We herein report a case of Behçet's disease with renal infarction due to mucormycosis. A 76-year-old man with entero-Behçet's disease had been treated with glucocorticoid and tumor necrosis factor ...(TNF) inhibitors. His entero-Behçet's disease was refractory to these treatments, and ileocecal resection was performed. After the operation, renal infarction that was unresponsive to anticoagulation therapy developed. He ultimately died of renal failure due to renal infarction. At the autopsy, histopathology of abundant hyphae in the renal vessel wall revealed mucormycosis. Renal mucormycosis is an important cause of renal failure with renal infarction in immunocompromised patients.
The quantitation of serum tocilizumab using liquid chromatography tandem-mass spectrometry (LC-MS/MS) method has not been widely applied in clinical settings because of its time-consuming and costly ...sample pretreatments. The present study aimed to develop a validated LC-MS/MS method for detecting serum tocilizumab by utilizing immobilized trypsin without an immunoglobulin G purification step and evaluate its applicability in the treatment of rheumatoid arthritis (RA) patients administered intravenously or subcutaneously with tocilizumab. The tocilizumab-derived signature peptide was deciphered using a nano-LC system coupled to a hybrid quadrupole-orbitrap mass spectrometer. The serum tocilizumab was rapidly digested by immobilized trypsin for 30 min. The chromatographic peak of the signature peptide and that of the internal standard were separated from the serum digests for a total run time of 15 min. The calibration curve of serum tocilizumab concentration was linear with a range of 2–200 μg/mL. The intra- and inter-day accuracy and relative standard deviation (RSD) were 90.7%–109.4% and <10%, respectively. The serum tocilizumab concentrations in the RA patients receiving intravenous and subcutaneous injections were 5.8–28.9 and 2.4–63.5 μg/mL, respectively. The serum tocilizumab concentrations using the current method positively correlated with those using the enzyme-linked immunosorbent assay, although a systematic error was observed between these methods. In conclusion, a validated LC-MS/MS method with minimal sample pretreatments for monitoring serum tocilizumab concentrations in RA patients was developed.
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•Tocilizumab was rapidly digested by immobilized trypsin without IgG purification.•Good analytical performance was observed in this method after rapid pretreatment.•This method is useful for therapeutic drug monitoring of intravenous and subcutaneous tocilizumab.•Serum tocilizumab levels were positively correlated with ELISA in this method.•This method showed statistically higher serum tocilizumab levels than ELISA.
Cardiac involvement of eosinophilic granulomatosis with polyangiitis is a rare but life-threatening complication. We present a case of eosinophilic granulomatosis with polyangiitis with moderately ...impaired ventricular function forming a ventricular thrombus. Pathological assessment of endomyocardial biopsy specimen revealed aggregated eosinophils in the subendocardium, suggesting ventricular endothelial damage leading to thrombus formation.
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The aim of this study was to identify factors affecting the pharmacokinetics of mycophenolic acid (MPA) and its 7-O-glucuronide (MPAG) in systemic lupus erythematosus (SLE) patients. Thirty-one SLE ...patients in remission maintenance phase treated with mycophenolate mofetil (median 1500 mg/d) and prednisolone and followed-up for up to 56 months (median 13 months) were enrolled. Creatinine clearance and metal medication were significant predictors accounting for interindividual variability in the dose-normalized predose plasma concentration (C0) of MPA (adjusted R2=0.305, p=0.01) in a multivariate analysis. Dose-normalized MPAG C0 was significantly correlated with only creatinine clearance (adjusted R2=0.135, p=0.03). The free fraction of MPA was significantly correlated with only serum albumin (adjusted R2=0.700, p<0.01). The free fraction of MPAG was significantly correlated with serum albumin, metal medication, and age (adjusted R2=0.598, p=0.02). In conclusion, renal function and co-administered metal influenced the pharmacokinetics of MPA and MPAG in SLE patients in remission maintenance phase.
Cardiac involvement in systemic sclerosis (SSc) is considerably frequent in autopsy, but the early identification is clinically difficult. Recent advantages in cardiac magnetic resonance (CMR) ...enabled to detect myocardial fibrotic scar as late gadolinium enhancement (LGE). We aimed to examine the prevalence and distribution of LGE in patients with SSc, and associate them with clinical features, electrocardiographic abnormalities and cardiac function. Forty patients with SSc (58 ± 14 years-old, 35 females, limited/diffuse 25/15, disease duration 106 ± 113 months) underwent serological tests, 12-lead electrocardiogram (ECG) and CMR. Seven patients (17.5 %) showed LGE in 26 segments of left ventricle (LV). LGE distributed mainly in the basal to mid inter-ventricular septum and the right ventricular (RV) insertion points, but involved all the myocardial regions. More patients with LGE showed NYHA functional class II and more (71 vs. 21 %,
p
< 0.05), bundle branch blocks (57 vs. 6 %,
p
< 0.05), LV ejection fraction (LVEF) < 50 % (72 vs. 6 %,
p
< 0.01), LV asynergy (43 vs. 0 %,
p
< 0.01) and RVEF < 40 % (100 vs. 39 %,
p
< 0.01). There was no difference in disease duration, disease types, or prevalence of positive autoimmune antibodies or high serum NT-proBNP level (>125 pg/ml). When cardiac involvement of SSc was defined as low LVEF, ECG abnormalities or high NT-proBNP, the sensitivity, specificity positive and negative predictive values of LGE were 36, 92, 71 and 72 %, respectively. We could clarify the prevalence and distribution of LGE in Japanese patients with SSc. The presence of LGE was associated with cardiac symptom, conduction disturbance and impaired LV/RV contraction.
