Tumour Necrosis Factor Receptor-1 Associated Periodic Syndrome (TRAPS)-Related AA Amyloidosis

A National Case Series and Systematic Review

Jérémie Delaleu; Samuel Deshayes; Francois Rodrigues; Lea Savey; Etienne Rivière; Nicolas Martin Silva; Achille Aouba; Serge Amselem; Marion Rabant; Gilles Grateau; Irina Giurgea; Sophie Georgin-Lavialle


Rheumatology. 2021;60(12):5775-5784. 

In This Article


We describe the clinical, biological and genetic features of 41 TRAPS patients with AA, including 38 individuals identified from a literature search and three new French cases. AA was described as being a complication of TRAPS in 11% of the patients carrying a pathogenic TNFRSF1A variation.[3,8,26,27] AA reveals TRAPS belatedly: the diagnosis of TRAPS is made after the diagnosis of AA in 96% of TRAPS-associated AA. Thus, AA is still a way to diagnose TRAPS. In comparison, AA has a similar prevalence in FMF (around 8–13%), but AA has been shown to reveal FMF in only 0.3% of FMF cases.[28]

The data revealed a delay of 30 years between the first TRAPS symptoms and AA proven diagnosis. One explanation for this delayed diagnosis is that TRAPS is a very rare disease for which there are no diagnostic criteria and no specific laboratory assays apart from genetic testing, available since the 2000s. Diagnosis of TRAPS is challenging, because most of the clinical features of TRAPS overlap with other autoinflammatory disorders and with common diseases.[1,29] Indeed, the diagnosis of TRAPS should only be considered after exclusion of infectious and neoplastic causes of recurrent fever. Particular hallmarks of TRAPS include the protracted duration of attacks (at least 6 days, though typically longer), prominent myalgias, migratory rash and rarely periorbital oedema.[8,30] Familial history of autosomal dominant transmission is often observed, although some carriers of pathogenic TRAPS mutations have few symptoms or are asymptomatic.[15]

In AA patients, when an autoinflammatory disease is suspected but no specific clinical features of an autoinflammatory disease are present, an NGS panel for genetic auto-inflammatory diseases including TNFRSF1A should be performed. Of note, in patients of Mediterranean origin, considering the high frequency of FMF in this population, targeted-gene sequencing of MEFV can be first performed, but if MEFV is wild type (WT), never forget to mention TRAPS which is a cosmopolitan disease.[31] TRAPS-related AA amyloidosis is a severe complication with almost half of patients who required renal replacement therapy and an important mortality estimated at 14% in this review, with a median follow-up of 23 months. Furthermore, AA frequently relapses on the kidney graft, particularly if inflammation induced by TRAPS is not controlled after transplantation.

In this review, the IL-1 antagonist anakinra seems to be a very effective biologic on AA and to prevent relapse of AA on kidney graft, even if the effectiveness is low. Anakinra is the recombinant form of the naturally occurring IL-1 receptor antagonist (IL-1Ra); IL-1Ra prevents the binding of IL-1α as well as IL-1β to IL-1R1. Interestingly, IL-1α is central to the pathogenesis of numerous conditions characterized by organ or tissue inflammation including graft rejection trough tissue damage and necrotic cell death.[32] Furthermore, IL-1 antagonism seems to be more effective than the TNF blockade etanercept.[26,27] The main limitations of our study are the retrospective analysis, stringent inclusion criteria, selective publication of cases showing treatment efficacy and missing data, including CRP and SAA levels between episodes.

In conclusion, TRAPS is revealed by AA in most cases. Therefore, clinical features of TRAPS should be screened for in AA patients. IL-1 antagonist can help to normalize inflammation and to preserve renal function.