Assessment of patients with hereditary transthyretin amyloidosis – understanding the impact of management and disease progression

Timely diagnosis of hereditary variant transthyretin (ATTRv) amyloidosis is critical for appropriate treatment and optimal outcomes. Significant differences are seen between patients receiving treatment and those who are not, though disease progression may continue despite treatment in some patients. Healthcare professionals caring for patients with ATTRv amyloidosis therefore need reliable ongoing assessments to understand the continuing course of disease and make appropriate treatment choices on an individual basis. Various signs and symptoms experienced by patients may be evaluated as indicators of disease progression, though there is currently no validated score that can be used for such ongoing assessment. Recognizing this situation, a group of clinicians highly experienced in ATTR amyloidosis developed an approach to understand and define disease progression in diagnosed and treated patients with ATTRv amyloidosis. The suggested approach is based on the recognition of distinct phenotypes which may usefully inform the particular tools, tests and investigations that are most likely to be appropriate for individual patients. It is aimed at implementing appropriate and ongoing assessment of patients being treated for ATTRv amyloidosis, such that the effectiveness of management can be usefully assessed throughout the course of disease and management can be tailored according to the patient's requirements.     

An autopsy case of multicentric Castleman’s disease associated with interstitial nephritis and secondary AA amyloidosis

It is quite rare to diagnose interstitial nephritis and secondary amyloidosis during the course of Castleman’s disease (CD). To our knowledge, only four cases of interstitial nephritis and 44 cases of amyloidosis associated with CD have been reported to date. A 51-year-old man with a 9-year history of hypergammaglobulinemia was diagnosed with multicentric Castleman’s disease of the plasma cell type. At the age of 55, it was complicated with interstitial nephritis, which was successfully treated with steroids and cyclophosphamide. At the age of 58, he was diagnosed with secondary AA amyloidosis and thrombocytopenia, which led to a fatal brain hemorrhage. The plasma cell type of this illness involves a relatively high incidence of amyloidosis, and the present patient suggests that some cases of multicentric Castleman’s disease could proceed rapidly, be unresponsive to steroid therapy, and may have a fatal outcome.     

Coexistence of Sjögren's syndrome and pulmonary nodular amyloidosis

There are very few cases in the literature on the coexistence of Sjögren's syndrome and pulmonary nodular amyloidosis being treated with rituximab. When nodules with central calcification and cystic lesions are seen on computed tomography, amyloid lung should be considered. Biopsy is recommended as it can be confused with malignancies. In this article, we present a 66-year-old female patient who has been followed up for Sjögren's syndrome for 26 years. Multiple cystic lesions with central calcification in the lung were detected and it was evaluated as amyloid nodule in the biopsy performed. The patient is being followed and is stable under rituximab treatment. Pulmonary noduler amyloidosis is very rare in Sjögren patients and there are very few cases where rituximab is used for treatment. We decided to publish in order to guide clinicians who will encounter similar cases.     

Graves' disease and gene polymorphism of TNF-α, IL-2, IL-6, IL-12, and IFN-γ

The role of genetic factors in the pathogenesis of Graves' disease (GD) is not clear. The purpose of this study was to investigate the association between single nucleotide polymorphisms in pro-inflammatory cytokine genes and GD in Iranian patients. A case-control hospital-based study was carried out on 107 GD patients and 140 healthy controls. Cytokine typing was performed by polymerase chain reaction with sequence-specific primers (PCR-SSP) assay. The allele and genotype frequencies of the following cytokine genes were determined: TNF-α (-308A/G, -238A/G), IL-2 (-330T/G, +166G/T), IL-6 (-174C/G, A/G nt565), IL-12 (-1188A/C), and IFN-γ (UTR 5644A/T). The following alleles and genotypes were significantly overrepresented in patients: TNF-α -308A allele (P < 0.01) and AA genotype (P < 0.05), IL-2 -330G allele (P < 0.01) and GG genotype (P < 0.01), IL-6 -174C allele (P < 0.01) and CC genotype (P < 0.01), IL-12 -1188C allele (P < 0.01) and CC genotype (P < 0.01), IFN-γ UTR5644T allele (P < 0.01) and TT genotype (P < 0.01). In conclusion, this is the first study to show a significant association between GD and IL-2 -330G, IL-12 -1188C, and IFN-γ UTR 5644T alleles. Our results support the hypothesis that polymorphism in pro-inflammatory cytokines might be involved in predisposition to GD.     

