How to Recognize, Diagnose Periodic Fever Syndromes in Adults

Attacks of fever can be accompanied by arthritis, serositis and rash. The rash presents with single or multiple patches, which spread distally down the extremities. Biopsy shows superficial and deep infiltration by lymphocytes and monocytes. Conjunctivitis and periorbital edema occur. About 15% of patients develop amyloidosis, especially with mutations that replace cysteine, because these are important in the intramolecular disulfide bonds that maintain the three-dimensional structure of TNF1.

TRAPS is caused by autosomal mutations with incomplete penetrance in the TNFRSF1A gene encoding the 55 kd TNF receptor (TNFR1). Sometimes this mutation results in impaired shedding of the TNFR1, which could diminish its antagonistic effects on TNF. Another possibility is that excess of retained surface TNFR1 could result in excess binding of TNF. A mutant receptor may bind TNF less efficiently, resulting in less TNF-

associated apoptosis. A more indirect effect of the mutation might result in misfolding of TNF1, triggering the unfolded protein response, a cellular stress response associated with the endoplasmic reticulum. Finally, this misfolded protein may initiate signaling within the cell, mediated by mitochondrial derived reactive oxygen species, which disturb intracellular signaling.

Unlike FMF, TRAPS does not respond to colchicine. Corticosteroids help, but often long courses of high doses are required. It seems obvious that etanercept would help by binding excess TNF. However, the IL-1 antagonists anakinra and canukinumab may also be effective. These biologic agents may help reduce the extent of amyloidosis.

Conclusion

In summary, three different auto­inflammatory syndromes may present during, or persist into, adulthood. Recognizing their characteristic features is essential to making the right diagnosis.

• Patients with AOSD, which more commonly presents in adulthood, have daily fevers that spike in the late afternoon or evening. The fevers are associated with the presence of the characteristic rash. Typically, the temperature returns to the normal range.
• FMF usually presents in childhood, with a fever that can last for one to three days without returning to normal. Abdominal pain with the febrile episodes is common. FMF almost always responds to colchicine.
• The fever in TRAPS may last up to two weeks; periorbital edema and the rash are unlike what is seen in AOSD.

Rick Brasington, MD, is a rheumatologist and fellowship program director at Washington University in St. Louis, as well as an associate editor of The Rheumatologist.

References

1. Arlet JB, Le TH, Marinho A, et al. Reactive haemophagocytic syndrome in adult-onset Still’s disease: A report of six patients and a review of the literature. Ann Rheum Dis. 2006 Dec;65(1):1596–1601.
2. Yamaguchi M, Ohta A, Tsunematsu T, et al. Preliminary criteria for classification of adult Still’s disease. J Rheumatol. 1992 Mar;19(3):424–430.