Progressive multifocal leukoencephalopathy (PML) may rarely develop in multiple sclerosis (MS) patients treated with certain disease-modifying drugs. A female patient weighing 40 kg developed PML with 12 copies/mL of prototype JC virus (JCV) DNA in the cerebrospinal fluid after 11 y of 4 mg/kg every 6 wk with natalizumab (NTZ) and intermittent holidays of fingolimod (FTY). The aim of this study was to analyze the PML risk of this case.
Methods
The lymphocyte subsets of CD4+ CD62L+ (central memory) and CD8+ CD62L− (effector memory) were analyzed. Additionally, the total dosage per kg for 1 y before the onset of PML and the transition of the JCV index were assessed.
Results
In PML-naïve MS patients, both lymphocyte-subset counts decreased during FTY therapy but recovered after FTY cessation. However, in this PML patient the recovery took more than 2 y. In the PML patient, the JCV index increased by 1.17 over 1 y until 10 mo before the onset of PML.
Conclusions
Although each factor alone is not sufficient to pose a risk in our present PML patient, the presence of multiple factors may increase the risk of PML. Administering drugs such as NTZ, which carry a PML risk, to patients with a history of FTY treatment warrants caution. Dosage and interval adjustments of NTZ should be considered. Our study suggests the possibility that FTY may increase PML risk, highlighting the importance of considering the history of immunosuppressive drug therapy when administering NTZ in MS patients.
{"title":"Risk of progressive multifocal leukoencephalopathy in patients with multiple sclerosis treated with low-dose natalizumab following fingolimod","authors":"Masami Tanaka, Kazuo Nakamichi, Keiko Tanaka","doi":"10.1111/cen3.12820","DOIUrl":"https://doi.org/10.1111/cen3.12820","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>Progressive multifocal leukoencephalopathy (PML) may rarely develop in multiple sclerosis (MS) patients treated with certain disease-modifying drugs. A female patient weighing 40 kg developed PML with 12 copies/mL of prototype JC virus (JCV) DNA in the cerebrospinal fluid after 11 y of 4 mg/kg every 6 wk with natalizumab (NTZ) and intermittent holidays of fingolimod (FTY). The aim of this study was to analyze the PML risk of this case.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>The lymphocyte subsets of CD4<sup>+</sup> CD62L<sup>+</sup> (central memory) and CD8<sup>+</sup> CD62L<sup>−</sup> (effector memory) were analyzed. Additionally, the total dosage per kg for 1 y before the onset of PML and the transition of the JCV index were assessed.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>In PML-naïve MS patients, both lymphocyte-subset counts decreased during FTY therapy but recovered after FTY cessation. However, in this PML patient the recovery took more than 2 y. In the PML patient, the JCV index increased by 1.17 over 1 y until 10 mo before the onset of PML.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Although each factor alone is not sufficient to pose a risk in our present PML patient, the presence of multiple factors may increase the risk of PML. Administering drugs such as NTZ, which carry a PML risk, to patients with a history of FTY treatment warrants caution. Dosage and interval adjustments of NTZ should be considered. Our study suggests the possibility that FTY may increase PML risk, highlighting the importance of considering the history of immunosuppressive drug therapy when administering NTZ in MS patients.</p>\u0000 </section>\u0000 </div>","PeriodicalId":10193,"journal":{"name":"Clinical and Experimental Neuroimmunology","volume":"16 3","pages":"227-235"},"PeriodicalIF":0.0,"publicationDate":"2024-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144782490","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
This study aimed to validate the clinical utility of cerebrospinal fluid (CSF) CXCL10 measurements in HTLV-1-associated myelopathy (HAM) using a CXCL10 ELISA “Cosmic” kit, a more widely applicable method than cytometric bead array (CBA).