Differential effect of IL-1β and TNF-α on the production of IL-6, IL-8 and PGE2 in fibroblast-like synoviocytes and THP-1 macrophages

Inflammation in the joint of rheumatoid arthritis is a complex immune reaction facilitated by various factors, such as cytokines, cells and hypoxia. Thus, we evaluated their relative capacity to produce proinflammatory mediators in response to IL-1β, TNF-α or IL-17 under hypoxia or normoxia in fibroblast-like synoviocytes (FLSs) and macrophages. The level of IL-6 expression was strongly increased in both FLSs and THP-1 macrophages in response to IL-1β and TNF-α, but the level by TNF-α was less than that by IL-1β. In contrast, the expression of IL-8 in both cell types was strongly stimulated by both IL-1β and TNF-α. In FLSs, PGE₂ production increased only in response to IL-1β; and no effect was observed in THP-1 cells and TNF-α-stimulated FLSs. In addition, the production by IL-17 was extremely low when compared with those induced by IL-1β or TNF-α in FLSs and THP-1 cells. Hypoxia (2% O₂) decreased IL-1β-stimulated production of PGE₂, even though it increased the expression of mRNA and protein of COX-2. These results suggest that IL-1β and TNF-α differentially regulate gene expression in FLSs and macrophages under hypoxia or normoxia.     

Gastrointestinal perforation in light chain amyloidosis in the era of novel agent therapy – a case series and review of the literature

Gastrointestinal (GI) perforation is remarkably rare in patients with light chain (AL) amyloidosis and has not yet been reported in patients with AL amyloidosis treated with novel agents. Only 24 cases of GI perforation have previously been reported in the setting of AL amyloidosis of which 15 had available information in English. All 15 did not receive novel agent therapy and six died early after experiencing GI perforation. This study reports the characteristics and outcome of AL patients that developed GI perforation in the era of novel agent treatment. Seven patients were reviewed. In two patients, GI perforation was the presenting symptom of AL amyloidosis, whereas five patients developed GI perforations following initiation of an anti-AL therapy (three after bortezomib-based, 1 after lenalidomide-based and 1 after thalidomide-based therapy). All patients underwent surgery and survived the perforation. Treatment was renewed following surgery in six of seven patients, with no further GI complications. In conclusion, GI perforation in AL amyloidosis is rare and mostly reported after treatment initiation. Urgent surgery appears to be lifesaving and renewal of the anti-AL novel therapy appears to be safe, with no significant risk for re-perforation or GI toxicity. Prognosis in these patients is related to severity of the disease and response to therapy rather than the development of GI perforation.     

Successful treatment with humanized anti–interleukin-6 receptor antibody (tocilizumab) in a case of AA amyloidosis complicated by familial Mediterranean fever

