Long-Term Maintenance of Golimumab Effectiveness for Injection Spacing in Rheumatoid Arthritis Patients with Low Disease Activity Who Previously Received Other TNF Inhibitors: Minimum 2-year Data From an Observational Study.

BACKGROUND: Golimumab (GLM) has been reported to have lower immunogenicity than do other TNF inhibitors used for treating rheumatoid arthritis (RA). We previously found a prolonged effect of and improvement similar to that associated with infliximab (IFX) after switching to subcutaneous GLM (GLM-SC) for control of RA activity or adverse events. Thus, this study aimed to evaluate the continued maintenance of treatment efficacy and safety for > 2 years by switching to GLM-SC in RA patients with low disease activity or in remission after previous treatment with another tumor necrosis factor (TNF) inhibitor. METHODS: Thirty-two patients treated with etanercept or infliximab were switched to GLM-SC and maintained low disease activity. The patients were divided into two groups (GLMq4w and GLMq8w) through discussion with each patient, considering their general condition and convenience. The groups included patients with low disease activity or in remission who switched to 50-mg GLM therapy at 4-week and 8-week intervals, respectively. RESULTS: The mean DAS28-ESR and DAS-CRP values in the GLMq4w group (17 patients) and GLMq8w group (15 patients) were maintained from baseline throughout the 104-week treatment period. Two patients from the GLMq4w group showed disease flaring to moderate disease activity. No serious adverse events occurred, and the treatment continuation rate at 104 weeks was 100% in both groups. After > 2 years of treatment, three patients in the GLMq8w group and one patient in the GLMq4w group discontinued GLM treatment due to relapse or complications. The 5-year survival rates were 88.2% and 75.5% in the GLMq4w and GLMq8w groups, respectively. The average treatment duration was 5.0 (2.0-7.5) years. CONCLUSION: Administration of GLM-SC at 4-week and 8-week intervals after switching from TNF inhibitors showed sustained long-term efficacy and acceptable safety in RA patients with low disease activity.

Music Intervention Reduces Persistent Fibromyalgia Pain and Alters Functional Connectivity Between the Insula and Default Mode Network.

OBJECTIVE: The aims of the present study were to examine the effects of short-term music interventions among patients with fibromyalgia (FM) and to clarify the alterations in functional connectivity and persistent pain. DESIGN: Pilot study. SETTING: All participants were evaluated at Juntendo University from November 2017 to January 2019. SUBJECTS: We enrolled female patients who had been clinically diagnosed with FM (N = 23). METHODS: All participants listened to Mozart's Duo for Violin and Viola No. 1, K. 423, in a quiet room for 17 minutes. We compared the degree of pain using resting-state functional magnetic resonance imaging and the numeric rating scale before and after listening to music. RESULTS: Pain scores were significantly reduced after listening to music. Further, we observed there was a significant difference in connectivity between the right insular cortex (IC) and posterior cingulate cortex (PCC)/precuneus (PCu) before and after listening to music. We also found that the difference between the right IC-PCu connectivity and the difference in pain scores were significantly correlated. CONCLUSIONS: We found that a short period of music intervention reduced chronic pain and altered functional IC-default mode network connectivity. Furthermore, music potentially normalized the neural network via IC-default mode network connectivity, yielding temporary pain relief in patients with FM. Further longitudinal studies with larger sample sizes are required to confirm these results.

A study of brain metabolism in fibromyalgia by positron emission tomography.

