Juvenile Idiopathic Arthritis

Key Points:

  • Juvenile idiopathic arthritis (JIA) is a heterogeneous group of childhood arthritis disorders
  • JIA classiefication is based on number of joints involved and systemic manifestations 
  • No laboratory studies are diagnostic but inflammatory markers are commonly elevated
  • Systemic juvenile idiopathic arthritis (s-JIA) is characterized by arthritis, fever, rash, lymphadenopathy, hepatosplenomegaly, and serositis<
  • Macrophage Activation Syndrome is the most feared complication of systemic JIA with a mortality rate of 20%

Description:

Juvenile idiopathic arthritis (JIA) is not a single disease, but a term used to encompass all forms of chronic arthritis of unknown origin that begin before the age of 16 years and persist for greater than 6 weeks. The classification according to the International League of Associations for Rheumatology includes the following: systemic, oligoarthritis, polyarthritis, psoriatic arthritis, enthesitis-related arthritis, and undifferentiated arthritis. (Viswanathan, 2016; Eisenstein, 2014; Prakken, 2011). Oligoarticular JIA is the most common form, affects < 5 joints, and occurs more often in girls than boys. Polyarticular JIA involves 5 or more joints. Systemic JIA is the most concerning form which presents as a febrile inflammatory illness which can mimic infection or neoplasm (Cimaz, 2016).

Epidemiology:

JIA is the most common childhood chronic rheumatologic disorder. There is a yearly incidence of 2-20 cases/100,000 individuals with a prevalence of 16-50 cases/100,000 individuals, meaning there is an estimated total of 294,000 children affected in the United States (Prakken, 2011). Prevalence can vary with ethnicity and is more common in northern Europeans (Eisenstein, 2014).

Clinical Findings:

The diagnosis of any form of JIA is a clinical one based upon history and examination findings. The arthritis must be present for at least 6 weeks in a child under 16 years of age without other etiology (Eisenstein, 2014).

Systemic juvenile idiopathic arthritis is characterized by fever, rash, lymphadenopathy, hepatosplenomegaly, and serositis. These findings can present early in an ill-appearing child prior to the onset of arthritis, which can make the diagnosis of systemic JIA more difficult (Hay 2012). The course of systemic JIA can be quite variable with up to 40% of children experiencing only a monocyclic course that responds completely to treatment.  Others may have a polycyclic course with repeated periods of active disease followed by remission, and up to 50% of children may have persistent disease (Hay, 2012).   Features of a poor prognosis include: active systemic symptoms requiring glucocorticoid administration, arthritis of the hip, and radiographic evidence of joint damage (Prakken, 2011).

To diagnose systemic JIA, strict clinical history and examination criteria set by the International League of Associations for Rheumatology must be met. Most importantly, the child must have arthritis in one or more joints with, or preceded by, a fever of at least two weeks duration that can be documented daily for at least three days. The child must also have one (or more) of the following: non-fixed erythematous rash, generalized lymphadenopathy, hepatomegaly or splenomegaly, or serositis (often manifesting as pericarditis) (Petty, 2004). Arthritic involvement of the knees, ankles, and wrists is most common, though any joint can be affected. Arthritic involvement is usually minimal at disease onset and increases in severity over time. The joint stiffness typically worsens with rest and improves with use. The fevers spikes will occur daily or twice daily and will often exceed 39˚C. The rash is characterized by “salmon-colored” macules 2-5mm in size. It is migratory and appears with fevers, disappearing several hours later (Hay, 2012).

Laboratory Studies

Anemia of chronic disease, leukocytosis and thrombocytosis can be signs of chronic inflammation but may all be normal in children with JIA (Viswanathan, 2016).

Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) are typically elevated in children with polyarticular and systemic disease (Cimaz, 2016) but often normal in oligoarticular disease (Viswanathan, 2016).

The anti-nuclear antibody (ANA) can be positive in up to 80% of children with oligoarticular and 30% of children with polyarticular arthritis (Viswanathan, 2016).  Elevated ANA concentrations suggest an increased risk of iridocyclitis as well (Gowdie, 2012).