Familial Mediterranean fever (FMF) is a well-known cause of secondary AA amyloidosis. Colchicine is generally considered to be the most effective treatment for FMF and FMF-associated amyloidosis, but the management of patients who are refractory to colchicine remains controversial. We encountered a 51-year-old Japanese man with suspected FMF, who had periodic fever with abdominal pain, polyarthritis, and nephropathy (serum creatinine of 1.9 mg/dL and 24-h protein excretion of 3.8 g). FMF was diagnosed by mutation analysis of the Mediterranean fever (MEFV) gene, which revealed that the patient was compound heterozygous for the marenostrin/pyrin variant E148Q/M694I. AA amyloidosis was diagnosed by renal and gastric biopsy. Colchicine was administered, but his arthritis persisted, and serum creatinine increased to 2.4 mg/dL. Therefore, a humanized anti–interleukin-6 receptor antibody (tocilizumab) was administered at a dose of 8 mg/kg on a monthly basis. Both arthritis and abdominal pain subsided rapidly, and C-reactive protein (CRP) decreased from 2.5 to 0.0 mg/dL. After 2 years, his serum creatinine was decreased to 1.5 mg/dL and proteinuria was improved to 0.3 g daily. In addition, repeat gastric biopsy showed a marked decrease of AA amyloidosis. This case suggests that tocilizumab could be a new therapeutic option for patients with FMF-associated AA amyloidosis if colchicine is not effective.     

The utility of TNF-α, IL-6 and IL-10 in the diagnosis and/or follow-up food allergy

BackgroundSeveral pro-inflammatory and anti-inflammatory mediators play a role in the immunopathogenesis of food allergy (FA). The aim of this study was to investigate the utility of serum biomarkers like interleukin (IL)-10, TNF-α, and IL-6 in the diagnosis and/or follow-up of FA.MethodsSixty (25 females, 41.6%) newly diagnosed FA patients [IgE mediated (group-1, n = 37), non-IgE (group-2, n = 23)] with a median age of nine (1–33) months were enrolled. Twenty-four healthy children with a median age of eight (1–36) months constituted the control group (CG). In all the subjects, serum TNF-α, IL-6 and IL-10 levels were evaluated at the time of diagnosis and reassessed four weeks after therapeutic elimination diet (TED).ResultsThe mean white blood cell count and median absolute eosinophile count of the CG were significantly lower than group-1 (p values were 0.019 and 0.006, respectively). The mean absolute neutrophile count and the median IL-6 were significantly higher in group-1 when compared with group-2 (p values were 0.005 and 0.032, respectively. Median TNF-α and IL-6 levels were significantly higher in the pre-TED among all patients (p values were 0.005 and 0.018, respectively). In group-1, median TNF-α and IL-6 levels decreased significantly after TED (p values were 0.01 and 0.029, respectively).ConclusionsOur findings support the role of inflammation in the pathogenesis of FA. Serum TNF-α and IL-6 levels may be useful markers for follow-up in FA, especially among IgE-mediated FA patients. Evaluation of IL-10 results was not sufficient for an interpretation of clinical tolerance.     

Correlation of High Levels of Hyaluronan and Cytokines (IL-1β, IL-6, and TGF-β) in Ascitic Fluid of Cirrhotic Patients

Our objective was to investigate the relationship between endotoxin and hyaluronan synthesis and release in serum and ascitic fluid from cirrhotic patients. We studied hyaluronan, endotoxin, albumin, and creatinine levels in ascitic fluid and plasma and cytokine levels (IL-1, IL-6, TGF-) in ascitic fluid. TGF-, IL-6, and IL-1 correlation analyses indicated a strong dependence of the production of these cytokines on endotoxin levels. Correlation analyses for TGF- and IL-6 indicated a strong dependence of the production of hyaluronan on cytokine levels and, to a lesser extent, on IL-1 levels. Hyaluronan analysis indicated that a certain glycosaminoglycan level is required in ascites before its appearance in plasma. Our results disclosed elevated plasma hyaluronan concentrations. The simultaneous increased hyaluronan levels in ascitic fluid do not seem to be derived from the systemic circulation. In conclusion, the high hyaluronan-ascites/hyaluronan-plasma ratio suggests an intrinsic hyaluronan production from peritoneal cells induced by endotoxins.     

