Risk of higher dose methotrexate for renal impairment in patients with rheumatoid arthritis

Renal impairment is a major concern in patients taking high-dose methotrexate (MTX) for malignancy, but it has not been fully explored in rheumatoid arthritis (RA) patients taking low-dose MTX. This study aimed to elucidate the dose-dependent effects of MTX on the renal function of patients with RA. We retrospectively reviewed 502 consecutive RA patients who were prescribed MTX for >= 1 year at Okayama University Hospital between 2006 and 2018. The primary outcome was the change in estimated glomerular filtration rate (eGFR) over 1 year. The association between MTX dosage (= 12 mg/week) and the change in eGFR was evaluated using multiple linear regression analysis with adjustment for possible confounding factors including age, sex, disease duration, body weight, comorbidity, baseline eGFR, concomitant treatment, and disease activity. Mean patient age was 63 years; 394 (78%) were female. Median disease duration was 77 months, while mean MTX dosage was 8.6 mg/week. The last 1-year change of eGFR (mean +/- SD) in patients treated with MTX= 12 mg/week (n=97) decreased by 0.2 +/- 7.3, 0.6 +/- 8.6, and 4.5 +/- 7.9 mL/min/1.73 m(2)/year, respectively (p= 12 mg/week was still correlated with a decrease in 1-year eGFR (beta-coefficient:-2.5; 95% confidence interval,-4.3 to-0.6; p=0.0089) in contrast to MTX 8-12 mg/week. Careful monitoring of renal function is required in patients with MTX >= 12 mg/week over the course of RA treatment regardless of disease duration

Association of explanatory histological findings and urinary protein and serum creatinine levels at renal biopsy in lupus nephritis: a cross-sectional study

Background The aim of the present study was to evaluate the association between the histology of active and chronic lesions and urinary protein and serum creatinine (SCr) levels, as common clinical endpoints in clinical trials for lupus nephritis (LN). Methods In total, 119 patients diagnosed with LN class III, IV, and V, as defined by the International Society of Nephrology/Renal Pathology Society, between 1990 and 2015, were enrolled in the present study. Multiple regression analysis was performed to explore semi-quantitative histological variables associated with urinary protein and SCr levels. Results The mean age of the enrolled patients was 45 years, and 79% were female. The mean SCr and mean urinary protein levels at the time of renal biopsy were 0.87 mg/dl and 3.00 g/gCr, respectively. Class IV (71%) was the most common type of LN followed by class III (17%), and class V (13%). Multicollinearity was confirmed between monocellular infiltration (variance inflation factor [VIF] = 10.22) and interstitial fibrosis (VIF = 10.29), and between karyorrhexis (VIF = 4.14) and fibrinoid necrosis (VIF = 4.29). Fibrinoid necrosis and monocellular infiltration were subsequently excluded, and multiple regression analysis revealed that only the urinary protein level was correlated with wire loop lesions (β-coefficient [β]: 1.09 and confidence interval [CI]: 0.35 to 1.83), and that the SCr level was correlated with glomerular sclerosis (β: 1.08 and CI: 0.43 to 1.74). Conclusion As urinary protein and SCr levels were not quantitatively associated with active lesions, they may not accurately reflect the response to remission induction therapy in patients with LN

Alternative to Rituximab Therapy for a Patient with Ankylosing Spondylitis Who Was Unable to Continue Anti-TNF Therapy

We herein present a case of a 38-year-old man who had bamboo spine and severe sacroiliitis and who was diagnosed with ankylosing spondylitis (AS). Infliximab (IFX) markedly improved the axial symptom but was discontinued due to the side effect of peripheral neuropathy. Switching from IFX to etanercept worsened the side effect. Rituximab (RTX) administration elicited a good response without side effects. RTX might be a suitable option for AS therapy when TNF inhibitors are difficult to use

Risk Factors for Chronic Damage Accumulation Across Different Onset Eras in Systemic Lupus Erythematosus: A Cross-sectional Analysis of a Lupus Registry of Nationwide Institutions (LUNA)

