A four year-old white female is brought to your office because her mother says, for the last two months, she has limped every morning for about an hour, which eventually improves. She has had no fevers or rash. On your exam, she is happy and playful but walks with a limp. She has swelling of her left knee and left ankle. Her CBC, ESR, and CRP are normal. Her rheumatoid factor, anti-CCP antibodies, and Lyme studies are negative. She has an ANA that is positive at 1:160.

What is the differential diagnosis for a patient with suspected juvenile idiopathic arthritis (JIA)?

Diagnostic considerations when making the diagnosis of JIA include:

1.  Lyme arthritis, which can cause significant joint swelling, especially of the knee
2. Trauma, which should not be associated with a morning preponderance of symptoms
3. Septic arthritis and osteomyelitis, which would be more acute in presentation and be associated with more systemic symptoms
4. Systemic autoimmune disease, such as pediatric lupus, juvenile dermatomyositis or systemic vasculitis, which would have more extraarticular features
5. Non-inflammatory causes of joint pain, including slipped capital femoral epiphysis and idiopathic avascular necrosis, which would be associated with activity-related pain, rather than morning stiffness.

What is the significance of the negative rheumatoid factor and anti-CCP antibodies and normal inflammatory markers?

Only about 3 - 4% of JIA patients are rheumatoid factor-positive (one reason why this disease is no longer called “juvenile rheumatoid arthritis”) and / or anti-CCP positive. In those patients in whom it is positive, it typically portends a more aggressive course, similar to that seen in adults with RA. JIA patients with just a few joints affected often have normal inflammatory markers.

What are the different JIA subtypes and how are they distinguished?

1. Oligoarticular: Four or less joints affected in the first six months of disease. Typically younger (2-5 year) females. Associated with the best prognosis but highest risk of uveitis.
2. RF-negative polyarticular: More than four joints in the first six months of disease. Bimodal (2-5 yo and 11-13 yo) age distribution. Also high risk of uveitis.
3. RF-positive polyarticular: Very similar to adult RA in aggressiveness and prognosis. Also known as Childhood-onset Rheumatoid Arthritis.
4. Systemic: Associated with quotidian (once daily, typically evenings) fever and evanescent (less than 24 hours) rash, serositis, lymphadenopathy, or hepatosplenomegaly
5. Psoriatic: similar to adult psoriatic arthritis
6. Enthesitis-related: similar to spondyloarthritis seen in adults

What is the major comorbidity associated with JIA?

Uveitis develops in about 10% of JIA patients. It is known as a silent, chronic uveitis, which means that patients do not typically have symptoms suggesting inflammation. It is only picked up by an ophthalmologist’s slit-lamp exam. Significant risk factors for its development include ANA-positivity, female sex, young age, and recent development of disease. Those highest-risk patients should be seen every three months by an ophthalmologist. Uveitis is rare is systemic JIA and RF+positive patients. Patients with enthesitis-related arthritis get acute uveitis, which manifests as a red, painful, photophobic eye.

What might you be worried about if a patient with systemic JIA comes to the ED with fevers, altered mental status, transaminitis, and pancytopenia?

Macrophage activation syndrome (MAS) is the most severe complication of systemic JIA (sJIA), and can be life-threatening. In clinical presentation, and possibly etiology, it resembles hemaphagocytic lymphohistiocytosis (HLH). It occurs in at least 7% of patients with sJIA and can occur during both inactive and active disease. Clinically, it is characterized by any of unremitting fever, bleeding, lymphadenopathy / hepatosplenomegaly, liver dysfunction, CNS involvement, and organ failure. Laboratory hallmarks of this condition include hyperferritinemia, cytopenias (or a lower platelet count than would be expected given the degree of inflammation), transaminase elevation, a paradoxically low or normal erythrocyte sedimentation rate, elevated triglycerides, and prolonged PT and PTT. Hemophagocytosis may or may not be seen on bone marrow examination.