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Novel Coronavirus Disease (COVID-19) swept the world and Led to a global pandemic SARS-CoV-2, which is thought to have derived from bats as their reservoir hosts, has over time and similarly as with SARS-CoV, combined with human angiotensin converting enzyme 2 (ACE2) Thus, this caused infections in cells and established them into a human 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-a, and other chemokines such as G-CSF, IP10, MCPl, to develop an increase the inflammatory responses In the case of COVID-19, it revealed that excessive inflammatory responses occur, and that the exaggerated proinflammatory cytokines and chemokines are detected in COVID-19 patients' sera resulting in cytokine release syndrome (CRS) or cytokine storm (CS) This causes coagulation abnormalities, excessive oxidation development, vital organ damages, immune system failure, and finally, progresses to disseminated intravascular coagulation (DIC) and multiple organ failure (MOF) Additionally, excessive inflammatory responses lead to mitochondrial dysfunction due to progressive and persistent stress which leads to cells and mitochondrial fracturing products containing mitochondrial DNA and damaged cell debris which in turn are involved in the chronic excessive inflammation as damage-associated molecular patterns (DAMPs) Thus, respiratory infection progressively leads to DIC from acute respiratory distress syndrome (ARDS) including vascular endothelial cell damages and coagulation-fibrinolysis system disorders Then, this worsens to central nervous system disorders, renal failure, liver failure, and finally to MOF With regards to treatments for COVID-19, the followings are progressive and multiple steps for mitigating the excessive inflammatory response and subsequent cytokine storm in patients Firstly, the administering of Favipiravir for the suppression of SARS-CoV-2, and Nafamostat for the inhibition of ACE2 function should be considered Then, the administration of anti-rheumatic drugs (monoclonal antibodies which combine with the leading cytokines (IL-1SS, IL-6) and/or cytokine receptors such as Tocilizumab) Finally, melatonin may be effective under recognition of the pathology of CRS/CS for the improvement of mitochondrial function The paper will further explore these subjects with reports mostly from China and Europe Новая коронавирусная болезнь (COVID-19) охватила весь мир и привела к глобальной пандемии Предполагается, что возбудитель заболевания - вирус SARS-CoV-2 использует летучих мышей в качестве промежуточных хозяев Попадая в организм человека, так же как и SARS-CoV, SARS-CoV-2 начинает взаимодействовать с ангиотензин-превращающим ферментом 2 (ACE2), рецептором на поверхности клетки В результате такого взаимодействия вирус проникает в клетки и запускает инфекционный процесс в организме человека, а заболевание получило название COVID-19 В ответ на вирусную инфекцию активируется система врожденного иммунитета, что приводит к усилению производства и высвобождению провоспалительных цитокинов, таких как IL-6, IL-1SS, IL-8, TNF-a, а также хемокинов, таких как G-CSF, IP10, MCP1, и развитию воспалительной реакции COVID-19 сопровождается чрезмерным воспалением и повышенным содержанием провоспалительных цитокинов и хемокинов в сыворотке крови, что свидетельствует о развитии синдрома высвобождения цитокинов, или «цитокинового шторма» В ходе развивающегося синдрома высвобождения цитокинов происходят нарушения коагуляции, чрезмерный оксидативный стресс, повреждение жизненно важных органов и нарушение функций иммунной системы Эти проявления прогрессируют и в конце концов приводят к развитию синдрома диссеминированного внутрисосудистого свертывания и полиорганной недостаточности Чрезмерные воспалительные реакции и прогрессирующий оксидативный стресс вызывают дисфункцию и повреждение митохондрий В результате в зоне воспаления накапливаются фрагменты разрушенных клеток и остатки разрушенных митохондрий, содержащие митохондриальную ДНК Эти продукты разрушения клеток, в свою очередь, действуя как молекулярные паттерны, связанные с повреждением, пролонгируют острое воспаление до развития хронического чрезмерного воспаления Таким образом, вирус, первоначально попадая в легкие, инициирует острый респираторный дистресс-синдром с последующим развитием синдрома диссеминированного внутрисосудистого свертывания Этот синдром сопровождается повреждением эндотелиальных клеток сосудов и нарушением системы свертывания крови Прогрессирование этих нарушений приводит к расстройствам центральной нервной системы, почечной и печеночной недостаточности и, наконец, к полиорганной недостаточности Лечение пациентов с COVID-19 должно быть основано на подавлении чрезмерного воспалительного ответа и «цитокинового шторма» Для этого есть несколько возможностей Целесообразно рассмотреть, во-первых, назначение фавипиравира для снижения активности SARS-CoV-2 и нафамостата для подавления функции ACE2, а во-вторых, назначение противоревматических препаратов (таких как моноклональные антитела, которые нейтрализуют или цитокины IL-1SS и IL-6, или рецепторы этих цитокинов, например тоцилизумаб) Наконец, для улучшения нарушенных функции митохондрий при синдроме высвобождения цитокинов/«цитокиновом шторме» может оказаться эффективным мелатонин В обзоре все эти вопросы рассмотрены в основном на материалах отчетов из Китая и стран Европы

