Amyloidosis associated with renal cell carcinoma of the AA type

Amyloid fibrils were found at postmortem examination in a 70 year old woman with generalized amyloidosis associated with renal carcinoma (hypernephroma). Clinically, her amyloid disease presented as nephrotic syndrome. It was demonstrated by electrophoretic and amino acid sequence analysis studies that the amyloid fibrils contained AA protein identical to that found in amyloidosis associated with chronic inflammatory and infectious diseases as well as in the genetic form of familial Mediterranean fever.     

French practical guidelines for the diagnosis and management of AA amyloidosis

AA amyloidosis is secondary to the deposit of excess insoluble Serum Amyloid A (SAA) protein fibrils. AA amyloidosis complicates chronic inflammatory diseases, especially chronic inflammatory rheumatisms such as rheumatoid arthritis and spondyloarthritis; chronic infections such as tuberculosis, bronchectasia, chronic inflammatory bowel diseases such as Crohn's disease; and auto-inflammatory diseases including familial Mediterranean fever. This work consists of the French guidelines for the diagnosis workup and treatment of AA amyloidosis. We estimate in France between 500 and 700 cases in the whole French population, affecting both men and women. The most frequent organ impaired is kidney which usually manifests by oedemas of the lower extremities, proteinuria, and/or renal failure. Patients are usually tired and can display digestive features anf thyroid goiter. The diagnosis of AA amyloidosis is based on detection of amyloid deposits on a biopsy using Congo Red staining with a characteristic green birefringence in polarized light. Immunohistochemical analysis with an antibody directed against Serum Amyloid A protein is essential to confirm the diagnosis of AA amyloidosis. Peripheral inflammatory biomarkers can be measured such as C Reactive protein and SAA. We propose an algorithm to guide the etiological diagnosis of AA amyloidosis. The treatement relies on the etiologic treatment of the undelying chronic inflammatory disease to decrease and/or normalize Serum Amyloid A protein concentration in order to stabilize amyloidosis. In case of renal failure, dialysis or even a kidney transplant can be porposed. Nowadays, there is currently no specific treatment for AA amyloidosis deposits which constitutes a therapeutic challenge for the future.     

Amyloid deposition in a renal transplant in familial Mediterranean fever.

A patient with familial Mediterranean fever and amyloidosis who received a cadaver renal transplant 6 1/2 years ago was studied to determine the relation of the serum precursor of secondary amyloid (SAA) to the clinical course and to the deposition of amyloid in the transplant. Amyloid fibrils extracted from the patient's kidneys contained protein AA as a major constituent, which identified the amyloid as secondary. Protein AA antiserum was used in an indirect immunofluorescent technique to stain amyloid deposits in sections of the original kidney. A renal biopsy at 2 years showed no amyloid, but a renal biopsy at 4 years showed amyloid. Serum levels of SAA from 3 years before transplant to 6 years after transplant were elevated throughout most of the course.     

Pathogenetic mechanisms of amyloid A amyloidosis

Systemic amyloid A (AA) amyloidosis is a serious complication of chronic inflammation. Serum AA protein (SAA), an acute phase plasma protein, is deposited extracellularly as insoluble amyloid fibrils that damage tissue structure and function. Clinical AA amyloidosis is typically preceded by many years of active inflammation before presenting, most commonly with renal involvement. Using dose-dependent, doxycycline-inducible transgenic expression of SAA in mice, we show that AA amyloid deposition can occur independently of inflammation and that the time before amyloid deposition is determined by the circulating SAA concentration. High level SAA expression induced amyloidosis in all mice after a short, slightly variable delay. SAA was rapidly incorporated into amyloid, acutely reducing circulating SAA concentrations by up to 90%. Prolonged modest SAA overexpression occasionally produced amyloidosis after long delays and primed most mice for explosive amyloidosis when SAA production subsequently increased. Endogenous priming and bulk amyloid deposition are thus separable events, each sensitive to plasma SAA concentration. Amyloid deposits slowly regressed with restoration of normal SAA production after doxycycline withdrawal. Reinduction of SAA overproduction revealed that, following amyloid regression, all mice were primed, especially for rapid glomerular amyloid deposition leading to renal failure, closely resembling the rapid onset of renal failure in clinical AA amyloidosis following acute exacerbation of inflammation. Clinical AA amyloidosis rarely involves the heart, but amyloidotic SAA transgenic mice consistently had minor cardiac amyloid deposits, enabling us to extend to the heart the demonstrable efficacy of our unique antibody therapy for elimination of visceral amyloid.     

