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.

The E3 ligase synoviolin controls body weight and mitochondrial biogenesis through negative regulation of PGC-1ß.

Obesity is a major global public health problem, and understanding its pathogenesis is critical for identifying a cure. In this study, a gene knockout strategy was used in post-neonatal mice to delete synoviolin (Syvn)1/Hrd1/Der3, an ER-resident E3 ubiquitin ligase with known roles in homeostasis maintenance. Syvn1 deficiency resulted in weight loss and lower accumulation of white adipose tissue in otherwise wild-type animals as well as in genetically obese (ob/ob and db/db) and adipose tissue-specific knockout mice as compared to control animals. SYVN1 interacted with and ubiquitinated the thermogenic coactivator peroxisome proliferator-activated receptor coactivator (PGC)-1ß, and Syvn1 mutants showed upregulation of PGC-1ß target genes and increase in mitochondrion number, respiration, and basal energy expenditure in adipose tissue relative to control animals. Moreover, the selective SYVN1 inhibitor LS-102 abolished the negative regulation of PGC-1ß by SYVN1 and prevented weight gain in mice. Thus, SYVN1 is a novel post-translational regulator of PGC-1ß and a potential therapeutic target in obesity treatment.

SPACIA1/SAAL1 Deletion Results in a Moderate Delay in Collagen-Induced Arthritis Activity, along with mRNA Decay of Cyclin-dependent Kinase 6 Gene.

This study was performed to elucidate the molecular function of the synoviocyte proliferation-associated in collagen-induced arthritis (CIA) 1/serum amyloid A-like 1 (SPACIA1/SAAL1) in mice CIA, an animal model of rheumatoid arthritis (RA), and human RA-synovial fibroblasts (RASFs). SPACIA1/SAAL1-deficient mice were generated and used to create mouse models of CIA in mild or severe disease conditions. Cell cycle-related genes, whose expression levels were affected by SPACIA1/SAAL1 small interfering RNA (siRNA), were screened. Transcriptional and post-transcriptional effects of SPACIA1/SAAL1 siRNA on cyclin-dependent kinase (cdk) 6 gene expression were investigated in human RASFs. SPACIA1/SAAL1-deficient mice showed later onset and slower progression of CIA than wild-type mice in severe disease conditions, but not in mild conditions. Expression levels of cdk6, but not cdk4, which are D-type cyclin partners, were downregulated by SPACIA1/SAAL1 siRNA at the post-transcriptional level. The exacerbation of CIA depends on SPACIA1/SAAL1 expression, although CIA also progresses slowly in the absence of SPACIA1/SAAL1. The CDK6, expression of which is up-regulated by the SPACIA1/SAAL1 expression, might be a critical factor in the exacerbation of CIA.

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.

Mogamulizumab, an anti-CCR4 antibody, targets human T-lymphotropic virus type 1-infected CD8+ and CD4+ T cells to treat associated myelopathy.

BACKGROUND: Human T-lymphotropic virus type 1 (HTLV-1) can cause chronic spinal cord inflammation, known as HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Since CD4(+)CCR4(+) T cells are the main HTLV-1 reservoir, we evaluated the defucosylated humanized anti-CCR4 antibody mogamulizumab as a treatment for HAM/TSP. METHODS: We assessed the effects of mogamulizumab on peripheral blood mononuclear cells from 11 patients with HAM/TSP. We also studied how CD8(+) T cells, namely CD8(+) CCR4(+) T cells and cytotoxic T lymphocytes, are involved in HTLV-1 infection and HAM/TSP pathogenesis and how they would be affected by mogamulizumab. RESULTS: Mogamulizumab effectively reduced the HTLV-1 proviral load (56.4% mean reduction at a minimum effective concentration of 0.01 µg/mL), spontaneous proliferation, and production of proinflammatory cytokines, including interferon γ (IFN-γ). Like CD4(+)CCR4(+) T cells, CD8(+)CCR4(+) T cells from patients with HAM/TSP exhibited high proviral loads and spontaneous IFN-γ production, unlike their CCR4(-) counterparts. CD8(+)CCR4(+) T cells from patients with HAM/TSP contained more IFN-γ-expressing cells and fewer interleukin 4-expressing cells than those from healthy donors. Notably, Tax-specific cytotoxic T lymphocytes that may help control the HTLV-1 infection were overwhelmingly CCR4(-). CONCLUSIONS: We determined that CD8(+)CCR4(+) T cells and CD4(+)CCR4(+) T cells are prime therapeutic targets for treating HAM/TSP and propose mogamulizumab as a new treatment.

