Effectiveness of tacrolimus concomitant with biological disease-modifying antirheumatic drugs in patients with rheumatoid arthritis.

OBJECTIVES: The study aimed to investigate the effectiveness and tolerance of biological disease-modifying antirheumatic drugs (bDMARDs) therapy administered concomitantly with tacrolimus (TAC) treatment in patients with rheumatoid arthritis. METHODS: 2792 patients who underwent therapy with five bDMARDs (etanercept: ETN, adalimumab, golimumab, tocilizumab, and abatacept: ABT) were enrolled. Among the study subjects, 1582 were concomitant methotrexate (MTX group), 147 were concomitant TAC (TAC group), and 1063 were non-concomitant MTX and TAC (non-MTX/TAC group). The primary outcome was the incident rate of discontinuation of bDMARDs by adverse events (AEs) or loss of efficacy. RESULTS: Concerning the analysis for each reasons of discontinuation, including AEs and loss of efficacy, the hazards ratio (HR) was significantly lower in the TAC group than in non-MTX/TAC groups (AEs: HR = 0.39, 95% confidence interval, 0.23-0.68, loss of efficacy: HR = 0.49, 95% confidence interval, 0.30-0.78). The loss of efficacy with the use of ETN and ABT was lower in the TAC group than in non-MTX/TAC groups. Concomitant TAC did not induce elevated risk for discontinuation of AEs in all bDMARD analyses. CONCLUSIONS: Concomitant TAC with ABT or ETN showed higher retention rates than bDMARDs therapy without TAC or MTX. AEs did not increase over long-term observation.

Reasons and risk factors for discontinuation of treatment with any biological disease-modifying antirheumatic drugs in patients with rheumatoid arthritis: A long-term observational study.

OBJECTIVES: Patients with rheumatoid arthritis (RA) usually switch to a second biological disease-modifying antirheumatic drugs (bDMARDs) when the first has proven to be ineffective, although some may discontinue bDMARDs treatment altogether. We investigated the total rate of bDMARDs retention and the risk of bDMARDs discontinuation in patients with RA. METHODS: The study included 564 patients with RA who started bDMARDs treatment before 2008 (<65 years old, n = 413; ≥65, n = 151). The primary outcome was the incidence of bDMARDs discontinuation due to adverse events (AEs). Risk factors were examined using Fine and Gray regression models. RESULTS: Among 564 patients, 74 had discontinued bDMARDs treatment due to AEs. Male sex and Steinbrocker class 3-4 were more frequent, while rheumatoid factor and concomitant methotrexate treatment were less frequent, in those aged ≥65 years than in those aged <65 years, respectively. The subdistribution hazard ratio for discontinuation was significantly higher in the ≥65 group than in the <65 years group (hazard ratio = 3.53, 95% confidence interval = 2.07-6.03). Lack of concomitant treatment with MTX was risk factor for discontinuation in patients ≥65 years. Advanced Steinbrocker class was a risk factor in patients <65 years. CONCLUSIONS: Older patients are at higher risk of discontinuing bDMARDs treatment due to AEs than younger patients.

Evaluation of an operation support system using the femoral anterior tangent line to determine intraoperative femoral component rotation in total knee arthroplasty.

BACKGROUND: The femoral anterior tangent (FAT) line refers to a line parallel to the anterior surface of the distal femur in the axial plane. This study aimed to evaluate the effectiveness of a new operation support system which uses the FAT line to set the femoral component rotational alignment in total knee arthroplasty (TKA). METHODS: A total of 170 consecutive knees in 139 patients undergoing primary TKA with the JIGEN (Jig Engaged Three-dimensional (3D) Pre-Operative Planning Software for TKA) operation support system was examined. The JIGEN system creates 3D models of bones using computed tomography data, allowing for surgical simulations such as positioning of implants while calculating positions of the intramedullary alignment rod (IM rod) and surgical jig. We retrospectively analyzed the FAT line angle relative to the surgical epicondylar axis (SEA) on the axis plane perpendicular to the IM rod and evaluated the accuracy of the femoral component alignment after TKA with the 3D measurement system. RESULTS: The FAT line was 9.6° ± 3.7° (range, 1.4°-20.4°) internally rotated relative to the SEA. The average absolute error was 1.4° ± 1.1° in the coronal plane, 2.0° ± 1.5° in the sagittal plane, and 1.6° ± 1.3° in the axial plane. The femoral component outliers (i.e., >3° away from the goal alignment) were 7.7% in the coronal plane, 20.6% in the sagittal plane, and 10.3% in the axial plane. CONCLUSIONS: Our findings suggest that the FAT line is a reliable and reproducibly identifiable axis for the accurate determination of proper rotational alignment in TKA. An operation support system which uses the FAT line for determining intraoperative femoral component rotation can effectively achieve highly accurate positioning of the femoral component in TKA.