Serum amyloid A – an indicator of inflammation in ankylosing spondylitis

Biological markers of inflammation are useful for the diagnosis and monitoring of inflammatory rheumatic diseases. The present study tested, whether serum amyloid A (SAA) could be used as a marker of inflammatory disease activity in ankylosing spondylitis (AS). In 72 patients with AS, the two valuable surrogate markers of disease activity, erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP), and an established clinical activity score (Bath Ankylosing Spondylitis Disease Activity Index, BASDAI) were correlated to the serum levels of SAA. It was found that SAA correlates well with ESR, CRP, and BASDAI. Because of its strong correlation, SAA seems to be an additional very useful disease activity marker. When used in diagnosis, and especially in monitoring of inflammation, further studies are required. Another interesting point of view is the described role of plasma SAA as a precursor of Amyloid A (AA) protein in secondary amyloidosis, a known complication in AS. In all probability, high circulating SAA levels are a predisposing indicator of disease activity. Received: 24 April 1999 / Accepted: 22 November 1999     

Cellular events associated with the initial phase of AA amyloidogenesis: insights from a human monocyte model

Reactive amyloidosis is a systemic protein deposition disease that develops in association with chronic inflammation. The deposits are composed of extracellular, fibrillar masses of amyloid A (AA) protein, an N-terminal fragment of the acute-phase serum protein serum amyloid A (SAA). The pathogenic conversion of SAA into amyloid has been studied in two human cell culture models, peritoneal cells and peripheral blood monocytes. Human monocyte cultures proved more robust than either mouse or human peritoneal cells at initiating amyloid formation in the absence of a preformed nidus such as amyloid-enhancing factor and particularly well suited for examination of individual cells undergoing amyloid formation. Amyloid-producing monocyte cultures were stained with Congo red and Alcian blue for detection of amyloid and glycosaminglycans, respectively; immunocytochemistry was performed to identify SAA/AA, CD68, CD14, lysosomal protein Lamp-1, and early endosomal protein EEA1. SAA interaction with monocytes was also visualized directly via fluorescence confocal microscopy. Amyloid was initially detected only in intracellular vesicles, but with time was seen extracellularly. Morphologic changes in lysosomes were noted during the early phase of amyloid formation, suggesting that exocytosis of fibrils may occur via lysosome-derived vesicles. Cultures engaged in amyloid formation remained metabolically active; no cytotoxic effects were observed. Mimicking in vivo phenomena, amyloid formation was accompanied by increased glycosaminoglycan content and C-terminal processing of SAA. The ability of human monocytes to endocytose and intracellularly transform SAA into amyloid via a mechanism that requires and maintains, rather than compromises, metabolic activity distinguishes them as a useful model for probing earliest events in the disease process.     

Cellular events associated with the initial phase of AA amyloidogenesis: insights from a human monocyte model.

Reactive amyloidosis is a systemic protein deposition disease that develops in association with chronic inflammation. The deposits are composed of extracellular, fibrillar masses of amyloid A (AA) protein, an N-terminal fragment of the acute-phase serum protein serum amyloid A (SAA). The pathogenic conversion of SAA into amyloid has been studied in two human cell culture models, peritoneal cells and peripheral blood monocytes. Human monocyte cultures proved more robust than either mouse or human peritoneal cells at initiating amyloid formation in the absence of a preformed nidus such as amyloid-enhancing factor and particularly well suited for examination of individual cells undergoing amyloid formation. Amyloid-producing monocyte cultures were stained with Congo red and Alcian blue for detection of amyloid and glycosaminglycans, respectively; immunocytochemistry was performed to identify SAA/AA, CD68, CD14, lysosomal protein Lamp-1, and early endosomal protein EEA1. SAA interaction with monocytes was also visualized directly via fluorescence confocal microscopy. Amyloid was initially detected only in intracellular vesicles, but with time was seen extracellularly. Morphologic changes in lysosomes were noted during the early phase of amyloid formation, suggesting that exocytosis of fibrils may occur via lysosome-derived vesicles. Cultures engaged in amyloid formation remained metabolically active; no cytotoxic effects were observed. Mimicking in vivo phenomena, amyloid formation was accompanied by increased glycosaminoglycan content and C-terminal processing of SAA. The ability of human monocytes to endocytose and intracellularly transform SAA into amyloid via a mechanism that requires and maintains, rather than compromises, metabolic activity distinguishes them as a useful model for probing earliest events in the disease process.     