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.

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.

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.

Overexpression of SPACIA1/SAAL1, a newly identified gene that is involved in synoviocyte proliferation, accelerates the progression of synovitis in mice and humans.

OBJECTIVE: To identify novel genes associated with dysregulated proliferation of activated synovial fibroblasts, which are involved in arthritic joint destruction. METHODS: We performed transcriptome analysis to identify genes that were up-regulated in the foot joints of mice with collagen-induced arthritis (CIA). The effect of candidate genes on proliferation of synovial fibroblasts was screened using antisense oligodeoxynucleotides and small interfering RNAs (siRNAs). We characterized the expression and function of a novel gene, synoviocyte proliferation-associated in collagen-induced arthritis 1 (SPACIA1)/serum amyloid A-like 1 (SAAL1) using antibodies and siRNA and established transgenic mice to examine the effect of SPACIA1/SAAL1 overexpression in CIA. RESULTS: Human and mouse SPACIA1/SAAL1 encoded 474 amino acid proteins that shared 80% homology. SPACIA1/SAAL1 was primarily expressed in the nucleus of rheumatoid arthritis (RA) synovial fibroblasts and was highly expressed in the hyperplastic lining of inflamed synovium. In addition, its expression level in RA- or osteoarthritis (OA)-affected synovial tissue was positively correlated with the thickness of the synovial lining. Furthermore, SPACIA1/SAAL1 siRNA inhibited the proliferation of synovial fibroblasts, especially tumor necrosis factor α-induced synovial fibroblasts, by blocking entry into the S phase without inducing apoptosis. Finally, transgenic mice overexpressing SPACIA1/SAAL1 exhibited early onset and rapid progression of CIA. CONCLUSION: These results suggest that SPACIA1/SAAL1 is necessary for abnormal proliferation of synovial fibroblasts and its overexpression is associated with the progression of synovitis in mice and humans. Thus, therapy targeting SPACIA1/SAAL1 might have potential as an inhibitor of synovial proliferation in RA and/or OA.

Repeat etanercept administration restores clinical response of patients with rheumatoid arthritis.

We determined whether repeated treatment with the tumor necrosis factor-α (TNF-α) antagonist etanercept can be effective after an initial clinical response to this drug is lost. We describe three female patients with active, refractory rheumatoid arthritis who were administered with a second course of etanercept after eventually becoming refractory to a first course. Disease activity was high in all three patients before initial etanercept therapy, and each of them had clinically responded by 24 weeks. However, the initial clinical effect was lost between 1.5 and 3.5 years thereafter, and tocilizumab was administered, but the effect was lost again between 3 and 18 months later. Two patients did not respond to subsequent treatment with adalimumab and infliximab. Etanercept administered once again reduced disease activity in all three patients, none of whom developed any acute side effects. Etanercept re-administration significantly improved clinical disease activity and inflammatory parameters in three patients with RA who were refractory to biological anti-TNF agents.

Which subgroup of rheumatoid arthritis patients benefits from switching to tocilizumab versus etanercept after previous infliximab failure? A retrospective study.