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.

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-1β, 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-1β, 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.

ObjectiveThe 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.DesignPilot study.SettingAll participants were evaluated at Juntendo University from November 2017 to January 2019.SubjectsWe enrolled female patients who had been clinically diagnosed with FM (N = 23).MethodsAll 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.ResultsPain 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.ConclusionsWe 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.

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 auto‑antibodies against citrullinated proteins. Genome wide association studies have revealed that peptidyl‑arginine 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 post‑translational 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.

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.

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.

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.

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.

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 β-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.

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.

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.

Synoviolin (Syvn1), an E3 ubiquitin ligase in endoplasmic reticulum‑associated protein degradation, is involved in rheumatoid arthritis, fibrosis, liver cirrhosis and obesity. We previously demonstrated that Syvn1 negatively regulates the function of peroxisome proliferator‑activated receptor gamma coactivator‑1β (PGC‑1β). In addition, treatment with a Syvn1 inhibitor suppressed weight gain in a mouse model of obesity by activating PGC‑1β 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 PGC‑1β and Syvn1 in an in vitro binding assay. Polyubiquitination of PGC‑1β by Syvn1 was suppressed by walnut extract in a concentration‑dependent 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 PGC‑1β 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 obesity‑associated metabolic diseases.

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.

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)-1β, and Syvn1 mutants showed upregulation of PGC-1β 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-1β by SYVN1 and prevented weight gain in mice. Thus, SYVN1 is a novel post-translational regulator of PGC-1β and a potential therapeutic target in obesity treatment.

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.

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.

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.

Summary Haemophilic arthropathy (HA) is characterized by chronic proliferative synovitis leading to cartilage destruction and shares some pathological features with rheumatoid arthritis (RA). Apoptosis has been implicated in RA pathogenesis, and an agonistic anti-Fas monoclonal antibody (mAb) was found to induce RA fibroblast-like synoviocyte (FLS) apoptosis and suppress synovial hyperplasia in animal models of RA. The aim of this study was to evaluate the effect of anti-Fas mAb on HA-FLS. FLS were isolated from knee synovial biopsies from six HA patients, six RA patients and six healthy subjects. The expression of Fas in synovial biopsies was investigated by immunohistochemistry. FLS were stimulated with anti-Fas mAb at different concentrations, alone or in combination with tumour necrosis factor-α (TNF-α) and basic fibroblast growth factor (bFGF). Fas expression in FLS was assessed by Western blot. Cell viability was studied with the WST-1 assay. Active caspase-3 levels were measured using ELISA and Western blot. A strong Fas-immunoreactivity was observed in different cells of HA synovium, including FLS, inflammatory cells and endothelial cells. Fas antigen was constitutively overexpressed in cultured HA-FLS. Anti-Fas mAb had a significant cytotoxicity on HA-FLS in a dose-dependent manner, either alone or in combination with TNF-α and bFGF. These cytotoxic effects were due to the ability of anti-Fas to induce HA-FLS apoptosis, as shown by the increased active caspase-3 levels. Anti-Fas mAb exhibited a more pronounced pro-apoptotic effect on HA-FLS than RA-FLS. Fas antigen is highly expressed on HA-FLS and its stimulation by anti-Fas mAb may be an effective strategy to induce HA-FLS apoptosis.

