Serum amyloid A serum concentrations and genotype do not explain low incidence of amyloidosis in Hyper-IgD syndrome.

BACKGROUND: Hyper-IgD and periodic fever syndrome (HIDS) is an autosomal recessively inherited disorder characterized by recurrent episodes of fever and inflammation. Unlike other chronic inflammatory conditions, amyloidosis is very rare in HIDS. For deposition of amyloid of the AA type, high concentrations of SAA are a prerequisite, together with certain SAA1 gene polymorphisms. The SAA1.1 genotype predisposes for amyloidosis, while SAA1.5 genotype exerts a protective effect. AIM OF THE STUDY: To determine if SAA concentrations and SAA1 gene polymorphisms could explain the virtual absence of amyloidosis in HIDS patients. METHODS: We measured SAA and CRP concentrations in serum of 20 HIDS patients during an attack and during the asymptomatic phase. Genotype of SAA1 gene was determined in 60 HIDS patients. RESULTS: SAA serum concentrations during attacks were very high (median 205 mg/l; range 75-520 mg/l, normal <3.1 mg/l). During attack-free periods 45% of patients still had elevated SAA concentrations. The distribution of the genotype of SAA1 gene in HIDS was similar to healthy controls (SAA1.1 0.41 vs. 0.50 p=0.32). CONCLUSION: Patients with HIDS have high SAA during attacks and show sub-clinical inflammation when asymptomatic. The low incidence of amyloidosis cannot be explained by a predominance of non amyloidogenic SAA related genotypes.     

Influence of Serum Amyloid A (SAA1) and SAA2 gene polymorphisms on renal amyloidosis, and on SAA/C-reactive protein values in patients with familial mediterranean fever in the Turkish population

OBJECTIVE: To evaluate the effect of serum amyloid A (SAA) 1 and SAA2 gene polymorphisms on SAA levels and renal amyloidosis in Turkish patients with familial Mediterranean fever (FMF). METHODS: SAA1 and SAA2 gene polymorphisms and SAA levels were determined in 74 patients with FMF (39 female, 35 male; median age 11.5 yrs, range 1.0-23.0). All patients were on colchicine therapy. SAA1 and SAA2 gene polymorphisms were analyzed using polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP). SAA and C-reactive protein (CRP) values were measured and SAA/CRP values were calculated. RESULTS: The median SAA level was 75 ng/ml (range 10.2-1500). SAA1 gene polymorphisms were: a/a genotype in 23 patients (31.1%), a/beta genotype in 30 patients (40.5%), a/g genotype in one patient (1.4 %), beta/beta genotype in 14 patients (18.9%), beta/g genotype in 5 patients (6.8 %), and g/g genotype in one patient (1.4%). Of the 23 patients who had a/a genotype for the SAA1 polymorphism, 7 patients had developed renal amyloidosis (30.4%) compared to only one patient without this genotype (1/51; 2.0%); p < 0.001. SAA2 had no effect on renal amyloidosis. SAA1 and SAA2 genotypes had no significant effect on SAA levels. SAA/CRP values were significantly lower in patients with the SAA1a/a genotype, compared to other SAA1 genotypes: 0.16 (0.025-1.96) versus 0.23 (0.012-28.20), p < 0.05. CONCLUSION: SAA1a/a genotype is one genetic factor that confers a significant risk for amyloidosis in the Turkish FMF population. Neither the SAA1 nor SAA2 genotypes had a significant effect on SAA level.     

Risk factors for AA amyloidosis in Germany

Objective: To identify risk factors for serum amyloid-A (AA) amyloidosis in patients living in Germany.

Methods: Clinical and genetic data were obtained from 71 patients with AA amyloidosis. SAA1 genotypes were analyzed in 231 individuals. Control groups comprised 45 patients with long-standing inflammatory diseases without AA amyloidosis and 56 age-matched patients without any inflammatory disease.