Effect of 17β-oestradiol on expression of IL-2, IL-6 and IFN-γ mRNA in human tonsillar cells

Oestradiol (E(2)) alters lymphocyte functionin vitro including T cell DNA synthesis and B cell immunoglobulin production in human tonsillar, splenic and peripheral blood cells. We have investigated whether one mechanism for this effect is that E(2) modifies the expression of IL-2, IL-6 and IFN-γ mRNA in human tonsillar mononuclear cells. Without E(2), addition of PHA (1 μg ml(-1)) for 10 h increased the expression of IL-2 and IL-6 mRNA but had no significant effect on IFN-γ mRNA. In separated T cells after 24 h incubation, E(2) (7×10(-8) M: ) increased only the IFN-γ mRNA levels. However, when E(2) was present in PHA-stimulated T cell cultures, mRNA levels from all cytokines were suppressed. E(2) decreased IL-2 mRNA levels in the T cell preparation after 24 h culture. For IL-6, E(2) decreased mRNA both in mononuclear cells and T cells after 10 h incubation. For IFN-γ, E(2) decreased mRNA levels in the mononuclear cell preparation after 24 h culture. Stimulation of the T cell preparation with PHA after 24 h incubation with E(2) decreased the IFN-γ mRNA levels compared to the cultures incubated with E(2) only. One part of the action of E(2) may be through a block in the up-regulation of the mRNA of IL-2, IL-6 and IFN-γ in activated cells.     

Effectiveness and patient safety of platelet aggregation inhibitors in the prevention of cardiovascular disease and ischemic stroke in older adults – a systematic review

Background

Platelet aggregation inhibitors (PAI) are among the most frequently prescribed drugs in older people, though evidence about risks and benefits of their use in older adults is scarce. The objectives of this systematic review are firstly to identify the risks and benefits of their use in the prevention and treatment of vascular events in older adults, and secondly to develop recommendations on discontinuing PAI in this population if risks outweigh benefits.

Methods

Staged systematic review consisting of three searches. Searches 1 and 2 identified systematic reviews and meta-analyses. Search 3 included controlled intervention and observational studies from review-articles not included in searches 1 and 2. All articles were assessed by two independent reviewers regarding the type of study, age of participants, type of intervention, and clinically relevant outcomes. After data extraction and quality appraisal we developed recommendations to stop the prescribing of specific drugs in older adults following the Grading of Recommendations Assessment Development and Evaluation (GRADE) methodology.

Results

Overall, 2385 records were screened leading to an inclusion of 35 articles reporting on 22 systematic reviews and meta-analyses, 11 randomised controlled trials, and two observational studies. Mean ages ranged from 57.0 to 84.6 years. Ten studies included a subgroup analysis by age. Overall, based on the evaluated evidence, three recommendations were formulated. First, the use of acetylsalicylic acid (ASA) for primary prevention of cardiovascular disease (CVD) in older people cannot be recommended due to an uncertainty in the risk-benefit ratio (weak recommendation; low quality of evidence). Secondly, the combination of ASA and clopidogrel in patients without specific indications should be avoided (strong recommendation; moderate quality of evidence). Lastly, to improve the effectiveness and reduce the risks of stroke prevention therapy in older people with atrial fibrillation (AF) and a CHA₂DS₂-VASc score of ≥?2, the use of ASA for the primary prevention of stroke should be discontinued in preference for the use of oral anticoagulants (weak recommendation; low quality of evidence).

Conclusions

The use of ASA for the primary prevention of CVD and the combination therapy of ASA and clopidogrel for the secondary prevention of vascular events in older people may not be justified. The use of oral anticoagulants instead of ASA in older people with atrial fibrillation may be recommended. Further high quality studies with older adults are needed.

     

Current status and prospects of clinical proteomics studies on detection of colorectal cancer： Hopes and fears

BACKGROUND In order to improve early detection, monitor disease out-come and find targets for more individualised therapy, there is an urgent demand for new biomarkers in oncology. A f ield of recent interest is clinical proteomics, which has been reporte…