Efficacy of anakinra in a patient with systemic amyloidosis presenting as amyloidoma

Amyloidosis is a heterogeneous group of disorders characterized by extracellular deposition of unique protein fibrils. The least common presentation of an amyloid deposition is as a discrete mass called amyloidoma or amyloid tumor. We report a case of a soft tissue amyloidoma in the abdomen of a 16‐year‐old girl who was diagnosed as having systemic amyloidosis. A girl aged 16 years was referred to our hospital with a pre‐diagnosis of a retroperitoneal mass documented with abdominal ultrasonography and tomography. A laboratory examination revealed nephrotic syndrome. She underwent surgery for a complete resection of the lesion. A histopathologic examination with Congo red and crystal violet dyes verified the diagnosis of amyloidoma. An immunohistochemical study for amyloid A protein was positive. A renal biopsy was also compatible with AA amyloidosis. A detailed search for the etiology of systemic amyloidosis revealed heterozygous mutation in the Mediterranean fever gene. Treatment with colchicine and anakinra were started with the diagnosis of familial Mediterranean fever because the other causes of secondary amyloidosis were ruled out. After 3 months of anakinra treatment, the laboratory findings returned to normal and excessive proteinuria disappeared. In countries where FMF and other autoinflammatory diseases are prevelant, systemic amyloidosis should be kept in mind in the differential diagnosis of children who present with nephrotic syndrome and abdominal mass. Taking previously reported cases and our case together, it appears that anti‐interleukin‐1 treatment represents a promising new approach in a subset of patients with systemic amyloidosis secondary to autoinflammatory diseases.     

Significant association between renal function and area of amyloid deposition in kidney biopsy specimens in both AA amyloidosis associated with rheumatoid arthritis and AL amyloidosis

The kidney is a major target organ for systemic amyloidosis, which results in proteinuria and an elevated serum creatinine level. The clinical manifestations and precursor proteins of amyloid A (AA) and light-chain (AL) amyloidosis are different, and the renal damage due to amyloid deposition also seems to differ. The purpose of this study was to clarify haw the difference in clinical features between AA and AL amyloidosis are explained by the difference in the amount and distribution of amyloid deposition in the renal tissues.

A total of 119 patients participated: 58 patients with an established diagnosis of AA amyloidosis (AA group) and 61 with AL amyloidosis (AL group). We retrospectively investigated the correlation between clinical data, pathological manifestations, and the area occupied by amyloid in renal biopsy specimens.

In most of the renal specimens the percentage area occupied by amyloid was less than 10%. For statistical analyses, the percentage area of amyloid deposition was transformed to a common logarithmic value (Log₁₀%amyloid). The results of sex-, age-, and Log₁₀%amyloid-adjusted analyses showed that systolic blood pressure (SBP) was higher in the AA group. In terms of renal function parameters, serum creatinine, creatinine clearance (Ccr) and estimated glomerular filtration rate (eGFR) indicated significant renal impairment in the AA group, whereas urinary protein indicated significant renal impairment in the AL group. Pathological examinations revealed amyloid was predominantly deposited at glomerular basement membrane (GBM) and easily transferred to the mesangial area in the AA group, and it was predominantly deposited at in the AL group. The degree of amyloid deposition in the glomerular capillary was significantly more severe in AL group. The frequency of amyloid deposits in extraglomerular mesangium was not significantly different between the two groups, but in AA group, the degree amyloid deposition was significantly more severe, and the deposition pattern in the glomerulus was nodular. Nodular deposition in extraglomerular mesangium leads to renal impairment in AA group.

There are significant differences between AA and AL amyloidosis with regard to the renal function, especially in terms of Ccr, eGFR and urinary protein, even after Log10%amyloid was adjusted; showing that these inter-group differences in renal function would not be depend on the amount of renal amyloid deposits. These differences could be explained by the difference in distribution and morphological pattern of amyloid deposition in the renal tissue.     