A retrospective study of 39 rheumatoid arthritis (RA) patients with an inadequate response to infliximab was conducted. The responses of subjects switching from infliximab to tocilizumab (n = 23) were compared to those of subjects switching to etanercept (n = 16). Disease activity was assessed by the Disease Activity Score 28-CRP ([C-reactive protein] DAS28-CRP), the Simplified Disease Activity Index (SDAI), and the Clinical Disease Activity Index (CDAI). Twenty-two patients completed 48 weeks of tocilizumab treatment, and 15 patients completed 48 weeks of etanercept treatment. In both treatment groups, 1 patient each discontinued treatment because of lack of efficacy. No serious adverse events occurred during the study, and no patients in either group withdrew due to adverse events. At week 48, there was a significant reduction from baseline in DAS28-CRP, SDAI, and CDAI values after switching to either tocilizumab or etanercept, and there was no significant difference in efficacy, as measured by the DAS28-CRP, SDAI, and CDAI, between the two treatment groups (p = 0.12, 0.76, and 0.86, respectively). These results suggest that safety and tolerability were similar for both treatments. A switch from infliximab to either tocilizumab or etanercept in patients with RA who have not responded to infliximab is a feasible, well-tolerated treatment option.

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.

Prostaglandin EP2 receptor signalling inhibits the expression of matrix metalloproteinase 13 in human osteoarthritic chondrocytes.

OBJECTIVES: Matrix metalloproteinase (MMP) 13 is a pathogenic collagenase that causes cartilage destruction and plays a leading role in causing osteoarthritis. This study focused on 114 genes that are differentially expressed between intact and damaged osteoarthritis cartilage, in order to determine which molecules are involved in suppressing MMP-13 expression. METHODS: MMP-13 concentrations were measured in the supernatant of human osteoarthritis chondrocyte cultures transfected with small interfering RNA (siRNA) against the 114 genes. MMP-13 levels changed most dramatically in response to siRNA against prostaglandin EP2 receptor. The authors performed further measurements of MMP-13 production in osteoarthritis chondrocytes stimulated by the EP2 agonist butaprost in the presence or absence of interleukin-1ß (IL-1ß) and/or cyclooxygenase-2 (COX-2) inhibitor. They also assessed the effect of butaprost on chondrocyte viability, and investigated the involvement of the cAMP-protein kinase A (PKA) pathway on EP2 signalling using inhibitors. Cartilage-related gene expression was examined in chondrocytes treated with butaprost. The authors also investigated which E series of prostaglandin (EP) receptors are expressed in osteoarthritis cartilage. RESULTS: MMP-13 messenger RNA expression was significantly affected by two molecules, EP2 receptor and SLC14A1, a urea transporter. In IL-1ß-treated osteoarthritis chondrocytes, butaprost suppressed MMP-13 production, which was further decreased by COX-2 inhibitor. EP2 signalling downregulated MMP-13 mRNA expression via the cAMP-PKA pathway without affecting cell viability. Although EP2 signalling enhanced IL-6 expression, the expressions of several catabolic factors (MMP-1, MMP-3, MMP-13, ADAMTS5, IL-1ß and tumour necrosis factor alpha) were inhibited. EP2 receptor was the major EP receptor in osteoarthritis cartilage. CONCLUSION: The results suggest that EP2 signalling has 'anti-catabolic' effects in osteoarthritis chondrocytes.

Severe loss of invariant NKT cells exhibiting anti-HTLV-1 activity in patients with HTLV-1-associated disorders.

Invariant natural killer T (iNKT) cells are unique T cells that regulate the immune response to microbes, cancers, and autoimmunity. We assessed the characteristics of iNKT cells from persons infected with human T-lymphotropic virus type 1 (HTLV-1). Whereas most infected persons remain asymptomatic carriers (ACs) throughout their lives, a small proportion, usually with high equilibrium proviral loads,develop 2 diseases: HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and adult T-cell leukemia (ATL). We demonstrated that the frequency of iNKT, NK, and dendritic cells in the peripheral blood of HAM/TSP and ATL patients is decreased. We also observed an inverse correlation between the iNKT cell frequency and the HTLV-1 proviral load in the peripheral blood of infected persons. Notably, in vitro stimulation of peripheral blood cells with alpha-galactosylceramide led to an increase in the iNKT cell number and a subsequent decrease in the HTLV-1-infected T-cell number in samples from ACs but not HAM/TSP or ATL patients. Our results suggest that iNKT cells contribute to the immune defense against HTLV-1, and iNKT-cell depletion plays an important role in the pathogenesis of HAM/TSP and ATL. Therefore, iNKT cell-based immunotherapy may be an effective strategy for preventing these HTLV-1-associated disorders.