Chronic damage accumulation affects not only mortality but also quality of life in patients with systemic lupus erythematosus (SLE). Risk factors for chronic damage were explored in SLE through different onset eras. Two hundred forty-five patients at Okayama University Hospital and Showa University Hospital were divided into three groups based on the onset era: a past-onset group (onset before 1995; n=83), middle-onset group (1996-2009; n=88), and recent-onset group (after 2010; n=74). The mean Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI) score as an index of chronic damage was 1.93, 1.24, and 0.53 in the past-, middle-, and recent-onset groups, respectively. In the pastonset group, the total SDI score was significantly associated with glucocorticoid monotherapy by linear regression analysis (β-coefficient [β]=0.63; 95% confidence interval [CI], 0.21-1.05) and C-reactive protein levels (β=0.67; 95% CI, 0.27-1.07). In the middle-onset group, the total SDI score was significantly associated with the SLE Disease Activity Index at registration (β=0.09; 95% CI, 0.03-0.12). Reducing the accumulation of chronic damage in SLE patients might be possible with the concomitant use of immunosuppressants and tight control of disease activity

Association of glucocorticoid doses and emotional health in lupus low disease activity state (LLDAS): a cross-sectional study

Background While survival of systemic lupus erythematosus (SLE) patients has improved substantially, problems remain in the management of their emotional health. Medium to high-dose glucocorticoid doses are known to worsen emotional health; the effect is unclear among patients receiving relatively low-dose glucocorticoids. This study aims to investigate the association between low glucocorticoid doses and emotional health in lupus low disease activity state (LLDAS). Methods This cross-sectional study drew on data from SLE patients in 10 Japanese institutions. The participants were adult patients with SLE duration of >= 1 year who met LLDAS criteria at the study visit from April 2018 through September 2019. The exposure was the daily glucocorticoid dose (mg oral prednisolone). The outcome was the emotional health score of the lupus patient-reported outcome scale (range: 0 to 100). Multiple linear regression analysis was performed with adjustment for confounders including disease-related damage, activity, and psychotropic drug use. Results Of 192 patients enrolled, 175 were included in the analysis. Their characteristics were as follows: female, 89.7%; median age, 47 years (interquartile range (IQR): 37.0, 61.0). Median glucocorticoid dose was 4.0 mg (IQR 2.0, 5.0), and median emotional health score 79.2 (IQR 58.3, 91.7). Multiple linear regression analysis showed daily glucocorticoid doses to be associated with worse emotional health (beta coefficient = - 2.54 [95% confidence interval - 4.48 to - 0.60], P = 0.01). Conclusions Daily glucocorticoid doses were inversely associated with emotional health among SLE patients in LLDAS. Further studies are needed to determine whether glucocorticoid tapering leads to clinically significant improvements in emotional health

Dynamical O-17 imaging in tumor bearing mice at 7T

Introduction: Oxygen consumption rate and blood flow are important parameters for the physiological and pathological evaluation of brain, myocardium and tumors1,2, where 15O PET has been utilized. 17O MRI will be another tool for the direct observation of tumor oxygenation. Measurements of the blood flow and oxygen consumption rate by in vivo 17O NMR has been reported recently3,4. We have developed 17O imaging by FISP and succeeded in the visualization of natural abundance H217O distribution in the mouse with 10 min data acquisition5. In this study, we will report the dynamical study of 17O imaging using 17O enriched saline in the tumor bearing mice. Phantom experiments demonstrated the feature of 17O in vivo NMR signals. Methods: MRS/MRI was performed on 7T/400mm/SS system (NIRS/KOBELCO/Bruker) with 40 mm 1H/17O Litz coil (Doty Scientific Inc.). Water, ethanol or 25-100 % ethyleneglycol -water was used in phantom experiments. 17O images of healthy and tumor bearing C3H/He mice (20 . 25 g) were obtained under Ketamine:Xylazine anesthesia by true FISP with a TR/TE = 4.3/2.15 ms. A saline (0.5ml) containing 5% 17O prepared from 10% 17O water (Cambridge Isotope Laboratories, Inc) was i.v. injected to tumor bearing mice. After imaging experiment, organs were excised for 17O spectral measurements. Results: Phantom studies: The 17O signal of ethyleneglycol or water in 25% ethyleneglycol-water phantom was detected by fid acquisition mode but not by echo mode within our experimental condition. Animal studies: The S/N in the 17O images of a mouse obtained by FISP with 10 min data acquisition was dramatically improved from 3.8 to 13.4 after the injection of a saline containing 5% 17O. The result of 10 sec dynamical imaging of H217O with under the spatial resolution of 2.5 mm without slicing was shown in Fig.1. The process of initial accumulation of the injected H217O in the heart and re-distribution to whole body was demonstrated. Spatial resolution of 1.25 mm was attained with the 10 min data acquisition. Discussion: The dynamical study of H217O was achieved in the tumor bearing mice with a temporal resolution of 10 sec. The temporal and spatial resolutions attained in this study will lead this imaging method to the evaluation of blood flow or oxygen consumption rate using 17O gas and water. FISP is shown to be an effective method for imaging in vivo 17O signals from free water. The phantom experiments with ethyleneglycol-water strongly suggest that the in vivo 17O images obtained here is from the mobile H217O and not from other molecular species or immobilized water. The echo image of 17O detecting solely the signal from free water, not from the body constituents contributing as background should have an advantage over the other NMR method with FID detection in the 17O2 gas study. Reference: (1) Secomb TW. et al, 34 :313 (1995), (2) Ando K, et al, Int J Radiat Biol 75 :505 (1999), (3) Zhu XH. et al, MRM 45:543 (2001), (4) Fiat D. et al, Neurol Res 26:803 (2004), (5) Narazaki M. et al, 14th ISMRM 3113 (2006)Joint Annual Meeting ISMRM-ESMRMB 200

