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.

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.

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.

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.

Identification of the inhibitory activity of walnut extract on the E3 ligase Syvn1.

Synoviolin (Syvn1), an E3 ubiquitin ligase in endoplasmic reticulum­associated protein degradation, is involved in rheumatoid arthritis, fibrosis, liver cirrhosis and obesity. We previously demonstrated that Syvn1 negatively regulates the function of peroxisome proliferator­activated receptor gamma coactivator­1ß (PGC­1ß). In addition, treatment with a Syvn1 inhibitor suppressed weight gain in a mouse model of obesity by activating PGC­1ß via Syvn1 inhibition. It has been suggested that the Syvn1 inhibitors may have therapeutic benefits in obese patients. The present study tested the inhibitory activity of walnut extract, a natural product, on Syvn1 activity. Walnut extract inhibited the effect of Syvn1 on the cell proliferation of rheumatoid synovial cells and repressed the interaction between PGC­1ß and Syvn1 in an in vitro binding assay. Polyubiquitination of PGC­1ß by Syvn1 was suppressed by walnut extract in a concentration­dependent manner, but walnut extract did not have an inhibitory effect on the autoubiquitination of Syvn1. Treatment with walnut extract in mouse embryonic fibroblasts increased the number of mitochondria, suggesting that exposure to the extract recovered PGC­1ß function. These results demonstrated that constituents of walnut extract may serve as lead compounds in drug development efforts aiming to produce drugs to treat patients with obesity and obesity­associated metabolic diseases.

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

This corrects the article DOI: 10.1038/srep36943.

Inhibitory effects of ubiquitination of synoviolin by PADI4.

Rheumatoid arthritis (RA) is a chronic inflammatory articular disease that is characterized by synovial hyperplasia. A number of signaling pathways are associated with the development and induced symptoms of RA. Notably, patients with RA have increased protein citrullination and generation of auto­antibodies against citrullinated proteins. Genome wide association studies have revealed that peptidyl­arginine deiminase 4 (PADI4) is an enzyme implicated in citrullination in the RA synovium. Autoantibodies targeting citrullinated proteins are used as diagnostic markers in patients with RA. The functions associated with citrullinated proteins are thought to induce autoimmunity, however, the regulatory mechanisms of citrullination via PADI4 are unclear. The group has previously cloned an E3 ubiquitin ligase, synoviolin (SYVN1), from the RA synovium, demonstrating that SYVN1 serves critical roles in synovial hyperplasia. The data indicated that the endoplasmic reticulum (ER) associated degradation system, which involves SYVN1, may have important roles in the proliferation of synoviocytes. In addition, ubiquitination by SYVN1 is associated with fibrosis, inflammation and cytokine production via the regulation of ER stress signals and quality control of proteins. The present study investigated the crosstalk between the representative post­translational signaling processes, citrullination and ubiquitination. The results revealed that PADI4 interacted with SYVN1 directly and that overexpression of PADI4 suppressed the ubiquitination of proteins. Thus, a reduction in ER stress induced by PADI4 may abrogate the initiation of chronic RA by suppressing the proliferative signals of RA synoviocytes.

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.

Efficacy of Switching from Infliximab to Subcutaneous Golimumab in Patients with Rheumatoid Arthritis to Control Disease Activity or Adverse Events.

BACKGROUND: Some rheumatoid arthritis (RA) patients initially respond to treatment with infliximab (IFX), but subsequently their responsiveness decreases. OBJECTIVES: Our objective was to evaluate the efficacy and safety of switching from IFX to subcutaneous golimumab (GLM-SC) in RA patients. METHODS: Thirty-three patients who had been treated for a mean 4.4 years with IFX (3-6 mg/kg/8 weeks) were switched to GLM-SC to control disease activity or adverse events. The patients with low disease activity (LDA) or remission were divided into two groups: the LDA group and the LDA every 8 weeks (q8w) group, which included patients with LDA or remission who switched to GLM therapy with 50 mg at 4- and 8-week intervals, respectively. The moderate disease activity (MDA) group included patients with MDA who switched to GLM therapy with 50 mg at 4-week intervals. Effects of the IFX to GLM-SC switch were evaluated at weeks 12, 24, and 52 after switching. RESULTS: The mean disease activity score 28-ESR and -C-reactive protein values in the LDA and LDAq8w groups were maintained from baseline throughout the 52-week treatment period. The mean disease activity score 28 values at 12, 24, and 52 weeks in the MDA group were improved significantly compared with baseline. Treatment discontinuations due to adverse events occurred in one patient in the MDA group, and no serious adverse events occurred during the observation period in the LDA group or the LDAq8w group. The GLM continuation rates at 52 weeks were 100% in the LDA and LDAq8w groups and 83.3% in the MDA group. Thus, GLM-SC treatment regimens were effective in controlling disease activity and improving the clinical response related to adverse events caused by IFX. CONCLUSION: The clinical efficacy of GLM-SC was sustained or improved in patients who switched from IFX without serious safety concerns.

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.

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.

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.

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.