Methods
CSF CXCL10 levels were measured in 165 samples from 111 patients with HAM and 18 controls using a CXCL10 ELISA “Cosmic” kit. We assessed the following: (1) CSF CXCL10 concentrations by HAM activity level (high, moderate, and low) versus controls; (2) correlation with CBA; (3) cutoff values, sensitivity, and specificity for differentiating among HAM activity levels; (4) changes in HAM activity after steroid therapy; and (5) relationship between HAM activity and prognosis in patients undergoing steroid therapy. A correlation coefficient of ≥0.9 with CBA was the primary endpoint.
Results
The median CSF CXCL10 levels in the high, moderate, low, and control groups were 4016.0, 841.0, 112.8, and 102.5 pg/mL, respectively. The ELISA findings were highly correlated with the CBA findings (r = 0.99). Cutoff values were set at 2500 pg/mL (sensitivity, 93.3%; specificity, 100%) to distinguish between high and moderate activity and 180 pg/mL (sensitivity, 81.8%; specificity, 100%) for low to moderate activity comparable to CBA. The new cutoffs enabled the detection of HAM activity changes and prediction of motor disability progression under steroid therapy.
Conclusion
CXCL10 ELISA “Cosmic” kit findings were strongly correlated with CBA findings, meeting the primary endpoint and demonstrating comparable sensitivity and specificity for distinguishing HAM activity. This product shows a promising ability to determine the therapeutic strategy.
{"title":"Performance evaluation of CXCL10 ELISA “cosmic” kit to measure CXCL10 in cerebrospinal fluid of patients with HTLV-1-associated myelopathy","authors":"Riyoko Ko, Katsunori Takahashi, Yasuo Kunitomo, Kenichiro Tanabe, Naoko Yagishita, Junji Yamauchi, Natsumi Araya, Makoto Nakashima, Erika Horibe, Takahiro Shimizu, Tomoo Sato, Yoshihisa Yamano","doi":"10.1111/cen3.12822","DOIUrl":"https://doi.org/10.1111/cen3.12822","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>This study aimed to validate the clinical utility of cerebrospinal fluid (CSF) CXCL10 measurements in HTLV-1-associated myelopathy (HAM) using a CXCL10 ELISA “Cosmic” kit, a more widely applicable method than cytometric bead array (CBA).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>CSF CXCL10 levels were measured in 165 samples from 111 patients with HAM and 18 controls using a CXCL10 ELISA “Cosmic” kit. We assessed the following: (1) CSF CXCL10 concentrations by HAM activity level (high, moderate, and low) versus controls; (2) correlation with CBA; (3) cutoff values, sensitivity, and specificity for differentiating among HAM activity levels; (4) changes in HAM activity after steroid therapy; and (5) relationship between HAM activity and prognosis in patients undergoing steroid therapy. A correlation coefficient of ≥0.9 with CBA was the primary endpoint.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>The median CSF CXCL10 levels in the high, moderate, low, and control groups were 4016.0, 841.0, 112.8, and 102.5 pg/mL, respectively. The ELISA findings were highly correlated with the CBA findings (<i>r</i> = 0.99). Cutoff values were set at 2500 pg/mL (sensitivity, 93.3%; specificity, 100%) to distinguish between high and moderate activity and 180 pg/mL (sensitivity, 81.8%; specificity, 100%) for low to moderate activity comparable to CBA. The new cutoffs enabled the detection of HAM activity changes and prediction of motor disability progression under steroid therapy.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>CXCL10 ELISA “Cosmic” kit findings were strongly correlated with CBA findings, meeting the primary endpoint and demonstrating comparable sensitivity and specificity for distinguishing HAM activity. This product shows a promising ability to determine the therapeutic strategy.</p>\u0000 </section>\u0000 </div>","PeriodicalId":10193,"journal":{"name":"Clinical and Experimental Neuroimmunology","volume":"16 3","pages":"258-264"},"PeriodicalIF":0.0,"publicationDate":"2024-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144782553","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Linda Sundvall, Litten S. Rossen, Vivien R. Schack, Bettina Bundgaard, Peter V. Rasmussen, Thor Petersen, Per Höllsberg
Objective
To evaluate the responsiveness of T cells from newly diagnosed multiple sclerosis (MS) patients to CD46 co-stimulation, a membrane co-factor protein potentially involved in MS pathogenesis.