Efficacy of add-on iguratimod in patients with rheumatoid arthritis who inadequately respond to either tocilizumab or tumor necrosis factor alpha inhibitors.

OBJECTIVES: This study aimed to evaluate the efficacy of add-on iguratimod (IGU) in patients with rheumatoid arthritis (RA patients) who inadequately respond to either tocilizumab (TCZ) or tumor necrosis factor alpha inhibitors (TNFi). METHODS: Twenty-three RA patients treated with TCZ (the TCZ group) and 23 RA patients treated with TNFi (the TNFi group) were enrolled in this 24-week retrospective study from our multicenter registry. All inadequate responders to either TCZ or TNFi received add-on IGU. Baseline demographics and disease activity at 24 weeks after initiating add-on IGU were compared between the two groups. RESULTS: Baseline clinical disease activity index (CDAI) values in the TCZ group and TNFi group were 14.1 and 11.8 (p = .24 between the two groups). At 24 weeks, CDAI values in the TCZ group and TNFi group were 5.1 and 7.5 (p = .002 and .002 compared to baseline, respectively) and ΔCDAI values were -9.0 and -4.3 (p = .007 between the two groups). Multiple linear regression analysis revealed that add-on IGU in the TCZ group was associated with greater improvement in CDAI relative to the TNFi group. CONCLUSION: Add-on IGU was more effective in inadequate responders to TCZ than in inadequate responders to TNFi.

Discontinuation of concomitant methotrexate in Japanese patients with rheumatoid arthritis treated with tocilizumab: An interventional study.

Objectives: To evaluate the efficacy and safety of methotrexate (MTX) discontinuation in Japanese rheumatoid arthritis (RA) patients with sustained low disease activity undergoing combination therapy with tocilizumab (TCZ) plus MTX.Methods: This multicenter, open-label, uncontrolled, prospective study included RA patients maintaining low disease activity (Clinical Disease Activity Index (CDAI) ≤10) for ≥12 weeks with TCZ plus MTX. Methotrexate was discontinued following 12 weeks of biweekly administration while continuing TCZ therapy. The primary endpoint was the proportion of patients maintaining low disease activity with no flare at week 36.Results: A total of 49 patients completed 36 weeks of therapy. The proportion of patients maintaining low disease activity at week 36 was 75.5%. The lower limit of the 95% confidence interval exceeded the assumed threshold response rate of 60%, demonstrating the clinical feasibility of MTX discontinuation. The prevalence of gastroesophageal reflux disease, defined as a Frequency Scale for Symptoms of Gastroesophageal reflux disease score ≥8, significantly decreased from week 0 to 12 (27.1-18.4%; p= .025).Conclusion: Discontinuation of concomitant MTX is clinically feasible for maintaining low disease activity, and may be beneficial from the perspective of reducing gastrointestinal symptoms in Japanese RA patients treated with TCZ. Trial registration number: UMIN000021247.

Hospital Anxiety and Depression Scale Score Is an Independent Factor Associated With the EuroQoL 5-Dimensional Descriptive System in Patients With Rheumatoid Arthritis.

