Publishing type：Research paper (scientific journal)   Publisher：Medical Association of Nippon Medical School  

DOI： 10.1272/jnms.jnms.2022_89-604

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Publishing type：Research paper (scientific journal)   Publisher：Frontiers Media SA  

Objective

To stratify patients with polymyositis/dermatomyositis-associated interstitial lung disease (ILD) who were initially treated with an intensive regimen consisting of high-dose corticosteroids, a calcineurin inhibitor, and intravenous cyclophosphamide (triple-combo therapy) into subgroups based on mortality outcomes by a cluster analysis using a large-scale multicenter retrospective cohort of Japanese patients with myositis-associated ILD (JAMI).

Methods

Two-step cluster analysis of preclustering and subsequent hierarchical clustering was conducted in 185 patients who received triple-combo therapy in an unbiased manner. Initial predictors for mortality previously reported in patients with myositis-associated ILD were used as variables and included age, sex, disease duration, classification of myositis, requirement of supplemental oxygen, anti-aminoacyl tRNA synthetase (ARS) antibody, anti-melanoma differentiation-associated gene 5 (MDA5) antibody, and serum levels of C-reactive protein (CRP) and Krebs von den Lungen-6 (KL-6). The cluster model was further applied to 283 patients who received conventional regimens consisting of corticosteroids with or without a single immunosuppressive agent (dual-combo therapy or monotherapy). Cumulative survival rates were compared using Kaplan-Meier analysis, and the log-rank test was used to test for significant differences between two groups.

Results

We developed a cluster model consisting of 6 clusters, which were categorized by age at onset, clinically amyopathic dermatomyositis, CRP, KL-6, requirement of supplemental oxygen, anti-ARS antibody, and anti-MDA5 antibody. This model was judged to be of good quality based on the silhouette measure of cohesion and separation of 0.6. These clusters were regrouped into three subsets based on low (<10%), moderate (10-50%), and high (>50%) mortality rates. The performance of the clustering was generally replicated in patients who received initial dual-combo therapy or monotherapy. Survival benefits of triple-combo therapy over dual-combo therapy or monotherapy were not observed in any of the clusters.

Conclusion

We successfully developed a cluster model that stratified patients with myositis-associated ILD who were treated with initial triple-combo therapy into subgroups with different prognoses, although this model failed to identify a patient subgroup that showed survival benefits from triple-combo therapy over dual-combo therapy or monotherapy.

DOI： 10.3389/fmed.2022.883699

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Publishing type：Research paper (scientific journal)   Publisher：SAGE Publications  

Objective:

Severe digital ischemia, including digital ulcers and gangrene, is considered rare in patients with antisynthetase antibodies. This study aimed to elucidate the clinical features of antisynthetase-positive patients complicated with digital ulcers and/or gangrene using a systematic literature review and case series in a single-center cohort.

Methods:

A systematic literature review was conducted to identify reports describing antisynthetase-positive cases with digital ulcers and/or gangrene. Our cohort of consecutive patients with antisynthetase antibodies was stratified by the history of severe digital ischemia. Demographic and clinical features and outcomes in patients with severe digital ischemia identified in the systematic literature review and our cohort were compared with those in patients without severe digital ischemia in our cohort.

Results:

The systematic literature review revealed 12 antisynthetase-positive patients with severe digital ischemia from one case series and eight case reports. Seven (7%) of 100 patients with antisynthetase antibodies in our cohort had a record of severe digital ischemia. Severe digital ischemia was often found at presentation and was associated with the classification of systemic sclerosis with or without myositis overlap. Clinical features associated with severe digital ischemia in antisynthetase-positive patients included Raynaud’s phenomenon ( p < 0.001), digital pitting scars ( p = 0.001), and nailfold capillary abnormality ( p = 0.02). Outcomes of severe digital ischemia were generally favorable with vasodilators.

Conclusion:

Severe digital ischemia is an overlooked complication in antisynthetase-positive patients. Antisynthetase antibodies should be measured in patients presenting with digital ulcers or gangrene, especially in those with systemic sclerosis phenotype and features associated with antisynthetase antibodies in the absence of systemic sclerosis-specific autoantibodies.