Results: The most frequent underlying diseases of AA amyloidosis were familial Mediterranean fever (FMF) (n?=?24, 34%) and inflammatory rheumatic diseases (n?=?30, 42%). Patients without any known underlying disease (n?=?11, 16%) were considered as having idiopathic AA amyloidosis. Patients with FMF were significantly younger at disease onset and younger at diagnosis of AA amyloidosis compared with patients with rheumatic diseases. Patients with idiopathic AA amyloidosis were older than patients with definite rheumatic diseases. Patients with FMF and high penetrance MEFV gene mutations had a relative risk of 1.73 for AA amyloidosis. Patients with FMF or a rheumatic disease and the SAA1 α/α genotype had a relative risk of 4.86 and 2.53, respectively, for developing an AA amyloidosis. The prevalence of this risk genotype was 36% in German patients without an inflammatory disease, 92% in German patients with AA amyloidosis and 100% in German patients with idiopathic AA amyloidosis.

Conclusions: Risk factors for AA amyloidosis are the presence of a hereditary autoinflammatory or chronic rheumatic disease, elevated C-reactive protein and SAA serum levels, a long delay of a sufficient therapy, an advanced age and the SAA1α/α genotype.     

Analysis of SAA1 gene polymorphisms in the Greek population: rheumatoid arthritis and FMF patients relative to normal controls. Homogeneous distribution and low incidence of AA amyloidosis

Objective. To address whether or not the rarity of amyloidosis in Greek patients with rheumatoid arthritis (RA) is related to specific alleles of single nucleotide polymorphisms (SNPs) in the 5′-flanking region and the exon 3 of the SSA1 gene.

Methods. The genotypes of the ?13T/C SNP in the 5′-flanking region of the SAA1 gene and the two SNPs within exon 3 of SAA1 (2995C/T and 3010C/T polymorphisms) were determined in 88 Greek patients with RA, 14 patients with familial Mediterranean fever (FMF) and 110 healthy controls. Linkage disequilibrium and haplotype frequencies involving ?13T/C, 2995C/T and 3010C/T in these populations were tested and estimated, respectively.

Results. The genotypic distribution and allelic frequencies were similar in all groups tested. SNPs 2995 and 3010 were in linkage disequilibrium for all study populations (p < 0.05), whereas SNP ?13 was not in linkage disequilibrium with either 2995 or 3010 (p ≥ 0.05). Two major haplotypes presented in all patients with RA and FMF and controls: ?13C; 2995T; 3010C (?13C; α) and ?13C; 2995C; 3010T (?13C; β). The ?13T allele was linked with the γ haplotype in Greek patients with RA and controls. The frequency of the ?13T allele was found to be very rare in all groups tested.

Conclusions. In conclusion, the rarity of the putative amyloidogenic ?13T allele in Greek populations may be related to low prevalence of AA amyloidosis development in Greek RA patients.     

Amyloid A amyloidosis in a Japanese patient with familial Mediterranean fever associated with homozygosity for the pyrin variant M694I/M694I

Abstract

Familial Mediterranean fever (FMF) is an autoinflammatory disease common in eastern Mediterranean populations. The most severe complication is the development of secondary amyloid A (AA) amyloidosis. A 51-year-old Japanese male who had been suffering from periodic fever since in his twenties was referred to our hospital for proteinuria. Histological findings from renal biopsy revealed the deposition of AA amyloid fibrils, suggesting that renal dysfunction was due to AA amyloidosis. Gene analysis of the patient and his mother showed that both were homozygous for the M694I mutation in the MEFV gene. His mother was also a carrier of the SAA1.3 allele, which is not only a univariate predictor of survival but also a risk factor for the association of AA amyloidosis with rheumatoid arthritis in Japanese patients, and the SAA1-13T allele in the 13T/C polymorphism on the 5′-flanking region of the SAA1 gene. The patient was also a carrier of the SAA-13T allele. Colchicine resulted in not only an amelioration of the acute febrile attacks of FMF inflammation, but also an improvement in kidney dysfunction due to AA amyloidosis.     

SAA1 gene polymorphisms and the risk of AA amyloidosis in Japanese patients with rheumatoid arthritis

Abstract

To investigate the precise modality of association between SAA1 gene polymorphisms and the development of AA amyloidosis in patients with rheumatoid arthritis (RA), Japanese patients with RA (n = 153), among whom 29 were histologically diagnosed as having amyloidosis, were genotyped for three single nucleotide polymorphisms (SNPs), C-13T, C2995T, and C3010T, in the SAA gene. Pairwise linkage disequilibrium coefficients between each pair of SNPs were calculated and estimated haplotype frequencies were compared between patients with and without amyloidosis. Possible associations between these SNPs and amyloidosis were analyzed by a case–control study and by the Kaplan–Meier method, in which the endpoint was defined as the time of diagnosis of AA amyloidosis. The -13T and 2995C alleles, which were in a tight linkage disequilibrium, were more frequent in the patients with amyloidosis, and the groups with the -13TT and 2995CC genotype had worse survival curves than patients without these genotypes, whereas C3010T was not associated with amyloidosis. Moreover, the haplotype containing ?13C and 2995T was found to be protective. Both C-13T and C2995T were associated with the development of amyloidosis. Examining both polymorphisms may be more useful than examining only one of them for estimating the risk of the development of amyloidosis.     