The aim of this study was to assess abatacept in rheumatoid arthritis (RA) patient. Patients (20 men, 89 women, aged 61.9 ± 10.4 y) who responded inadequately to conventional synthetic ...disease-modifying anti-rheumatic drug were treated with abatacept for 24-months. Disease activity score in 28 joints (DAS28-CRP) was evaluated. Of 109 patients, 82 (75.2%) were on methotrexate (MTX; mean dosage 9.0 ± 2.7 mg/week); 48 (44.0%) were naive to biologics and 61 (56.0%) had failed biologics. The 1- and 2-year retention rates were 77% and 53%, respectively. At 24-months, the DAS28-CRP remission rates were 62.8% in the biologic-naïve patients, and 33.3% in the biologic-failure patients (p < .01), while the structural remission rates were 83.9% and 73.1%, respectively (p = .461). Abatacept was equally effective in RA patients who were and were not on concomitant MTX. Biologic-naïve was associated with better clinical outcome. Abatacept was effective in patients who showed decreasing anti-CCP antibody titers or serum MMP-3 levels during treatment. Infection was the most frequent adverse effect of abatacept therapy. In conclusion, abatacept is more effective in biologic-naïve than in biologic-failure RA patients with or without concomitant use of MTX. Abatacept is more effective in RA patients with than without decreasing serum MMP-3 or anti-CCP antibody titers during treatment.
A 64 year-old, female was diagnosed as rheumatoid arthritis（RA）in x-28 year. Administration of methotrexate（MTX）was started However, she developed immunodeficiency-associated lymphoproliferative ...disorders associated with MTX. MTX was stopped, and she received rituximab-CHOP chemotherapy, and the lymphoproliferative disorder attained remission. RA disease activity was stabilized after tocilizumab was started in x-9 year. After 8 days since the last tocilizumab administration, pain and swelling of the left thigh developed. She was hospitalized, and was suspected to have necrotizing fasciitis. However, necrotizing fasciitis was not confirmed because the Laboratory Risk Indicator for Necrotizing Fasciitis score（LRINEC score）was 3 points. She died due to multiple organ failure on the same day in spite of collective treatment. Blood culture revealed positive for streptococcus pyogenes infection. Finally, she was diagnosed as toxic shock syndrome complicated with necrotizing fasciitis caused by streptococcus pyogenes infection. In RA patients treated with biologics such as tocilizumab, the diagnosis of necrotizing fasciitis could be difficult due to the strong immunosuppressive effect of IL-6 inhibition.
Anticentromere antibody (ACA) is generally considered to be a serological marker for systemic sclerosis (SSc). ACA-positive patients with primary Sjögren's syndrome (pSS) have also been reported. ACA ...often recognizes centromere proteins (CENPs): CENP-A, CENP-B, and CENP-C, and sometimes reacts to heterochromatin protein 1 (HP1)α. We compared the reactivity against six different epitopes for three ACA-positive clinical subgroups: 29 patients with pSS, 36 SSc patients with sicca symptoms, and 28 SSc patients without sicca symptoms.
We utilized enzyme-linked immunosorbent assays (ELISAs) with recombinant proteins covering six different epitope regions of ACA (the amino terminus (Nt) of CENP-A, CENP-B, and CENP-C, the carboxyl terminus (Ct) of CENP-B and CENP-C, and HP1α).
The patients with pSS were found to have IgG-class autoantibodies against CENP-C-Nt and HP1α, and IgA-class autoantibodies against CENP-C-Ct with significantly higher frequencies than the SSc patients with or without sicca symptoms. The positive predictive value and the negative predictive value of the combination of these three autoantibodies for pSS were 73% and 82%, respectively, for pSS.
Based on the result that reactivities against CENP-C and HP1α in patients with pSS differ from those in patients with SSc, we propose ACA-positive pSS as a clinical subset of SS that is independent of SSc.
We summarize our experience and propose methods for early diagnosis and treatment of intravascular large B cell lymphoma (IVL). A total of 16 patients with IVL between 1994 and 2007 were included and ...analyzed in this study. Predicted survival durations were short until September 2003. However, there have been marked improvement since the introduction of rituximab, and all patients responded to treatment and survived for more than 1 year following diagnosis of IVL. We propose an early clinical diagnostic strategy for starting treatment for IVL patients with quite poor performance status (PS) and in whom time is a limiting factor: (1) age >40 years, (2) fever above 38°C with poor PS (ECOG 2-4), (3) lactate dehydrogenase (LDH) more than twice the upper limit of the normal level and/or sIL2R >5,000 IU/ml in serum, (4) worsening PS and/or elevation of serum LDH on a daily basis, and (5) confirmation of pathological lymphoid cells in peripheral blood or bone marrow smear and/or flow cytometry. Although accurate pathological diagnosis is quite important, time is a limiting factor for most of IVL patients. In such cases, we can start chemotherapy based on early clinical diagnostic strategy with high sensitivity and obtain good clinical outcome.
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