OBJECTIVE: This study aimed to examine anxiety and depression experienced by patients with rheumatoid arthritis (RA) using EuroQoL 5-Dimensional Descriptive System (EQ-5D) and Hospital Anxiety and Depression Scale (HADS) scores. METHODS: We analyzed 1005 Japanese patients with RA. Stepwise multiple linear regression analysis was performed to evaluate the independent influence of variables on EQ-5D and HADS scores. Pearson correlation coefficients were also calculated to explore relationships between variables. RESULTS: The mean EQ-5D score was 0.74 for all patients (mean age, 63.2 years; mean disease duration, 13.6 years; mean Health Assessment Questionnaire Disability Index [HAQ-DI], 0.78; mean HADS total [HADS-T] score, 10.3; mean disease activity score assessed by 28 joints based on CRP [DAS28-CRP], 2.8). The EQ-5D score was strongly correlated with HAQ-DI and was moderately correlated with age, Steinbrocker functional class, HADS-T score, tender joint count assessed by 28 joints, pain on a visual analog scale (pain-VAS), patient's global assessment of disease activity (general-VAS), and DAS28-CRP. The HADS-T score was moderately correlated with HAQ-DI, pain-VAS, general-VAS, and DAS28-CRP. Factors that influenced the EQ-5D score included HAQ-DI (ß = -0.533), pain-VAS (ß = -0.128), HADS-T score (ß = -0.142), DAS28-CRP (ß = -0.187), and prednisolone use (ß = -0.056). Factors that influenced the HADS score included HAQ-DI (ß = 0.348), general-VAS (ß = 0.145), disease duration (ß = 0.094), and worklessness (ß = 0.083). CONCLUSIONS: The HADS score is an independent factor associated with EQ-5D in patients with RA. Our findings suggest that the assessment of anxiety and depression is essential in achieving better quality of life for patients with RA.

Steroid therapy and renal dysfunction are independently associated with serum levels of matrix metalloproteinase-3 in patients with rheumatoid arthritis.

OBJECTIVE: This study aimed to evaluate whether the level of serum matrix metalloproteinase-3 (MMP-3), a marker of synovium inflammation, is affected by clinical characteristics of patients in rheumatoid arthritis (RA) patients. METHODS: We analyzed data from 1087 female patients with RA. Pearson's correlation coefficients were calculated to explore associations between variables. Stepwise multiple linear regression analysis was performed to evaluate patient background variables that could potentially affect serum MMP-3 levels. RESULTS: Serum MMP-3 was moderately correlated with C-reactive protein (CRP) (r: 0.478). Factors that independently influenced serum MMP-3 levels were CRP (ß: 0.450), prednisolone (PSL) use (ß: 0.100), estimated glomerular filtration rate (eGFR) (ß: -0.085), swollen joint count assessed on 28 joints (ß: 0.072), and body mass index (ß: -0.061) in female patients with RA. In RA patients with PSL use, factors that independently influenced serum MMP-3 levels were CRP (ß: 0.480), eGFR (ß: -0.175), and PSL dose (ß: 0.171). CONCLUSIONS: Our findings suggest that steroid therapy and renal dysfunction affect serum MMP-3 levels in patients with RA.

High rate of improvement in serum matrix metalloproteinase-3 levels at 4 weeks predicts remission at 52 weeks in RA patients treated with adalimumab.

OBJECTIVE: This study aimed to determine whether serum matrix metalloproteinase-3 (MMP-3) levels can predict remission in rheumatoid arthritis (RA) patients treated with adalimumab (ADA). METHODS: Subjects were 114 RA patients continuously treated with ADA for 52 weeks. Predictive factors at baseline and 4 weeks after initiation of ADA therapy for the achievement of remission (28-point count Disease Activity Score-CRP (DAS28-CRP) < 2.3) at 52 weeks were evaluated by multivariate logistic regression analysis. RESULTS: DAS28-CRP at 4 weeks (odds ratio (OR) 0.614, 95% confidence interval (CI) 0.382-0.988) and improvement in serum MMP-3 levels at 4 weeks (OR 1.057, 95% CI 1.002-1.032) were independent predictors of remission at 52 weeks. The best cut-off level of DAS28-CRP and improvement in serum MMP-3 levels at 4 weeks for predicting remission at 52 weeks was 3.73 (sensitivity: 90%, specificity: 50%, area under the receiver operating characteristic curve (AUC): 62%) and 39.93% (sensitivity: 47%, specificity: 83%, AUC: 64%), respectively. CONCLUSION: Our findings suggest that a high rate of improvement in serum MMP-3 levels at 4 weeks after initiation of ADA therapy can predict remission at 52 weeks in RA patients.