PURPOSE: The aim of the present study was to determine the brain regions with altered metabolism in patients with treatment-naïve fibromyalgia (FM). METHODS: We used [18F] fluoro-d-glucose positron emission tomography to examine a total of 18 treatment-naïve FM patients and 18 age- and sex-matched healthy controls not suffering from pain. A voxel-by-voxel group analysis was performed using statistical parametric mapping. RESULTS: No significant voxel (peak)-level results were detected in this study; however, some regions were detected as significant-size clusters. There were no significant differences in brain metabolism between FM patients and controls. However, the right thalamus and left lentiform nucleus were hypermetabolic areas in FM patients with poor prognosis compared to the healthy controls. In contrast, the left insula and left lentiform nucleus were hypometabolic areas in FM patients with good prognosis compared to the healthy controls. Compared to FM patients with good prognosis, FM patients with poor prognosis showed significant hypermetabolism in the left thalamus, bilateral lentiform nucleus, and right parahippocampal gyrus. CONCLUSION: The present findings suggest an association between the metabolism in the thalamus, lentiform nucleus, and parahippocampal gyrus and prognosis in FM patients. Further study with a larger number of patients is required to confirm this association.

Maintenance of efficacy and safety with subcutaneous golimumab in rheumatoid arthritis patients with low disease activity who previously received TNF inhibitors.

The study was conducted to evaluate continued maintenance of the efficacy and safety of therapy by switching to subcutaneous golimumab (GLM-SC) in rheumatoid arthritis patients with low disease activity or remission who previously received a tumor necrosis factor (TNF) inhibitor. Thirty patients who had been treated with etanercept or infliximab were switched to GLM-SC in maintaining disease activity at a low level. The patients were divided into two groups through discussion with each patient, considering general condition and convenience: the low disease activity (LDA) group and the LDAq8w group, which included patients with low disease activity or remission who switched to 50 mg GLM therapy at 4- and 8-week intervals, respectively. The effects of the TNF inhibitors to GLM-SC switch were evaluated at 12, 24, and 52 weeks after switching. The mean DAS28-ESR and DAS-CRP values in the LDA groups (16 patients) and LDAq8w groups (14 patients) were maintained from baseline throughout the 52-week treatment period. DAS28-ESR remission (93.8 and 92.3%) rates were also maintained through week 52 from the baseline remission rate (75.0 and 78.6%) in the LDA and LDAq8w groups, respectively. Thus, both GLM-SC treatment regimens were effective in maintaining the clinical response achieved with LDA secondary to TNF inhibitors. No serious adverse events occurred, and the continuation rate at 52 weeks was 100% in both groups. Therapeutic efficacy is adequately maintained in most patients switching from TNF inhibitor to GLM-SC (50 mg/4-8 weeks). Patients receiving TNF inhibitor can seamlessly switch to GLM-SC without serious safety concerns.

High prevalence of anti-TSH receptor antibody in fibromyalgia syndrome.

AIM: Fibromyalgia syndrome (FMS) is defined as chronic widespread pain that cannot be accounted for by any other medical disorder. Our aim was to explore the prevalence of thyroid autoimmunity in patients with FMS. METHODS: For determining thyroid function in 207 FMS patients, we tested for the titers of free tri-iodothyronine, free thyroxine, thyroid-stimulating hormone (TSH), anti-thyroid peroxidase antibody (TPOAb), anti-thyroglobulin antibody (TgAb) and anti-TSH receptor antibody (TRAb). RESULTS: Twenty-five patients who had either subclinical hyper- or hypothyroidism, or overt hypothyroidism were excluded. Sixty-nine FMS patients with autoimmune thyroid diseases (AITD) (37.9%, 69/182) were identified. The prevalence of positivity for TRAb, TgAb and TPOAb was 20.3% (n = 37), 16.5% (n = 30) and 13.2% (n = 24), respectively. Compared to control populations in previous studies, the prevalence of TRAb positivity was high, and titers of TRAb were low (1.0-1.5 IU/L). The prevalence of TPOAb and TgAb positivity was not significantly higher than that reported in FMS patients in previous studies. Clinical symptom profiles were identical for FMS patients with and without AITD. CONCLUSION: We found a high prevalence of AITD among 207 patients with clinically defined FMS, with TRAb being especially prominent among these patients. Further study is needed to evaluate changes in thyroid function among FMS patients with AITD.

An open-label, long-term, phase III extension trial of duloxetine in Japanese patients with fibromyalgia.

