Tanaka Y.,University of Occupational and Environmental Health Japan |
Yamanaka H.,Tokyo Women's Medical University |
Ishiguro N.,Nagoya University |
Miyasaka N.,Tokyo Medical and Dental University |
And 4 more authors.
Arthritis Research and Therapy | Year: 2017
Background: This study was conducted to evaluate the feasibility of long-term adalimumab (ADA) discontinuation after achievement of low disease activity (LDA) in Japanese patients with early rheumatoid arthritis (RA) and to identify predictors of LDA maintenance. Methods: In the HOPEFUL-1 study, patients received initial therapy with either ADA plus methotrexate (MTX; intensive therapy) or MTX alone (standard therapy) for 26 weeks, followed by ADA + MTX for 26 weeks. In the HOPEFUL-2 study, patients received ADA + MTX (ADA continuation) or MTX alone (ADA discontinuation) for 52 weeks. HOPEFUL-3 was an observational study that enrolled patients who had completed HOPEFUL-2; these patients were followed for an additional 104 weeks. Results: Of the 172 patients enrolled in the HOPEFUL-3 study, 135 (ADA continuation, n = 61; ADA discontinuation, n = 74) with 28-joint Disease Activity Score using C-reactive protein (DAS28-CRP) values at both week 52 (start of HOPEFUL-2) and week 208 (end of HOPEFUL-3) were included in the effectiveness analysis. At week 208, 58 (95.1%) of 61 patients and 59 (79.7%) of 74 patients who continued or discontinued ADA, respectively, had LDA (DAS28-CRP <3.2). Initial intensive therapy was associated with a better outcome than standard therapy in terms of change in modified total Sharp score from week 0 to week 208, which was ≤0.5 (64% vs. 30%). The incidence of adverse events was significantly lower in the ADA discontinuation group than in the ADA continuation group (9.7% vs. 32.9%; p < 0.001). Conclusions: Approximately 80% of patients who discontinued ADA for 3 years after achieving LDA with ADA + MTX were still in LDA, with a lower incidence of adverse events than patients who continued ADA. Trial registration: ClinicalTrials.gov identifier: NCT01346501. Registered 29 April 2011. © 2017 The Author(s).
Koike T.,Nippon Telegraph and Telephone |
Harigai M.,Tokyo Medical and Dental University |
Ishiguro N.,Nagoya University |
Inokuma S.,Red Cross |
And 7 more authors.
Modern Rheumatology | Year: 2014
Objectives. To confirm the safety and effectiveness of adalimumab and to evaluate the influence of the concomitant use of methotrexate (MTX). Methods. Postmarketing surveillance of 7740 Japanese rheumatoid arthritis (RA) patients was performed. All patients who received adalimumab in the registration period were followed for 28 weeks after starting treatment for safety and 24 weeks for effectiveness. Effectiveness was measured by duration of morning stiffness, swollen and tender joint counts (28 joints), patient global assessment of disease activity, erythrocyte sedimentation rate and serum C-reactive protein. Results. Comparable rates of adverse drug reactions (ADRs) were reported in this study and in the interim analysis. Age, pulmonary disease history or comorbidity, co-existing diabetes mellitus, concomitant MTX at doses of > 8 mg/week and concomitant glucocorticoids at doses of > 5 mg/day were risk factors for infections. All mean values of effectiveness measurements improved. Relatively lower disease activity at baseline, biologic-naïve, concomitant MTX use and early RA stage/low functional class were background factors contributing to the effectiveness. The combination of adalimumab with MTX improved the response to adalimumab treatment. Conclusion. Adalimumab, especially with concomitant use of MTX, provided significant improvement in disease activity, without any unexpected ADRs in Japanese RA patients. © 2014 Japan College of Rheumatology.
PubMed | Red Cross, Tokyo Women's Medical University, Juntendo University, Nippon Telegraph and Telephone and 6 more.
