Shogo Banno

Infliximab counteracts tumor necrosis factor-α-enhanced induction of matrix metalloproteinases that degrade claudin and occludin in non-pigmented ciliary epithelium.

Infliximab, a monoclonal antibody directed against human tumor necrosis factor-alpha (TNF-α), effectively treats anterior uveitis, which can accompany Behçets disease. Here, we investigated the underlying mechanism of this action. We examined human, non-pigmented ciliary epithelial cells (HNPCECs), which make up the blood-aqueous barrier (BAB) in the uvea. We measured the expression levels of matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs in the presence or absence of TNF-α using quantitative, real-time polymerase chain reaction and enzyme-linked immunosorbent assays. The expression of MMP-1, MMP-3, and MMP-9 increased in the presence of TNF-α, and the addition of infliximab reversed the increase. The TNF-α effects were more attenuated when infliximab was added before than when it was added after TNF-α exposure. Gelatin zymography demonstrated that the protease activity of these MMPs was also increased in the presence of TNF-α and attenuated with infliximab. Immunostaining showed that MMP-1, MMP-3, and MMP-9 degraded claudin-1 and occludin in HNPCECs and in non-pigmented ciliary epithelial cells of the swine ciliary body. In a monolayer of HNPCECs, we found that permeability was significantly increased with MMP treatment. Thus, TNF-α increased levels of MMPs in cells that form the BAB, and MMPs degraded components of the tight junctions in the BAB, which increased permeability through the cellular barrier. Furthermore, infliximab effectively attenuated the TNF-α-induced increases in MMP expression in cells that make up the BAB. These findings might suggest a basis for the clinical prevention of anterior uveitis.

Differential diagnosis of localized and systemic amyloidosis based on coagulation and fibrinolysis parameters

Background: A simple assay that can discriminate between localized and systemic amyloidosis is needed. Methods: Coagulation and fibrinolysis parameters were measured in subjects with active or progressive systemic amyloidosis (Group A; 9 patients), systemic amyloidosis in complete remission (Group B; 6 patients), localized AL amyloidosis (Group C; 6 patients), monoclonal gammopathy of undetermined significance (Group D; 5 patients), chronic glomerulonephritis with proteinuria (Group E; 22 patients), or glomerulonephritis in complete remission (Group F; 11 patients). Results: No significant differences were noted between Group A and the other groups in the international normalized ratio of prothrombin time, activated partial thromboplastin time, and levels of antithrombin and plasminogen. Levels of thrombin–antithrombin (TAT) complexes, fibrinogen, fibrinogen degradation product d-dimers, and plasmin-α2–plasmin inhibitor complexes (PIC) were significantly elevated in Group A. All patients that showed TAT complexes, fibrinogen, and PIC levels greater than 4.2 ng/mL, 399 mg/dL, and 1.4 μg/mL, respectively, had active or progressive systemic amyloidosis. All patients with TAT complex levels less than 3.6 ng/mL, fibrinogen levels less than 355 mg/dL, and PIC levels less than 0.9 μg/mL had localized AL amyloidosis. Conclusion:Analyses of TAT complexes, fibrinogen, and PIC can be used to differentiate localized AL amyloidosis from systemic amyloidosis.

Comparison of severity classification in Japanese patients with antineutrophil cytoplasmic antibody-associated vasculitis in a nationwide, prospective, inception cohort study

Abstract Objective: To compare disease severity classification systems for six-month outcome prediction in patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). Methods: Patients with newly diagnosed AAV from 53 tertiary institutions were enrolled. Six-month remission, overall survival, and end-stage renal disease (ESRD)-free survival were evaluated. Results: According to the European Vasculitis Study Group (EUVAS)-defined disease severity, the 321 enrolled patients were classified as follows: 14, localized; 71, early systemic; 170, generalized; and 66, severe disease. According to the rapidly progressive glomerulonephritis (RPGN) clinical grading system, the patients were divided as follows: 60, grade I; 178, grade II; 66, grade III; and 12, grade IV. According to the Five-Factor Score (FFS) 2009, 103, 109, and 109 patients had ≤1, 2, and ≥3 points, respectively. No significant difference in remission rates was found in any severity classification. The overall and ESRD-free survival rates significantly differed between grades I/II, III, and IV, regardless of renal involvement. Severe disease was a good predictor of six-month overall and ESRD-free survival. The FFS 2009 was useful to predict six-month ESRD-free survival but not overall survival. Conclusions: The RPGN grading system was more useful to predict six-month overall and ESRD-free survival than the EUVAS-defined severity or FFS 2009.