Anaemia of chronic disease in AA amyloidosis is associated with allele 2 of the interleukin-1beta-511 promoter gene and raised levels of interleukin-1beta and interleukin-18

OBJECTIVE: In amyloid A (AA) amyloidosis the receptor for advanced glycation end products is a target for the circulating amyloid precursor protein (SAA) resulting in upregulation of the proinflammatory cytokine pathway. Besides inducing hepatic SAA synthesis the interleukin-1 cytokine family is involved in the regulation of haematopoiesis. We therefore studied the relationship between the circulating levels of interleukin-1beta (IL-1beta) and interleukin-18 (IL-18), a new member of the IL-1 complex, as well as polymorphisms within the IL-1 cluster with the occurrence of anaemia in patients with AA amyloidosis. DESIGN, SETTING AND SUBJECTS: The study included 54 adult patients with biopsy-proven reactive amyloidosis allocated into three groups on the basis of haemoglobin (Hb) level: group I included all patients with Hb < 110 g L(-1) (n = 16); group II patients (Hb > 110 g L(-1), n = 16) were selected to match group I patients with respect to sex, age, underlying disease (seropositive, erosive rheumatoid arthritis) and renal function; and group III patients (n = 38) represented all patients (unselected) with Hb > or = 110 g L(-1). Gene polymorphisms were studied by polymerase chain reaction restriction length assay and included the base exchange at position-889 of the IL-1alpha gene, the polymorphic region at position-511 and the polymorphic locus at exon 5, position +3954 of the IL-1beta gene, as well as the IL-1 receptor antagonist (IL-1Ra) exon 2 polymorphism caused by the 86-bp tandem repeats. Plasma IL-1beta, IL-1alpha, IL-18, IL-1 Ra, SAA, ferritin, soluble transferrin receptor and erythropoietin levels were studied by enzyme immunoassays. RESULTS: Circulating IL-beta and IL-18 were significantly raised in the anaemic patients with AA amyloidosis when compared with group II patients (matched, Hb > 110 g L(-1)) as well as group III patients (nonmatched, Hb > or = 110 g L(-1)). A significant inverse relationship was found between IL-1beta and haemoglobin levels, as well as between IL-18 and haemoglobin levels. The frequency of allele 2 (T) of the IL-1beta-511 promoter gene was significantly increased and that of allele 1 (C) decreased in anaemic amyloid patients (group I) when compared with group II and III patients. Circulating IL-1beta levels tended to be higher amongst the IL-1beta-511 allele 2 carriers than amongst the noncarriers, as well as amongst the anaemic amyloid patients filling all criteria of anaemia of chronic disease. CONCLUSION: The occurrence of anaemia in patients with AA amyloidosis is associated with allele 2 (T) of the IL-1beta-511 promoter gene and elevated levels of circulating IL-1beta and IL-18. In AA amyloidosis the raised cytokine levels may generate a vicious cycle leading to accelerated amyloidogenesis, suppression of erythropoiesis and aggravation of the underlying inflammatory disorder.     

Kidney biopsy in AA amyloidosis: impact of histopathology on prognosis

In AA amyloidosis, while kidney biopsy is widely considered for diagnosis by clinicians, there is no evidence that the detailed investigation of renal histopathology can be utilized for the prognosis and clinical outcomes. In this study, we aimed to obtain whether histopathologic findings in kidney biopsy of AA amyloidosis might have prognostic and clinical value.

This is a retrospective cohort study that included 38 patients who were diagnosed with AA amyloidosis by kidney biopsy between 2005 and 2013.The kidney biopsy specimens of patients were evaluated and graded for several characteristics of histopathological lesions and their relationship with renal outcomes.