Type: Journal Article | Journal: Rheumatology and therapy | Year: 2016
There is insufficient evidence regarding the appropriate dose of methotrexate (MTX) required to achieve specific treatment goals in patients with rheumatoid arthritis (RA) receiving biologic drugs in Japan. The present study aimed to assess the dose-response effect of MTX in combination with adalimumab (ADA) to achieve low disease activity (LDA) and/or remission at 24weeks in RA patients.This analysis used data of the ADA all-case survey in Japan (n=7740), and 5494 patients who received ADA and MTX were classified into five groups by weighted average MTX dose (>0-<4, 4-<6, 6-<8, 8-<10, and 10mg/week). Of the 5494 patients, 3097 with baseline 28-joint disease activity score based on erythrocyte sedimentation rate >3.2 were analyzed for effectiveness by MTX dose.In biologic-nave patients (n=1996/3097), LDA/remission rates increased with MTX up to 6-<8mg/week and then plateaued at higher doses (LDA, p=0.0440; remission, p=0.0422). In biologic-exposed patients (n=1101/3097), LDA/remission rates increased with MTX dose (LDA, p=0.0009; remission p=0.0143). The incidences of serious adverse drug reactions (ADRs) and serious infections did not differ by MTX dose, but total ADRs and infections were significantly higher (p<0.05) with increased MTX doses.The appropriate MTX doses in combination with ADA to achieve LDA and/or remission at week 24 were different between biologic-nave and biologic-exposed patients with RA, suggesting that 8mg/week of MTX would be enough for biologic-nave patients.ClinicalTrials.gov identifier, NCT01076959.AbbVie and Eisai Co., Ltd.
PubMed | LSI Corporation, Nippon Institute for Biological Science, Alcon and AbbVie GK
Type: Journal Article | Journal: Journal of toxicologic pathology | Year: 2015
Histopathology of the eye is an essential part of ocular toxicity evaluation. There are structural variations of the eye among several laboratory animals commonly used in toxicity studies, and many cases of ocular lesions in these animals are related to anatomical and physiological characteristics of the eye. Since albino rats have no melanin in the eye, findings of the fundus can be observed clearly by ophthalmoscopy. Retinal atrophy is observed as a hyper-reflective lesion in the fundus and is usually observed as degeneration of the retina in histopathology. Albino rats are sensitive to light, and light-induced retinal degeneration is commonly observed because there is no melanin in the eye. Therefore, it is important to differentiate the causes of retinal degeneration because the lesion occurs spontaneously and is induced by several drugs or by lighting. In dogs, the tapetum lucidum, a multilayered reflective tissue of the choroid, is one of unique structures of the eye. Since tapetal cells contain reflecting crystals in which a high level of zinc has been demonstrated chemically, drug-induced tapetum degeneration is possibly related to zinc chelation. The eye of the monkey has a macula similar to that of humans. The macula consists only of cones with a high density, and light falls directly on the macula that plays an important role in visual acuity. Macular degeneration occurring in monkeys resembles histopathologically that of humans. Hence, the eye of the monkey is a suitable model to investigate macular degeneration and to assess drug-induced macular lesions.
Othman A.A.,Clinical Pharmacology and Pharmacometrics |
Othman A.A.,Cairo University |
Chatamra K.,Neuroscience Development |
Mohamed M.-E.F.,Clinical Pharmacology and Pharmacometrics |
And 4 more authors.
Clinical Pharmacokinetics | Year: 2015
Background and Objective: Oral levodopa-carbidopa (LC-oral) treatment in advanced Parkinson’s disease (PD) is associated with motor complications due to large fluctuations in levodopa plasma concentrations. Levodopa–carbidopa intestinal gel (LCIG) provides individualized continuous levodopa–carbidopa delivery through intrajejunal infusion. This study evaluated the pharmacokinetics, safety, and efficacy of LCIG relative to LC-oral in Japanese subjects with advanced PD. Methods: Subjects with advanced PD were converted from their anti-PD medications to individually optimized doses of LC-oral (10:1 levodopa:carbidopa ratio) for 28 days (baseline; period 1) followed by switching to intrajejunal infusion of LCIG (4:1 ratio) for 21 days (period 2). Pharmacokinetics, adverse events (AEs), and efficacy were assessed. Results: Eight patients were enrolled. Six received LCIG and four reported at least one AE [most common: fall (33.3 %), dyskinesia (33.3 %)]; one discontinued due to an AE. The average daily dose was 1230/123 and 1370/342 mg levodopa/carbidopa for LC-oral and LCIG, respectively, at the end of each period. The degree of fluctuation and intra-subject variability of levodopa plasma concentrations were 5.5- and 4-fold lower, respectively, with LCIG than with LC-oral. Levodopa bioavailability was 99 % for LCIG relative to LC-oral. Compared with baseline, LCIG decreased “Off” time (2.68 h, P = 0.002) and increased “On” time without troublesome dyskinesia (2.35 h, P = 0.006) in the PD Diary©. With the small sample size, no statistically significant changes were seen on other efficacy endpoints. Conclusions: In Japanese subjects with advanced PD, LCIG resulted in an improved pharmacokinetic profile that appeared to be associated with reduced motor complications compared with LC-oral. These results extend previous findings in mainly Caucasian populations. © 2015, The Author(s).