Quantitative 17O imaging towards oxygen consumption study in tumor bearing mice at 7 T

17O magnetic resonance imaging (MRI) using a conventional pulse sequence was explored as a method of quantitative imaging towards regional oxygen consumption rate measurement for tumor evaluation in mice. At 7 T, fast imaging with steady state (FISP) was the best among gradient echo, fast spin echo and FISP for the purpose. The distribution of natural abundance H2 17O in mice was visualized under spatial resolution of 2.5x2.5 mm2 by FISP in 10 min. The signal intensity by FISP showed a linear relationship with 17O quantity both in phantom and mice. Following the injection of 5% 17O enriched saline, 17O redistribution was monitored in temporal resolution down to 5 sec with an image quality sufficient to distinguish each organ. The image of labeled water produced from inhaled 17O2 gas was also obtained. The present method provides quantitative 17O images under sufficient temporal and spatial resolution for the evaluation of oxygen consumption rate in each organ. Experiments using various model compounds of ROH type clarified that the signal contribution of body constituents other than water in the present in vivo 17O FISP image was negligible

17O imaging for the evaluation of physiological function in the tumor bearing mice

Introduction: The application of 17O MRI method has been proposed in the measurements of regional cerebral blood flow and cerebralmetabolic rate of oxygen consumption1-3. Since hypoxic tumor cells are resistant to the radiation, monitoring the tumor oxygenation and blood flow is important for the effective treatment. Irrespective of such expectation, low sensitivity and short T2 of 17O make the direct measurement difficult. In order to overcome these difficulties, proton-detected 17O MRI4, Chemical Shift Imaging5, gradient echo and projection reconstruction6 have been proposed. In this study, FISP was employed for H2 17O imaging at 7.0 T.International Society for Magnetic Resonance in Medicine(ISMRM) 14th Scientific Meeting and Exhibitio

Comparisons of EPR imaging and T(1)-weighted MRI for efficient imaging of nitroxyl contrast agents.

The resolution and signal to noise ratio of EPR imaging and T1-weighted MRI were compared using an identical phantom. Several solutions of nitroxyl contrast agents with different EPR spectral shapes were tested. The feasibility of T1-weighted MRI to detect nitroxyl contrast agents was described. T1-weighted MRI can detect nitroxyl contrast agents with a complicated EPR spectrum easier and quicker; however, T1-weighted MRI has less quantitative ability especially for lipophilic nitroxyl contrast agents, because T1-relaxivity, i.e. accessibility to water, is affected by the hydrophilic/hydrophobic micro-environment of a nitroxyl contrast agent. The less quantitative ability of T1-weighted MRI may not be a disadvantage of redox imaging, which obtains reduction rate of a nitroxyl contrast. Therefore, T1-weighted MRI has a great advantage to check the pharmacokinetics of newly modified and/or designed nitroxyl contrast agents. 2007 Elsevier Inc. All rights reserved