OBJECTIVES: We aimed to evaluate the long-term safety and efficacy of duloxetine 60 mg in Japanese patients with fibromyalgia enrolled from a preceding randomized, placebo-controlled, phase III duloxetine trial. METHODS: This was a long-term, open-label extension study. Patients received oral duloxetine once daily at a dose of 20 mg for 1 week, followed by 40 mg for 1 week, and then 60 mg for 48 weeks. The primary outcome was the frequency of adverse events (AEs) and adverse drug reactions (ADRs) of duloxetine. Efficacy and health outcomes were assessed. RESULTS: In total, 149 patients were enrolled from the preceding study. The median length of treatment was 364.0 days. The incidence of AEs and ADRs was 92.6 and 63.8%, respectively. ADRs occurring at an incidence of ≥5% were somnolence, constipation, nausea, weight increase, thirst, and malaise. The proportion of patients with mild, moderate, and severe AEs was 80.5, 10.1, and 2.0%. There were no serious treatment-related AEs in this study. The Brief Pain Inventory average pain score improved at all time-points compared with baseline (mean change ± standard deviation at Week 50 was -1.31 ± 1.70). CONCLUSIONS: Duloxetine was safe and effective in the long-term treatment of Japanese patients with fibromyalgia.

Murine hypothalamic destruction with vascular cell apoptosis subsequent to combined administration of human papilloma virus vaccine and pertussis toxin.

Vaccination is the most powerful way to prevent human beings from contracting infectious diseases including viruses. In the case of the human papillomavirus (HPV) vaccine, an unexpectedly novel disease entity, HPV vaccination associated neuro-immunopathetic syndrome (HANS), has been reported and remains to be carefully verified. To elucidate the mechanism of HANS, we applied a strategy similar to the active experimental autoimmune encephalitis (EAE) model - one of the most popular animal models used to induce maximum immunological change in the central nervous system. Surprisingly, mice vaccinated with pertussis toxin showed neurological phenotypes that include low responsiveness of the tail reflex and locomotive mobility. Pathological analyses revealed the damage to the hypothalamus and circumventricular regions around the third ventricle, and these regions contained apoptotic vascular endothelial cells. These data suggested that HPV-vaccinated donners that are susceptible to the HPV vaccine might develop HANS under certain environmental factors. These results will give us the new insight into the murine pathological model of HANS and help us to find a way to treat of patients suffering from HANS.

Mitochondrial ubiquitin ligase activator of NF-κB regulates NF-κB signaling in cells subjected to ER stress.

The nuclear factor-κB (NF-κB) transcription factor family members control various biological processes, such as apoptosis and proliferation. The endoplasmic reticulum (ER) has emerged as a major site of cellular homeostasis regulation. The accumulation of misfolded protein in the ER causes stress and ER stress-induced NF-κB activation to protect cells from apoptosis. In this study, we found a putative ER stress-response element (ERSE) on the promoter of mitochondrial ubiquitin ligase activator of NF-κB (MULAN), and that MULAN expression was upregulated by ER stress. MULAN specifically activated NF-κB dependent gene expression in an E3 ligase activity-dependent manner. The ectopic expression of MULAN induced the nuclear translocation of endogenous p65 and the degradation of IκB. Binding assay revealed that MULAN was associated with transforming growth factor ß-activated kinase (TAK1). The knockdown of MULAN using siRNA inhibited the activation of NF-κB in the cells subjected to ER stress. The findings of our study indicate that MULAN is an E3 ligase that regulates NF-κB activation to protect cells from ER stress-induced apoptosis.

Fibromyalgia syndrome and cognitive dysfunction in elderly: a case series.