To assess the long-term safety and efficacy of pregabalin for the treatment of Japanese patients with fibromyalgia (FM). 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. 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. These data indicate that the long-term treatment of Japanese FM patients with pregabalin may be both safe and effective.

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.

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.

Purpose The aim of the present study was to determine the brain regions with altered metabolism in patients with treatment-naive fibromyalgia (FM). Methods We used [18F] fluoro- d -glucose positron emission tomography to examine a total of 18 treatment-naive 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.

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.

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).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.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.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.

Rheumatoid arthritis (RA) significantly affects quality of life. We recently cloned synoviolin, a RING-type E3 ubiquitin ligase implicated in the endoplasmic reticulum-associated degradation (ERAD) pathway. Synoviolin is highly expressed in rheumatoid synovial cells and may be involved in the pathogenesis of RA. Inhibition of synoviolin activity is a potentially useful therapeutic approach for the treatment of RA. We conducted a high-throughput screen of small molecules to find inhibitors of synoviolin autoubiquitination activity. We identified two classes of small molecules, named LS-101 and LS-102, which inhibited synoviolin activity. LS-102 selectively inhibited synoviolin enzymatic activity, while LS-101 inhibited a broad array of RING-type E3 ligases. Moreover, these inhibitors suppressed the proliferation of rheumatoid synovial cells, and significantly reduced the severity of disease in a mouse model of RA. Our results suggest that inhibition of synoviolin is a potentially useful approach in the treatment of RA.

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.

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.

Aim: To perform a psychometric assessment of the Japanese version of the Fibromyalgia Impact Questionnaire (JFIQ). Methods: Data for the psychometric assessment were collected from Japanese fibromyalgia (FM) patients who visited a clinic. Analyses were performed to examine the reliability and validity of the JFIQ. Results: A total of 56 patients were included in the analysis. There was no remarkable floor or ceiling effect for the JFIQ item or total scores. In the analysis of reproducibility, the interclass correlation coefficients of each item score and total score ranged from 0.61 to 0.95. Cronbach’s alpha coefficient was 0.92. For the concurrent validity, the total score and most of the item scores correlated to every domain of Short Form-36 or Beck Depression Inventory-II to a moderate or great extent. The results of the known-group comparisons indicated that the total score tended to increase with the increase in severity of FM and pain (P-values for trend

The objective of this study is to compare the long-term outcomes of infliximab therapy with lower-dose methotrexate (MTX;or = 4 mg per week) and with standard-dose MTX (or = 6 mg per week) in Japanese rheumatoid arthritis (RA) patients. One hundred thirty-eight patients with refractory RA were treated with intravenous infliximab; 106 patients underwent lower-dose MTX therapy, and 32 patients underwent standard-dose MTX therapy. Treatment responses at 54 weeks or last observation carried forward (LOCF) assessed using the European League Against Rheumatism (EULAR) response criteria were compared between the two groups. Eighty-eight patients (81.1%) in the lower-dose MTX group and 27 patients (84.3%) in the standard-dose MTX therapy completed 54 weeks of infliximab treatment. A EULAR response criteria good and moderate response was seen in 70.9% in the lower-dose group and 74.1% in the standard-dose group. Good and moderate treatment responses at 54 weeks or LOCF were seen in 66.0% in the lower-dose group and 68.7% in the standard-dose group. The outcome in the lower-dose MTX group was not significantly different from that in the standard-dose group. Therapy with MTX and infliximab was effective in Japanese RA patients, regardless of MTX dosage.

Asia is home to more than half of the world's population and is a region of diverse ethnicity, culture, microbial endemicity, and economic backgrounds. This diversity is also reflected in the heterogeneity among Asian patients with rheumatic diseases in terms of clinical manifestations, disease courses, treatment responses and outcomes, which provides opportunities for researchers to conduct some unique studies. Several disease entities, such as Behçet syndrome, Takayasu arteritis, Kawasaki disease, and immunological disorders associated with human T-lymphotropic virus type 1 (HTLV-1), were first observed and defined in Asia. In addition, the region's researchers have been at the forefront of research in some interesting scientific topics, which has opened up new research avenues in rheumatology, such as the direct targeting of synovial cells in patients with rheumatoid arthritis via activation of the agonistic Fas pathway, establishment of the field of osteoimmunology, the discovery of regulatory T cells and synoviolin, and the development of tocilizumab, a humanized monoclonal antibody against interleukin-6 receptor.

