extremities, but are not commonly seen on the palms, soles, or the face. Persistent plaques, periorbital oedema or erythema are less common but may be observed.

Although rashes in juvenile idiopathic arthritis are seldom pruritic, they can be elicited by cutaneous injury or scratching (Koebner phenomenon), in which case the lesions exhibit a linear appearance.

Children with juvenile idiopathic arthritis often present with limping and stiffness, without any known injury or prior infections. Common non-cutaneous manifestations include:

  • Joint pain and swelling
  • High spiking daily fever (quotidian pattern)
  • Myalgia
  • Limited movement
  • Enthesitis
  • Sore throat
  • Lymphadenopathy
  • Hepatosplenomegaly [1,2,3].

What are the complications of juvenile idiopathic arthritis?

Musculoskeletal complications may occur secondary to ongoing inflammation and poor disease control, including:

  • Leg length discrepancy
  • Joint erosion
  • Sacroiliac joint and spine ankylosis.

Sometimes juvenile idiopathic arthritis may result in more severe complications with devastating outcomes.

  • Uveitis — this may lead to vision loss; screening and close monitoring by a paediatric ophthalmologist is warranted for severe, active uveitis.
  • Macrophage activation syndrome (MAS) — this may be life-threatening; it is characterised by fever, cytopenias, liver dysfunction, coagulopathy, purpura, hypofibrinogenaemia, hypertriglyceridaemia, and very high level of ferritin [1,3].

How is juvenile idiopathic arthritis diagnosed?

The diagnosis of systemic juvenile idiopathic arthritis is made clinically after exclusion of other entities, such as malignancies and infections that can also present with high fever and arthralgia. According to the International League of Associations for Rheumatology (ILAR) criteria for systemic juvenile idiopathic arthritis, arthritis must have persisted for at least six weeks and fever for two weeks (that is daily for at least 3 days), accompanied by one or more of the following:

  • Transient erythematous rash
  • Generalised lymphadenopathy
  • Hepatosplenomegaly
  • Serositis [4].

When juvenile idiopathic arthritis is suspected, paediatric rheumatology should be involved promptly to initiate the appropriate investigations and to minimise any delay in treatment. Further investigations including laboratory tests and imaging are helpful to confirm the diagnosis or to classify the arthritis into a specific subtype. The test results can also be useful to guide treatment and to monitor the disease course.

The most relevant laboratory tests for juvenile idiopathic arthritis are:

  • Complete blood count (CBC) — anaemia, thrombocytosis, and leucocytosis are often present in systemic juvenile idiopathic arthritis whereas they are not typically seen in oligoarticular juvenile idiopathic arthritis
  • Erythrocyte sediment rate (ESR) — this is significantly elevated in systemic juvenile idiopathic arthritis but may be normal or mild to moderately elevated in other subtypes
  • C-reactive protein (CRP) — this is elevated to varying degrees in the different subtypes of juvenile idiopathic arthritis
  • Antinuclear antibody (ANA) — this is often negative in systemic juvenile idiopathic arthritis but may be positive in oligoariticular and polyarticular forms of juvenile idiopathic arthritis.
  • Rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCP); these are useful to identify RF-positive polyarthritis.

Pathology is not required for a definitive diagnosis of juvenile idiopathic arthritis, but the exanthem in systemic juvenile idiopathic arthritis characteristically exhibits a perivascular and interstitial neutrophil-dominant infiltrate; this can also be referred to as neutrophilic urticarial dermatosis, a common pattern in autoinflammatory processes [1].

Imaging can provide information of the involved joints if the clinical examination findings are equivocal. An ultrasound scan can assess for synovitis in the joints, and magnetic resonance imaging (MRI) may be used to rule out other conditions such as pigmented villonodular synovitis [3].

What is the differential diagnosis for juvenile idiopathic arthritis?

Several conditions may present similarly to systemic-onset juvenile idiopathic arthritis, including having a transient exanthem, fever, and arthritis. These include:

What is the treatment for juvenile idiopathic arthritis?

Treatment of systemic juvenile idiopathic arthritis is directed at symptom management, improving or managing joint function, and minimising complications. Non-steroidal anti-inflammatory drugs (NSAIDs) are typically first-line agents for mild articular or extra-articular presentations to control pain. Other pharmacological agents include:

Drugs that block inflammatory cytokines, such as TNF-alpha, IL-6, and IL-1, have proven efficacy, especially in longstanding juvenile idiopathic arthritis. These include:

  • Anakinra — an IL-1 receptor antagonist
  • Canakinumab — a human monoclonal antibody directed against IL-1
  • Tocilizumab — this blocks IL-6 [1,3,5].

What is the outcome for juvenile idiopathic arthritis?

The disease course of systemic juvenile idiopathic arthritis is variable. Reports have indicated that 40–60% of patients reach remission of arthralgia. Systemic manifestations may remain active and may persist after years. A better prognosis is associated with early treatment of active disease [1,3].

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References

  1. Bolognia JL, Schaffer JV, Cerroni L. Dermatology, 4th edn. Philadelphia: Elsevier, 2018.
  2. Goldsmith LA, Katz SI, Gilchrest BA, Paller AS, Leffell DJ, Wolff K. Fitzpatrick’s Dermatology in General Medicine, 8th edn. New York: McGraw-Hill, 2012.
  3. BMJ Best Practice. Juvenile idiopathic arthritis. November 2017. Available at: http://bestpractice.bmj.com/topics/en-us/806/pdf/806.pdf
  4. Petty RE, Southwood TR, Manners P, et al. International League of Associations for Rheumatology classification of juvenile idiopathic arthritis: second revision, Edmonton, 2001. J Rheumatol. 2004; 31: 390–2. PubMed
  5. Prakken B, Albani S, Martini A. Juvenile idiopathic arthritis. Lancet 2011; 377: 2138–49. DOI: 10.1016/S0140-6736(11)60244-4. Journal

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