AIM: Fibromyalgia syndrome (FMS) is an extremely rare complication of neurocognitive disorders (NCDs). We experienced seven such cases, and we discuss their clinical manifestation and pathomechanisms. METHODS: Seven patients with FMS as a complication of NCD were enrolled. We used the patients' medical records to identify clinical manifestations and obtain experimental data, such as pain questionnaire scores, cognitive tests, genetics and radiological imaging of the brain. RESULTS: The seven patients were clinically diagnosed with frontotemporal NCD (n = 3) or Alzheimer's disease (n = 4). No patient presented with any organic disorder that would explain their chronic pain. Through their courses, they experienced refractory widespread pain continuously despite analgesics. Brain magnetic resonance imaging revealed moderate or severe atrophic changes in the temporal lobes and hippocampus. Three-dimensional stereotactic surface projection (3D-SSP) analysis of brain single photon emission computed tomography (SPECT), indicated severe hypoperfusion on the right side of the medial temporal lobe, both sides of the anterior corpus callosum, anterior cingulate gyrus, and primary sensory area. Genetic analysis uncovered no pathogenic mutations. CONCLUSIONS: Neurodegenerative disorders are rarely complicated by FMS, which is associated with relatively severe pain. Central sensitization may be a possible risk factor of widespread pain in elderly patients with NCD.

A randomized, double-blind, placebo-controlled phase III trial of duloxetine in Japanese fibromyalgia patients.

INTRODUCTION: Fibromyalgia is characterized by widespread pain and is often accompanied by accessory symptoms. There are limited treatment options for this condition in Japan. Therefore, we conducted a phase III study to assess the efficacy and safety of duloxetine in Japanese patients with fibromyalgia. METHODS: This randomized, double-blind, placebo-controlled, parallel-group trial was conducted in Japan. Outpatients who met the American College of Rheumatology 1990 criteria for fibromyalgia and whose Brief Pain Inventory (BPI) average pain score was ≥4 were randomized to duloxetine 60 mg or placebo once daily for 14 weeks. The primary efficacy measure was the change in the BPI average pain score from baseline. Secondary efficacy, quality of life (QoL), and safety outcomes were also evaluated. Mixed-effects model repeated-measures (MMRM) analysis and last observation carried forward (LOCF) analysis of covariance were used to evaluate the primary efficacy measure. RESULTS: Overall, 393 patients were randomized to receive either duloxetine (n = 196) or placebo (n = 197). The MMRM analysis revealed no significant difference between duloxetine and placebo regarding the change in BPI average pain scores at week 14. Based on LOCF analysis, a statistically significant improvement in the change in BPI average pain scores at week 14 was observed for patients treated with duloxetine compared with placebo. Duloxetine treatment was associated with improved outcomes in nearly all secondary and post hoc analyses. The treatment was generally well tolerated. Somnolence, nausea, and constipation were the most common treatment-emergent adverse events in the duloxetine group. The discontinuation rates due to treatment-emergent adverse events were similar in both groups. CONCLUSIONS: Although the MMRM analysis did not demonstrate superiority of duloxetine over placebo, duloxetine treatment was associated with improved outcomes in secondary and post hoc analyses of the mean change in the BPI average pain score and most of the secondary outcomes, including analgesia and QoL. Duloxetine treatment was safe and well tolerated. These results suggest that duloxetine treatment could be associated with improvements in pain relief and QoL in Japanese patients with fibromyalgia. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01552057 . Registered 9 March 2012.

HTLV-1 induces a Th1-like state in CD4+CCR4+ T cells.

Human T-lymphotropic virus type 1 (HTLV-1) is linked to multiple diseases, including the neuroinflammatory disease HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and adult T cell leukemia/lymphoma. Evidence suggests that HTLV-1, via the viral protein Tax, exploits CD4+ T cell plasticity and induces transcriptional changes in infected T cells that cause suppressive CD4+CD25+CCR4+ Tregs to lose expression of the transcription factor FOXP3 and produce IFN-γ, thus promoting inflammation. We hypothesized that transformation of HTLV-1-infected CCR4+ T cells into Th1-like cells plays a key role in the pathogenesis of HAM/TSP. Here, using patient cells and cell lines, we demonstrated that Tax, in cooperation with specificity protein 1 (Sp1), boosts expression of the Th1 master regulator T box transcription factor (T-bet) and consequently promotes production of IFN-γ. Evaluation of CSF and spinal cord lesions of HAM/TSP patients revealed the presence of abundant CD4+CCR4+ T cells that coexpressed the Th1 marker CXCR3 and produced T-bet and IFN-γ. Finally, treatment of isolated PBMCs and CNS cells from HAM/TSP patients with an antibody that targets CCR4+ T cells and induces cytotoxicity in these cells reduced both viral load and IFN-γ production, which suggests that targeting CCR4+ T cells may be a viable treatment option for HAM/TSP.

