The introduction of biological disease-modifying anti-rheumatic drugs (bDMARDs) into clinical practice has dramatically improve the clinical outcomes of individuals with rheumatoid arthritis (RA). However, bDMARDs are associated with high costs, which has resulted in restricted treatment access and a burden on medical insurance finances. Although biosimilars offer cost-saving, their effectiveness and safety must be established in Post-Marketing Surveillance (PMS). Infliximab (IFX), a chimeric monoclonal antibody to TNF-alpha, is the first bDMARD; its biosimilar, CT-P13, is the first biosimilar DMARD approved for RA treatment in Japan. We will evaluate whether switching from originator IFX to CT-P13 is not inferior for maintaining non-clinical relapse to continued treatment with originator IFX in RA patients achieving clinical remission.This study is an interventional, multicenter, open-label, single-arm against historical control and noninferiority clinical trial with a 24-week follow-up. Eighty RA patients who are treated by originator IFX for ≥24 weeks and are achieving clinical remission will be included. Patients will be switched to CT-P13 with the unchanged dosing regimen. We will evaluate disease activity by measuring clinical disease activity indices and by using musculoskeletal ultrasound (MSUS). The primary endpoint is the ratio of patients who experience a nonclinical relapse during the study period. Important secondary endpoints are the changes from the baseline of the MSUS scores. We will also comprehensively analyze the serum levels of many biomarkers such as cytokines and chemokines.The study results are expected to show the noninferiority of switching to CT-P13 over the continuation of originator IFX. The strength of this study is its prospective evaluation of therapeutic efficacy using not only clinical disease activity indices but also MSUS to accurately and objectively evaluate disease activity at the joint level among patients drawn from multiple centers with a standardized evaluation by MSUS. We will explore whether parameters at baseline can predict a nonclinical relapse after switching from originator IFX to CT-P13 by integrating multilateral assessments, i.e., clinical disease activity indices, MSUS findings, and serum biomarkers.This study was registered in the Japan Registry of Clinical Trials (https://jrct.niph.go.jp) on October 11, 2019 as jRCTs071190030.
Background and Purpose: Aneurysmal rebleeding is a major cause of death and morbidity in patients with aneurysmal subarachnoid hemorrhage (SAH). Recognizing the predictors of rebleeding might help to identify patients who will benefit from acute management. This study was performed to investigate the predictors of aneurysmal rebleeding and their impact on clinical outcomes in the preoperative, intraoperative, and postoperative periods. Methods: The incidence of rebleeding, demographic data, and clinical data from 4933 patients with aneurysmal SAH beginning in the year 2000 were retrospectively analyzed in the Nagasaki SAH Registry Study. We performed multiple logistic regression analyses to identify the risk factors contributing to rebleeding and the outcome after SAH. Results: Preoperative rebleeding occurred in 7.2% of patients. Patient age (P = 0.01), multiple aneurysms (P < 0.01), aneurysm size (P < 0.0001), and heart disease (P = 0.03) were significantly associated with preoperative rebleeding. Conversely, intraoperative rebleeding occurred in 11.2% of patients. Aneurysm location (anterior communicating artery [ACoA]), family history (P = 0.02), preoperative rebleeding (P < 0.01), and clipping/coiling (P < 0.0001) were significantly associated with intraoperative rebleeding. Interaction analysis showed that clipping significantly affected intraoperative rebleeding at the ACoA (OR, 4.00; 95% CI, 1.82-8.80; P < 0.001). Postoperative rebleeding occurred in 2.4% of patients. Coiling/clipping (P < 0.0001) and intraoperative rebleeding (P < 0.01) were significantly associated with postoperative rebleeding. Rebleeding in all time periods examined significantly contributed to the clinical outcome after SAH. Conclusions: Aneurysmal rebleeding after SAH has specific characteristics in the preoperative, intraoperative, and postoperative periods, and all of these characteristics contribute to the clinical outcome. The ACoA has a higher risk of intraoperative rebleeding, and endovascular coiling could be a good candidate in terms of techniques for preventing intraoperative rebleeding, although complete aneurysm obliteration should be accomplished.
The introduction of biological disease-modifying anti-rheumatic drugs into clinical practice has dramatically improved the clinical outcomes of individuals with rheumatoid arthritis (RA). We are conducting the IFX-SIRIUS STUDY I that evaluates whether switching from originator infliximab (IFX) to its biosimilar, CT-P13, is not inferior in maintaining nonclinical relapse to continue treatment with originator IFX in patients with RA achieving clinical remission. It is the next great issue whether disease activity can be maintained in good condition after discontinuation of CT-P13 because no evidence is available regarding the clinical value of discontinuing biosimilars in patients with RA. Thus, we will evaluate whether a condition without clinical relapse will be maintained after discontinuation of CT-P13 in patients with RA, achieving clinical remission or low disease activity during the IFX-SIRIUS STUDY I.