First report of systemic reactive (AA) amyloidosis in a patient with the hyperimmunoglobulinemia D with periodic fever syndrome

Systemic reactive (AA) amyloidosis, leading to renal failure, is a severe complication of most hereditary periodic fever syndromes. The risk of developing this life-threatening condition varies widely among these disorders, being higher for patients affected by familial Mediterranean fever and tumor necrosis factor receptor-associated periodic syndrome. In spite of an acute-phase response during attacks, amyloidosis has never, to date, been described in patients affected with the hyperimmunoglobulinemia D with periodic fever syndrome (HIDS). This is the first report to describe the occurrence of renal AA amyloidosis causing severe nephrotic syndrome in a young Italian man affected with HIDS. The diagnosis of HIDS was established according to clinical, laboratory, and genetic criteria as required by the international Nijmegen HIDS registry. In this patient, 2 mutations in the mevalonate kinase gene were identified, one of which, the leucine-to-arginine substitution at codon 265, is novel.     

Obesity is a significant susceptibility factor for idiopathic AA amyloidosis

Background: To investigate obesity as susceptibility factor in patients with idiopathic AA amyloidosis.

Methods: Clinical, biochemical and genetic data were obtained from 146 patients with AA amyloidosis. Control groups comprised 40 patients with long-standing inflammatory diseases without AA amyloidosis and 56 controls without any inflammatory disease.

Findings: Patients with AA amyloidosis had either familial Mediterranean fever (FMF) or long-standing rheumatic diseases as underlying inflammatory disease (n?=?111, median age 46 years). However, in a significant proportion of patients with AA amyloidosis no primary disease was identified (idiopathic AA; n?=?37, median age 60 years). Patients with idiopathic AA amyloidosis were more obese and older than patients with AA amyloidosis secondary to FMF or rheumatic diseases. Serum leptin levels correlated with the body mass index (BMI) in all types of AA amyloidosis. Elevated leptin levels of more than 30?µg/l were detected in 18% of FMF/rheumatic?+?AA amyloidosis and in 40% of patients with idiopathic AA amyloidosis (p?=?.018). Finally, the SAA1 polymorphism was confirmed as a susceptibility factor for AA amyloidosis irrespective of the type of the disease.

Conclusions: Obesity, age and the SAA1 polymorphism are susceptibility factors for idiopathic AA amyloidosis. Recent advances in treatment of FMF and rheumatic disorders will decrease the incidence of AA amyloidosis due to these diseases. Idiopathic AA, however, might be an emerging problem in the ageing and increasingly obese population.     

AA amyloidosis – Benefits and prospects of IL-6 inhibitors

Abstract

AA amyloidosis may develop in patients with active chronic inflammation. Serum amyloid A (SAA), the precursor of the AA protein, is strongly amplified in the liver under the stimulation of inflammation-associated cytokines, such as IL-6, TNF, and IL-1. Sustained inflammation, aging, and polymorphisms in the SAA1.3 genotype are dependent risk factors for the formation of AA amyloidosis. The most rational treatment strategy for AA amyloidosis is to inhibit the production of SAA. Treatments for AA amyloidosis involving biologics have recently been emphasized. TNF inhibitors and abatacept reduce SAA levels; however, complete normalization is not always achieved. IL-6 inhibitors may normalize SAA levels in most patients in whom a sufficient concentration of medication is maintained in the blood. Therefore, treatments with IL-6 inhibitors represent an excellent therapeutic strategy for AA amyloidosis and have been verified by recent studies.     