An epidemiologic internet survey of fibromyalgia and chronic pain in Japan.

OBJECTIVE: To determine the epidemiologic features and symptom characteristics of fibromyalgia (FM) in Japan, and compare them with those for other chronic pain (CP) diagnoses. METHODS: An internet survey was conducted in June and July 2011. The questionnaire consisted of 111 questions, including assessments of the Japanese version of the 2010 American College of Rheumatology preliminary diagnostic criteria for FM, the Japanese Fibromyalgia Impact Questionnaire, and additional questions regarding pain and lifestyle. RESULTS: The questionnaire was completed by 20,407 male and female respondents in all prefectures of Japan. Of the survey population, 2,524 respondents (12.4%) reported symptoms consistent with CP; of these, 425 (2.1%) reported symptoms consistent with FM. Among respondents with FM and CP, 61% and 53%, respectively, were women. Pain severity and Widespread Pain Index scores were significantly higher in respondents meeting the diagnostic criteria for FM than in those meeting the criteria for CP. In terms of symptom severity scores, the proportions of respondents reporting the 3 major symptoms as "highly applicable" and greater numbers of 41 somatic symptoms were higher among respondents with FM than among those with CP. The incidence of FM in the present survey was similar to that reported (1.7%) in a study of FM in Japan in 2003, despite the use of the newer, easier to use 2010 diagnostic criteria. CONCLUSION: Because FM usually presents with more severe and more widely distributed pain, as well as more nonpainful symptoms than CP, our results suggest that FM is a different clinical phenotype of CP.

Vulnerability to traumatic stress in fibromyalgia patients: 19 month follow-up after the great East Japan disaster.

INTRODUCTION: The aim of this study was to investigate vulnerability and long-term influence of traumatic stress caused by the Great East Japan Disaster which occurred on March 11, 2011, in patients with fibromyalgia, which is a chronic pain syndrome probably involving central sensitization. METHODS: A total of 60 female patients with fibromyalgia were compared with female patients with rheumatoid arthritis (RA, n = 23) as another chronic pain disease, and with female healthy controls (HC, n = 26) in the observational study. To evaluate responses to traumatic stress, the scores of Impact of Event Scale-Revised (IES-R) were assessed one month after the disaster and every six months until 19 months after the disaster. We also evaluated levels of depression during the study period. To know the score of IES-R of patients with fibromyalgia during usual living, we assessed IES-R in another population of fibromyalgia patients without exposure to a great disaster. RESULTS: The mean score of IES-R one month after the disaster in the fibromyalgia group (24.6 [SD 18.9]) was significantly higher than that of RA group (13.4 [SD 14.5]) or HC group (9.1 [9.2]) (F = 9.96, p < 0.0001). However, the mean score of IES-R in fibromyalgia patients without exposure to a great disaster was (20.3 [SD 18.7]), which was almost the same value as the fibromyalgia group seven months after the disaster (20.2 [SD 19.5]). Repeated measures analysis of variance showed significant effect of time course in the depression-related symptoms (F = 6.68, P = 0.001), and a post-hoc test revealed that the number of depression-related symptoms one month before the disaster was significantly different from other time points until 19 months after the disaster, respectively. CONCLUSIONS: Although response to acute stress induced by the great earthquake was likely to be settled within seven months after the disaster, depression-related symptoms have been increasing for more than one year after the disaster, despite exclusion of patients with major depression at baseline. This long-lasting worsening of depression-related symptoms may have been in response to chronic stress induced by the fear of radiation due to the nuclear power disaster. These findings suggest that patients with fibromyalgia are vulnerable to chronic stress rather than acute stress.