Abstract Background Previous studies have shown conflicting evidence regarding the incidence of cancer in patients with systemic lupus erythematosus (SLE) compared with that in healthy individuals. Calcineurin inhibitors (CNIs) such as cyclosporine and tacrolimus have been widely used to treat SLE; however, their effects on cancer risk remain unclear. We aimed to investigate the incidence of cancer in patients with SLE and determine the potential association between CNI use and cancer risk. Methods The standardized incidence ratio (SIR) of cancer among patients with lupus in the Lupus Registry of Nationwide Institutions (LUNA) was calculated based on the age-standardized incidence rate of cancer reported by Japan’s Ministry of Health, Labour and Welfare. We also examined the association between CNI exposure and cancer risk, while considering potential confounding factors. The analysis accounted for confounding variables such as age, sex, smoking history, maximum glucocorticoid dose, treatment history with cyclophosphamide, ongoing hydroxychloroquine, Systemic Lupus International Collaboration Clinics/American College of Rheumatology Damage Index (SDI) value (excluding cancer occurrence), comorbidity of diabetes mellitus, and smoking history. Results The study included 704 patients with SLE (625 females; 88.8%) with a median age of 44 years [interquartile range (IQR) = 34–55] years. The median past maximum glucocorticoid dose was 40 mg/day [IQR = 30–60 mg/day], and the SDI at registration was 1 [IQR = 0–2]. Among the patients, 246 (35.1%) had smoking histories, and 38 (5.4%) experienced cancer complications. Gynecological malignancies accounted for 63.2% of all cancers. The SIR of cancer in the LUNA cohort was 1.08 (95% confidence interval [CI] = 0.74–1.43). No statistically significant risks of cancer were found in relation to CNI treatment history; the odds ratio using multiple logistic regression was 1.12 (95% CI = 0.42–3.00), the risk ratio using standardization was 1.18 (95% CI = 0.47–2.16), and the risk ratio using inverse probability weighting was 1.8 (95% CI = 0.41–4.66). Conclusions The incidence of cancer in patients with SLE in the LUNA cohort did not significantly differ from that in the general population. These findings suggest that CNI treatment in this cohort did not pose a risk factor for cancer development.
Post-thoracotomy pain is an obstacle for lung-cancer patients even after introduction of less invasive surgical procedures. The aim of this prospective study was to evaluate if early postoperative administration of pregabalin is beneficial for patients with non-small cell lung cancer (NSCLC).We conducted a randomized open control trial. Patients with NSCLC were allocated randomly to epidural and nonsteroidal anti-inflammatory drug (NSAID) use for analgesia (control group) or pregabalin use (pregabalin group). Primary endpoint was the frequency of additional administration of a NSAID. Secondary endpoints were intensity of ongoing pain, frequency of neuropathic pain, and pain catastrophizing.Seventy-two patients were registered and allocated. Thirty-four cases in the control group and 33 in the pregabalin group were assessed. Age, sex, body mass index (BMI), type of surgical procedure, type of lymph-node dissection, operation time, bleeding, duration of chest-tube insertion, and postoperative hospital stay between the two groups was not significantly different. Frequency of additional NSAID use between the control group (2±4 suppositories) and pregabalin group (2±3 suppositories) was not significantly different (P=0.62). Numeric Rating Scale (NRS) for the intensity of ongoing pain, frequency of neuropathic pain, and Pain Catastrophizing Scale (PCS) between each group were not significantly different at any time until 3 months after surgery.Early postoperative administration of pregabalin is not beneficial for patients with NSCLC.
Familial Mediterranean fever (FMF) is an inherited disorder caused by a number of mutations of the Mediterranean fever (MEFV) gene, coding a protein named pyrin that acts as a major regulatory component of the inflammasome. The first-line drug for FMF treatment is colchicine, but 10% of patients with FMF do not respond well to colchicine. Although the efficacy of tocilizumab (TCZ), which is a recombinant, humanized, antihuman interleukin 6 (IL-6) receptor monoclonal antibody, has been reported to prevent FMF attacks, the effects of TCZ on individuals with colchicine-resistant or colchicine-intolerant FMF have not been evaluated in a randomized clinical trial. In this phase III, investigator-initiated, multicenter, double-blind, randomized, parallel-group trial, the efficacy and safety of TCZ will be compared with placebo in patients with colchicine-resistant or colchicine-intolerant FMF. The study will be conducted in nine centers in Japan. Participants (n = 24) will be randomly assigned to receive 162 mg of TCZ (n = 12) or placebo (n = 12) administered subcutaneously once weekly for 24 weeks. Rescue treatment will be allowed if rescue criteria are met. A primary endpoint is the number of fever attacks until 24 weeks. Secondary endpoints include the number of occurrences of accompanying symptoms during attacks; the time until a fever attack occurs; the duration of fever attacks; serum C-reactive protein and serum amyloid A; 36-item Short Form Health Survey; general evaluation by a physician (100-mm visual analogue scale); body temperature; the percentage of subjects who achieve FMF 50 at 12 weeks and 24 weeks; and pharmacodynamic assessment, including the measurement of serum TCZ level and soluble IL-6 receptor. The study is expected to produce evidence regarding the efficacy of a potential new therapeutic agent, TCZ, in improving the clinical course and outcome for patients with colchicine-resistant or colchicine-intolerant FMF. University Hospital Medical Information Network Clinical Trials Registry, UMIN000028010 . Registered on 7 July 2017.
