T.R.A.P.S.

TRAPS stands for Tumor Necrosis Factor Receptor-Associated Periodic Syndrome. It is a rare disorder characterized by prolonged episodes of periodic fever and skin changes (in humans) manifested as erythematous macules, patches and edematous dermal plaques. The skin changes may last anywhere from 4-21 days. There are numerous other systemic signs and symptoms associated with the syndrome including conjunctivitis, periorbital edema, abdominal pain, myalgia, arthralgia, pleuritic chest pain, sterile peritonitis and headache. Amyloidosis can occur in this syndrome. The dermatologic lesions are characterized by a perivascular dermal infiltrate of lymphocytes and monocytes. In the past the syndrome has been known as Familial Hiberian Fever, Benign Autosomal Dominant Familial Periodic Fever and Autosomal Dominant Periodic fever with Amyloidosis. This disease is closely related to two other inherited conditions characterized by periodic fever – Familial Mediterranean Fever and Hyperimmunoglobulinemia D Syndrome.

TNF is a naturally occurring cytokine that is involved in normal inflammatory and immune responses. TNF along with another cytokine FasL mediate apoptotic cell death through interaction with structurally related receptors belonging to the TNF/nerve growth factor super-family. TNF is found in two forms, TNF-a and TNF-ß. Two distinct receptors for TNF (TNFRs) are found. One is a 55 kilodalton protein called p55 and the other is a 75 kilodalton protein called p75. These exist as monomeric molecules on cell surfaces and in soluble forms. Biological activity of TNF is dependent upon binding to either cell surface TNFR. TRAPS is an autosomal dominant condition caused by missense mutations in the gene encoding type I TNFR (tumor necrosis factor receptor p55). The p75 TNFR is known as type II TNFR. TNF-receptor 1 and Fas receptor are connected to a cytoplasmic region called the “death domain”, which activates specific caspases with subsequent selective release of mitochondrial proteins. These processes lead to morphologic changes of cellular structures, as well as to degradation of the chromosomal DNA with subsequent cell death. The gene encoding for the p55 tumor necrosis factor receptor is TNFRSF1A (TNF receptor super family 1A). The mutations may produce an inability to cleave the extracellular domain of the TNFR, thereby leading to a persistent, exaggerated response to TNF (tumor necrosis factor). Normally cleavage of TNFR has a negative homeostatic effect by reducing the number of receptors on the cell surface and creating a pool of potentially antagonistic soluble receptor (shedding). Defective shedding of TNFR can only partially explain the pathophysiologic mechanisms of TRAPS, since some mutations have normal shedding. TRAPS patients have reduced levels of soluble p55 TNFR and these levels show minimal increase during inflammatory episodes. A total of 20 mutations have been identified since 1999. These include missense mutations resulting in amino acid substitutions within the first cysteine-rich domains (CRDs) of the extracellular portion of the receptor. A single splicing mutation in this region has also been identified.

A potential therapy for TRAPS is the use of the drug etanercept (Enbrel®). Etanercept is a dimeric fusion protein consisting of the extracellular ligand-binding portion of the human -75 tumor necrosis factor receptor (TNFR) linked to the Fc portion of human IgG. Etanercept binds specifically to tumor necrosis factor (TNF), both TNFa and TNFß and blocks its interaction with cell surface TNF receptors. Etanercept can bind two TNF molecules. The drug can also modulate biological responses that are induced or regulated by TNF including expression of adhesion molecules responsible for leukocyte migration, serum levels of cytokines such as IL-6 and serum levels of matrix metalloproteinase-3.

Other molecules that inhibit TNF-a production or release are pentoxifylline and thalidomide.