Systemic AA amyloidosis in a patient with lung metastasis from renal cell carcinoma

AA amyloidosis occurs in patients with high levels of serum amyloid A protein (SAA), which is produced by liver cells in response to signals from several pro-inflammatory cytokines. Chronic inflammatory disease is a major cause of AA amyloidosis; however, malignant neoplasms are rarely reported to be associated with AA amyloidosis. We report herein a case of a solitary lung metastasis of renal cell carcinoma associated with systemic AA amyloidosis. Pathological specimens of the resected lung tumor demonstrated renal cell carcinoma, and the presence of IL-1β, IL-6, and TNF-α in the lymphocytes and plasma cells surrounding the tumor cells, and AA amyloid in the vascular area, but not in metastatic clear cells. Four weeks after surgery, serum IL-6, SAA, and CRP levels normalized. Although this case is very rare, it is full of interesting suggestions about the pathogenesis of malignancy-related systemic amyloidosis.

Clinical characteristics of and risk factors for serious infection in Japanese patients within six months of remission induction therapy for antineutrophil cytoplasmic antibody-associated vasculitis registered in a nationwide, prospective, inception cohort study.

Abstract Objectives: The purpose of this study was to identify the clinical characteristics and predictors of serious infections (SIs) in the RemIT-JAV, a nationwide, prospective, inception cohort study for Japanese patients with antineutrophil cytoplasmic antibody-associated vasculitis (AAV). Methods: We analyzed SIs within six months of remission induction therapy in 156 AAV patients. Hazard ratios with 95% confidence intervals (CIs) for SIs were calculated using the COX proportional hazard model. Results: Sixty-three SIs in 42 patients were identified. The incidence rate (IR) of SIs was 87.59/100 patient-years. The median length of time to the onset of first SIs was 54 days. Hazard ratios (95%CI) for SIs were 1.97 (0.99–3.95) for age >65 years, 0.47 (0.25–0.89) for female sex, 2.11 (1.05–4.27) for the severe form of AAV, and 2.88 (1.49–5.88) for initial PSL >0.8 mg/kg/day in the first model, and 2.64 (1.39–5.01) for smoking and 3.27 (1.66–6.45) for initial PSL >0.8 mg/kg/day in the second model. Conclusions: Lowering the IR of SIs in Japanese AAV patients is mandatory to improve the vital prognosis of these patients. For remission induction therapy of AAV patients with these risk factors, risk management of immunosuppressive treatment should be carefully considered.

A comparative analysis of two interferon-γ releasing assays to detect past tuberculosis infections in Japanese rheumatoid arthritis patients

Abstract Objectives: To compare the utility of QuantiFERON-TB Gold in tube (QFT-GIT) and T-SPOT.TB assays to detect past tuberculosis infection in Japanese rheumatoid arthritis patients receiving methotrexate. Methods: We compared the sensitivities and specificities, the rates of indeterminate results, and the rates of positive results in patients with total and CD4-positive lymphocyte counts of both assays simultaneously performed on 68 rheumatoid arthritis patients receiving methotrexate, in whom 33 had evidence of past tuberculosis infection by chest computed tomography and the other had neither history of tuberculosis exposure nor abnormalities in chest computed tomography. Results: The sensitivities, specificities, and the rates of indeterminate results of QFT-GIT were 21.2%, 100%, and 4.4%, and those of T-SPOT.TB were 21.9%, 100%, and 1.5%, respectively. The overall agreement of both assays was good (κ = 0.68). In patients with past tuberculosis infection, there are significant positive linear trends in positive rates of both assays across ranges of larger numbers of total and CD4-positive lymphocyte counts. Conclusions: Both assays were equally useful with high specificities, but may falsely identify past tuberculosis infection owing to low sensitivities. In patients with low total and CD4-positive lymphocyte counts, both assays might give higher rates of false negative results.