Segmental amyloid deposition in the kidney biopsy was seen in 29%, global amyloid deposition in 71, diffuse involvement of glomeruli in 84.2%, focal involvement in 7%, glomerular enlargement in 53%, tubular atrophy in 75% and interstitial fibrosis in 78% of patients. Histopathologically, glomerular enlargement, interstitial fibrosis, tubular atrophy, interstitial inflammation and global amyloid deposition were significantly associated with lower estimated glomerular filtration rate (eGFR) (p?=?.02, p?p?=?.001, p?=?.009, p?=?.002, respectively) in univariate analysis. In multivariate analysis, tubular atrophy was the only predictor of eGFR (p?=?.019 B?=??20.573). In the follow-up at an average of 27?months, 18 patients developed end-stage renal disease (ESRD). Among them, global amyloid deposition was the only risk factor for the development of ESRD (p?=?.01, OR?=?18.750, %95?CI=?2.021–173.942).

This is the first study showing that the histopathological findings in kidney biopsy of AA amyloidosis might have a prognostic and clinical value for renal outcomes.     

Changing epidemiology of AA amyloidosis: clinical observations over 25 years at a single national referral centre

Objective: Systemic AA amyloidosis is a serious complication of chronic inflammation; however, there are relatively few published data on its incidence. We investigated the changing epidemiology of AA amyloidosis over a 25-year period at a single national referral centre.

Methods: We conducted a retrospective study of all patients diagnosed with AA amyloidosis who had attended the centre between 1990 and 2014 inclusive. Six hundred and twenty-five patients were studied in three cohorts: C1: 1990–1997; C2: 1998–2006; C3: 2007–2014.

Results: Mean age at presentation increased from 46 in C1 to 56 in C3 (p?p?=?.0006). Comparison of underlying diseases between C1 and C3 revealed a reduction in patients with juvenile idiopathic arthritis from 25% to 2% (p?p?p?<.0001). More patients were in end-stage renal failure at presentation in C3 (29%) than C1 (15%) (p?=?.0028). Median age at death was later in C3 (62 years) than C1 (54 years) (p?=?.0012).

Conclusion: These data suggest both falling incidence and better outcome in AA amyloidosis over a quarter of a century, reflecting advances in therapeutics and overall management of complex chronic disease in an ageing population. AA amyloidosis of uncertain aetiology presents an emerging major problem. Newer techniques such as next-generation sequencing may aid diagnosis and effective treatment, thereby improving overall survival.     

Efficacy and safety of interleukin-1 inhibitors in familial Mediterranean fever patients complicated with amyloidosis

Abstract

Background: Colchicine is the mainstay of the treatment of familial Mediterranean fever (FMF). However, 10% of FMF patients do not respond well to colchicine. Efficacy of interleukin (IL)-1 inhibitors in reducing attacks have been demonstrated in colchicine-resistant FMF (crFMF) patients recently. Colchicine is still the only approved drug for the prevention of amyloidosis in FMF and utility of IL-1 inhibitors in crFMF cases who already has amyloidosis remain to be elucidated. Herein, we evaluated efficacy and safety of IL-1 inhibitors in patients with crFMF-associated AA amyloidosis in a relatively large single center study.

Methods: Medical records of FMF patients complicated with AA amyloidosis in our dedicated FMF center were retrospectively reviewed and those patients who ever treated with IL-1 inhibitors were enrolled into the study. Patient global, physician global assessments (on 0–10?cm visual analog scale), C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), serum creatinine and 24-h urinary protein excretion values for each visit were recruited from computer-based hospital records. Treatment response of patients were assessed with clinical symptoms, serum albumin, CRP and ESR values. Renal outcome parameters were analyzed on those not receiving renal replacement therapy.

Results: Seventeen patients were identified with crFMF-amyloidosis that ever treated with IL-1 inhibitors. Background colchicine therapy was continued in all patients in maximal-tolerated dose along with IL-1 inhibitors. All patients benefit from IL-1 antagonists assessed by patient and physician global assessments. Inflammatory markers, CRP and ESR, were significantly reduced in all and normalized in 12 out of 17 patients. More importantly, the amount of proteinuria was remarkably improved following IL-1 inhibitor therapy (1606?mg/day to 519?mg/day, p?=?.008). Both anakinra and canakinumab were well-tolerated without severe side effects. All patients were initially treated with anakinra but switched to canakinumab in seven patients (one leukopenia, four injection site reaction, two inefficacy).

