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


Case Series

Patient 1. Patient 1 reported recurrent episodes of fever, abdominal pain, myalgias, arthralgias and diarrhoea, lasting 10 days and occurring twice a year since the age of 2 years. He had no family history. When he was 24 years old, he was diagnosed with encapsulating peritonitis requiring multiple surgeries. Five years later, he was referred to the internal medicine department for significant proteinuria at 3 g/24 h and severe renal failure (creatinine level at 292 μmol/l). The diagnosis of AA was confirmed by an anatomopathological examination of a duodenal biopsy. Increased CRP and SAA levels of up to 236 mg/l and 104 mg/l, respectively, were observed during fever episodes. CRP and SAA levels remained high between episodes (50 and 25 mg/l, respectively). No autoimmune diseases or chronic infectious diseases, including tuberculosis, were identified. Sanger targeted-gene sequencing revealed one heterozygous variant in the TNFRSF1A gene, p. Thr79Met (previously called T50M), leading to the diagnosis of TRAPS. The patient was unsuccessfully treated with colchicine, 25 mg of etanercept twice weekly and 8 mg/kg tocilizumab once monthly. IL-1 blockade (100 mg anakinra for 123 months, then 150 mg canakinumab every 8 weeks, then every 4 weeks) initiated at the age of 33 years led to CR, and to partial recovery of the renal function (creatinine level at 143 μmol/l), CRP rates normalisation and a decrease in proteinuria (0.5 g/24 h).

Patient 2. Patient 2 reported recurrent episodes with fever, abdominal pain, myalgias, segmental swelling and erythematous macules lasting 3 weeks and occurring 3–4 times a year, associated with increased CRP (150 mg/l) and SAA (330 mg/l) levels since the age of 12 years. CRP levels remained high (around 70 mg/l) between fever episodes. At 34 years old, she was referred to the nephrology department for nephrotic syndrome without renal failure, associated with biological inflammatory syndrome. Her father had paroxysmal abdominal pain and myalgias, End-stage renal disease (ESRD) requiring dialysis and died young. AA was diagnosed after renal biopsy (Figure 1). Sanger targeted-gene analysis revealed one heterozygous variant in the TNFSFR1A gene, p. Thr79Met (T50M). A daily dose of 100 mg anakinra led to CR and decreased proteinuria (2 g/24 h). The renal function and CRP rates have remained normal since this treatment began.

Patient 3. Since he was 3 years old, this patient has suffered from fever, abdominal pain with diarrhoea, macular erythematous rash, arthromyalgia and conjunctival redness episodes of 3 weeks in duration, occurring three times a year. He had no family history. Increased CRP (340 mg/l) and SAA (23 mg/l) levels were observed during episodes of fever. CRP and SAA remained high (50 and 11 mg/l, respectively) between episodes. At 24 years old, he developed ESRD requiring haemodialysis and renal biopsy provided the diagnosis of AA. One year later, he received a kidney transplantation. Neither autoimmune diseases, nor chronic infectious diseases, including tuberculosis, were identified. At the age of 42, a next-generation sequencing (NGS) panel for hereditary recurrent fevers was performed and found one heterozygous variant in the TNFSFR1A gene, p. Cys99Arg. Since then, he has been receiving 100 mg anakinra subcutaneously every 48 h (renal adjustment dose), leading to CR, CRP rate normalization and stabilization of the renal function (around 265 μmol/l before anakinra and around 250 μmol/l after). Until now, AA did not recur in the kidney graft.

Literature Review

The literature review[3,5–23] yielded 1224 articles, among which 20 were analysed in this study and included 38 patients, among whom 36 represented independent cases presenting with AA and carrying a pathogenic TNFRS1A mutation (Figure 2). Overall, a total of 41 cases were studied: three new unpublished French patients and 38 cases reported in the literature with available individual data (Table 1).

Figure 2.

Anatomopathological examination of a kidney biopsy from patient 2
The mesangium is expanded by pinkish amorphous material (PAS, ×200) (A). This material showed positive Congo red staining (×200) (B) and immunoreactivity to the anti-amyloid A antibody (×200) (C).

TRAPS and AA Features. For the 41 patients (20 men and 21 women), the median age at the onset of TRAPS symptoms was 5 years old (range: 1–49) and AA proven diagnosis was 40 years (range: 13–75). For the 36 patients with available duration between the first TRAPS signs and AA diagnosis, the median delay was 30 years (range: 3–71). The diagnosis of AA preceded that of TRAPS in 23/24 cases (96%). Biological features of AA were available for 26 patients and included: isolated proteinuria (n = 5/26; 19%), isolated nephrotic syndrome (n = 10/26; 38%), isolated renal failure (n = 3/26; 12%) or proteinuria and renal failure (n = 6/26; 23%). The other organs affected by AA (when searched) were the gut (n = 6/20; 30%), the liver (n = 4/20; 20%), the spleen (n = 4/20; 20%) and/or the thyroid (n = 2/20; 20%). In all cases, AA was histologically confirmed by kidney or digestive tract biopsies. The outcome of the renal disease included ESRD, which required renal replacement therapy (hemodialysis or kidney graft) in 17/36 (47%). Death was noticed in 5/36 (14%), of which four directly related to TRAPS and AA diseases, with a median follow-up of 23 months.

Biologics Effects on AA (Renal Function and Relapse in the Kidney Graft). Twenty-four patients received biologics: seven received etanercept then anakinra; six etanercept only; 10 anakinra only and one patient received etanercept, tocilizumab, anakinra and canakinumab successively. Effect of biologics regimen on AA were available for 21 regimens in 19 patients:

  • etanercept: three improved, one worsened renal function;

  • anakinra: six improved, seven stabilized, and three worsened renal function and

  • canakinumab: one improved renal function.

Four patients (36% of transplanted patients) relapse AA on kidney graft, whose only one was under biologic treatment (etanercept).

Molecular Analyses. We report here three novel AA patients, two carrying the p. Thr79Met recurrent mutation and one patient carrying p. Cys99Arg, a novel TNFRSF1A mutation. The TNF receptor consists of an extracellular ligand-binding domain, a transmembrane domain and an intracellular effector domain. The extracellular region includes four cysteine-rich domains (CRDs).[24] The majority of the TNFRSF1A mutations identified in the TRAPS-associated AA patients are located in the first two CRD1 and CRD2 (Figure 3). To assess the correlation between the occurrence of AA and the TNFRSF1A mutations, we compared the group of AA patients from this study with non-AA TRAPS patients from the CéRéMAIA and EUROTRAPS cohorts.[2,25] The p. Tyr49His, p. Tyr67Ser, p. Cys84Ser, p. Ser88Pro, p. Cys99Tyr, p. Arg121Pro, p. Ile199Asn, p. Arg121_ Asp122insAlaArgHisArg mutations have been only identified in AA patients so far (Figure 3).

Figure 3.

Schematic representation of the localization of variants in the TNFRSF1 gene harboured by TNF receptor-1 associated periodic syndrome (TRAPS)-related AA amyloidosis (AA) (top) and TRAPS patients without AA (bottom)
SP: 1–29; CRD1: 44–81; CRD2: 84–125; CRD3: 127–166; CRD4: 167–196. In red: novel patients reported in this study; in bold: the most frequent recurrent mutations; underlined: mutations observed only in patients presenting with AA (compared with the CéRéMAIA and EUROTRAPS cohorts and the literature review). CRD1/2/3/4: cysteine-rich domain 1/2/3/4; DD: death domain;SP: signal peptide; TM: transmembrane domain.