Clinical strategies for amyloid A amyloidosis secondary to rheumatoid arthritis

Secondary amyloid A (AA) amyloidosis is an important complication of rheumatoid arthritis (RA) and has remarkable variation in frequency worldwide. It is a serious, potentially life-threatening disorder caused by deposition in organs of AA fibrils, which are derived from the circulatory, acute-phase-reactant, serum amyloid A protein (SAA). The SAA1.3 allele can serve not only as a risk factor for the association of AA amyloidosis but also as a poor prognostic factor in Japanese RA patients. Both the association of AA amyloidosis arising early in RA disease course and symptomatic variety and severity were found in amyloidotic patients carrying the SAA1.3 allele. Etanercept for patients with AA amyloidosis who carry the SAA1.3 allele showed the amelioration of rheumatoid inflammation, including marked reduction of SAA and improvement of renal function. In light of the SAA1.3 allele significance in Japanese RA patients, both a tight control by disease-modifying antirheumatic drugs and an early intervention of biologics for RA inflammation should be applied to suppress acute-phase response, thus preventing the association of AA amyloidosis. It is suggested that SAA plays not only an important role in the development of AA amyloidosis but also interacts with events closely involved in metabolic syndrome as a high- and low-grade inflammatory modulator, respectively.     

Systemic AA amyloidosis induced by benign neoplasms

Amyloidosis is a systemic disorder characterized by the extracellular tissue deposition of insoluble, toxic aggregates in bundles of beta-sheet fibrillar proteins. These deposits are typically identified on the bases of their apple-green birrefringence under a polarized light microscope after staining with Congo red, and by the presence of rigid, nonbranching fibrils 8 to 10 nm in diameter on electron microscopy. The type of amyloid fibril unit can be further defined by immunohistology or by immunoelectron microscopy. It has been described at least 25 different human protein precursors of amyloid fibrils, which will describe its corresponding amyloid disease. The most common types of amyloidosis are AL (primary) and AA (secondary) types; the former, is the most frequent and is due to deposition of proteins derived from immunoglobulin light chain fragments, occurring alone or in association with multiple myeloma. The later (AA), is caused by deposition of fibrils composed of fragments of the acute phase reactant serum amyloid A (SAA) and complicates chronic diseases with ongoing or recurring inflammation, namely; rheumatoid arthritis (RA), juvenile chronic polyarthritis, ankylosing spondylitis, familial periodic fever syndromes (Familial Mediterranean Fever), chronic infections and furthermore, some neoplasms (mainly renal cell carcinoma and Hodgkin's disease). Despite its less frequent association, some benign neoplasms can subsequently complicate to AA amyloidosis, therefore, an early diagnose and successful treatment may lead indeed, to regression of the amyloid disease. Herein, we present two cases of AA amyloidosis, both of them caused by 2 different benign neoplasms: 1. A 34 year-old woman, after chronic oral contraceptive use, developed an hepatic adenoma (fig. 1) which finally lead to AA amyloidosis with primary kidney presentation (pure nephrotic syndrome) (table 1). Post-surgical complications yield to acute renal failure from which unfortunately could not be recovered. After being on hemodialysis therapy during 10 months she received a first renal allograft without any complication. 2. A 20 year old woman, was diagnosed of AA amyloidosis after a renal biopsy (fig. 2) because of nephrotic syndrome (table 1). Further investigation lead to the finding of a hialyne-vascular type Castleman's disease located in the retroperitoneum (fig. 2). Despite surgical resection and medical treatment (colchicine) she developed progressive renal failure requiring initialization of hemodialysis therapy. After 6 years being on hemodialysis, she received a first renal allograft which is currently functioning after one year of follow- up. Although other chronic inflammatory diseases complicate more frequently to AA amyloidosis, benign tumors have to be taken into account as a potential ethiological cause for secondary amyloidosis.     

