Efficacy of mycophenolate mofetil as a remission induction therapy in antineutrophil cytoplasmic antibody: associated vasculitis-a meta-analysis.

OBJECTIVES: A few studies on antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) treatments have shown the therapeutic efficacy of mycophenolate mofetil (MMF). However, the therapeutic efficacy of MMF compared with that of cyclophosphamide (CYC) in patients with AAV has not been established. We conducted a systematic review and meta-analysis to assess the efficacy of MMF as a remission induction therapy in patients with AAV comparing it with the efficacy of CYC. METHODS: We searched randomised controlled trials (RCTs) comparing the efficacy of MMF with that of CYC in patients with AAV on three different websites: PubMed, Cochrane Library and Google Scholar. We compared the difference in the relative risk (RR) of each outcome based on a Mantel-Haenszel random-effects model. RESULTS: We analysed data from four RCTs with 300 patients for the study. The 6-month remission rate (RR 1.09, 95% CI 0.86 to 1.38, p=0.48), the 6-month ANCA negativity (RR 1.31, 95% CI 0.91 to 1.90, p=0.15) and the long-term relapse rate (RR 1.36, 95% CI 0.80 to 2.31, p=0.26) were all similar between the two treatments. The rates of death, infection and leucopenia were also similar between the two groups (RR 1.05, 95% CI 0.40 to 2.74, p=0.93; RR 1.26, 95% CI 0.79 to 2.01, p=0.33; RR 0.45, 95% CI 0.16 to 1.32, p=0.15, respectively). CONCLUSIONS: We found no difference between the therapeutic efficacy of MMF and that of CYC in patients with AAV. MMF may be an alternative remission induction therapy in patients with non-life-threatening AAV.

Systemic Sclerosis and Systemic Lupus Erythematosus Overlap Syndrome with Pulmonary Arterial Hypertension Successfully Treated with Immunosuppressive Therapy and Riociguat.

We report the case of a 40-year-old patient with systemic sclerosis (SSc) and systemic lupus erythematosus (SLE) overlap syndrome with pulmonary arterial hypertension (overlap-PAH) that was successfully treated with a combination of immunosuppressive therapy and the soluble guanylate cyclase stimulator riociguat. She was diagnosed with mixed connective tissue disease (MCTD) two years prior to admission. She was admitted to our hospital with dyspnea on exertion and progressive skin sclerosis. She fulfilled both SLE and SSc classification criteria and was re-diagnosed with overlap syndrome. The tricuspid valve pressure gradient (TRPG) on echocardiography was 64 mmHg at admission. On right heart catheterization, mean pulmonary arterial pressure (mPAP) was 43 mmHg and pulmonary capillary wedge pressure was 15 mmHg. We diagnosed her with SSc-SLE overlap-PAH and started treatment with corticosteroids and intravenous cyclophosphamide. We also started treatment with riociguat because we speculated she had a component of SSc-PAH and that immunosuppressive therapy alone may be insufficient. We chose riociguat because of its favorable treatment effect on SSc-PAH. Two months after treatment, her TRPG improved to 33 mmHg and the skin sclerosis improved dramatically, suggesting the efficacy of multi-drug treatment and the importance of early intervention.

Diffusion Weighted Whole Body Imaging with Background Body Signal Suppression (DWIBS) Was Useful for the Diagnosis and Follow-up of Giant Cell Arteritis.

A 66-year-old woman with symptoms of fatigue and headache was diagnosed with giant cell arteritis (GCA). Fluorodeoxyglucose (FDG)-positron emission tomography (PET)/computed tomography (CT) revealed the strong accumulation of FDG in the descending aorta, abdominal aorta, bilateral subclavian artery, and total iliac artery. Diffusion-weighted whole-body imaging with background body signal suppression (DWIBS) showed signal enhancement at the descending aorta and abdominal aorta. We repeated FDG-PET and DWIBS 2 months after the initiation of therapy with prednisolone. In line with the FDG-PET findings, the signal enhancement of the aortic wall completely vanished on DWIBS. DWIBS may be a novel useful tool for the diagnosis and follow-up of GCA treatment.

Diffusion-weighted Whole-body Imaging with Background Body Signal Suppression (DWIBS) as a Novel Imaging Modality for Disease Activity Assessment in Takayasu's Arteritis.

A 26-year-old woman with Takayasu's arteritis (TAK) experienced back and neck pain during tocilizumab (TCZ) treatment. The levels of C-reactive protein were normal, and ultrasonography revealed no significant changes. Diffusion-weighted whole-body imaging with background body signal suppression (DWIBS) showed signal enhancement in the walls of several arteries. Contrast computed tomography showed arterial inflammation in the same lesion. After increasing the dose of prednisolone and TCZ, all signal enhancements decreased and continued to decrease, as observed on days 76 and 132. Thus, DWIBS may be a novel imaging modality for assessing the disease activity of TAK, particularly during follow-up.