Diagnostic performance of amyloid A protein quantification in fat tissue of patients with clinical AA amyloidosis

Objective.?Amyloid A protein quantification in fat tissue is a new immunochemical method for detecting AA amyloidosis, a rare but serious disease. The objective was to assess diagnostic performance in clinical AA amyloidosis.

Methods.?Abdominal subcutaneous fat tissue of patients with AA amyloidosis was studied at the start of an international clinical trial with eprodisate (NC-503; 1,3-propanedisulfonate; Kiacta?), an antiamyloid compound. All patients had renal findings, i.e. proteinuria (≥1 g/day) or reduced creatinine clearance (20 – 60 ml/min). Controls were patients with other types of amyloidosis and arthritic patients without amyloidosis. Amyloid A protein was quantified by ELISA using monoclonal antihuman serum amyloid A antibodies. Congo red stained slides were scored by light microscopy in a semiquantitative way (0 to 4+).

Results.?Ample fat tissue (>50 mg) was available for analysis in 154 of 183 patients with AA amyloidosis and in 354 controls. The sensitivity of amyloid A protein quantification for detection of AA amyloidosis (>11.6 ng/mg fat tissue) was 84% (95% CI: 77 – 89%) and specificity 99% (95% CI: 98 – 100%). Amyloid A protein quantification and semiquantitative Congo red scoring were concordant. Men had lower amyloid A protein values than women (p < 0.0001) and patients with familial Mediterranean fever had lower values than patients with arthritis (p < 0.001) or other inflammatory diseases (p < 0.01).

Conclusions.?Amyloid A protein quantification in fat tissue is a sensitive and specific method for detection of clinical AA amyloidosis. Advantages are independence from staining quality and observer experience, direct confirmation of amyloid AA type, and potential for quantitative monitoring of tissue amyloid over time.

Trial registration: ClinicalTrials.gov identifier: NCT00035334.     

Ageing: a risk factor for amyloid A amyloidosis in rheumatoid arthritis

Abstract

Objective.?Acceleration of amyloid A (AA) amyloidosis induction by ageing has not been extensively studied in rheumatoid arthritis (RA). The aim of this study is to clarify contribution of ageing to the development of AA amyloidosis associated with RA in our large cohort.

Methods.?388 adult-onset RA patients whose RA was complicated by biopsy-proven AA amyloidosis were enrolled. The ages of RA onset and AA amyloidosis diagnosis were estimated in each patient. The contributions of ageing, inflammatory activity, SAA1 exon 3 polymorphism as well as gender to the pathogenesis of AA amyloidosis in 144 cases were also studied by multiple regression analysis.

Results.?Subjects with RA onset at older age had a shorter period to develop amyloidosis than those with disease onset at younger age (p < 0.001). The interval between RA onset and AA amyloidosis diagnosis was significantly shorter in the SAA1.3 positive group than in the SAA1.3 negative (p?=?0.001). Multiple regression analysis indicated that the interval from RA onset to diagnosis of AA amyloidosis is determined by age at RA onset (p < 0.001), the most recent median annual CRP concentration (p?=?0.006) and SAA1.3 allele (p?=?0.058). Gender did not significantly contribute to the onset of AA amyloidosis (p?=?0.569).

Conclusion.?Ageing is an independent risk factor for the induction of AA amyloidosis complicating RA.     

SAA1 gene polymorphisms and the risk of AA amyloidosis in Japanese patients with rheumatoid arthritis

To investigate the precise modality of association between SAA1 gene polymorphisms and the development of AA amyloidosis in patients with rheumatoid arthritis (RA), Japanese patients with RA (n = 153), among whom 29 were histologically diagnosed as having amyloidosis, were genotyped for three single nucleotide polymorphisms (SNPs), C-13T, C2995T, and C3010T, in the SAA gene. Pairwise linkage disequilibrium coefficients between each pair of SNPs were calculated and estimated haplotype frequencies were compared between patients with and without amyloidosis. Possible associations between these SNPs and amyloidosis were analyzed by a case–control study and by the Kaplan–Meier method, in which the endpoint was defined as the time of diagnosis of AA amyloidosis. The -13T and 2995C alleles, which were in a tight linkage disequilibrium, were more frequent in the patients with amyloidosis, and the groups with the -13TT and 2995CC genotype had worse survival curves than patients without these genotypes, whereas C3010T was not associated with amyloidosis. Moreover, the haplotype containing −13C and 2995T was found to be protective. Both C-13T and C2995T were associated with the development of amyloidosis. Examining both polymorphisms may be more useful than examining only one of them for estimating the risk of the development of amyloidosis.     