Methods
T cells from MS patients and non-diseased symptomatic controls (SC) were activated in vitro with or without αCD46 antibody co-stimulation. Cytokine responses were measured to assess T-cell responsiveness. The fold difference between αCD3/CD46 and αCD3/isotype responses was calculated to determine the enhancement of CD46 activation in MS compared with SC. Additionally, the CD46 receptor phenotype, including the expression of the CD46 CYT-1 and CYT-2 isoforms, was analyzed.
Results
In the absence of αCD46 co-stimulation, MS T cells showed weaker cytokine responses compared to SC. However, CD46 engagement neutralized this deficit, resulting in a higher fold difference in MS αCD3/CD46 responses compared to SC. MS T cells also showed a trend toward a biased CD46 receptor phenotype, with a preference for the CD46 CYT-2 isoform.
Conclusions
CD46 activation enhances T-cell responses in newly diagnosed MS patients. A bias toward the CD46 CYT-2 isoform is observed, aligning with the previous findings that the absence of CYT-2 downregulation in MS might contribute to a pro-inflammatory environment.
{"title":"T cells from newly diagnosed multiple sclerosis patients have enhanced responsiveness to CD46 activation","authors":"Linda Sundvall, Litten S. Rossen, Vivien R. Schack, Bettina Bundgaard, Peter V. Rasmussen, Thor Petersen, Per Höllsberg","doi":"10.1111/cen3.12818","DOIUrl":"https://doi.org/10.1111/cen3.12818","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>To evaluate the responsiveness of T cells from newly diagnosed multiple sclerosis (MS) patients to CD46 co-stimulation, a membrane co-factor protein potentially involved in MS pathogenesis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>T cells from MS patients and non-diseased symptomatic controls (SC) were activated <i>in vitro</i> with or without αCD46 antibody co-stimulation. Cytokine responses were measured to assess T-cell responsiveness. The fold difference between αCD3/CD46 and αCD3/isotype responses was calculated to determine the enhancement of CD46 activation in MS compared with SC. Additionally, the CD46 receptor phenotype, including the expression of the CD46 CYT-1 and CYT-2 isoforms, was analyzed.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>In the absence of αCD46 co-stimulation, MS T cells showed weaker cytokine responses compared to SC. However, CD46 engagement neutralized this deficit, resulting in a higher fold difference in MS αCD3/CD46 responses compared to SC. MS T cells also showed a trend toward a biased CD46 receptor phenotype, with a preference for the CD46 CYT-2 isoform.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>CD46 activation enhances T-cell responses in newly diagnosed MS patients. A bias toward the CD46 CYT-2 isoform is observed, aligning with the previous findings that the absence of CYT-2 downregulation in MS might contribute to a pro-inflammatory environment.</p>\u0000 </section>\u0000 </div>","PeriodicalId":10193,"journal":{"name":"Clinical and Experimental Neuroimmunology","volume":"16 3","pages":"214-226"},"PeriodicalIF":0.0,"publicationDate":"2024-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cen3.12818","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144782814","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Myositis-specific autoantibodies (MSAs) and myositis-associated autoantibodies (MAAs) have emerged as crucial biomarkers in idiopathic inflammatory myopathies (IIMs).
Methods
This review synthesizes recent research on MSAs and MAAs in various IIM subtypes.
Results
Specific autoantibodies correlate with distinct clinical manifestations and pathological features. For example, anti-MDA5 antibodies are linked to rapidly progressive interstitial lung disease, while anti-TIF1-γ antibodies are associated with increased malignancy risk in adult dermatomyositis. Animal models have demonstrated the pathogenic potential of certain antibodies, such as anti-TIF1-γ, anti-SRP, and anti-HMGCR, in inducing experimental myositis.
Conclusions
Understanding the roles of MSAs and MAAs is crucial for elucidating disease mechanisms, developing targeted therapies, and improving patient outcomes. Further research is needed to fully characterize their functional implications and explore their potential as biomarkers for disease activity, prognosis, and treatment response.