Repeated positive rheumatoid factor (RF) tests in polyarticular arthritis carries a poorer prognosis. Positive anti-cyclic citrullinated peptide (CCP) antibodies are less common in children than in adults with rheumatoid arthritis (Viswanathan, 2016).

Imaging Studies:

There are a number of findings on imaging that can be seen, especially in systemic JIA. Early radiographic changes include periarticular osteopenia, joint effusions, and juxtasynovial soft tissue swellings. In untreated and progressive disease, late radiographs may show severe arthritis, joint ankylosis, and significant angular deformity. Ultrasonography is useful in the assessment of subclinical synovitis and can differentiate tendinous from articular involvement. 

In all forms of JIA, findings of chronic inflammation on MRI include: erosions, pannus formation, and rice bodies, which are representative of fibrinous exudate. MRI protocols using contrast-enhanced assessment of inflammation have been described and may provide prognostic information related to response to treatment. As MRI and ultrasound protocols become better established, these modalities could be used to identify patients at increased risk for poor outcomes, thereby allowing earlier initiation of aggressive treatment protocols that may alter the disease course (Kan, 2013). 

 

Etiology:

Traditional teaching has looked for an association with auto-antibodies or human leukocyte antigen (HLA) as a causative factor in JIA. Recent literature has demonstrated a specific lack of this consistent association, leading to a rethinking of JIA as an auto inflammatory rather than an autoimmune disease (Prakken, 2011).  The pathogenesis of oligoarticular JIA and polyarticular JIA is thought to involve genetic predisposition and abnormalities in the adaptive immune system of lymphocytes B cells and T cells (Eisenstein, 2014). 
      
Systemic JIA is thought to be a dysregulation of the innate immune system which includes cytokines and the complement system. Clinically, the difficulty lies in identifying the disease triggers prior to initiation of the whole-body inflammatory cascade (Hay, 2012). This systemic response is related to an overproduction of IL-6 and a correlation between IL-6 levels and disease activity has been demonstrated (De Benedetti, 1998; Bruck, 2015).

Treatment:

Per the American College of Rheumatology, treatment recommendations for JIA are based on the number of involved joints and presence of sacroiliac arthritis. Medical management includes nonsteroidal (NSAID) medications, disease modifying drugs (DMARDs) such as methotrexate, corticosteroids (oral or intra-articular injection), biological agents such as tumor necrosis factor (TNF-1). With aggressive treatment with these newer agents, remission is possible and a better long term prognosis and quality of life expected (Viswanathan, 2016).

Due to the systemic nature of systemic JIA, treatment protocols should focus on the entire child and not on just one aspect of the disease. Successful therapy involves a combination of pharmacologic and surgical interventions, physical and occupational therapy, and psychosocial support (Prakken, 2011). Initially, NSAIDs and glucocorticoids are used to control the disease. Due to an unwanted side effect profile associated with consistent use, current treatment protocols aim to taper and/or completely stop the use of these medications after a diagnosis has been made (Hay, 2012). 

Anti-IL-1 (Anakinra, Canakinumab) and anti-IL-6 (Tocilizumab) medications have had great efficacy in treating the systemic manifestations of JIA. Anti-TNF drugs are not effective in treating systemic JIA (Hay, 2012). Growth hormone can be administered to improve final height, increase bone mass, and normalize body composition by helping to improve lean muscle mass (Bechtold, 2014). Chronic pain from all forms of JIA can be managed with a combination of acetaminophen, NSAIDs, opioid medications, and evidenced-based psychological interventions such as relaxation strategies and cognitive behavioral therapy (Weiss, 2014).

Surgical treatment in systemic JIA is aimed at restoring joint function limited by the progressive arthropathy leading to end stage arthritis, often at a young age. Hip joint involvement in JIA is the most significant prognostic factor affecting mobility and function in afflicted patients (Abdel, 2014). Given the propensity for bony destruction, abnormal alignment, and joint contractures, successful hip and knee replacement can be challenging and requires meticulous planning, often necessitating the use of custom implants (Helyse, 2014). Preoperative assessment should include evaluation for basilar invagination and/or C1-C2 instability. In addition, mandibular hypoplasia can make intubation difficult (Abdel, 2014). 