Novel Coronavirus Disease 2019 (COVID-19) and Cytokine Storms for More Effective Treatments from an Inflammatory Pathophysiology.

The Novel Coronavirus Disease 2019 (COVID-19) has swept the world and caused a global pandemic. SARS-CoV-2 seems to have originated from bats as their reservoir hosts over time. Similar to SARS-CoV, this new virus also exerts its action on the human angiotensin-converting enzyme 2. This action causes infections in cells and establishes an infectious disease, COVID-19. Against this viral invasion, the human body starts to activate the innate immune system in producing and releasing proinflammatory cytokines such as IL-6, IL-1ß, IL-8, TNF-α, and other chemokines, such as G-CSF, IP10 and MCPl, which all develop and increase the inflammatory response. In cases of COVID-19, excessive inflammatory responses occur, and exaggerated proinflammatory cytokines and chemokines are detected in the serum, resulting in cytokine release syndrome or cytokine storm. This causes coagulation abnormalities, excessive oxidation developments, mitochondrial permeability transition, vital organ damage, immune system failure and eventually progresses to disseminated intravascular coagulation and multiple organ failure. Additionally, the excessive inflammatory responses also cause mitochondrial dysfunction due to progressive and persistent stress. This damages cells and mitochondria, leaving products containing mitochondrial DNA and cell debris involved in the excessive chronic inflammation as damage-associated molecular patterns. Thus, the respiratory infection progressively leads to disseminated intravascular coagulation from acute respiratory distress syndrome, including vascular endothelial cell damage and coagulation-fibrinolysis system disorders. This condition causes central nervous system disorders, renal failure, liver failure and, finally, multiple organ failure. Regarding treatment for COVID-19, the following are progressive and multiple steps for mitigating the excessive inflammatory response and subsequent cytokine storm in patients. First, administering of favipiravir to suppress SARS-CoV-2 and nafamostat to inhibit ACE2 function should be considered. Second, anti-rheumatic drugs (monoclonal antibodies), which act on the leading cytokines (IL-1ß, IL-6) and/or cytokine receptors such as tocilizumab, should be administered as well. Finally, melatonin may also have supportive effects for cytokine release syndrome, resulting in mitochondrial function improvement. This paper will further explore these subjects with reports mostly from China and Europe.

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.

ARG098, a novel anti-human Fas antibody, suppresses synovial hyperplasia and prevents cartilage destruction in a severe combined immunodeficient-HuRAg mouse model.

BACKGROUND: The anti-human Fas/APO-1/CD95 (Fas) mouse/human chimeric monoclonal IgM antibody ARG098 (ARG098) targets the human Fas molecule. The cytotoxic effects of ARG098 on cells isolated from RA patients, on normal cells in vitro, and on RA synovial tissue and cartilage in vivo using implanted rheumatoid tissues in an SCID mouse model (SCID-HuRAg) were investigated to examine the potential of ARG098 as a therapy for RA. METHODS: ARG098 binding to each cell was analyzed by cytometry. The effects of ARG098 on several cells were assessed by a cell viability assay in vitro. Effects on the RA synovium, lymphocytes, and cartilage were assessed in vivo using the SCID-HuRAg mouse model. RESULTS: ARG098 bound to cell surface Fas molecules, and induced apoptosis in Fas-expressing RA synoviocytes and infiltrating lymphocytes in the RA synovium in a dose-dependent manner. However, ARG098 did not affect the cell viability of peripheral blood mononuclear cells of RA patients or normal chondrocytes. ARG098 also induced apoptosis in RA synoviocytes and infiltrating lymphocytes in the RA synovium in vivo. The destruction of cartilage due to synovial invasion was inhibited by ARG098 injection in the modified SCID-HuRAg mouse model. CONCLUSIONS: ARG098 treatment suppressed RA synovial hyperplasia through the induction of apoptosis and prevented cartilage destruction in vivo. These results suggest that ARG098 might become a new therapy for RA.