Rheumatologic and public health services of Central Asia's republics have suffered hugely as a result of social and economic declines following the dissolution of the Union of Soviet Socialist Republics (USSR) and transition of these republics to market economies. Between 1990 and 2000 there was a mass outflow of highly skilled rheumatologists and teachers and researchers in rheumatology to countries abroad, leading to significant deprivation of rheumatological service in Central Asian countries. During this time, there was continued growth of various rheumatic diseases (RDs) including rheumatic fever, and musculoskeletal and connective tissue disorders. The medical and social burden of RDs imposed on society was strongly underestimated until recent times. There is an urgent need to define the epidemiology of RDs and their impact on the quality of life of people afflicted by these conditions, and to improve the diagnostics and treatment of these conditions.

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 α-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.

The epidemiological situation involving rheumatic fever (RF) and rheumatic heart disease (RHD) not only remains unresolved but is also a cause of serious concern due to the rapid increase in the incidence of RF/RHD in many developing countries. After the collapse of the Soviet Union, the republics of Central Asia experienced an economic decline that directly affected the public health sector of this region. This is the main cause of the high prevalence of many infectious diseases in Central Asia, including streptococcal tonsillopharyngitis, which carries the risk of complications such as RF. The difficulty involved in early diagnosis of RF and the development of RHD among children and adolescents causes early mortality and sudden death, leading to economic damage in these countries due to the loss of the young working population. Among all the developing countries, Kyrgyzstan, which is located in the heart of Central Asia, has the highest prevalence of RF/RHD. The increase in the prevalence of RF in Central Asia can be attributed to factors such as the low standard of living and changes in the virulence of streptococci and their sensitivity to antibiotics.

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.

Synoviolin is involved in endoplasmic reticulum (ER)-associated degradation (ERAD), a process that reduces the burden caused by unfolded proteins on the ER. Synoviolin is overexpressed in synovial cells in patients with rheumatoid arthritis; this overexpression causes a hyper-ERAD state, which might result in the autonomous proliferation and aberrant protein production observed in rheumatoid synovial cells. Rheumatoid arthritis is a disease associated with painful joints that affects approximately 1% of the population worldwide, and for which no specific cure is available. Among other functions, the endoplasmic reticulum (ER) has an important role in protein folding. When the level of unfolded proteins in the ER exceeds the folding capacity of this organelle, defective proteins are eliminated by ER-associated degradation (ERAD), an ATP-dependent ubiquitin–proteasome degradation process, to reduce the burden on the ER. Synoviolin is an E3 ubiquitin ligase that is involved in ERAD. This protein is a pathogenic factor for arthropathy; it is overexpressed in the synovial cells of patients with rheumatoid arthritis. This overexpression results in a 'hyper-ERAD' state, in which the cell deals with accumulated unfolded proteins excessively. Rheumatoid synovial cells produce large amounts of various proteins such as cytokines and proteases, which consequently might confer an autonomous proliferation property on the cells. At least 30% of all newly synthesized, ER-sorted proteins are unfolded. Although degradation of unfolded proteins consumes large amounts of ATP and would seem an unconventional process, it is essential for joint homeostasis.

Recent data are presented which indicate a critical role for interleukin (IL)‐18 in rheumatoid arthritis (RA). The T cells and macrophages invading the synovium or in the synovial fluid are the chief cellular targets of IL‐18 in RA. Neutrophils, dendritic cells and endothelial cells may also be cellular mediators of IL‐18. The direct effect of IL‐18 on fibroblast‐like synoviocytes or chondrocytes may not be essential or important. In RA, IL‐18, which is mainly produced by macrophages, activates T cells and macrophages to produce proinflammatory cytokines, chemokines, adhesion molecules and RANKL which, in turn, perpetuate chronic inflammation and induce bone and cartilage destruction.