Endoscopic and histopathological features of gastrointestinal amyloidosis

Amyloidosis is a rare disorder, characterized by the extracellular deposition of an abnormal fibrillar protein, which disrupts tissue structure and function. Amyloidosis can be acquired or hereditary, and systemic or localized to a single organ, such as the gastrointestinal (GI) tract. Clinical manifestations may vary from asymptomatic to fatal forms. Primary amyloidosis (monoclonal immunoglobulin light chains, AL) is the most common form of amyloidosis. AL amyloidosis has been associated with plasma cell dyscrasias, such as, mul- tiple myeloma. Secondary amyloidosis is caused by the deposition of fragments of the circulating acute-phase reactant, serum amyloid A protein (SAA). Common causes of AA amyloidosis are chronic inflammatory dis-orders. Although GI symptoms are usually nonspecific, histopathological patterns of amyloid deposition are associated with clinical and endoscopic features. Amyloid deposition in the muscularis mucosae, submucosa, and muscularis propria has been dominant in AL amyloidosis, leading to polypoid protrusions and thickening of the valvulae conniventes, whereas granular amyloid deposition mainly in the propria mucosae has been related to AA amyloidosis, resulting in the fine granular appearance, mucosal friability, and erosions. As a result, AL amyloidosis usually presents with constipation, mechanical obstruction, or chronic intestinal pseudoobstruction while AA amyloidosis presents with diarrhea and malabsorption Amyloidotic GI symptoms are mostly refractory and have a negative impact on quality of life and survival. Diagnosing GI amyloidosis requires high suspicion of evaluating endoscopists. Because of the absence of specific treatments for reducing the abundance of the amyloidogenic precursor protein, we should be aware of certain associations between patterns of amyloid deposition and clinical and endoscopic features.     

Significance of SAA1.3 allele genotype in Japanese patients with amyloidosis secondary to rheumatoid arthritis

OBJECTIVE: To clarify the clinical significance of the SAA1.3 allele in the development and outcome of AA amyloidosis in Japanese patients with rheumatoid arthritis (RA). METHODS: One hundred and twenty RA patients (60 alive and 60 dead) fulfilling the 1987 ACR criteria and 62 RA patients with biopsy-confirmed amyloid A (AA) amyloidosis (36 alive and 26 dead) were enrolled. The SAA1 genotypes were determined by PCR-based restriction fragment length polymorphism. To predict the clinical outcome of AA amyloidosis, we investigated characteristics and survival, focusing on the SAA1.3 allele retrospectively. RESULTS: The SAA1.3 allele genotype was not only a risk factor for the association of AA amyloidosis but also a poor prognostic factor for the development of AA amyloidosis (P=0.015). Both the association of AA amyloidosis arising early in the RA disease course and symptomatic variety and severity were found in amyloidotic patients with the SAA1.3 allele. The presenting factors adversely influenced were age (P=0.001), lowered serum albumin (P=0.001) and creatinine concentration (P=2.14 x 10(-5)). Renal involvement was associated with poor survival in patients with AA amyloidosis (P=0.011) and the presence of cardiac involvement was likely to be a risk factor for survival (P=0.062). The rate of the causes of death in respect to the category of infection, gastrointestinal diseases, and renal failure was higher in patients with AA amyloidosis than in those without amyloidosis, gastrointestinal diseases and renal failure. Cyclophosphamide was found to be superior to methotrexate in the management of RA patients with AA amyloidosis. CONCLUSION: Our data support the fact that homozygosity for the SAA1.3 allele is a univariate predictor of survival in addition to a risk factor for the association of AA amyloidosis adversely influencing the outcome in Japanese RA patients. Renal involvement is a pivotal clinical manifestation in the development of AA amyloidosis, as is likely to be cardiac involvement in AA amyloidosis secondary to RA.     