<Emphasis Type="Italic">SAA1</Emphasis> α/α alleles in Behçet’s disease related amyloidosis

Behçet’s disease (BD) related amyloidosis is relatively rare. Serum amyloid A protein (SAA) protein gene polymorphism is one of the factors implicated in the pathogenesis of AA type amyloidosis. The aim of this study is to investigate SAA1 gene polymorphism in different patient groups: (1) BD related amyloidosis, (2) BD without amyloidosis, and (3) healthy controls. One hundred eleven patients from three main groups were included in the study: (1) BD related amyloidosis (n?=?9), (2) BD without amyloidosis (n?=?39), and (3) healthy controls (n?=?63). Homozygous α/α is present in 78% of patients with BD and amyloidosis. The SAA1 α/α genotype is significantly more common among patients with BD and amyloidosis. This study demonstrated increased frequency of α/α genotype in BD related amyloidosis. To our knowledge, the relationship between α/α genotype and BD related amyloidosis was not studied previously. In conclusion, the SAA1 α/α genotype is a risk factor for amyloidosis in BD.     

Effect of inflammatory attacks in the classical type hyper-IgD syndrome on immunoglobulin D, cholesterol and parameters of the acute phase response

BACKGROUND: Classical type hyper-immunoglobulin D (IgD) syndrome (HIDS) is an hereditary auto-inflammatory disorder, characterized by recurrent episodes of fever, lymphadenopathy, abdominal distress and a high serum concentration of IgD. It is caused by mevalonate kinase deficiency. OBJECTIVE: To further characterize the acute phase response during fever attacks in HIDS in order to improve diagnosis. SUBJECTS: Twenty-two mevalonate kinase-deficient HIDS patients. METHODS: Blood samples were drawn during and in between febrile attacks, and concentrations ofC-reactive protein (CRP), ferritin, procalcitonin, pentraxin 3, IgD and cholesterol in several lipoprotein fractions were determined. RESULTS: The marked acute phase response at the time of a fever attack in classical type HIDS is reflected by a rise in CRP accompanied by a moderate but statistically significant rise in procalcitonin and pentraxin 3. In only two of 22 patients, procalcitonin concentration rose above 2 ng mL(-1) during fever attack, compatible with the noninfectious nature of these attacks. Ferritin does not reach the high concentrations found in adult-onset Still's disease. Despite the defect in mevalonate kinase, a component of cholesterol metabolism, serum cholesterol did not change during attacks. IgD concentration is elevated regardless of disease activity, although there is appreciable variation during life. Its role in HIDS remains unclear. CONCLUSION: The combination of high CRP concentration plus procalcitonin concentration <2 ng mL(-1) in a symptomatic HIDS patient might indicate a febrile attack without (bacterial) infection; this observation warrants further investigation for its usefulness as a marker in clinical practice.     

Differential affinity of serum amyloid A1 isotypes for high-density lipoprotein

Serum amyloid A (SAA), a precursor of reactive amyloid deposits, is a multigene product. SAA1, predominant both as an amyloid precursor and in plasma, consists of three allelic variants (SAA1.1, SAA1.3, and SAA1.5). Several investigations have shown that the SAA1.3 allele is associated with susceptibility to AA-amyloidosis in Japanese, and the SAA1.5 allele is related with higher serum concentrations of SAA. However, these results have not been interpreted functionally. This study assessed the affinity of SAA isotypes for high-density lipoprotein (HDL), to which SAA binds in plasma. Using a surface plasmon resonance-based apparatus (BIAcore), the affinity between immobilized recombinant human SAAs and HDL was determined. The SAA concentration was measured in fractions after ultracentrifugation (d?=?1.23) of sera from patients with rheumatoid arthritis, whose SAA1 genotypes were determined. In the BIAcore analysis, as the dissociation reaction under the conditions used was too rapid to fit the typical kinetic model, the steady-state affinity model was used. The affinity (kd) of SAA1.1, SAA1.3, and SAA1.5 for HDL was 1.4?×?10^?5, 1.8?×?10^?5, and 3.7?×?10^?6, respectively. rSAA1.5 showed significantly (p?<?0.05) stronger affinity than the other two. The fraction of lipid-free SAA in serum was significantly (p?<?0.001) lower in the patients with larger numbers of the 1.5 allele at the SAA1 locus. These results suggest that the relatively high affinity of SAA1.5 may cause the high serum concentration and may be related to the low susceptibility to amyloidosis.     