Positive feedback loop via astrocytes causes chronic inflammation in virus-associated myelopathy.

Human T-lymphotropic virus type 1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a rare neurodegenerative disease characterized by chronic inflammation in the spinal cord. We hypothesized that a positive feedback loop driven by chemokines may be responsible for the chronic inflammation in HAM/TSP. We aimed to determine the identity of these chemokines, where they are produced, and how they drive chronic inflammation in HAM/TSP. We found that patients with HAM/TSP have extraordinarily high levels of the chemokine CXCL10 (also known as IP-10) and an abundance of cells expressing the CXCL10-binding receptor CXCR3 in the cerebrospinal fluid. Histological analysis revealed that astrocytes are the main producers of CXCL10 in the spinal cords of patients with HAM/TSP. Co-culture of human astrocytoma cells with CD4+ T cells from patients with HAM/TSP revealed that astrocytes produce CXCL10 in response to IFN-γ secreted by CD4+ T cells. Chemotaxis assays results suggest that CXCL10 induces migration of peripheral blood mononuclear cells to the central nervous system and that anti-CXCL10 neutralizing antibody can disrupt this migration. In short, we inferred that human T-lymphotropic virus type 1-infected cells in the central nervous system produce IFN-γ that induces astrocytes to secrete CXCL10, which recruits more infected cells to the area via CXCR3, constituting a T helper type 1-centric positive feedback loop that results in chronic inflammation.

Hip score and disease activity correlation in patients with rheumatoid arthritis after total hip arthroplasty.

PURPOSE: The disease activity score including 28 joints (DAS28), the simplified disease activity index and the clinical disease activity index (CDAI) were developed in order to provide a quantifiable measure of rheumatoid arthritis (RA) activity. Although inflamed hip joints greatly impact activities of daily living (ADL) and walking ability, the hip joint was not included in the DAS28, SDAI or CDAI assessments. Although excellent clinical results have been reported for total hip arthroplasty (THA) in RA patients, correlations between disease activity and hip function in RA patients after THA remain unknown. METHODS: We analysed the effect of RA disease activity on a hip function score in an observational cohort of RA patients after THA. Twenty-five registered RA patients who had undergone THA (33 joints) were included. Hip function was recorded and RA disease activity was measured on the same day. The mean age of the patients was 65.17 years. They were followed up for a mean of 5.24 years after surgery. The mean duration of disease following RA diagnosis for this patient group was 19.47 years. The Japanese Orthopaedic Association (JOA) hip score was used as a clinical outcome measure for hip dysfunction. RA disease activity and health-related quality of life were measured using the DAS28, SDAI, CDAI and the modified health assessment questionnaire (MHAQ). RESULTS: The mean JOA score for hip function was 80.48 at the final follow-up. The mean DAS28-ESR, DAS28-CRP, SDAI, CDAI and MHAQ measuring RA disease activity levels were 3.38, 2.65, 9.59, 8.63 and 0.44, respectively, at the final follow-up. There was a significant negative correlation between the JOA hip score and all disease activity assessments observed after THA (DAS-ESR [P = 0.0067], DAS-CRP [P = 0.0008]), SDAI [P = 0.0034], CDAI [P = 0.0003]) and MHAQ [P = 0.0002]). CONCLUSION: We found significant negative correlations between JOA hip scores and all disease activity assessments in RA patients treated with THA.

The Japanese version of the modified ACR preliminary diagnostic criteria for fibromyalgia and the fibromyalgia symptom scale: reliability and validity.