Summary Objectives To evaluate osteoarthritis (OA) of the knee using positron emission tomography (PET) with 2- 18 F-fluoro-2-deoxy-d-glucose ( 18 F-FDG) as a tracer. Materials and methods Fifteen patients with medial-type knee OA and three healthy subjects were enrolled in the study. After clinical examination and conventional radiography, 18 F-FDG PET and magnetic resonance imaging (MRI) were performed. 18 F-FDG uptake was quantified as a standardized uptake value (SUV) and the localization of 18 F-FDG uptake was identified using fusion images created with MRI scans. Results 18 F-FDG generally accumulated in periarticular lesions and was absent in the articular cartilage. SUVs of the whole knee were higher in OA than in controls, and those in the medial condyle were higher than in the lateral condyle in OA. Prominent 18 F-FDG uptake was found in the intercondylar notch in OA and extended along the posterior cruciate ligament (PCL) in some cases. Periosteophytic accumulation was found in one-half of cases with definite osteophytes. Accumulation was also found in subchondral lesions and bone marrow, which corresponded with bone edema diagnosed by MRI. No significant correlation was found between SUV and clinical manifestations. Conclusions 18 F-FDG uptake was upregulated in OA and generally accumulated in periarticular lesions. Increased uptake was found in the intercondylar notch extending along the PCL, periosteophytic lesions, and bone marrow. These results provide in vivo pathognomonic insights into OA.

Endopalsmic reticulum (ER) is specialized organelle to maintain the integrity of secreted and membranous proteins. ER also senses so-called "ER stress", which is a result of various internal and external stresses, and triggers apoptosis when the diverse attempts to accommodate with the stress are in fail. The impairment these ER functions has been implicated in several human diseases, in which aberrant ER stress induced apoptosis is observed. We discuss about another disease model related with ER mediated apoptosis based on the recent studies about Synoviolin, an E3 ubiquitin ligase inherently utilized for ER associated degradation (ERAD). In addition to its canonical role in ERAD, Synoviolin targets tumor suppressor gene p53 for proteasomal degradation, suggesting the crosstalk between ERAD and p53 mediated apoptotic pathway under ER stress. Together with the anti-apoptotic property of Synoviolin previously elucidated by both in vitro and in vivo analyses, its new function in p53 regulation may provide a new insight into the pathomechanism of proliferative diseases such as cancer or rheumatoid arthritis.

Objective To identify pathogenic and/or disease-specific short peptides in sera from patients with systemic sclerosis (SSc). Methods Serum samples from 40 patients with SSc, 30 patients with systemic lupus erythematosus, 21 patients with rheumatoid arthritis, 30 patients with osteoarthritis, and 26 healthy donors were tested. Short peptides with molecular weights of smaller than ∼3 kd, purified from the sera by magnetic bead–based hydrophobic interaction chromatography 18, were detected and their amino acid sequences determined using matrix-assisted laser desorption ionization–time-of-flight mass spectrometry. Effects of the identified peptides on fibroblasts and microvascular endothelial cells were tested using synthesized peptides and sera containing the peptides. Results A group of peptides with mass/charge (m/z) values of 1,865, 1,778, 1,691, 1,563, and 1,450 were detected predominantly in the SSc sera. These peptides were identified as family members of complement C3f-des-arginine (DRC3f) derived from C3b. The level of DRC3f (m/z 1,865) was related to vascular involvement in SSc and to SSc disease activity. The synthesized peptides of DRC3f and C3f, as well as the filtrated sera containing DRC3f, enhanced proliferation of microvascular endothelial cells, but not fibroblasts. Both DRC3f and C3f increased production of transforming growth factor β1 by dermal microvascular endothelial cells. Conclusion This comprehensive peptidomics analysis revealed the predominance of DRC3f in the sera of patients with SSc. Investigation of DRC3f may be a useful tool for the diagnosis and evaluation of disease activity in SSc. Moreover, its demonstrated effects on endothelial cells suggest a potential role for DRC3f in the pathophysiologic mechanisms of SSc.

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.