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


Three unpublished French patients diagnosed with TRAPS and AA between January 2000 and February 2020 and referred to CeReMAIA were included. This observational study was based on data extracted from the Juvenile Inflammatory Rheumatism (JIR)-cohort, an international multicentre data repository established by the National Commission on Informatics and Liberty (CNIL, authorization number no. 914677). All French patients consented to be included in the JIR-cohort and were informed that data collected in medical records might be used for research studies in compliance with privacy rules. The manuscript was prepared in accordance with Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines.

A systematic literature review of cases of TRAPS-related AA was also carried out, following the Preferred Reporting Items for Systematic Reviews and Meta-analyses statements. The pathogenicity of variants was cross-checked with the Infevers database (a large international registry compiling variants reported in hereditary recurrent fever genes, https://infevers.umai-montpellier.fr/web/index.php). Consistent with the new EUROFEVER PRINTO classification criteria for hereditary recurrent fevers, only patients carrying pathogenic (class 5), a likely pathogenic mutation (class 4) or a variant of unknown significance (class 3) were included in the study. Nevertheless, two particular variants of unknown significance, i.e. p. Arg121Gln (also called R92Q) and p. Pro75Leu (also called P46L), were excluded from our review because their involvement in TRAPS pathogenesis is highly debated and these patients should not be considered for sure as TRAPS cases.[4] To assess the correlation between the occurrence of AA and TRAPS mutations, we compared the group of AA patients from this study with non-AA patients with TRAPS identified in the EUROTRAPS and CeReMAIA cohorts.[2]

Databases were systematically searched by two independent authors (J.D. and F.R.) for studies dated up to up to February 2021. We searched for articles reported cases with a given established pathogenic mutation in the TNFRS1A gene using Medline [search terms: (amyloidosis) OR (amyloid) AND ((TNFRSF1A) OR (TNF receptor-associated periodic syndrome) OR (TNF receptor-associated periodic syndrome) OR (tumour necrosis factor receptor-associated periodic syndrome) OR (familial Hibernian fever) OR (Hibernian familial fever)] and EMBASE [search terms: ('amyloid' OR 'amyloidosis') AND ('TNFRSF1A' OR 'TNF receptor-associated periodic syndrome' OR 'tumour necrosis factor receptor-associated periodic syndrome' OR 'familial hibernian fever' OR 'hibernian familial fever'). References within retrieved articles were also consulted to identify additional studies. Articles were eligible if written in English, Spanish or French. Two authors (J.D. and F.R.) independently screened all relevant titles and abstracts for eligibility. When needed, the full text was also assessed for eligibility (Figure 1). Two reviewers (J.D. and F.R.) extracted data from the included studies independently. The following information was then extracted from the included studies, based on predefined data fields: age, sex, TNFRS1A mutation, age at AA diagnosis, age at first TRAPS symptoms, diagnostic delay, proteinuria, renal function, renal transplantation or dialysis, treatment regimen and efficacy on TRAPS, AA and renal function. AA was demonstrated by pathological examination of amyloid deposits stained with Congo red and showing green birefringence under polarized light, and positive immunohistochemistry with an anti-serum amyloid A (SAA) antibody.

Figure 1.

Flowchart of the article selection process following preferred reporting items for systematic reviews and meta-analyses guidelines

For the three French patients, a complete remission (CR) of TRAPS was defined as the total absence of clinical TRAPS symptoms along with a CRP level of <5 mg/l; a partial remission (PR) was defined as the total absence of clinical TRAPS symptoms plus CRP decreased by >70% from the baseline level (but >5 mg/l). Patients not fulfilling these criteria were considered as non-responders (NRs). For the patients from the literature review, CR, PR or NR were recorded as evaluated by the authors. When individual data were not available, the corresponding author was contacted.