{"title":"Myositis-specific/associated autoantibodies as diagnostic keys and disease drivers","authors":"Satoshi Yamashita","doi":"10.1111/cen3.12819","DOIUrl":"https://doi.org/10.1111/cen3.12819","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Myositis-specific autoantibodies (MSAs) and myositis-associated autoantibodies (MAAs) have emerged as crucial biomarkers in idiopathic inflammatory myopathies (IIMs).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>This review synthesizes recent research on MSAs and MAAs in various IIM subtypes.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Specific autoantibodies correlate with distinct clinical manifestations and pathological features. For example, anti-MDA5 antibodies are linked to rapidly progressive interstitial lung disease, while anti-TIF1-γ antibodies are associated with increased malignancy risk in adult dermatomyositis. Animal models have demonstrated the pathogenic potential of certain antibodies, such as anti-TIF1-γ, anti-SRP, and anti-HMGCR, in inducing experimental myositis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Understanding the roles of MSAs and MAAs is crucial for elucidating disease mechanisms, developing targeted therapies, and improving patient outcomes. Further research is needed to fully characterize their functional implications and explore their potential as biomarkers for disease activity, prognosis, and treatment response.</p>\u0000 </section>\u0000 </div>","PeriodicalId":10193,"journal":{"name":"Clinical and Experimental Neuroimmunology","volume":"16 1","pages":"44-54"},"PeriodicalIF":0.0,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143455722","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Neuroimmunology frontiers: Unveiling immune mechanisms in central nervous system repair and pathology","authors":"Ryo Yamasaki","doi":"10.1111/cen3.12817","DOIUrl":"https://doi.org/10.1111/cen3.12817","url":null,"abstract":"","PeriodicalId":10193,"journal":{"name":"Clinical and Experimental Neuroimmunology","volume":"15 4","pages":"201-202"},"PeriodicalIF":0.0,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142749048","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
IgPro20, a subcutaneous immunoglobulin replacement therapy, is approved in Japan for chronic inflammatory demyelinating polyneuropathy (CIDP). This post-marketing surveillance study characterized real-world treatment patterns and safety profile of injection site reactions associated with IgPro20 treatment in Japanese patients with CIDP.
Methods
Patients with CIDP initiating IgPro20 between October 2019 and September 2022 at medical institutions in Japan were followed for 6 months. The primary outcome was the incidence of injection site reactions. Other outcomes included patient clinicodemographic characteristics, IgPro20 treatment status, CIDP-related concomitant medications and any concurrent therapies.
Results
The analysis included 108 patients from 38 sites. CIDP subtypes were typical (61.1%), multifocal acquired demyelinating sensory and motor neuropathy (multifocal; 19.4%), others (14.8%) or unknown (4.6%). Approximately one-fifth (21.3%) of patients commenced IgPro20 at a dosage of <200 mg/kg, 27.8% at ≥200 to ≤300 mg/kg, 37.0% at >300 to ≤400 mg/kg and 11.1% at >400 mg/kg. Most doses (82.7%) were given at home: 62.0% self-administered, 11.7% with caregiver and 8.9% with healthcare professional assistance. A total of 55 patients used CIDP-related concomitant medications, including corticosteroids (35.2%), immunosuppressants (19.4%) or intravenous immunoglobulin G (7.4%). The data also showed that various treatment patterns were used for these combinations. A total of 40 patients (37.0%) experienced injection site reactions, most frequently injection site erythema (21.3%) and injection site swelling (17.6%); one case of ulcer occurred (0.9%). No significant relationship between injection dosage/speed and the incidence of injection site reactions was observed.
Conclusions
This study of the use of subcutaneous IgPro20 for CIDP in Japan showed a real-world safety profile consistent with phase III trial data.