DOI： 10.1177/23971983221090857

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Other Link： http://journals.sagepub.com/doi/full-xml/10.1177/23971983221090857

Language：Japanese   Publisher：(一社)日本リウマチ学会  

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Language：Japanese   Publisher：(一社)日本リウマチ学会  

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Language：English   Publishing type：Research paper (scientific journal)  

OBJECTIVES: The management of elderly-onset rheumatoid arthritis (EORA) is challenging due to progressive functional disability, increased comorbidities, and high drug-related risks. EORA is defined as disease onset after 60 years since 1985. We assessed whether this cut-off age was optimal in a progressively ageing society. METHODS: This study used two cohorts of consecutive rheumatoid arthritis (RA) patients: the Nippon Medical School (NMS) cohort (n = 204) and the Keio cohort (n = 296). Clinical findings independently correlated with the age of RA onset were selected as 'EORA features' from previously reported EORA characteristics using univariable and multivariable regression analyses. Receiver operating characteristic curve analysis was conducted to determine the cut-off age that best selected patients with all EORA features. RESULTS: Acute onset, negative anti-cyclic citrullinated peptide antibody, and high erythrocyte sedimentation rate were selected as 'EORA features' in both cohorts. Patients with all EORA features were more numerous with age and almost exclusively older than 65 years. The optimal EORA cut-off age was 73 years with an area under the curve (AUC) of 0.82 in the NMS cohort and 68 with an AUC of 0.93 in the Keio cohort. In the NMS cohort, Health Assessment Questionnaire-Disability Index and comorbidities in patients with disease onset between 60 years and the projected cut-off age were similar to those in younger-onset RA, but differed from those in patients with disease onset older than the projected cut-off age. CONCLUSION: The optimal EORA cut-off age was greater than the conventional definition, but this needs to be validated in different patient populations.

DOI： 10.1093/mr/roab013

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OBJECTIVE: To investigate histologic features of immunological components in the primary tumor site of patients with cancer-associated myositis (CAM) by focusing on tumor-infiltrating lymphocytes (TILs) and tertiary lymphoid structures (TLSs), which play major roles in antitumor immunity. METHODS: Cancer-associated myositis patients were selected from the single-center idiopathic inflammatory myopathy cohort based on the availability of primary tumor specimens obtained before the introduction of immunomodulatory agents. Control cancer subjects without CAM were selected from the cancer tissue repository at a ratio of 1:2 matched for demographics and cancer characteristics of CAM cases. A series of immunohistochemical analyses was conducted using sequential tumor sections. TLS was defined as an ectopic lymphoid-like structure composed of DC-LAMP+ mature dendritic cells, CD23+ follicular dendritic cells (FDCs) and PNAd+ high endothelial venules. TLS distribution was classified into the tumor center, invasive margin, and peritumoral area. RESULTS: Six CAM patients and 12 matched non-CAM controls were eligible for the study. There was no apparent difference in the density or distribution of TILs between the groups. TLSs were found in 3 CAM patients (50%) and 4 non-CAM controls (33%). TLSs were exclusively located at the tumor center or invasive margin in CAM cases but were mainly found in the peritumoral area in non-CAM controls. FDCs and class-switched B cells colocalized with follicular helper T cells were abundantly found in the germinal center-like area of TLSs from CAM patients compared with those from non-CAM controls. CONCLUSION: The adaptive immune response within TLSs in the primary tumor site might contribute to the pathogenic process of CAM.

DOI： 10.3389/fmed.2022.1066858

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The prognosis of patients with connective tissue disease (CTD) has improved significantly in recent years, but interstitial lung disease (ILD) associated with connective tissue disease (CTD-ILD) remains a refractory condition, which is a leading cause of mortality. Because it is an important prognostic factor, many observational and interventional studies have been conducted to date. However, CTD is a heterogeneous group of conditions, which makes the clinical course, treatment responses, and prognosis of CTD-ILD extremely diverse. To summarize the current understanding and unsolved questions, the Japanese Respiratory Society and the Japan College of Rheumatology collaborated to publish the world's first guide focusing on CTD-ILD, based on the evidence and expert consensus of pulmonologists and rheumatologists, along with radiologists, pathologists, and dermatologists. The task force members proposed a total of 27 items, including 7 for general topics, 9 for disease-specific topics, 3 for complications, 4 for pharmacologic treatments, and 4 for non-pharmacologic therapies, with teams of 2-4 authors and reviewers for each item to prepare a consensus statement based on a systematic literature review. Subsequently, public opinions were collected from members of both societies, and a critical review was conducted by external reviewers. Finally, the task force finalized the guide upon discussion and consensus generation. This guide is expected to contribute to the standardization of CTD-ILD medical care and is also useful as a tool for promoting future research by clarifying unresolved issues.