Association Between Reappearance of Myeloperoxidase-Antineutrophil Cytoplasmic Antibody and Relapse in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis: Subgroup Analysis of Nationwide Prospective Cohort Studies

To evaluate clinical links between levels of myeloperoxidase (MPO)–antineutrophil cytoplasmic antibody (ANCA) and relapse in patients with ANCA‐associated vasculitis (AAV) using a data set from 2 nationwide prospective cohort studies.

Light Chain Deposition Disease Diagnosed with Laser Micro-dissection, Liquid Chromatography, and Tandem Mass Spectrometry of Nodular Glomerular Lesions

A 42-year-old man developed nephrotic syndrome and rapidly progressive renal failure. Kidney biopsy demonstrated nodular glomerulosclerosis, negative Congo red staining, and no deposition of light or heavy chains. Laser micro-dissection and liquid chromatography with tandem mass spectrometry of nodular lesions revealed the presence of a kappa chain constant region and kappa III variable region, which signified light chain deposition disease. Dexamethasone and thalidomide were effective in decreasing the serum levels of free kappa light chain from 147.0 to 38.0 mg/L, eliminating proteinuria, and halting the worsening of the kidney dysfunction, with serum creatinine levels stable around 4.0 mg/dL for 3 years.

Acid–base disturbances in nephrotic syndrome: analysis using the CO2/HCO3 method (traditional Boston model) and the physicochemical method (Stewart model)

BackgroundThe Stewart model for analyzing acid–base disturbances emphasizes serum albumin levels, which are ignored in the traditional Boston model. We compared data derived using the Stewart model to those using the Boston model in patients with nephrotic syndrome.MethodsTwenty-nine patients with nephrotic syndrome and six patients without urinary protein or acid–base disturbances provided blood and urine samples for analysis that included routine biochemical and arterial blood gas tests, plasma renin activity, and aldosterone. The total concentration of non-volatile weak acids (ATOT), apparent strong ion difference (SIDa), effective strong ion difference (SIDe), and strong ion gap (SIG) were calculated according to the formulas of Agrafiotis in the Stewart model.ResultsAccording to the Boston model, 25 of 29 patients (90%) had alkalemia. Eighteen patients had respiratory alkalosis, 11 had metabolic alkalosis, and 4 had both conditions. Only three patients had hyperreninemic hyperaldosteronism. The Stewart model demonstrated respiratory alkalosis based on decreased PaCO2, metabolic alkalosis based on decreased ATOT, and metabolic acidosis based on decreased SIDa. We could diagnose metabolic alkalosis or acidosis with a normal anion gap after comparing delta ATOT [(14.09 − measured ATOT) or (11.77 − 2.64 × Alb (g/dL))] and delta SIDa [(42.7 − measured SIDa) or (42.7 − (Na + K − Cl)]). We could also identify metabolic acidosis with an increased anion gap using SIG > 7.0 (SIG = 0.9463 × corrected anion gap—8.1956).ConclusionsPatients with nephrotic syndrome had primary respiratory alkalosis, decreased ATOT due to hypoalbuminemia (power to metabolic alkalosis), and decreased levels of SIDa (power to metabolic acidosis). We could detect metabolic acidosis with an increased anion gap by calculating SIG. The Stewart model in combination with the Boston model facilitates the analysis of complex acid–base disturbances in nephrotic syndrome.

Hypertensive Crisis and Left Ventricular Thrombi after an Upper Respiratory Infection during the Long-term Use of Oral Contraceptives

A 34-year-old woman who had been using oral contraceptives for 10 years developed hypertensive crisis with papilloedema after an upper respiratory infection. Laboratory data showed hyperreninemic hyperaldosteronism and elevated levels of fibrinogen, fibrin, and fibrinogen degradation products. Echocardiography demonstrated two masses (18 mm) in the left ventricle. On the fourth hospital day, cerebral infarction, renal infarction, and upper mesenteric artery occlusion suddenly occurred despite the blood pressure being well-controlled using anti-hypertensive drugs. Echocardiography revealed the disappearance of the left ventricular masses, which suggested left ventricular thrombi. Cessation of the contraceptives and administration of heparin, warfarin, and anti-platelets drugs improved her general condition.