{"title":"Real-world safety and treatment patterns of subcutaneous IgPro20 for chronic inflammatory demyelinating polyneuropathy: Post-marketing surveillance in Japan","authors":"Naoki Terasaka, Takanori Mizushima, Yuki Niwa, Tetsushi Akasaki, Hideo Usui","doi":"10.1111/cen3.12816","DOIUrl":"https://doi.org/10.1111/cen3.12816","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>IgPro20, a subcutaneous immunoglobulin replacement therapy, is approved in Japan for chronic inflammatory demyelinating polyneuropathy (CIDP). This post-marketing surveillance study characterized real-world treatment patterns and safety profile of injection site reactions associated with IgPro20 treatment in Japanese patients with CIDP.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Patients with CIDP initiating IgPro20 between October 2019 and September 2022 at medical institutions in Japan were followed for 6 months. The primary outcome was the incidence of injection site reactions. Other outcomes included patient clinicodemographic characteristics, IgPro20 treatment status, CIDP-related concomitant medications and any concurrent therapies.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>The analysis included 108 patients from 38 sites. CIDP subtypes were typical (61.1%), multifocal acquired demyelinating sensory and motor neuropathy (multifocal; 19.4%), others (14.8%) or unknown (4.6%). Approximately one-fifth (21.3%) of patients commenced IgPro20 at a dosage of <200 mg/kg, 27.8% at ≥200 to ≤300 mg/kg, 37.0% at >300 to ≤400 mg/kg and 11.1% at >400 mg/kg. Most doses (82.7%) were given at home: 62.0% self-administered, 11.7% with caregiver and 8.9% with healthcare professional assistance. A total of 55 patients used CIDP-related concomitant medications, including corticosteroids (35.2%), immunosuppressants (19.4%) or intravenous immunoglobulin G (7.4%). The data also showed that various treatment patterns were used for these combinations. A total of 40 patients (37.0%) experienced injection site reactions, most frequently injection site erythema (21.3%) and injection site swelling (17.6%); one case of ulcer occurred (0.9%). No significant relationship between injection dosage/speed and the incidence of injection site reactions was observed.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>This study of the use of subcutaneous IgPro20 for CIDP in Japan showed a real-world safety profile consistent with phase III trial data.</p>\u0000 </section>\u0000 </div>","PeriodicalId":10193,"journal":{"name":"Clinical and Experimental Neuroimmunology","volume":"16 2","pages":"108-117"},"PeriodicalIF":0.0,"publicationDate":"2024-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cen3.12816","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143919872","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Sota Kyuragi, Shogo Inamine, Masahiro Ohgidani, Takahiro A. Kato
Recent studies have highlighted the importance of microglia as key immunomodulators in a variety of neuropsychiatric diseases. Postmortem brain analysis and positron emission tomography are representative research approaches to assess microglial activation in human patients and this research has revealed microglial activation in the brains of patients with various neuropsychiatric disorders. However, only limited aspects of microglial activation can be assessed with these methods. To overcome the technical and ethical limitations of collecting human-derived microglia in brain biopsies, we first developed a method to generate directly induced microglia-like (iMG) cells from fresh human peripheral blood monocytes in 2014. These iMG cells can be used to perform dynamic morphological and molecular analyses regarding phagocytic capacity and cytokine release following stress stimulation at the cellular level. Patient-derived iMG cells can potentially serve as an important surrogate marker for estimating microglial activation in the human brain, and may provide previously unknown insights into the dynamic pathophysiology of microglia in patients with neuropsychiatric disorders. Thus, the iMG-based technology could be used as a valuable reverse translational tool and provide new insights into the dynamic molecular pathophysiology of microglia in a wide variety of psychiatric and physical disorders.