Yamaguchi Y.,AbbVie GK |
Hearing V.J.,U.S. National Institutes of Health
Cold Spring Harbor Perspectives in Medicine | Year: 2014
Human melanocytes are distributed not only in the epidermis and in hair follicles but also in mucosa, cochlea (ear), iris (eye), and mesencephalon (brain) among other tissues. Melanocytes, which are derived from the neural crest, are unique in that they produce eu-/pheomelanin pigments in unique membrane-bound organelles termed melanosomes, which can be divided into four stages depending on their degree ofmaturation. Pigmentation production is determined by three distinct elements: enzymes involved in melanin synthesis, proteins required for melanosome structure, and proteins required for their trafficking and distribution. Many genes are involved in regulating pigmentation at various levels, and mutations in many of them cause pigmentary disorders, which can be classified into three types: hyperpigmentation (including melasma), hypopigmentation (including oculocutaneous albinism [OCA]), and mixed hyper-/hypopigmentation (including dyschromatosis symmetrica hereditaria). We briefly review vitiligo as a representative of an acquired hypopigmentation disorder. © 2014 Cold Spring Harbor Laboratory Press; all rights reserved.
Yokoyama K.,Kitasato University |
Yamazaki K.,Abbvie GK |
Katafuchi M.,Abbvie GK |
Ferchichi S.,Creativ Ceutical
Advances in Therapy | Year: 2016
Introduction: Crohn’s disease (CD) is a chronic and progressive disease in which the long-term management is important. This study sought to assess treatment persistence and dose escalation in the maintenance phase with adalimumab (ADA) or infliximab (IFX) in a Japanese real-world setting. Methods: A retrospective analysis was conducted using the Japan Medical Data Center database. CD patients with either ADA or IFX prescriptions between January 2012 and February 2015 were included. Outcomes of interest were (1) failure in the induction phase (defined as switch or discontinuation) and (2) persistence in the maintenance phase (defined as the absence of switch or discontinuation over 12 months since maintenance initiation). Results: Overall, 133 patients (53 ADA; 80 IFX) were included. Of them, treatment failed in 26 patients (19.6%) in the induction phase. During the induction phase, there was a trend towards fewer treatment failures with ADA than IFX (88.7% vs. 75.0%; p = 0.051). Of those who completed induction, 64 patients (33 ADA; 31 IFX) had at least 12 months of valid insurance enrolment after the initiation of maintenance and 13 (5 ADA; 8 IFX) had either switch or discontinuation within 12 months after the initiation of maintenance. Probabilities of switch or discontinuation over 12 months after the maintenance date were 15.2% and 20.9% for ADA and IFX groups, respectively (p-log rank = 0.7764). Conclusion: Japanese patients have a high primary response to anti-tumor necrosis factor therapy in the real-world setting, in line with the results of clinical trials. This initial therapeutic advantage can be lost during the maintenance phase, leading to dose escalation, treatment switch, or discontinuation. This study suggests that those events occurred in comparable proportions of patients treated with either ADA or IFX. However, these findings should be considered with caution given the retrospective nature and small size of the study. Funding: Abbvie GK, Tokyo, Japan. © 2016 The Author(s)
Tanaka Y.,University of Occupational and Environmental Health Japan |
Hirata S.,University of Occupational and Environmental Health Japan |
Kubo S.,University of Occupational and Environmental Health Japan |
Fukuyo S.,University of Occupational and Environmental Health Japan |
And 7 more authors.