Conclusion: We evaluated the clinical and laboratory responses to IL-1 inhibitors in crFMF-associated amyloidosis patients. We found significant decreases in CRP, ESR and proteinuria after IL-1 inhibitor therapy. This study confirmed that IL-1 inhibitors are effective for controlling attacks and inflammatory activity in FMF patients complicated with AA amyloidosis. Moreover, they reduce or stabilize amount of proteinuria and preserve renal function in short-term follow-up. Prolonged prospective clinical trials are warranted to assess their long-term efficacy in this particular patient group.     

Interleukin-1 inhibition by anakinra in refractory chronic tophaceous gout

Since the discovery of the inflammasome, interleukin 1 production has been found to be integral in the pathophysiology of gout. Interleukin 1 inhibition by Anakinra has been shown to effective for the treatment of gout. We report three cases of resistant chronic tophaceous gout who responded to anakinra subcutaneous injections on an intermittent basis.     

Modelling disease risk for amyloid A (AA) amyloidosis in non-human primates using machine learning

Objective: Amyloid A (AA) amyloidosis is found in humans and non-human primates, but quantifying disease risk prior to clinical symptoms is challenging. We applied machine learning to identify the best predictors of amyloidosis in rhesus macaques from available clinical and pathology records. To explore potential biomarkers, we also assessed whether changes in circulating serum amyloid A (SAA) or lipoprotein profiles accompany the disease.

Methods: We conducted a retrospective study using 86 cases and 163 controls matched for age and sex. We performed data reduction on 62 clinical, pathological and demographic variables, and applied multivariate modelling and model selection with cross-validation. To test the performance of our final model, we applied it to a replication cohort of 2,775 macaques.

Results: The strongest predictors of disease were colitis, gastrointestinal adenocarcinoma, endometriosis, arthritis, trauma, diarrhoea and number of pregnancies. Sensitivity and specificity of the risk model were predicted to be 82%, and were assessed at 79 and 72%, respectively. Total, low density lipoprotein and high density lipoprotein cholesterol levels were significantly lower, and SAA levels and triglyceride-to-HDL ratios were significantly higher in cases versus controls.

Conclusion: Machine learning is a powerful approach to identifying macaques at risk of AA amyloidosis, which is accompanied by increased circulating SAA and altered lipoprotein profiles.     

Lipid membranes accelerate amyloid formation in the mouse model of AA amyloidosis

Introduction: AA amyloidosis develops as a result of prolonged inflammation and is characterized by deposits of N-terminal proteolytic fragments of the acute phase reactant serum amyloid A (SAA). Macrophages are usually found adjacent to amyloid, suggesting their involvement in the formation and/or degradation of the amyloid fibrils. Furthermore, accumulating evidence suggests that lipid membranes accelerate the fibrillation of different amyloid proteins.

Methods: Using an experimental mouse model of AA amyloidosis, we compared the amyloidogenic effect of liposomes and/or amyloid-enhancing factor (AEF). Inflammation was induced by subcutaneous injection of silver nitrate followed by intravenous injection of liposomes and/or AEF to accelerate amyloid formation.

Results: We showed that liposomes accelerate amyloid formation in inflamed mice, but the amyloidogenic effect of liposomes was weaker compared with AEF. Regardless of the induction method, amyloid deposits were mainly found in the marginal zones of the spleen and coincided with the depletion of marginal zone macrophages, while red pulp macrophages and metallophilic marginal zone macrophages proved insensitive to amyloid deposition.

Conclusions: We conclude that increased intracellular lipid content facilitates AA amyloid fibril formation and show that the mouse model of AA amyloidosis is a suitable system for further mechanistic studies.     