PURPOSE: The aim of this study is to investigate the reliability and validity of the Japanese version of the modified American College of Rheumatology (ACR) Preliminary Diagnostic Criteria for Fibromyalgia (mACR 2010-J) and the Fibromyalgia Symptom Scale (mFS-J). METHODS: According to the ACR 1990 classification criteria, patients with chronic pain were divided into the fibromyalgia group and nonfibromyalgia group (rheumatoid arthritis and osteoarthritis). Patients in both groups were assessed using mACR 2010-J and mFS-J. RESULTS: 294 of 462 (64 %) patients in the fibromyalgia group met mACR 2010-J, whereas 4 % (9/231) of the nonfibromyalgia group did, with sensitivity of 64 %, specificity of 96 %, positive predictive value of 97 %, negative predictive value of 56 %, and positive likelihood ratio of 16.3. Mean total scores on mFS-J significantly differentiated the fibromyalgia from the nonfibromyalgia group. According to the value of the Youden index, the best cutoff score for the mFS-J was 9/10. CONCLUSION: Our findings indicate that mACR 2010-J as a positive test and mFS-J as a quantification scale might be suitable for assessing fibromyalgia among Japanese chronic pain populations.

An open-label long-term phase III extension trial to evaluate the safety and efficacy of pregabalin in Japanese patients with fibromyalgia.

OBJECTIVES: To assess the long-term safety and efficacy of pregabalin for the treatment of Japanese patients with fibromyalgia (FM). METHODS: This 53-week, open-label extension study was conducted at 20 study sites in Japan in patients with FM who had completed a preceding 16-week, placebo-controlled, double-blind trial. Patients received pregabalin, starting at 150 mg/day and increasing to a maintenance dose of 300 or 450 mg/day. The primary endpoint was safety, and secondary endpoints included measures of pain, sleep, and physical functioning. RESULTS: 106 patients entered the trial and received at least one dose of the study drug. The most common treatment-related adverse events were somnolence, dizziness, increased weight, and constipation. There were no treatment-related serious or severe adverse events. There were five (4.7%) discontinuations due to adverse events, of which three (2.8%) were considered related to the study drug. Most adverse events resolved over time and could be managed without dose reduction or treatment discontinuation. Improvements in secondary efficacy endpoints of pain, sleep, and physical functioning emerged early in the study and were maintained for the duration of treatment. CONCLUSIONS: These data indicate that the long-term treatment of Japanese FM patients with pregabalin may be both safe and effective.

Clinical outcome in patients with rheumatoid arthritis switched to tocilizumab after etanercept or infliximab failure.

The present study retrospectively assessed the efficacy of tocilizumab in patients with rheumatoid arthritis (RA) who failed to respond to treatment with etanercept or infliximab. A retrospective study of 33 RA patients who did not respond to etanercept or infliximab was conducted. Responses of subjects switching from etanercept to tocilizumab (n = 17) were compared with those switching from infliximab to tocilizumab (n = 16). Treatment with disease-modifying antirheumatic drugs before the switch, especially methotrexate (MTX), was maintained. Disease activity was assessed by the Disease Activity Score 28-C Reactive Protein (DAS28-CRP), the Simplified Disease Activity Index (SDAI), and the Clinical Disease Activity Index (CDAI). Patients who switched from etanercept were significantly less likely to have used MTX and were significantly older than patients who switched from infliximab. In both groups, there was a significant reduction from baseline in DAS28-CRP, SDAI, and CDAI values at 24 weeks with no significant differences between groups. However, at week 52, DAS28-CRP, SDAI, and CDAI values in the group switched from etanercept were significantly worse than those in the group switched from infliximab. All patients switched from infliximab were using MTX. In the evaluation between patients who switched from etanercept monotherapy, etanercept plus MTX, and infliximab plus MTX, a significant improvement from baseline was seen in DAS28-CRP, SDAI, and CDAI for all patients at 24 weeks with no significant differences between groups. Disease activity was maintained at 52 weeks in the group that switched from etanercept plus MTX and infliximab plus MTX. However, the efficacy of tocilizumab was decreased in the group that switched from etanercept monotherapy. Switching from etanercept plus MTX or from infliximab plus MTX to tocilizumab plus MTX improved response to therapy, but switching from etanercept monotherapy to tocilizumab monotherapy did not improve response to therapy.

