It’s been a long time since my last blog post, so I have decided to catch up by writing about two cases I saw in my transplant clinic. However, they have the same disease, a brother and sister who inherited the same autosomal dominant disease called tumor necrosis factor (TNF) receptor-1 associated periodic syndrome (TRAPS, formerly known as familial Hibernian fever). The genetic defect in TRAPS resides in the gene that encodes the 55 kDa receptor for tumor necrosis factor, TNFR1. These mutations lead to loss of normal function rather than gain of function as you may think, and thus the pathogenesis of TRAPS is an enigma. A recent PNAS publication shed some light on the pathogenesis of the disease. They showed that mutant TNFR1 accumulates intracellularly in peripheral blood mononuclear cells of TRAPS patients and in multiple cell types from two independent lines of knock-in mice harboring TRAPS-associated TNFR1 mutations. Mutant TNFR1 did not function as a surface receptor for TNF but rather enhanced activation of MAPKs and secretion of proinflammatory cytokines. These patients will present with recurrent fevers over months or years, in the absence of associated viral or bacterial infections. They also may have focal or sometimes migratory myalgias, conjunctivitis, periorbital edema, abdominal pain, monoarticular arthritis, and rash.
You might be wondering how they ended up in my transplant clinic. The answer is secondary (AA) amyloidosis primarily involving the kidney. However it only occurs in a minority of patients (approximately 15 percent in the United States).
Managing patients with TRAPS consists mainly of Etanercept, a fusion protein consisting of two copies of the 75kDa TNF receptor (TNFR2) bound to the Fc portion of human IgG. Etanercept can be highly effective in many patients with TRAPS, though not all respond and the response is sometimes partial.
Finally, the major question remains, do those patients need to be on Etanercept after transplantation, considering that they are already immunosuppressed with our maintenance regimen? Well, it’s not clear in the literature…. In our cases, the brother was maintained on Etanercept and he didn’t have any flare of the disease with stable kidney function and no recurrence of amyloidosis. The sister however, was not on Etanercept and she had recurrence of AA amyloidosis in the transplanted kidney. My approach will be to keep those patients on Etanercept and have low threshold to reduce maintenance immunosuppression.