Crosstalk between tumor necrosis factor-alpha signaling and aryl hydrocarbon receptor signaling in nuclear factor -kappa B activation: A possible molecular mechanism underlying the reduced efficacy of TNF-inhibitors in rheumatoid arthritis by smoking.

OBJECTIVES: To examine the influence of smoking on biologics treatment against different therapeutic targets, such as TNFα, IL-6, and T cell, in rheumatoid arthritis (RA) and elucidate the underlying molecular mechanism. METHODS: The association between drug-discontinuation due to poor therapeutic response and smoking status was analyzed individually in biologics against different therapeutic targets by a multivariable logistic regression analysis using the "NinJa" Registry, one of the largest cohorts of Japanese RA patients. In vitro enhancement of TNFα-induced NF-κB activation and subsequent proinflammatory cytokine production by cigarette chemical components was examined by RT-PCR, qPCR, ELISA, and western blotting using an immortalized rheumatoid synovial cell line, MH7A. RESULTS: The rate of drug-discontinuation due to poor therapeutic response was higher in the current smoking group than in the never- or ever-smoking groups (the odds ratio of current/never smoking: 2.189, 95%CI; 1.305-3.672,P = 0.003; current/ever: 1.580, 95%CI; 0.879-2.839,P = 0.126) in the TNF inhibitor (TNFi) treatment group. However, this tendency was not observed in either the IL-6 or T cell inhibitor treatment groups. Cigarette smoke chemical components, such as benzo[α]pyrene, known as aryl hydrocarbon receptor (AhR) ligands, themselves activated NF-κB and induced proinflammatory cytokines, IL-1ß and IL-6. Furthermore, they also significantly enhanced TNFα-induced NF-κB activation and proinflammatory cytokine production. This enhancement was dominantly inhibited by Bay 11-7082, an NF-κB inhibitor. CONCLUSIONS: These results suggest a crosstalk between TNFα signaling and AhR signaling in NF-κB activation which may constitute one of the molecular mechanisms underlying the higher incidence of drug-discontinuation in RA patients undergoing TNFi treatment with smoking habits.

Proteomics analysis identified peroxiredoxin 2 involved in early-phase left ventricular impairment in hamsters with cardiomyopathy.

Given the hypothesis that inflammation plays a critical role in the progression of cardiovascular diseases, the aim of the present study was to identify new diagnostic and prognostic biomarkers of myocardial proteins involved in early-phase cardiac impairment, using proteomics analysis. Using the two-dimensional fluorescence difference gel electrophoresis (2D-DIGE) combined with MALDI-TOF/TOF tandem mass spectrometry, we compared differences in the expression of proteins in the whole left ventricles between control hamsters, dilated cardiomyopathic hamsters (TO-2), and hypertrophy cardiomyopathic hamsters (Bio14.6) at 6 weeks of age (n = 6, each group). Proteomic analysis identified 10 protein spots with significant alterations, with 7 up-regulated and 3 down-regulated proteins in the left ventricles of both TO-2 and Bio 14.6 hamsters, compared with control hamsters. Of the total alterations, peroxiredoxin 2 (PRDX2) showed significant upregulation in the left ventricles of TO-2 and Bio 14.6 hamsters. Our data suggest that PRDX2, a redox regulating molecule, is involved in early-phase left ventricular impairment in hamsters with cardiomyopathy.

Involvement of oxidative modification of proteins related to ATP synthesis in the left ventricles of hamsters with cardiomyopathy.

Inflammation enhanced by accumulation of reactive oxygen species plays an essential role in the progression of cardiovascular diseases. Using the 2D-oxyblot analysis and 2D-difference image gel electrophoresis (2D-DIGE), we compared the levels of ROS-induced carbonyl modification of myocardial proteins in the whole left ventricles between 6-week-old hamsters with dilated (TO-2) and hypertrophic cardiomyopathy (Bio14.6) and control hamsters (F1B). Then, 2D electrophoresis combined with MALDI-TOF/TOF tandem mass spectrometry detected 18 proteins with increased carbonyl level in cardiomyopathy hamsters compared with control hamster. Carbonyl modification of proteins related to ATP synthesis, including citric acid cycle and electron transport system, was observed in the hearts of hamsters with both types of cardiomyopathy. Further analysis indicated that left ventricular carbonyl production correlated negatively with succinyl-CoA:3-ketoacid-coenzyme A transferase 1 activity (r 2 = 0.60, P = 0.0007) and ATP concentration (r 2 = 0.29, P = 0.037), suggesting that protein carbonylation has negative effects on the levels of these biomolecules. Furthermore, carbonyl production significantly correlated with plasma Troponin T level (r 2 = 0.33, P = 0.026). Reduction of energy metabolism by oxidative damage may contribute to the development of left ventricular impairment in cardiomyopathy.