Flea Bytes: Adult Onset Still’s Disease

Overview

Adult onset Still’s Disease (AoSD) is a auto-inflammatory disorder characterized by a triad of daily fevers, arthritis and salmon-colored evanescent rash. Etiology of AoSD remains obscure as no definitive infections or gene mutations have been identified. Patients commonly develop diffuse lymphadenopathy and hepatosplenomegaly.

Clinical Course

The clinical course is generally thought to occur in 3 typical patterns. Monophasic disease pattern is where patients have a disease course marked by fever, rash, serositis and hepatosplenomegaly  which lasts weeks to months and then resolves.  Intermittent disease pattern have flares with complete remission in between and recurrent flares tend be less severe than primary episodes. Timing of recurrence is difficult to predict. Last, chronic disease pattern features persistently active disease where musculoskeletal symptoms predominate. Long standing disease may result in bone and cartilage destruction.

Symptoms
Fever

Typically daily – more often in the evening- and quite transient. Reported to have 4C changes in temperature in 4 hours. Fever spikes are often accompanied with musculoskeletal symptoms and rash.

Arthralgias/Arthritis

Symptoms are virtually universal, but may be mild, transient (associated with fever) and oligoarticular. Knees are most commonly affected followed by wrists, ankles, elbows, PIP, and shoulders. Synovial fluid is typically inflammatory

Rash

Evanescent, salmon colored, maculopapular rash that occurs with fever. Predominantly involves the trunk and extremities but palms and soles maybe involved. Rash maybe elicited by stroking the skin and may only be seen in areas that are under pressure from clothing.

Other Findings

Up to half will have liver involvement with hepatomegaly or elevated enzymes.

Diffuse lymphadenopathy is seen in 2/3 of patients as hyperplasia of the reticuloendothelial system is common.

Non-suppurative pharyngitis is present in nearly 70% and may precede fever and rash.

Macrophage activation syndrome (MAS) may occur in 15-20% of cases. Often difficult to distinguish from flares of AoSD, as anemia, hyperferritinemia, and CRP elevations can be seen in both. However, in MAS, leukopenia, thrombocytopenia, and hypertriglyceridemia are seen. Interestingly, may have a low sedimentation rate.

More rarely, microangiopathic hemolytic anemia and DIC may occur.

Diagnosis
Yamaguchi Criteria

AoSD is a diagnosis of exclusion and must exclude rheumatic disease, infection, and malignancy.

Major Criteria

Fever > 39C for at least 1 week
Athralgias for at least 2 weeks
Typical Rash
Leukocytosis > 10K with > 80% granulocytes

Minor Criteria

Lymphadenopathy and/or splenomegaly
Sore throat
Liver dysfunction
Negative RF and ANA

Need to have at least 5 criteria with at least 2 major criteria.

Laboratory Markers

No universal biomarker for the diagnosis of AoSD has been established.

Ferritin

5-fold increase in ferritin has a specificity of 41% and sensitivity of 80%.

Ferritin > 2500 + Yamaguchi criteria is 99.9% specific for AoSD.

Normally the glycosylated fraction of ferritin is 50-80%. Gylcosylated fraction of ferritin is often lowered in inflammatory diseases, 20-50%. Glycosylated ferritin is notably low in AoSD often around 20%.  Remains low during remissions. Maybe due to saturation of the glycosylation mechanism or decreased clearance by the histiocyte-macrophage system. Hyperferritinemia with glycosylated fraction < 20% has a sensitivity of 70.5% and specificity of 83.2%.

Interluekin-18

IL-18 is marked elevated in AoSD. It is a potent stimulator for IFN-γ production.

IL-18 > 148.9 pg/mL has a specificity of 78.3% and sensitivity of 88.6% and may help distinguish AoSD from sepsis.

Procalcitonin

Increases in sepsis when exposed to endotoxin. It is often helpful in autoimmune conditions to distinguish if a fever is related to an underlying infection. However, procalcitonin is less helpful in AoSD as it may be elevated without infection. 80% of AoSD patients had an elevated procalcitonin with a mean of 19.6 ng/mL.

Treatment

Methotrexate appears to be more effective in treating joint symptoms when used early in the disease. Anti-TNF-α agents have not shown to be effective in the treatment of systemic juvenile idiopathic arthrtitis (sJIA – an entity thought to be similar to and on the spectrum with AoSD). Anakinra, an anti-IL-1 agent, is beneficial in both AoSD and sJIA.

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