A randomized, double-blind, multicenter, placebo-controlled phase III trial to evaluate the efficacy and safety of pregabalin in Japanese patients with fibromyalgia.

INTRODUCTION: Fibromyalgia is a chronic disorder characterized by widespread pain and tenderness. Prior trials have demonstrated the efficacy of pregabalin for the relief of fibromyalgia symptoms, and it is approved for the treatment of fibromyalgia in the United States. However, prior to this study, there has not been a large-scale efficacy trial in patients with fibromyalgia in Japan. METHODS: This randomized, double-blind, multicenter, placebo-controlled trial was conducted at 44 centers in Japan to assess the efficacy and safety of pregabalin for the symptomatic relief of pain in fibromyalgia patients. Patients aged ≥18 years who had met the criteria for fibromyalgia were randomized to receive either pregabalin, starting at 150 mg/day and increasing to a maintenance dose of 300 or 450 mg/day, or placebo, for 15 weeks. The primary efficacy endpoint was mean pain score at final assessment. Secondary endpoints included Patient Global Impression of Change (PGIC) together with measures of sleep, physical functioning and quality of life. RESULTS: A total of 498 patients (89% female) were randomized to receive either pregabalin (n = 250) or placebo (n = 248). Pregabalin significantly reduced mean pain score at final assessment (difference in mean change from baseline, compared with placebo -0.44; P = 0.0046) and at every week during the study (P <0.025). Key secondary endpoints were also significantly improved with pregabalin treatment compared with placebo, including PGIC (percentage reporting symptoms "very much improved" or "much improved", 38.6% vs 26.7% with placebo; P = 0.0078); pain visual analog scale (difference in mean change from baseline, compared with placebo -6.19; P = 0.0013); Fibromyalgia Impact Questionnaire total score (-3.33; P = 0.0144); and quality of sleep score (-0.73; P <0.0001). Treatment was generally well tolerated, with somnolence and dizziness the most frequently reported adverse events. CONCLUSIONS: This trial demonstrated that pregabalin, at doses of up to 450 mg/day, was effective for the symptomatic relief of pain in Japanese patients with fibromyalgia. Pregabalin also improved measures of sleep and functioning and was well tolerated. These data indicate that pregabalin is an effective treatment option for the relief of pain and sleep problems in Japanese patients with fibromyalgia. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00830167.

The Japanese version of the 2010 American College of Rheumatology Preliminary Diagnostic Criteria for Fibromyalgia and the Fibromyalgia Symptom Scale: reliability and validity.

The aim of this study was to investigate the reliability and the validity of the Japanese version of the 2010 American College of Rheumatology Preliminary Diagnostic Criteria for Fibromyalgia (ACR 2010-J), and its quantification scale, the Fibromyalgia Symptom Scale (FS-J). In this study, we divided patients with chronic pain without psychiatric disorders other than depression into two groups according to the 1990 ACR Diagnostic Criteria for Fibromyalgia, a fibromyalgia group and a non-fibromyalgia group (rheumatoid arthritis, osteoarthritis, and gout). Patients in both groups were assessed using the ACR 2010-J and FS-J. Seventy-seven of 94 (82%) patients in the fibromyalgia group met the ACR 2010-J, whereas 9% (4/43) of the non-fibromyalgia group did so, with a sensitivity of 82%, specificity of 91%, positive predictive value of 95%, negative predictive value of 70%, and positive likelihood ratio of 8.8. Mean total scores on the FS-J significantly differentiated the fibromyalgia from the non-fibromyalgia group. The scale had high inter-rater reliability and high internal consistency. With a cutoff score of 10, the positive likelihood ratio was 10.1. Our findings indicate that the ACR 2010-J and FS-J have high reliability and validity, and are useful for assessing fibromyalgia in Japanese populations with chronic pain. As regards the positive likelihood ratio, that of the FS-J might be suitable as a positive test.