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Contributor: Jay Mehta, MD, MS
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?
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.
You get called to a consult in the ED because there is a nine year-old Latino male who has a red raised rash on his legs and buttocks. When you see him, you also notice that his knee is swollen, but he seems to be walking without difficulty. Otherwise he looks happy and well. His CBC, ESR, and coagulation studies are normal.
What are the distinguishing histologic features of this vasculitis?
Henoch-Schonlein purpura (HSP) is a small vessel vasculitis; indeed, it can be thought of as a capillaritis. On histology, its characteristic features are leukocytoclasis (vascular damage caused by nuclear debris from infiltrating neutrophils) and IgA deposition. For this reason, it is also known as IgA-mediated vasculitis.
What are the major clinical manifestations of HSP?
HSP can be thought of as a clinical tetrad with (1) purpura: usually on the dependent (typically lower extremities) areas. The rash can also look petechial, vesicular, or bullous; (2) arthritis, often painless and accompanied by prominent periarticular swelling; 3) GI involvement, which can range from mild abdominal pain to hematochezia to intussusception to necrosis and perforation; 4) renal involvement, which can range from microscopic hematuria to nephrotic syndrome to acute or chronic renal failure.
What is the treatment of HSP?
HSP treatment is generally supportive with NSAIDs for pain if no GI or renal contraindications. The time-course is typically 1-2 months with about a 1/3 of patients having recurrences after this period. The role of steroids is controversial. While they provide short-term relief of symptoms, it is unclear whether they alter the long-term outcome, specifically renal, of the disease.
A five year-old boy has had seven days of fever up to 104F. Over the last two days, he has developed a large right-sided cervical lymph node, a maculopapular rash, and injected sclera. His lips are red and cracked.
What are the clinical criteria for Kawasaki Disease (KD)?
Diagnosis of Kawasaki Disease requires fever for more than 5 days plus at least 4 of (1) Bilateral conjunctival injection (occurs in 80-90% of patients; typically limbic-sparing); (2) Oropharyngeal mucous membrane changes (80-90%; injected and / or fissured lips, strawberry tongue, injected pharynx); (3) Peripheral extremity changes (80%; Erythema and / or edema of the hands and feet or periungual desquamation); (4) Polymorphous rash (>90%); (5) Cervical lymphadenopathy with node >1.5 cm (50%)
What is the major complication of Kawasaki Disease and how is it prevented?
In 25% of untreated patients, coronary artery aneursyms develop. KD is the leading cause of childhood acquired heart disease worldwide. Aneurysms may lead to coronary insufficiency, thrombus, myocardial infarction, and death. Treatment with IVIG (usually during the acute, febrile phase) reduces the incidence of aneurysms by 85%. It also reduces the incidence of giant aneurysms otwand overall mortality.
In clinic, a 14 year-old female is seen for erythematous plaques over her knuckles,elbows, and knees. She also has a purplish rash on her eyelids and some erythema on her cheeks. When you ask her to stand up so you can examine her back, she has trouble getting up out of the chair.
What are the differences between the juvenile and adult forms of dermatomyositis?
In children, the differential diagnosis of a chronic inflammatory myopathy is much smaller than that seen in adults as polymyositis (2 - 8% of childhood idiopathic inflammatory myopathy) is much rarer than juvenile dermatomyositis (JDM) and inclusion body myositis and malignancy-associated myositis are exceedingly rare. Children with JDM are more likely than adults with DM to get calcinosis, lipodystrophy, and gastrointestinal and cutaneous ulcerations. Children with JDM get anti-synthetase antibodies 0 - 5% of the time, compared to 20 - 25% of adult patients.
What should you be worried about if a patient with JDM presents with acute onset of abdominal pain?
A small percentage of children with JDM may develop visceral vasculopathy which may lead to death. Severe abdominal pain, with or without melena or hematemesis, may signify vasculopathy of the gastrointestinal tract and resulting tissue ischemia or mesenteric infarction. The presence of cutaneous ulceration signifies a patient who is at higher risk for visceral ulceration and may warrant more aggressive therapy with cytotoxic agents.
(Answer questions 1 - 5 on a piece a paper. Find Answer Key at the bottom of this page.)
The risk factors for development of asymptomatic uveitis associated with JIA include ANA positivity, young age, female sex, and being early in the disease course. Systemic JIA and RF-positive disease are not associated with uveitis. Enthesitis-related arthritis is associated with acute, as opposed to asymptomatic, uveitis.
The initial high presentation of daily high fevers, evanescent rash, and arthritis is strongly suggestive of systemic JIA. A life-threatening associated condition is macrophage activation syndrome. Sepsis (Answer A) could explain the constellation of features. However this patient is not on any immunosuppressives that would put him at higher risk for this. You are not told that this patient is on methotrexate (Answer B). Megalobastic anemia (Answer D) can cause pancytopenia and mental status changes. It should not, however, cause purpura and hepatitis, and in the absence of a known cause, it would be unlikely that this patient has megaloblastic anemia. There is no association of non-Hodgkin’s lymphoma (answer E) with systemic JIA. While lymphoma may cause fevers and arthritis, it usually affects a few joints rather than the many joints described here, and is not associated with an evanescent rash.
Renal disease (answer E) is not commonly associated with JDM. The other answers are well-known complications.
The combination of high fever with lymphadenopathy, non-purulent conjunctivitis, extremity edema, mucous membrane changes, and rash is strongly suggestive of Kawasaki Disease. IVIG (Answer C) has been proven to be highly effective at preventing coronary aneurysms. Penicillin prophylaxis (Answer A)is used for prophylaxis of cardiac disease in acute rheumatic fever, which this patient does not have. Regular ophthalmologic screening (Answer B) is recommended to evaluate for silent uveitis in patients with JIA. Influenza vaccine (choice D) is recommended for patients on immunosuppression, which you are not told this patient is on. Methotrexate (Answer D) is used to treat and prevent long-term joint damage associated with JIA, which this patient does not have.
Long-term morbidity in Henoch-Schonlein Purpura is related to renal disease (Answer A), which can cause nephrotic syndrome, acute renal failure, or chronic renal failure. While GI (Answer B) and cutaneous (Answer D) manifestations can cause short-term discomfort, they are rarely associated with long-term sequelae. Neurologic (Answer C) and cardiac (Answer E) morbidity can occur, but they are much less common than renal disease.
Updated April 2016