[Development of the Japanese version of the Thought Control Ability Questionnaire and evaluation of its reliability and validity].

Intrusive thoughts and difficulty in controlling thoughts are common, not only for people with psychological disorders, but also for healthy people. Individual differences in thought control ability may underlie such problems. The Thought Control Ability Questionnaire (TCAQ), which consists of 25 items, was developed by Luciano et al. (2005) in order to measure individual differences in the perceived ability to control unwanted intrusive thoughts. The purpose of the present study was to develop the Japanese version of the TCAQ and evaluate its reliability and validity. We translated the English version of the TCAQ into Japanese. We also conducted confirmatory factor analysis with a one factor solution, similar to the previous study. Based on the analysis, we excluded items whose factor loadings were lower than .30, resulting in 22 items for the Japanese version of the TCAQ. The model exhibited acceptable goodness-of-fit. The Japanese version of the TCAQ also demonstrated good reliability as well as evidence of construct validity. Thus, the development of the Japanese version of the TCAQ was successful.

PROSPECTIVE ASSOCIATIONS OF DEPRESSIVE RUMINATION AND SOCIAL PROBLEM SOLVING WITH DEPRESSION: A 6-MONTH LONGITUDINAL STUDY(.).

The main purpose of this study was to examine whether depressive rumination and social problem solving are prospectively associated with depressive symptoms. Nonclinical university students (N = 161, 64 men, 97 women; M age = 19.7 yr., SD = 3.6, range = 18-61) recruited from three universities in Japan completed the Beck Depression Inventory-Second Edition (BDI-II), the Ruminative Responses Scale, Social Problem-Solving Inventory-Revised Short Version (SPSI-R:S), and the Means-Ends Problem-Solving Procedure at baseline, and the BDI-II again at 6 mo. later. A stepwise multiple regression analysis with the BDI-II and all subscales of the rumination and social problem solving measures as independent variables indicated that only the BDI-II scores and the Impulsivity/carelessness style subscale of the SPSI-R:S at Time 1 were significantly associated with BDI-II scores at Time 2 (ß = 0.73, 0.12, respectively; independent variables accounted for 58.8% of the variance). These findings suggest that in Japan an impulsive and careless problem-solving style was prospectively associated with depressive symptomatology 6 mo. later, as contrasted with previous findings of a cycle of rumination and avoidance problem-solving style.

[A negative meta-cognitive belief about thought suppression induces intrusive thoughts].

The purpose of the present study was to investigate the causal relationship between meta-cognitive beliefs about thought suppression and intrusive thoughts. We conducted structural equation modeling using a cross-lagged effect model and a synchronous effect model. Results revealed that the Paradoxical Effect subscale score synchronously increased the frequency of intrusive thoughts. On the other hand, the frequency of intrusive thoughts did not affect the degree of confidence in meta-cognitive beliefs. These results demonstrate a causal relationship between meta-cognitive beliefs about thought suppression and intrusive thoughts. The cognitive processes underlying this causal relationship and future directions of research about thought suppression are discussed.

[Remembering past events activates temporal concepts of future].

The cognitive function to project oneself into the specific past or future is labeled mental time travel (MTT). MTT to the past is considered "episodic memory" and the future is termed "episodic future thinking". Remembering the past and imaging the future during MTT both draw on information stored in episodic memory: a process that enables integration of episodic information into a coherent event representation. Recent studies suggested that episodic information in past/future event representations varies with temporal distance from the present to the event. However, it is unclear whether the influence on temporal distance is actually caused by the function of episodic memory retrieval. The present study investigated the relationship between episodic memory and temporal concepts with a lexical decision task. The results indicate that remembering the past activated temporal concepts of the near future more than that of the far future. This finding suggests that the rich information derived from episodic memory modulates the subjective sense of time in episodic future thinking.

[The effect of self-reflection on depression mediated by hardiness].