Annals of the Rheumatic Diseases | Year: 2015
Objectives: To investigate the possibility of discontinuing adalimumab (ADA) for 1 year without flaring (DAS28-erythrocyte sedimentation rate (ESR) ≥3.2), and to identify factors enabling established patients with rheumatoid arthritis (RA) to remain ADA-free. Methods: Of 197 RA patients treated with ADA +methotrexate (MTX), 75 patients who met the ADA-free criteria (steroid-free and sustained DAS28-ESR remission for 6 months with stable MTX doses) were studied for 1 year. Results: The mean disease duration and DAS28-ESR score in 75 patients was 7.5 years and 5.1 at baseline, respectively. The proportion of patients who sustained DAS28-ESR <2.6 (48%) and DAS28-ESR <3.2 (62%) for 1 year were significantly lower in the ADA discontinuation group than in the ADA continuation group; however, in patients with deep remission (DAS28-ESR ≤1.98) identified by receiver operating characteristics analysis following logistic analysis, these rates increased to 68% and 79%, respectively, with no significant difference between both groups. Remarkably, ADA readministration to patients with flare was effective in returning DAS28-ESR to <3.2 within 6 months in 90% and 9 months in 100% patients; among the patients who sustained DAS28-ESR <3.2 during ADA discontinuation, 100% remained in structural remission and 94% in functional remission. Conclusions: The possibility of remaining ADA-free for 1 year was demonstrated in established patients with RA with outcomes that ADA can be discontinued without flaring in 79% patients with deep remission, with similar rates in the ADA continuation group, and showed no functional or structural damage in patients with DAS28-ESR <3.2. ADA readministration to patients with flare during ADA discontinuation was effective. © 2015, BMJ Publishing Group. All rigths reserved.
PubMed | Kitasato University, Abbvie GK and Creativ Ceutical
Type: Journal Article | Journal: Advances in therapy | Year: 2016
Crohns disease (CD) is a chronic and progressive disease in which the long-term management is important. This study sought to assess treatment persistence and dose escalation in the maintenance phase with adalimumab (ADA) or infliximab (IFX) in a Japanese real-world setting.A retrospective analysis was conducted using the Japan Medical Data Center database. CD patients with either ADA or IFX prescriptions between January 2012 and February 2015 were included. Outcomes of interest were (1) failure in the induction phase (defined as switch or discontinuation) and (2) persistence in the maintenance phase (defined as the absence of switch or discontinuation over 12months since maintenance initiation).Overall, 133 patients (53 ADA; 80 IFX) were included. Of them, treatment failed in 26 patients (19.6%) in the induction phase. During the induction phase, there was a trend towards fewer treatment failures with ADA than IFX (88.7% vs. 75.0%; p=0.051). Of those who completed induction, 64 patients (33 ADA; 31 IFX) had at least 12months of valid insurance enrolment after the initiation of maintenance and 13 (5 ADA; 8 IFX) had either switch or discontinuation within 12months after the initiation of maintenance. Probabilities of switch or discontinuation over 12months after the maintenance date were 15.2% and 20.9% for ADA and IFX groups, respectively (p-log rank=0.7764).Japanese patients have a high primary response to anti-tumor necrosis factor therapy in the real-world setting, in line with the results of clinical trials. This initial therapeutic advantage can be lost during the maintenance phase, leading to dose escalation, treatment switch, or discontinuation. This study suggests that those events occurred in comparable proportions of patients treated with either ADA or IFX. However, these findings should be considered with caution given the retrospective nature and small size of the study.Abbvie GK, Tokyo, Japan.
Ueno F.,Ofuna Chuo Hospital |
Kurimoto S.,AbbVie GK |
Hibi T.,Kitasato University
Journal of Gastroenterology | Year: 2016
Background: Inflammatory bowel disease (IBD) has a significant negative impact on quality of life (QOL); however, the direct impact of IBD on several aspects of patients’ lives is unknown. The IMPACT survey was conducted in Europe in 2010–2011 to determine this impact. We conducted the IMPACT survey in Japan and compared the results between subgroups of patients with ulcerative colitis (UC) and Crohn’s disease (CD). Methods: The 52-item IMPACT survey questionnaire assessing treatment and the impact of IBD on patients’ lives was translated into Japanese and administered to IBD patients recruited through patient advocacy groups. Results: Between June 2013 and January 2014, 172 Japanese IBD patients completed the questionnaire (including 84 UC and 83 CD patients). Half of all patients (84/172, 48.8 %) were satisfied with their treatment plan, and half of those who had undergone surgery were satisfied with the outcome (46/87, 52.9 %). Although 34.9 % (60/172) of patients had not been hospitalized in 5 years, 50.0 % (86/172) had been hospitalized for more than 10 days. During the most recent flare, 49.4 % (85/172) of patients had to reschedule appointments because of IBD. Moreover, 32.0 % (55/172) of patients had to make adjustments such as working part-time or at home to avoid taking sick days; 35.5 % (61/172) of patients felt that they had lost a job because of IBD. Conclusions: Our survey results indicate that IBD patients’ lives and social activities are affected by the deterioration of QOL due to IBD and its symptoms. © 2016 The Author(s)