DOI： 10.1016/j.resinv.2021.04.011

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Progressive multifocal leukoencephalopathy (PML) is a rare opportunistic infection of the central nervous system caused by reactivation of JC virus (JCV). Typical PML shows confluent, bilateral but asymmetric, subcortical lesions in the supratentorial white matter on magnetic resonance imaging (MRI). We report here a 50-year-old woman with systemic lupus erythematosus complicated with lymphoma who developed PML with atypical brain MRI findings limited to the infratentorial area at presentation. She presented with numbness on the right side of the face, including her tongue, clumsiness of the right hand, and gait disturbance, after completion of remission induction therapy for lymphoma, including rituximab. Brain MRI demonstrated a solitary lesion limited to the cerebellum and brainstem, but a definitive diagnosis could not be made from cerebrospinal fluid study or tentative histologic evaluation of brain biopsy specimens. Despite methylprednisolone pulse therapy, her neurological deficits progressively worsened. One month later, in-depth analysis of her cerebrospinal fluid and brain biopsy specimens confirmed the presence of JCV. Eventually, the localised unilateral crescent-shaped cerebellar lesions on MRI expanded to the contralateral cerebellum, middle cerebellar hemisphere, pons, and midbrain and finally developed multifocal invasion into the white matter of the cerebral hemispheres. Our case suggests that PML could first present with a solitary infratentorial lesion in immunocompromised patients.

DOI： 10.1080/24725625.2021.1899763

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OBJECTIVE: To evaluate upstream and downstream regulators leading to macrophage activation and subsequent cytokine storm in patients with anti-melanoma differentiation-associated gene 5 (MDA5) antibody-associated interstitial lung disease (ILD). METHODS: We conducted an integrated miRNA-mRNA association analysis using circulating monocytes from 3 patients with anti-MDA5-associated ILD and 3 healthy controls and identified disease pathways and a regulator effect network by Ingenuity Pathway Analysis (IPA). The expression of relevant genes and proteins was verified using an independent validation cohort, including 6 patients with anti-MDA5-associated ILD, 5 with anti-aminoacyl tRNA synthetase antibody-associated ILD, and 6 healthy controls. RESULTS: IPA identified 26 matched pairs of downregulated miRNA and upregulated mRNAs and revealed that canonical pathways mediated by type I IFN signaling and C-C motif ligand 2 (CCL2) were responsible for the pathogenic process (P < 0.05 for all pathways). The regulatory network model identified IFN-β; Toll-like receptors 3, 7, and 9; and PU.1 as upstream regulators, while the downstream effect of this network converged at the inhibition of viral infection. mRNA and protein expression analysis using validation cohort showed a trend towards the increased expression of relevant molecules identified by IPA in patients with anti-MDA5-associated ILD compared with those with anti-aminoacyl tRNA synthetase antibody-associated ILD or healthy controls. The expression of all relevant genes in monocytes and serum levels of CCL2 and IFN-β declined after treatment in survivors with anti-MDA5-associated ILD. CONCLUSION: An antiviral proinflammatory network orchestrated primarily by activated monocytes/macrophages might be responsible for cytokine storm in anti-MDA5-associated ILD.

DOI： 10.1093/rheumatology/keab371

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Language：Japanese   Publisher：(一社)日本リウマチ学会  

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OBJECTIVE: To establish predictive models for mortality in patients with polymyositis/dermatomyositis (PM/DM)-associated interstitial lung disease (ILD) using a combination of initial serum biomarkers. METHODS: A multicenter JAMI cohort database of 497 incident cases of PM/DM-ILD was used as a derivation cohort, and 111 cases were additionally collected as a validation cohort. Risks for predicting all-cause mortality were identified by univariate and multivariable Cox regression analyses using candidate serum biomarkers as explanatory variables. The predictive models for mortality were generated in patients with and without anti-melanoma differentiation-associated gene 5 (MDA5) antibody, using a combination of risk factors. Cumulative survival rates were assessed using Kaplan-Meier analysis, and were compared between the subgroups with Breslow test. RESULTS: In a derivation cohort, C-reactive protein (CRP) and Krebs von den Lungen-6 (KL-6) were identified as independent risk factors for mortality in both anti-MDA5-positive and negative patients. We then developed a prediction model termed MCK (MDA5, CRP, and KL-6) model, identifying patients at low (<15%), moderate (15-50%), or high risk (≥50%) of mortality, based on the number of risk factors. The MCK model successfully differentiated cumulative survival rates in anti-MDA5-positive patients (P < 0.01 between low and moderate risk and P = 0.03 between moderate and high risk) and in anti-MDA5-negative patients (P < 0.001 between low and moderate risk). Utility of the MCK model was replicated in the validation cohort. CONCLUSION: The evidence-based risk prediction model using CRP and KL-6 combined with anti-MDA5 antibody might be useful for predicting prognosis in patients with PM/DM-ILD.