{"title":"Human monocyte-derived microglia-like (iMG) cells: A tool to explore microglial dynamics","authors":"Sota Kyuragi, Shogo Inamine, Masahiro Ohgidani, Takahiro A. Kato","doi":"10.1111/cen3.12815","DOIUrl":"https://doi.org/10.1111/cen3.12815","url":null,"abstract":"<p>Recent studies have highlighted the importance of microglia as key immunomodulators in a variety of neuropsychiatric diseases. Postmortem brain analysis and positron emission tomography are representative research approaches to assess microglial activation in human patients and this research has revealed microglial activation in the brains of patients with various neuropsychiatric disorders. However, only limited aspects of microglial activation can be assessed with these methods. To overcome the technical and ethical limitations of collecting human-derived microglia in brain biopsies, we first developed a method to generate directly induced microglia-like (iMG) cells from fresh human peripheral blood monocytes in 2014. These iMG cells can be used to perform dynamic morphological and molecular analyses regarding phagocytic capacity and cytokine release following stress stimulation at the cellular level. Patient-derived iMG cells can potentially serve as an important surrogate marker for estimating microglial activation in the human brain, and may provide previously unknown insights into the dynamic pathophysiology of microglia in patients with neuropsychiatric disorders. Thus, the iMG-based technology could be used as a valuable reverse translational tool and provide new insights into the dynamic molecular pathophysiology of microglia in a wide variety of psychiatric and physical disorders.</p>","PeriodicalId":10193,"journal":{"name":"Clinical and Experimental Neuroimmunology","volume":"15 4","pages":"222-227"},"PeriodicalIF":0.0,"publicationDate":"2024-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cen3.12815","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142749318","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Blood–tissue barriers play crucial roles in specialized tissues such as the central nervous system (CNS), eye, testis, and placenta. Tissue-resident macrophages in these tissues are indispensable for maintaining tissue homeostasis and responding to pathological conditions. Recent advances in high-throughput and high-dimensional single-cell analysis techniques, coupled with fate-mapping tools, have revealed a remarkable diversity of tissue-resident macrophages at the blood–tissue barrier. However, while comprehensive expression profiling has revealed the heterogeneity of macrophages within individual tissues, the commonalities of macrophages across anatomically similar structures like blood–tissue barriers remain poorly understood. This review focuses on the diversity and functional specialization of macrophages in tissues with blood–tissue barriers, highlighting recent insights into their anatomical distribution, developmental origins, phenotypic characteristics, and roles in maintaining tissue homeostasis. These findings may deepen our understanding of macrophage adaptation mechanisms in tissues with blood–tissue barriers, potentially leading to improved therapies for related disorders. Furthermore, examining the similarities and differences of macrophages across tissues may elucidate the molecular underpinnings of tissue-specific adaptation mechanisms and functional specialization.
{"title":"Common principles of macrophage biology in blood–tissue barriers","authors":"Shin-ichiro Hiraga, Takahiro Masuda","doi":"10.1111/cen3.12812","DOIUrl":"https://doi.org/10.1111/cen3.12812","url":null,"abstract":"<p>Blood–tissue barriers play crucial roles in specialized tissues such as the central nervous system (CNS), eye, testis, and placenta. Tissue-resident macrophages in these tissues are indispensable for maintaining tissue homeostasis and responding to pathological conditions. Recent advances in high-throughput and high-dimensional single-cell analysis techniques, coupled with fate-mapping tools, have revealed a remarkable diversity of tissue-resident macrophages at the blood–tissue barrier. However, while comprehensive expression profiling has revealed the heterogeneity of macrophages within individual tissues, the commonalities of macrophages across anatomically similar structures like blood–tissue barriers remain poorly understood. This review focuses on the diversity and functional specialization of macrophages in tissues with blood–tissue barriers, highlighting recent insights into their anatomical distribution, developmental origins, phenotypic characteristics, and roles in maintaining tissue homeostasis. These findings may deepen our understanding of macrophage adaptation mechanisms in tissues with blood–tissue barriers, potentially leading to improved therapies for related disorders. Furthermore, examining the similarities and differences of macrophages across tissues may elucidate the molecular underpinnings of tissue-specific adaptation mechanisms and functional specialization.</p>","PeriodicalId":10193,"journal":{"name":"Clinical and Experimental Neuroimmunology","volume":"15 4","pages":"203-214"},"PeriodicalIF":0.0,"publicationDate":"2024-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142748836","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Noriko Sato, Koji Wakimoto, Kyoko Kato, Yutaka Susuta, Kengo Ueda, Yoshihisa Satou, Takayoshi Sasajima, Jun-ichi Kira
Objective
Fingolimod is the first oral sphingosine-1-phosphate receptor modulator approved in Japan for multiple sclerosis (MS). A large Japanese observational study of fingolimod in patients with MS was carried out to support its safety and effectiveness in a real-world setting.