Previous studies have shown that two types of private self-consciousness result in opposing effects on depression; one of which is self-rumination, which leads to maladaptive effect, and the other is self-reflection, which leads to an adaptive effect. Although a number of studies have examined the mechanism of the maladaptive effect of self-rumination, only a few studies have examined the mechanism of the adaptive effect of self-reflection. The present study examined the process of how self-reflection affected depression adaptively, Based on the previous findings, we proposed a hypothetical model assuming that hardiness acts as a mediator of self-reflection. To test the validity of the model, structural equation modeling analysis was performed with the cross-sectional data of 155 undergraduate students. The results. suggest that the hypothetical model is valid. According to the present results and previous findings, it is suggested that self-reflection is associated with low levels of depression and mediated by "rich commitment", one component of hardiness.

Depressive rumination and past depression in Japanese university students: comparison of brooding and reflection.

The Ruminative Responses Scale, a measure of depressive rumination, contains two subscales: Brooding and Reflection. Treynor, Gonzalez, and Nolen-Hoeksema (2003) proposed that Brooding is maladaptive and Reflection is adaptive. This article examined the relationships among Brooding, Reflection, and previous depression in two samples of Japanese undergraduates, who were non-depressed at the time of their participation. Based on answers to a self-report measure, participants were divided into a formerly depressed group, who had experienced an episode that met the criteria for major depression, and a never-depressed group. Logistic regression analyses were conducted with Brooding, Reflection, and current depression as the independent variables and past depression as the dependent variable. Brooding had consistent positive associations with past depression. The relationship between Reflection and past depression was not significant for one sample, but was statistically significant and positive in the second sample. In the second sample, Brooding and Reflection both were related with past depression after controlling for worry.

[Meta-cognitive beliefs about thought suppression and associated paradoxical effects].

The purpose of this study was to clarify the contents of meta-cognitive beliefs about thought suppression and to investigate the relationship between these beliefs and the paradoxical effects of thought suppression. In Study 1, we developed a scale measuring the endorsement of meta-cognitive beliefs about thought suppression. This measure, the Meta-cognitive Beliefs about Thought Suppression Questionnaire (BTQ, has four subscales: Distraction, Paradoxical Effect, Regret, and Promotion of Concentration. In Study 2 and Study 3, the BTQ showed sufficient criterion-related validity and test-retest reliability. In Study 4, we conducted an experiment to investigate the relationship between meta-cognitive beliefs about thought suppression and its paradoxical eftects. Results showed that the Paradoxical Effect subscale score significantly predicted the number of intrusive thoughts during thought suppression. The development process of meta-cognitive beliefs about thought suppression and implications for research about cognitive control are discussed.

Twenty-four-week clinical results of adalimumab therapy in Japanese patients with rheumatoid arthritis: retrospective analysis for the best use of adalimumab in daily practice.

OBJECTIVE: We evaluated patient drug adherence to and efficacy and safety of adalimumab (ADA) based on data collected from approximately 200 patients to retrospectively examine the best use of ADA in Japanese patients with longstanding rheumatoid arthritis (RA) managed in daily practice. METHODS: For explorative comparisons, patients were stratified by prior use or no use of biologics (Bio-naïve vs. Bio-switch) and concomitant use (+) or no use (-) of methotrexate (MTX) into four subgroups. The primary efficacy endpoint was extent of improvement in the Disease Activity Score in 28 joints using erythrocyte sedimentation rate (DAS28-ESR) from baseline to 24 weeks assessed as European League Against Rheumatism (EULAR) good response. Secondary endpoints included ADA treatment continuation as represented by Kaplan-Meier survival curves and percentages of patients achieving remission as defined by DAS28-ESR <2.6. RESULTS: Overall, mean DAS28-ESR significantly decreased from 5.6 ± 1.2 at baseline to 4.1 ± 1.7 at week 24 (p < 0.0001), and >30 % of patients achieved EULAR good response. Subgroup analyses indicated that patients in the Bio-naïve and MTX (+) subgroup showed the highest EULAR good response rate of 37.3 % at week 24. The three most commonly reported adverse events (AEs) were skin allergies such as injection-site reactions, infections, and respiratory disorders such as interstitial lung lesions and organizing pneumonia. CONCLUSION: In conclusion, ADA therapy resulted in significant clinical response in established Japanese patients with RA treated in daily practice. It also demonstrated generally good safety and tolerability. It was suggested that the best use of ADA may be in biologically naïve patients with concomitant administration of MTX.