Abstract Background The fatty infiltration (FI) of rotator cuff muscles in patients with rotator cuff tear is affected by a range of factors, but the associations between FI grade and patient factors, as well as the location and severity of adjacent rotator cuff tears, are not well-known. The hypothesis of this study is the progression of FI grade of each of the rotator cuff muscles is affected by the severity of any tear in the adjacent rotator cuff. Methods The study examined 373 shoulders of 348 patients (264 males and 109 females; mean age was 62.8 years old) who had undergone arthroscopic rotator cuff surgery. Age at surgery, sex, body mass index (BMI), and duration of symptoms were investigated. The FI grades of the supraspinatus (SSP), infraspinatus (ISP), and subscapularis (SSc) muscles were assessed on preoperative MRI according to the Goutallier classification. Intraoperatively, the severity of the posterior-superior rotator cuff (SSP-ISP) tear was classified on a six-grade scale modified the Cofield classification, and that of the SSc tear on a six-grade scale according to the Lafosse classification. We performed descriptive statistics on these results and examined their relationship with FI grade. Results The FI grades of the SSP and the ISP were significantly associated with the severity of the tears in those muscles, and the FI grade of the SSc was significantly associated with the severity of the tear in that muscle. Furthermore, the FI grades of the SSP and the ISP were significantly associated with SSc tear severity, and the FI grade of the SSc was significantly associated with SSP-ISP tear severity. Conclusions The progression of FI grade of each of the rotator cuff muscles is affected not only by the tear severity in the muscle concerned, but also by the severity of any tear in the adjacent rotator cuff.
2Faculty of Environmental Studies, Nagasaki University, 3 AIDS Medical Center, National Hospital Organization, Osaka National Hospital Background and Objective : Patients unknowingly infected with human immunodefi ciency virus (HIV) comprise a strong potential source of transmission. Therefore, minimizing the time that patients spend between infection and diagnosis in the source is important. Obtaining suffi cient information about such patients was diffi cult in Japan due to the small population of individuals who were HIV-infected. Therefore, we tracked such individuals over the course of 8 years. Subjects and Methods : Of HIV-infected patients registered at Osaka National Hospital, 492 who had been untreated for at least 30 days were enrolled. A Cox proportional hazard regression analysis was performed using the time between the initial diagnosis and the initiation of antiretroviral therapy (ART) as a response variable. The annual rates of decrease of untreated patients with HIV infection were also calculated. Results : Kaplan-Meier survival curves were drawn for patients with HIV who had average, high or low CD4 + cell (CD4) counts and HIV RNA loads. Risk ratios were
The effects of daily teriparatide (20 μg) (D-PTH), weekly high-dose teriparatide (56.5 μg) (W-PTH), or bisphosphonates (BPs) on areal bone mineral density (aBMD), bone turnover markers (BTMs), volumetric BMD (vBMD), microarchitecture, and estimated strength were investigated in postmenopausal osteoporosis patients. The study participants were 131 women with a history of fragility fractures. They were randomized to receive D-PTH, W-PTH, or BPs (alendronate or risedronate) for 18 months. Dual-energy X-ray absorptiometry (DXA), BTMs, and high-resolution peripheral quantitative CT (HR-pQCT) parameters were evaluated at baseline and after 6 and 18 months of treatment. The primary endpoint was the change (%) in cortical thickness (Ct.Th) after 18 months' treatment compared with baseline. DXA showed that D-PTH, W-PTH, and BPs increased lumbar spine aBMD (+12.0%, +8.5%, and +6.8%) and total hip aBMD (+3.0%, +2.1%, and +3.0%), but D-PTH and W-PTH decreased 1/3 radius aBMD (−4.1%, −3.0%, −1.4%) after 18 months. On HR-pQCT, D-PTH increased trabecular vBMD (Tb.vBMD) at the distal radius and tibia after 18 months (+6.4%, +3.7%) compared with the BPs group, decreased cortical volumetric tissue mineral density (Ct.vTMD) (−1.8%, −0.9%) compared with the other groups, increased Ct.Th (+1.3%, +3.9%), and increased failure load (FL) (+4.7%, +4.4%). W-PTH increased Tb.vBMD (+5.3%, +1.9%), maintained Ct.vTMD (−0.7%, +0.2%) compared with D-PTH, increased Ct.Th (+0.6%, +3.6%), and increased FL (+4.9%, +4.5%). The BPs increased Tb.vBMD only in the radius (+2.0%, +0.2%), maintained Ct.vTMD (−0.6%, +0.3%), increased Ct.Th (+0.5%, +3.4%), and increased FL (+3.9%, +2.8%). D-PTH and W-PTH comparably increased Ct.Th, the primary endpoint. D-PTH had a strong effect on trabecular bone. Although D-PTH decreased Ct.vTMD, it increased Ct.Th and total bone strength. W-PTH had a moderate effect on trabecular bone, maintained Ct.vTMD, and increased Ct.Th and total bone strength to the same extent as D-PTH.