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 (> or =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.     

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.     

Efficacy of etanercept in patients with AA amyloidosis secondary to rheumatoid arthritis

OBJECTIVE: The efficacy of biological therapies in rheumatoid arthritis (RA) is well known, but their hypothetical benefit in amyloid A (AA) amyloidosis secondary to RA still remains to be considered. We evaluated the efficacy and safety of etanercept in serum amyloid A (SAA) 1.3 allele Japanese patients with AA amyloidosis secondary to RA. METHODS: Seven RA patients with histologically confirmed AA amyloidosis and renal involvement who were treated with etanercept were enrolled. They all had the SAA1.3 allele, which has been shown to be a risk factor not only for the association of AA amyloidosis but also for a poor prognosis in Japanese RA patients. Efficacy was assessed as a sustained decrease in RA inflammation and an amelioration of renal function. RESULTS: RA inflammation and AA amyloidosis were improved and stabilized after 43.4 +/- 16.5 weeks. At week 20 the number of tender (p = 0.017) and swollen (p = 0.017) joints, and levels of serum C-reactive protein (p = 0.018) and albumin (p = 0.045) had improved. The values for SAA, serum creatinine, calculated creatinine clearance, and proteinuria also ameliorated. No severe adverse events were observed. One patient eventually had to go on hemodialysis but her tolerance of etanercept remained stable. CONCLUSION: Etanercept can be used safely and effectively in AA amyloidosis secondary to RA with renal involvement, and is of clinical benefit in the short-term, even in patients on hemodialysis. It appears that SAA1.3 allele may be used as a clinical parameter for the introduction of etanercept in Japanese RA with AA amyloidosis.     

Efficacy of cyclophosphamide combined with prednisolone in patients with AA amyloidosis secondary to rheumatoid arthritis

Secondary amyloid A (AA) amyloidosis is an uncommon yet important complication of rheumatoid arthritis (RA). It is one of the most relentless of the extra-articular features of RA, and suitable treatments have not yet been found. We studied the efficacy of cyclophosphamide (CYC) combined with prednisolone (PSL) in amyloidotic patients who had serum amyloid A (SAA) 1.3 genotype, which is a risk factor for secondary amyloidosis in Japanese RA patients. Fifteen RA patients who were SAA1.3 homo- and heterozygotes with biopsy-confirmed AA amyloidosis were treated with a combination of CYC and PSL. Laboratory variables of C-reactive protein (CRP), rheumatoid factor (RF), erythrocyte sedimentation rate (ESR), serum albumin (Alb), serum creatinine (Cre) and Lansburys index were carried out by statistical analysis of changes between before and during the medication. According to the Mann–Whitney rank test, CRP, RF, ESR, Alb and Cre levels improved significantly with the combination treatment (p<0.05). Also, paired t-tests showed significance in Lansburys index between before and during the medication (p=0.007). CYC combined with PSL ameliorated not only laboratory markers but also clinical rheumatoid activity in patients with amyloidosis secondary to RA, whose genotypes were SAA1.3 homo- and heterozygous. CRP, ESR, RF, Alb and Cre will be surrogate markers of therapeutic efficacy. The combination of CYC and PSL appears to be beneficial for Japanese RA patients who are SAA1.3 homo- and heterozygous carriers, associated with secondary AA amyloidosis.Abbreviations AA Amyloid A - CRP C-reactive protein - Ccr Creatinine clearance - CYC Cyclophosphamide - DMARD Disease-modifying antirheumatic drugs - ESR Erythrocyte sedimentation rate - NSAID Non-steroidal anti-inflammatory drugs - PCR Polymerase chain reaction - PSL Prednisolone - RA Rheumatoid arthritis - RF Rheumatoid factor - SAA Serum amyloid A     

Combined treatment with cyclophosphamide and prednisolone is effective for secondary amyloidosis with SAA1γ/γ genotype in a patient with rheumatoid arthritis