Serum amyloid A1 and tumor necrosis factor-alpha alleles in Turkish familial Mediterranean fever patients with and without amyloidosis.

The major complication of familial Mediterranean fever (FMF) is AA amyloidosis. The influence of FMF gene (MEFV) mutations and/or unknown environmental factors and other genetic modifiers are likely to affect the phenotypic variations of the disease and the development of amyloidosis. Serum amyloid A is a serum precursor of AA amyloid that is induced by inflammatory cytokines including TNF-alpha. Our analysis of SAA1.1 frequency in Turkish FMF-amyloidosis patients, revealed a higher frequency compared to non FMF-amyloidosis patients but the difference was not significant. On the other hand, the distribution of SAA1.1 homozygosity among FMF-amyloidosis patients was 55.5% compared to FMF-non-amyloidosis patients (30.8%) which was statistically significant revealing a 2.5 fold risk for the occurrence of amyloidosis. There was no significant difference between the controls and FMF patients with and without amyloidosis for the TNF-alpha-308 G-A allele. It is worth noting that all TNF-alpha-308 G-A carriers (n = 6) in FMF-amyloidosis group have SAA1.1 homozygosity compared to 2/11 in FMF-non-amyloidosis group. Further evaluation of these polymorphisms may have importance and need further study.     

A novel single‐nucleotide polymorphism at the 5′‐flanking region of SAA1 associated with risk of type AA amyloidosis secondary to rheumatoid arthritis

Objective

To address whether the γ haplotype at exon 3 of the SAA1 gene is directly associated with type AA amyloidosis or is merely in linkage with an unknown polymorphism that is primarily associated with disease risk, we examined the SAA1 gene for new polymorphisms.

Methods

We analyzed DNA samples from 44 rheumatoid arthritis (RA) patients with AA amyloidosis (amyloid group), 55 RA patients without AA amyloidosis (RA group), and 58 non‐RA healthy subjects (non‐RA group). We also examined DNA samples from 50 Caucasians to compare linkage disequilibrium relationships involving SAA1 region polymorphisms between Japanese and Caucasoid populations.

Results

We observed 3 novel single‐nucleotide polymorphisms (SNPs) in the 5′‐flanking region of SAA1: −61C/G, −13T/C, and −2G/A. Comparison of allele frequencies and ratios of individuals with particular alleles between the study groups revealed statistically significant differences between the amyloid and RA groups and between the amyloid and non‐RA groups. Statistical analysis revealed that the −13T/C SNP was strongly associated with AA amyloidosis. In addition, we found tight linkage between the −13T allele and the α haplotype, rather than the β haplotype, at exon 3 in the Caucasoid population, while −13T was closely linked to the γ and β haplotypes, rather than the α haplotype, in the Japanese population. Since the linkage disequilibrium relationship was reversed between the Japanese and Caucasoid populations, different exon 3 haplotypes of SAA1 are found to be associated with the risk of AA amyloidosis in different ethnic groups.

Conclusion

Our data suggest that the SAA1 −13T allele, rather than SAA1 exon 3 haplotypes, is primarily associated with AA amyloidosis risk.

     

The contribution of genotypes at the MEFV and SAA1 loci to amyloidosis and disease severity in patients with familial Mediterranean fever