Cell assay for the identification of amyloid inhibitors in systemic AA amyloidosis

Systemic AA amyloidosis is still, up to this day, a life-threatening complication of chronic inflammatory diseases. Despite the success of anti-inflammatory treatment, the prognosis of some AA patients is still poor, which is why therapies directed at the amyloidogenic pathway in AA amyloidosis are being sought after. The cell culture model of amyloid formation from serum amyloid A1 (SAA1) protein remodels crucial features of AA amyloid deposit formation in vivo. We here demonstrate how the cell model can be utilized for the identification of compounds with amyloid inhibitory activity. Out of five compounds previously reported to inhibit self-assembly of various amyloidogenic proteins, we found that epigallocatechin gallate (EGCG) inhibited the formation of SAA1-derived fibrils in cell culture. From a series of compounds targeting the protein quality control machinery, the autophagy inhibitor wortmannin reduced amyloid formation, while the other tested compounds did not lead to a substantial reduction of the amyloid load. These data suggest that amyloid formation can be targeted not only via the protein self-assembly pathway directly, but also by treatment with compounds that impact the cellular protein machinery.     

Comparison of the clinical utility of tocilizumab and anti-TNF therapy in AA amyloidosis complicating rheumatic diseases

Abstract

Objectives Anti-cytokine therapy is reportedly useful in amyloid A (AA) amyloidosis complicating rheumatic diseases. However, to date no studies have directly compared the utility of tumour necrosis factor (TNF) inhibition to that of interleukin-6. The aim of our retrospective study was to compare the clinical utility of tocilizumab (TCZ) and anti-TNF (TNF inhibitor) therapy.

Methods We studied 42 patients treated with anti-cytokine agents at our hospital: 31 had received a single agent, ten had received two agents and one had received three agents. Patients were divided into a TCZ group (22 patients) and a TNF inhibitor group (32 patients). The main parameters compared were treatment retention rate, serum amyloid A (SAA) profile, renal function profile and clinical disease activity index.

Results The 5-year retention rates were 90.4 (TCZ group) and 34.3 % (TNF inhibitor group) (p = 0.0154, log-rank test). The median SAA fell from 219.2 μg/mL at treatment initiation to 5.0 μg/mL at last observation (TCZ), and from 143.6 to 38.1 μg/mL (TNF inhibitor) (p = 0.0194). Estimated glomerular filtration rate was improved in 72.7 (TCZ) and 34.4 % (TNF inhibitor) of patients (p = 0.0062). The rates of clinical remission or low disease activity at last observation for the TCZ and TNF inhibitor groups were 72.7 and 40.7 % (p = 0.0201), respectively.

Conclusions Based on these results, we conclude that TCZ was of greater clinical utility than anti-TNF therapy in our patients with AA amyloidosis complicating rheumatic diseases.     

Effect of heating on the stability of amyloid A (AA) fibrils and the intra- and cross-species transmission of AA amyloidosis

Amyloid A (AA) amyloidosis is a protein misfolding disease characterized by extracellular deposition of AA fibrils. AA fibrils are found in several tissues from food animals with AA amyloidosis. For hygienic purposes, heating is widely used to inactivate microbes in food, but it is uncertain whether heating is sufficient to inactivate AA fibrils and prevent intra- or cross-species transmission. We examined the effect of heating (at 60?°C or 100?°C) and autoclaving (at 121?°C or 135?°C) on murine and bovine AA fibrils using Western blot analysis, transmission electron microscopy (TEM), and mouse model transmission experiments. TEM revealed that a mixture of AA fibrils and amorphous aggregates appeared after heating at 100?°C, whereas autoclaving at 135?°C produced large amorphous aggregates. AA fibrils retained antigen specificity in Western blot analysis when heated at 100?°C or autoclaved at 121?°C, but not when autoclaved at 135?°C. Transmissible pathogenicity of murine and bovine AA fibrils subjected to heating (at 60?°C or 100?°C) was significantly stimulated and resulted in amyloid deposition in mice. Autoclaving of murine AA fibrils at 121?°C or 135?°C significantly decreased amyloid deposition. Moreover, amyloid deposition in mice injected with murine AA fibrils was more severe than that in mice injected with bovine AA fibrils. Bovine AA fibrils autoclaved at 121?°C or 135?°C did not induce amyloid deposition in mice. These results suggest that AA fibrils are relatively heat stable and that similar to prions, autoclaving at 135?°C is required to destroy the pathogenicity of AA fibrils. These findings may contribute to the prevention of AA fibril transmission through food materials to different animals and especially to humans.     