Abstract

A 41-year-old woman, who had been diagnosed with rheumatoid arthritis (RA), was admitted because of proteinuria, and rheumatoid and gastrointestinal symptoms just 1 year after onset. Renal biopsy revealed marked amyloid deposits of AA (amyloid A)-type. Genotyping of serum amyloid A (SAA) showed that she was homozygous for SAA1γ. Combined treatment with cyclophosphamide and prednisolone led to remission of both RA disease activity and proteinuria. Since the renal dysfunction arose from amyloidosis, arrested renal deterioration and a remission of proteinuria would result from a reduction of amyloid deposits. Therefore, early usage of immunosuppresive therapy such as a combined treatment with these two medicines would be useful against systemic amyloidosis secondary to RA, even if the patient has the risky SAA1γ/γ genotype.     

Treatment of renal amyloidosis with etanercept in tumour necrosis factor receptor-associated periodic syndrome

OBJECTIVE: To describe the effect of Etanercept treatment in systemic AA amyloidosis in tumour necrosis factor receptor-associated periodic syndrome (TRAPS). METHODS: Etanercept therapy was given to a 27 year old woman, with systemic amyloidosis and nephrotic syndrome, and to her 51 year old father, also affected by TRAPS, who had previously undergone renal transplant for amyloidosis. Serum SAA levels, plasma cytokines, glomerular filtration rate and serum amyloid P scanning were monitored. RESULTS: Etanercept treatment resulted in initial clinical resolution of nephrotic syndrome in the 27 year old female. Both subjects demonstrated improvements in GFR and initial reduction or stabilisation of amyloid deposits on SAP scanning. CONCLUSION: Etanercept may reverse or slow the progression of systemic AA amyloidosis in subjects with C33Y TNFRSF1A mutation. Treatment may however need to be continuous and life-long to prevent progression to end stage disease.     

Reversible “end-stage” lupus nephritis: Analysis of patients able to discontinue dialysis

Seventeen of 41 patients with lupus nephritis who underwent dialysis for renal failure recovered renal function and discontinued dialysis. Two of these 17 had confounding factors unrelated to lupus that contributed to renal dysfunction (one meningococcemia, one vigorous diuresis). Indications for dialysis were identical both in patients who discontinued dialysis (short-term) and in those who did not (long-term). The rate of progression to dialysis, measured as the slope of the reciprocal of the serum creatinine level versus time, was significantly more rapid in the short-term group (p < 0.001). Patients who underwent short-term dialysis were more likely to have had lupus for less than two years (p = 0.015). Anti-DNA antibody binding values, total hemolytic complement levels, extent of extrarenal disease, and hypertension did not differentiate the short-term from long-term dialysis groups. Renal biopsy performed within three months of first dialysis did not demonstrate a consistent picture in the short-term dialysis group. Dialysis is not equivalent to irrevocable end-stage renal disease in patients with lupus nephritis. Thirteen of 22 patients (59 percent) with a 10 percent reduction time for renal function of less than three weeks were able to discontinue dialysis. Ten of these 13 were alive without need for dialysis six months later, with a mean follow-up serum creatinine level of 2.9 ± 1.9 mg/dl.     

Association of hyperestrogenemia and coronary heart disease in men in the Framingham cohort

The serum levels of estradiol and testosterone as well as established risk factors for coronary heart disease were estimated in 61 men (mean age 70.0 ± 6.4 [SD] years) with coronary heart disease and in 61 matched control subjects enrolled in the Framingham Heart Study. The mean serum estradiol level was significantly higher in the subjects with coronary disease (p = 0.011). This difference in estradiol level increased with the exclusion of subjects older than 75 years (p < 0.001). The mean serum testosterone level was not significantly different. None of the established risk factors for coronary heart disease was different between subjects with coronary disease and control subjects except blood glucose level, which was higher in the subjects with coronary disease (p = 0.025). We conclude that hyperestrogenemia is an important correlate of coronary heart disease in men.     

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 gamma 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 alpha haplotype, rather than the beta haplotype, at exon 3 in the Caucasoid population, while -13T was closely linked to the gamma and beta haplotypes, rather than the alpha 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.