Methods
This 2-year, prospective, multicenter, single-cohort, observational study included all Japanese patients with MS who initiated fingolimod (0.5 mg/day). Safety endpoints included adverse events and adverse drug reactions. Effectiveness endpoints included the annualized relapse rate, Kurtzke's Expanded Disability Status Scale score and physician clinical global impression. All endpoints were analyzed in fingolimod-naïve patients.
Results
Of the 1792 patients who started fingolimod between 28 November 2011 and 31 May 2013, 1624 and 1623 fingolimod-naïve patients were included in the safety and effectiveness analysis sets, respectively. The most common MS type was relapsing–remitting MS (89.47%). Adverse events, adverse events leading to discontinuation of fingolimod, adverse drug reactions and serious adverse drug reaction incidences were 64.10%, 15.33%, 57.88% and 23.46%, respectively. No new/unexpected safety signals were identified. The annualized relapse rate was 0.97 during the 1 year before baseline, and decreased to 0.22 after treatment. The mean Expanded Disability Status Scale score remained stable throughout treatment, irrespective of the baseline Expanded Disability Status Scale score (≥3 or <3). Physician clinical global impression was classified as ‘effective’ in the majority of patients (70.3%–90.1%) throughout the treatment period.
Conclusion
Fingolimod was well tolerated and no new safety concerns were identified in this Japanese 2-year post-marketing study. Additionally, fingolimod was effective in preventing MS relapse and physical disability progression in this real-world population comprising mainly relapsing–remitting MS patients.
{"title":"Safety and effectiveness of fingolimod in Japanese patients with multiple sclerosis: Results of a post-marketing surveillance study","authors":"Noriko Sato, Koji Wakimoto, Kyoko Kato, Yutaka Susuta, Kengo Ueda, Yoshihisa Satou, Takayoshi Sasajima, Jun-ichi Kira","doi":"10.1111/cen3.12814","DOIUrl":"https://doi.org/10.1111/cen3.12814","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>Fingolimod is the first oral sphingosine-1-phosphate receptor modulator approved in Japan for multiple sclerosis (MS). A large Japanese observational study of fingolimod in patients with MS was carried out to support its safety and effectiveness in a real-world setting.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>This 2-year, prospective, multicenter, single-cohort, observational study included all Japanese patients with MS who initiated fingolimod (0.5 mg/day). Safety endpoints included adverse events and adverse drug reactions. Effectiveness endpoints included the annualized relapse rate, Kurtzke's Expanded Disability Status Scale score and physician clinical global impression. All endpoints were analyzed in fingolimod-naïve patients.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Of the 1792 patients who started fingolimod between 28 November 2011 and 31 May 2013, 1624 and 1623 fingolimod-naïve patients were included in the safety and effectiveness analysis sets, respectively. The most common MS type was relapsing–remitting MS (89.47%). Adverse events, adverse events leading to discontinuation of fingolimod, adverse drug reactions and serious adverse drug reaction incidences were 64.10%, 15.33%, 57.88% and 23.46%, respectively. No new/unexpected safety signals were identified. The annualized relapse rate was 0.97 during the 1 year before baseline, and decreased to 0.22 after treatment. The mean Expanded Disability Status Scale score remained stable throughout treatment, irrespective of the baseline Expanded Disability Status Scale score (≥3 or <3). Physician clinical global impression was classified as ‘effective’ in the majority of patients (70.3%–90.1%) throughout the treatment period.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Fingolimod was well tolerated and no new safety concerns were identified in this Japanese 2-year post-marketing study. Additionally, fingolimod was effective in preventing MS relapse and physical disability progression in this real-world population comprising mainly relapsing–remitting MS patients.</p>\u0000 </section>\u0000 </div>","PeriodicalId":10193,"journal":{"name":"Clinical and Experimental Neuroimmunology","volume":"16 2","pages":"118-131"},"PeriodicalIF":0.0,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cen3.12814","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143919960","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Reports of real-world data concerning chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) are limited in Japan. This study aimed to investigate the diagnostic testing and treatment performed in patients diagnosed with CIDP in Japan.