Clinical efficacy of abatacept in Japanese rheumatoid arthritis patients.

OBJECTIVES: The purpose of this study was to examine the treatment retention and efficacy of abatacept, the first member of a new class of biologic agents, in Japanese rheumatoid arthritis (RA) patients during clinical practice. METHODS: A retrospective multicenter study was conducted with patients who underwent abatacept therapy for 24 weeks (n = 143). RESULTS: Patients at baseline had a mean age of 63.5 years, a mean disease duration of 11.3 years, and a mean disease activity score in 28 joints (DAS28) of 4.5. Overall retention of abatacept treatment was 83.2 % at 24 weeks, when 46.2 % of patients achieved DAS28-defined low disease activity (LDA; DAS28 <3.2) and 26.6 % achieved DAS28-defined remission (DAS28 <2.6). LDA was achieved in a significantly higher proportion of patients without prior biologics therapy compared to those with prior biologics (60.9 vs. 34.2 %, p = 0.001). There was no significant difference between patients with or without concomitant methotrexate (MTX) therapy (45.2 vs. 47.5 %). CONCLUSIONS: Abatacept therapy appears to be highly effective and well tolerated during clinical treatment of RA. Abatacept was particularly effective in patients with no history of biologics use, and did not appear to be dependent on concomitant MTX therapy.

Monitoring C-reactive protein levels to predict favourable clinical outcomes from tocilizumab treatment in patients with rheumatoid arthritis.

OBJECTIVES: The inflammatory cytokine interleukin-6 (IL-6) directly stimulates C-reactive protein (CRP) expression. The present study aimed to examine how clinical treatment outcomes of rheumatoid arthritis (RA) with tocilizumab (TCZ), a humanised monoclonal anti-IL-6 receptor antibody, are related to CRP levels monitored for 52 weeks. METHODS: One hundred and twenty-two RA patients who underwent TCZ treatment between May 2008 and September 2009 were registered in the Tsurumai Biologics Communication Registry. Data were collected at initiation of treatment (baseline) and over 52 weeks for Disease Activity Score 28-ESR (DAS28-ESR), Boolean core measurements, serum CRP levels and matrix metalloproteinase-3 levels. To compare clinical results, patients were divided into three groups based on treatment time required to achieve normal CRP levels. RESULTS: Multivariate analysis using the Cox proportional-hazards regression model found that higher CRP levels at baseline was a significant and independent factor in predicting normal CRP levels over 52 weeks (hazard ratio 0.86 per 1 mg/dL). In contrast, disease duration, concomitant methotrexate use and previous tumour necrosis factor inhibitor failure were not significant factors. Patients with normal CRP levels at 12 weeks of TCZ treatment achieved better clinical outcomes, including remission based on DAS28-ESR criteria, compared to patients with elevated CRP levels at 12 weeks. CONCLUSIONS: Adequate suppression of pathological IL-6 signalling during TCZ treatment improves clinical outcomes and can be monitored with serum CRP levels, a readily available biomarker in clinical practice.

Longitudinal predictions of the Brooding and Reflection subscales of the Japanese Ruminative Responses Scale for depression.

The Ruminative Responses Scale (RRS) is a measure of depressive rumination which has two subscales: Brooding and Reflection. This article examines the longitudinal predictions for depression and the test-retest reliability of the Brooding and Reflection of the Japanese RRS. Japanese university students (N = 378) completed the RRS, the Center for Epidemiologic Studies Depression Scale (CES-D), and the Inventory to Diagnose Depression, Lifetime Version (IDDL) which was modified to assess symptoms experienced in the 8-wk. follow-up period. The standardized betas of the initial Brooding and Reflection subscales for the IDDL scores were significant and positive after controlling for baseline CES-D scores, but those for the CES-D scores at Time 2 were not significant. Longitudinal predictions of Brooding were partially consistent with those of other language versions (significant in almost all studies); however, longitudinal predictions of Reflection were not consistent with those of other language versions (negative in previous studies). The test-retest correlations of both subscales were similar to those obtained in Western countries.