OBJECTIVE: The clinical profile in familial Mediterranean fever (FMF), including its major manifestation, amyloidosis, is influenced by MEFV allelic heterogeneity and other genetic and/or environmental factors. In this study, we analyzed the contribution of genotypes at the MEFV and SAA1 loci to disease severity and to the development of amyloidosis, and further defined the factors affecting the clinical profile of FMF. METHODS: We investigated a sample of 277 FMF patients (154 men and 123 women), including 62 patients with nephropathic amyloidosis, in whom both FMF alleles had been identified. A detailed chart review, interview, and physical examination were undertaken to determine the patients' demographic characteristics, medical history, clinical manifestations, and treatment. The disease severity score was calculated from the Tel-Hashomer key. Genotypes at the SAA1 locus (isoforms alpha, beta, and gamma) were determined in all patients. The SAA1 13C/T polymorphism of the SAA1 promotor was analyzed in a subset of cases. RESULTS: The male:female ratio (154:123, or 1.3) was higher among patients with amyloidosis (40:22, or 1.8) compared with patients without amyloidosis (114:101, or 1.1). Logistic regression analysis showed that homozygosity for the M694V allele (odds ratio [OR] 4.27, 95% confidence interval [95% CI] 2.01-9.07), the presence of the SAAalpha/alpha genotype (OR 2.99, 95% CI 1.47-6.09), the occurrence of arthritis attacks (OR 2.43, 95% CI 1.17-5.06), and male sex (OR 1.73, 95% CI 0.90-3.33) were significantly and independently associated with renal amyloidosis. Disease severity was mainly influenced by MEFV mutations and was not associated with genotypes at the SAA1 locus. The SAA1 13T allele was rare, being associated mainly with the SAA gamma isoform, and not related to renal amyloidosis. CONCLUSION: Overall, disease severity and the development of amyloidosis in FMF are differentially affected by genetic variations within and outside the MEFV gene.     

An allele of serum amyloid A1 associated with amyloidosis in both Japanese and Caucasians.

Serum amyloid A1 (SAA1), one of the two isotypes of acute phase SAA, is the predominant precursor to amyloid A (AA) protein, the chief constituent of fibrillar deposits in reactive (AA) amyloidosis. Prolonged hyperexpression of SAA protein accompanying chronic inflammation is critical to, but seems not to be sufficient for, the development of AA amyloidosis. Several previous studies have investigated the possibility of linkage between SAA1 exon 3 polymorphisms and susceptibility to amyloidosis. While the SAA1.1 allele was found to have a negative association with amylodosis in Japanese subjects, it showed a positive association in Caucasians. Moriguchi and colleagues recently showed that a single nucleotide polymorphism (SNP) at position -13 in the SAA1 5' flanking region was more strongly associated with amyloidosis than was the exon 3 polymorphism. To test whether this SNP may be an amyloidogenic factor common to Japanese and Caucasians, we have analyzed the SAA1 gene in amyloid and non-amyloid patients of both ethnic groups for the presence of T or C at position -13 and for exon 3 polymorphisms (SAA1.1, 1.3 or 1.5). The frequency of the -13T allele was 0.708 and 0.521 in Japanese rheumatoid arthritis patients with and patients without AA amyloidosis, respectively, and 0.536 and 0.196 in American Caucasian patients with AA amyloidosis and control subjects, respectively. In Caucasians, the -13T allele had a stronger association with amyloidosis than did the SAA1.1 allele. These findings suggest that -13T is a genetic background for AA amyloidosis in both Japanese and Caucasians and the difference in prevalence of AA amyloidosis in the two ethnic groups may be due, at least in part, to a difference in the frequency of the -13T SAA1 allele.     

Safety and efficacy of empirical interleukin-1 inhibition using anakinra in AA amyloidosis of uncertain aetiology

Objective: AA amyloidosis is a serious complication of persistent inflammation, which, untreated will progress to renal failure and death. Effective suppression of the underlying inflammatory disease is the focus of treatment. However, in approximately 20% of cases the underlying condition remains uncertain, presenting a dilemma as to choice of treatment.

Methods: We conducted a retrospective study of a cohort of 11 patients diagnosed with AA amyloidosis of unknown aetiology, who had been empirically treated with anakinra.

Results: In anakinra-responders, median pre-treatment SAA was 74 (IQR 34–190) mg/L, and median on-treatment SAA was 6 (4–16) mg/L (p?=?.0047), with the response having been maintained for a median on-treatment follow-up of 1.8 (1–7.6) years. Six dialysis patients were treated effectively and safely with 100?mg anakinra three times weekly post-dialysis. Four patients remained well on daily anakinra post-renal transplant. Five anakinra-responders showed regression and three showed stabilization of amyloid load on serial SAP scintigraphy.

Conclusions: This small cohort shows that even in potentially high risk cases with organ damage secondary to AA amyloidosis or in the presence of a renal graft, anakinra, when used appropriately and carefully monitored, has proved remarkably effective and well tolerated. Longer follow-up of this off-label use is required.