Methods
Using a Japanese commercial medical information database, we analyzed diagnostic tests, differential diseases, and treatments for patients with a diagnosis code for CIDP between April 13, 2008 and August 31, 2018.
Results
Of the 4564 patients with a diagnosis code for CIDP, 1658 patients were confirmed as newly assigned with the diagnosis code during the study period. Diagnostic tests performed before assignment of the diagnosis code for CIDP included nerve conduction studies in 48.1%, magnetic resonance imaging in 40.5%, and cerebrospinal fluid tests in 38.4%. Other diseases with codes that were assigned at the time of the CIDP diagnosis included Guillain–Barré syndrome in 8.1%, Sjögren syndrome in 4.4%, and systemic lupus erythematosus in 3.7%. Initial treatments performed after the assignment of the new diagnosis code for CIDP were intravenous immunoglobulin (IVIg) in 54.3%, corticosteroids (CS) in 45.4%, and plasmapheresis in 2.3%. The event-free survival rates for predefined specific safety-related events at 1000 d were 90.0% for any event in patients receiving IVIg monotherapy and 71.7% for any event in patients receiving CS monotherapy.
Conclusion
Diagnostic testing and treatment performed in clinical practice was shown through the analysis of real-world data of Japanese patients with a diagnosis code for CIDP. These findings might contribute to developments in clinical practice for Japanese CIDP patients.
{"title":"Diagnostic testing and treatment in Japanese patients with a diagnosis code for chronic inflammatory demyelinating polyradiculoneuropathy: A claims database analysis","authors":"Motoi Kuwahara, Susumu Kusunoki, Ataru Igarashi, Satoshi Akiyama, Taku Fukushima, Mamoru Doi","doi":"10.1111/cen3.12813","DOIUrl":"https://doi.org/10.1111/cen3.12813","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>Reports of real-world data concerning chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) are limited in Japan. This study aimed to investigate the diagnostic testing and treatment performed in patients diagnosed with CIDP in Japan.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Using a Japanese commercial medical information database, we analyzed diagnostic tests, differential diseases, and treatments for patients with a diagnosis code for CIDP between April 13, 2008 and August 31, 2018.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Of the 4564 patients with a diagnosis code for CIDP, 1658 patients were confirmed as newly assigned with the diagnosis code during the study period. Diagnostic tests performed before assignment of the diagnosis code for CIDP included nerve conduction studies in 48.1%, magnetic resonance imaging in 40.5%, and cerebrospinal fluid tests in 38.4%. Other diseases with codes that were assigned at the time of the CIDP diagnosis included Guillain–Barré syndrome in 8.1%, Sjögren syndrome in 4.4%, and systemic lupus erythematosus in 3.7%. Initial treatments performed after the assignment of the new diagnosis code for CIDP were intravenous immunoglobulin (IVIg) in 54.3%, corticosteroids (CS) in 45.4%, and plasmapheresis in 2.3%. The event-free survival rates for predefined specific safety-related events at 1000 d were 90.0% for any event in patients receiving IVIg monotherapy and 71.7% for any event in patients receiving CS monotherapy.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Diagnostic testing and treatment performed in clinical practice was shown through the analysis of real-world data of Japanese patients with a diagnosis code for CIDP. These findings might contribute to developments in clinical practice for Japanese CIDP patients.</p>\u0000 </section>\u0000 </div>","PeriodicalId":10193,"journal":{"name":"Clinical and Experimental Neuroimmunology","volume":"16 2","pages":"98-107"},"PeriodicalIF":0.0,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cen3.12813","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143919967","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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