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.     

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.     

Safety and efficacy of long-term diflunisal administration in hereditary transthyretin (ATTR) amyloidosis

Background: A recent 2-year randomized controlled trial indicated that the transthyretin (TTR) tetramer stabilizer, diflunisal, inhibits polyneuropathy progression and preserves quality of life in hereditary ATTR amyloidosis. However, its long-term outcomes are unknown. Here, we report tolerance and efficacy of long-term diflunisal administration in hereditary ATTR amyloidosis.

Methods: Diflunisal was administered orally at 500?mg/day to 40 Japanese hereditary ATTR amyloidosis patents who were not candidates for liver transplantation. The observation period ranged from 2 to 116 months (mean?±?SD: 38.0?±?31.2 months).

Results: Diflunisal-related adverse events included deterioration of renal function and thrombocytopenia resulting in discontinuation of the drug in three patients. Orally administered diflunisal significantly increased serum TTR concentration (p?=?0.001) and stabilized TTR tetramer structure in each patient. Longitudinal analyses of data collected at baseline, 24 months, and after 24 months confirmed sustaining effects of diflunisal on both neurological and cardiac functions. Notably, ulnar compound muscle action potential amplitude, cardiac wall thickness, and ejection fraction were not deteriorated after 24 months of treatment.

Conclusions: Diflunisal was tolerated well by most hereditary ATTR amyloidosis patients, although renal function and blood cell counts must be carefully monitored. Clinical effects of diflunisal were sustained after 2 years of treatment.     

Increasing fatal AA amyloidosis in hunting falcons and how to identify the risk: a report from the United Arab Emirates

In hunting falcons, a fatal syndrome of wasting, weight loss, green mutes and, finally, sudden death of emaciated birds has been observed in the United Arab Emirates (UAE). Histological examination using Congo red has revealed amyloid in most organs, in particular in the liver, spleen, kidney, and adrenal glands. Moreover, a retrospective study revealed amyloidosis in 100 cases among a total of 623 necropsied falcons between August 1995 and March 2004 in Dubai/UAE (16%; varying from 8 to 30% in different raptor bird species). The amyloid was immunohistochemically classified as amyloid A (AA), which was confirmed by Western blot analysis and N-terminal amino acid sequence analysis, suggesting it to be secondary to a chronic inflammatory process. Retrospective analysis has indicated a significantly increased prevalence of bumble foot and visceral gout among falcons with amyloidosis. In addition, a significant increase of amyloidosis from 5.6% of necropsied falcons with amyloidosis in 1995 to 40.0% in 2004 has been noticed.

Finally, a semi-quantitative serum test for falcon serum amyloid A (f-SAA) has been developed. Among 38 falcons with fatal AA amyloidosis, f-SAA was increased pathologically in 36, whereas f-SAA was elevated in only one of 15 apparently disease-free falcons (p < 0.001). This significant result indicates that a normal f-SAA will indicate a minimal or even absent risk of succumbing to AA amyloidosis.     

Importance of interleukin-1 and interleukin-1 receptor antagonist in short-term glucose sensor function in vivo

Background

The importance of the interleukin (IL)-1 cytokine family in inflammation and immunity is well established as a result of extensive in vitro and in vivo studies. In fact, much of our understanding of the in vivo importance of interleukin-1beta (IL-1B) is the result of research utilizing transgenic mice, such as overexpression or deficiencies of the naturally occurring inhibitor of IL-1 known as interleukin-1 receptor antagonist (IL-1RA). For the present studies, we utilized these transgenic mice to determine the role of IL-1B in glucose sensor function in vivo.