Complications:

In terms of complications related to medical treatment, biologic agents have been shown to have a relatively good safety profile in children. Despite suggestion in the literature of an increased risk of lymphoproliferative malignancies in children receiving biologic agents, a true causal relationship has not been defined (Hay, 2012). As discussed previously, surgical management of joint disease in systemic JIA is not without significant challenges. 

The most feared complication of systemic JIA is macrophage activation syndrome, which can have a mortality rate upwards of 20% (Hay, 2012). As a result of over-activation and expansion of T cells and macrophages, the body produces an overwhelming anti-inflammatory response. Clinical features of macrophage activation syndrome include: persistent fever, hepatosplenomegaly, liver dysfunction, mental status changes, lymphadenopathy, cytopenia, mucosal bleeding, and purpura. In severe cases, renal and respiratory failure, hypotension, and shock can occur (Hay, 2012). Laboratory findings will show a decrease in Vitamin-K dependent clotting factors and a paradoxical decrease in the ESR while the CRP remains elevated. Prompt treatment with high dose methylprednisolone is required to treat this life-threatening condition (Hay, 2012).
      
Owing to the negative effect of chronic inflammation on the growth hormone/insulin-like growth factor axis, 10-20% of children with any form of JIA will show a reduced final height. This reduction in height can also be traced to medication use, particularly the use of glucocorticoids for longer than twelve months duration. Finally, children with JIA will also typically have a decreased lean muscle mass and an increased fat mass (Bechtold, 2014).

References:

  1. ​Abdel, MP., and Figgie, MP. Surgical management of the juvenile idiopathic arthritis patient with multiple joint involvement. Orthop Clin N Am. 2014;45:435-42.
  2. Bechtold, S. and Simon, D. Growth abnormalities in children and adolescents with juvenile idiopathic arthritis. Rheumatol Int. 2014;34:1483-88.
  3. Bruck, N., Schnabel, A., Hedrich, CM. Current understanding of the pathophysiology of systemic juvenile idiopathic arthritis (sJIA) and target-directed therapeutic approaches. Clinical Immunology. 2015;159:72-83.
  4. Cimaz R. Systemic-onset juvenile idiopathic arthritis. Autoimmun Rev. 2016;15:931-934.
  5. De Benedetti, F., Martini, A. Is systemic juvenile idiopathic arthritis an interleukin 6 mediated disease? J Rheumatol. 1998;25:203-7.
  6. Eisenstein EM, Berkun Y. Diagnosis and classification of juvenile idiopathic arthritis. J Autoimmun. 2014;48:31-33.
  7. Gowdie, PJ. and Tse, SML. Juvenile idiopathic arthritis. Pediatr Clin N Am. 2012;59:301-27.
  8. Hay, AD., and Ilowite, NT. Systemic juvenile idiopathic arthritis: a review. Pediatric Annals. 2012;41:1-6.
  9. Helyse, TJ., et. al. Total knee arthroplasty in patients with juvenile idiopathic arthritis. Clin Orthop Relat Res. 2014;472(1):147-54.
  10. Kan, JH. Juvenile idiopathic arthritis and enthesitis-related arthropathies. Pediatr Radiol. 2013;43:S172-80.
  11. Petty, RE., et. al. International League of Associations for Rheumatology classification of juvenile idiopathic arthritis: second revision. J Rheumatol. 2004;31(2):390-92.
  12. Prakken, B., Albani, S., and Martini, A. Juvenile idiopathic arthritis. Lancet. 2011;377:2138-49.
  13. Viswanathan V, Murray KJ. Management of children with juvenile idiopathic arthritis. Indian J Pediatr. 2016;83(1):63-70.
  14. Weiss, JE., et. al. Assessment and management of pain in juvenile idiopathic arthritis. Pediatr Drugs. 2014;16:473-81.

Top Contributors:

Brian E. Kaufman, MD
Karen Bovid, MD
Teresa Cappello, MD