Involvement of post-translational modification of neuronal plasticity-related proteins in hyperalgesia revealed by a proteomic analysis.

To clarify roles of an endogenous pain modulatory system of the central nervous system (CNS) in hyperalgesia, we tried to identify qualitative and quantitative protein changes by a proteomic analysis using an animal model of hyperalgesia. Specifically, we first induced functional hyperalgesia on male Wistar rats by repeated cold stress (specific alternation of rhythm in temperature, SART). We then compared proteomes of multiple regions of CNS and the dorsal root ganglion between the hyperalgetic rats and non-treated ones by 2-D PAGE in the pI range of 4.0-7.0. We found that SART changed the proteomes prominently in the mesencephalon and cerebellum. We thus analyzed the two brain regions in more detail using gels with narrower pI ranges. As a result, 29 and 23 protein spots were significantly changed in the mesencephalon and the cerebellum, respectively. We successfully identified 12 protein spots by a MALDI-TOF/TOF MS and subsequent protein database searching. They included unc-18 protein homolog 67K, collapsin response mediator protein (CRMP)-2 and CRMP-4, which were reported to be involved in neurotransmitter release or axon elongation. Interestingly, mRNA expression levels of these three proteins were not changed significantly by the induction of hyperalgesia. Instead, we found that the detected changes in the protein spots are caused by the post-translational modification (PTM) of proteolysis or phosphorylation. Taken together, development of the hyperalgesia would be linked to PTM of these three CNS proteins. PTM regulation may be one of the useful ways to treat hyperalgesia.

Proteomic surveillance of retinal autoantigens in endogenous uveitis: implication of esterase D and brain-type creatine kinase as novel autoantigens.

PURPOSE: Various retinal proteins are newly exposed to immune system in a process of tissue destructive endogenous uveitis. Some of such proteins could be autoantigens that extend the ocular inflammation in human endogenous uveitis. In this study, we aimed to investigate the possibility of such spreading of autoantigens in endogenous uveoretinitis using a proteomic approach. METHODS: Experimental autoimmune uveoretinitis (EAU) was induced in mice by inoculation with a peptide consisting of amino acids 1-20 (GPTHLFQPSLVLDMAKVLLP) of interphotoreceptor retinoid binding protein (IRBP). Six weeks after immunization, the presence of autoantibodies against the retinal proteins in mice with EAU were examined by two-dimensional electrophoresis followed by western blotting (2D-WB). Retinal proteins targeted by the autoantibodies were identified by mass spectrometry (MS) and their autoantigenicity in patients with endogenous uveitis, such as Behcet's disease (BD, n=36), Vogt-Koyanagi-Harada disease (VKH, n=16), and sarcoidosis (n=17) were examined by enzyme-linked immunosorbent assay. RESULTS: Six new candidate autoantigens, which were detected in mice with EAU using 2D-WD were identified by MS as beta-actin, esterase D (EsteD), tubulin beta-2, brain-type creatine kinase (BB-CK), voltage-dependent anion-selective channel protein, and aspartate aminotransferase. Among the patients with endogenous uveitis, 25% of BD and 25% of VKH patients were positive for anti-EsteD antibody, and 25% of VKH and 38.4% of sarcoidosis patients were positive for anti-BB-CK antibody. CONCLUSIONS: Autoantibodies to EsteD and BB-CK produced in EAU-induced mice were also detected in some endogenous uveitis patients, suggesting that these proteins might be autoantigens spreading in a process of endogenous uveoretinitis.