Methods

To investigate the role of IL-1B in glucose sensor function in vivo, we compared glucose sensor function in trans-genic mice that (1) overexpressed IL-1RA [B6.Cg-Tg(II1rn)1Dih/J] and (2) are deficient in IL-1RA (B6.129S-Il1rn^tm1Dih/J), with mice that have normal levels of IL-1RA (C57BL/6).

Results

Our studies demonstrated that, during the first 7 days post-sensor implantation (PSI), mice deficient in IL-1RA had extensive inflammation and decreased sensor function when compared to normal or IL-1RA-overexpressing mice.

Conclusion

These data directly support our hypothesis that the IL-1 family of cytokines and antagonists play a critical role in controlling tissue reactions and thereby sensor function in vivo during the first 7 days PSI.     

Study on the safety and efficacy of tocilizumab,an anti-IL-6 receptor antibody,in patients with rheumatoid arthritis complicated with AA amyloidosis

Abstract

Objectives: Although treatment of rheumatoid arthritis (RA) has progressed by the use of biologics, amyloid A (AA) amyloidosis is still an intractable complication in patients with RA. In the present study, safety and efficacy of 1-year treatment with an anti-IL-6 receptor antibody tocilizumab (TCZ) on RA and AA amyloidosis were estimated.

Methods: TCZ (8 mg/kg every 4 weeks) was administered to five RA patients complicated with AA amyloidosis. The primary end point was improvement in renal dysfunction and the secondary end point was CDAI at 1 year after the treatment.

Results: An improvement in the renal dysfunction, including urinary protein secretion, was found, in four patients including two patients who were refractory to etanercept, with a remarkable decrease of SAA concentration, and the progression of organ dysfunction was prevented at 1 year in all patients treated with TCZ. The mean clinical disease activity index decreased from 33.9 to 4.7 (p = 0.012) in five patients treated with TCZ for 1 year. Three non-serious adverse events were observed in two patients.

Conclusions: TCZ ameliorates renal dysfunction in RA patients complicated with AA amyloidosis who are refractory to conventional therapies, thereby suggesting that TCZ has a potential to regulate AA amyloidosis.     

IL-1RⅠ IL-1RⅡ IL-1RAcP在骨关节炎滑膜中的表达及其生物学意义

目的探讨白细胞介素-1受体(IL-1R)家族中的3个成员IL-1RⅠ、IL-1RⅡ和IL-1R协同蛋白(IL-1RAcP)在骨关节炎(OA)滑膜中的表达和生物学意义。方法采用免疫组织化学和反转录聚合酶链反应(RT-PCR)方法检测了不同病程的107例OA患者膝关节滑膜组织中三者的表达情况。结果免疫组织化学显示IL-1RⅠ和IL-1RAcP在OA滑膜中强阳性表达,IL-1RⅡ在OA滑膜中阳性表达,在对照组中均呈阴性或弱阳性表达。RT-PCR显示IL-1RⅠ、IL-1RⅡ、IL-1RAcP在Ⅰ度OA滑膜中的表达均显著高于正常滑膜(P＜0．05),且IL-1RⅠ的表达显著高于IL-1RⅡ(P＜0．05),而与IL-1RAcP的差异无统计学意义(P＞0．05)。但在Ⅱ度和Ⅲ度OA滑膜中,IL-1RⅠ、IL-1RAcP的表达与在正常滑膜中的表达差异无统计学意义(P＞0．05),IL-1RⅡ在Ⅲ度OA滑膜中的表达显著高于正常组(P＜0．05)。结论IL-1RⅠ、IL-1RⅡ、IL-1RAcP在OA的发病机制中起着重要的作用,尤以IL-1RⅠ和IL-1RAcP为主,但其表达只在OA早期短期增加,与OA病情的发展可能无关。