Introduction
AA amyloidosis is the most severe complication of hereditary autoinflammatory diseases. In TRAPS it has been reported to occur in approximately 25% of patients in the absence of an effective treatment. However, susceptibility to AA is difficult to predict. Identification of key risk factors affecting the development of AA would improve the clinical management of TRAPS patients, by allowing a more tailored treatment approach.
Objectives
To evaluate the relative contribution of clinical and genetic factors to the risk of AA amyloidosis in TRAPS.
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Methods
Clinical data were obtained from the EUROFEVER/EUROTRAPS web-based registry. Inclusion criteria for this study were: age ≥ 18 years at last follow-up, identification of a TNFRSF1A mutation and written informed consent. DNA was available for patients recruited into the EUROTRAPS research project and SAA1 was genotyped by direct sequencing of exon 3.
Results
104 patients (51 males, 49%) with TRAPS (39 different mutations) were included in the study. Median age was 41 years (range 18-88), median age at TRAPS onset was 6 years (range 0.5-63), and median age at diagnosis was 37 years (10-81). 21 patients had AA amyloidosis, with a median age at AA onset of 38 years (range 18-76). Family history for AA amyloidosis was observed in 33 patients (32%). SAA1 genotype was established in 89/104 patients and 31 (35%) were homozygous for the SAA1.1 allele. 77 patients (74%) had a clearly pathogenic TNFRSF1A variant. 27 had either P46L or R92Q.
At univariate analysis, family history for amyloidosis, SAA1.1 homozygosity, disease course, age at TRAPS onset and the type of mutation were significantly associated with AA amyloidosis. At multivariate analysis homozygosity for SAA1.1 and age at TRAPS onset independently predicted development of renal amyloidosis. SAA1.1/1.1 genotype was the variable with the strongest influence on AA development, with a 5.3 fold increased risk whereas older age at TRAPS onset was associated with a reduced risk of AA amyloidosis. Survival according to SAA1 genotype (SAA1.1/SAA1.1 versus all other genotypes) was estimated by Kaplan-Meier analysis. Median amyloid free survival from birth was 47 years vs. not reached (p=0.01).
Conclusion
Homozygosity for the SAA1.1 allele is the strongest predictor of AA risk in TRAPS. This result is extremely relevant for the clinical management of TRAPS patients and supports SAA1 genotyping on a routine basis to guide treatment approach.
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Disclosure of interest
None declared.
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.