DOI： 10.1002/art.41566

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OBJECTIVES: Galectin-3 is involved in various biological activities, including immune activations and fibrosis. Idiopathic inflammatory myopathies (IIMs) are autoimmune diseases of unknown aetiology, often complicated by interstitial lung disease (ILD). The aim of this study was to evaluate the expression of galectin-3 in sera and tissues of patients with IIM and assess the associations of galectin-3 with patient characteristics and disease activity. RESULTS: Serum galectin-3 levels were significantly higher in IIM patients than in healthy controls. The serum galectin-3 levels positively correlated with serum levels of inflammatory markers and proinflammatory cytokines/chemokines and the Myositis Intention-to-Treat Activity Index. Stratification analysis revealed that patients with IIM-associated ILD (IIM-ILD) had significantly higher levels of serum galectin-3 than those without IIM-ILD. In addition, patients with acute/subacute interstitial pneumonia had significantly higher levels of serum galectin-3 than those with chronic interstitial pneumonia. Furthermore, serum galectin-3 levels in IIM-ILD patients correlated with the radiological assessments of parenchymal lung involvement and treatment response. Immunohistochemical analysis revealed that galectin-3 was expressed in inflammatory cells of myositis and dermatitis sections, whereas in ILD sections, galectin-3 was expressed in interstitial fibrosis and inflammatory cells. CONCLUSION: Galectin-3 may be involved in the pathogenesis of inflammatory and fibrotic conditions in IIM and can serve as a potential biomarker of disease activity, especially in patients with IIM-ILD.

DOI： 10.1093/rheumatology/keaa305

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OBJECTIVES: To investigate whether the onset of polymyositis (PM)/dermatomyositis (DM)-associated interstitial lung disease (ILD) is influenced by season and residence in the context of myositis-specific autoantibodies. METHODS: For patients with PM/DM-associated ILD enrolled in a multicentre cohort, 365 and 481 patients were eligible for seasonal and geographical analysis, respectively, based on the availability of reliable clinical information. The patients were divided into three groups: (1) anti-melanoma differentiation-associated gene 5 (MDA5) antibody-positive patients, (2) anti-aminoacyl tRNA synthetase (anti-ARS) antibody-positive patients and (3) patients negative for those antibodies. Seasonality was assessed by the Rayleigh test. Distance from residence to the nearest waterfront was measured on Google Map and was compared between groups by the exact Wilcoxon rank-sum test. RESULTS: In anti-MDA5-positive patients, the disease developed more frequently in October-March (p=0.03), whereas a seasonal relationship was not found in the remaining two patient groups. Residence at disease onset in anti-MDA5-positive patients was significantly closer to the waterfront, especially to freshwater, compared with that in anti-ARS-positive or anti-MDA5-/ARS-negative patients (p=0.003 and 0.006, respectively). CONCLUSIONS: Anti-MDA5-associated ILD occurred predominantly from October to March in individuals residing near freshwater, suggesting an environmental influence on the onset of this disease subset.

DOI： 10.1136/rmdopen-2020-001202

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OBJECTIVE: The aim of this study was to clarify predictive factors for sustained remission in adult patients with PM/DM, particularly focusing on stratification by myositis-specific autoantibodies (MSAs). METHODS: A total of 162 adult patients with PM/DM who were followed up for >1 year after diagnosis were retrospectively enrolled. MSAs were evaluated comprehensively in 102 patients whose sera were available. Sustained remission was defined as no evidence of disease activity (active skin rash, active myositis or active interstitial lung disease) for longer than a 6-month continuous period while undergoing myositis therapy or no medication. Clinical data were reviewed in patients' medical charts. RESULTS: The sustained remission rate for all patients was 58% during the median follow-up period at 4 years. With regard to MSAs, the achievement rate of sustained remission among MSA-negative patients was significantly higher than that for patients with anti-aminoacyl-tRNA synthetase (P = 0.004), anti-melanoma differentiation-associated gene 5 (P = 0.037) or anti-transcriptional intermediary factor 1-γ (P = 0.013) antibodies. MSA-negative status (odds ratio 5.84, P = 0.009) and absence of severe muscle weakness requiring assistance at diagnosis (odds ratio 43.6, P < 0.001) were independent factors associated with sustained remission in multivariate analysis. Cumulative remission rates were significantly higher (P < 0.001) in patients with both the MSA-negative status and absence of severe muscle weakness at diagnosis than the others. CONCLUSION: MSA-negative status and the absence of severe muscle weakness requiring assistance at diagnosis are independent predictive factors for sustained remission in adult PM/DM patients.

DOI： 10.1093/rheumatology/kez328

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© 2019 The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. Objective: To clarify the incidence, risk factors, and impact of malignancy in patients with PM/DM-associated interstitial lung disease (ILD). Methods: This study used data from 497 patients with PM/DM-associated ILD enrolled in a multicentre, retrospective and prospective cohort of incident cases. Cancer-associated myositis (CAM) was defined as malignancy diagnosed within 3 years before or after PM/DM diagnosis. Demographic and clinical information was recorded at the time of diagnosis, and data about the occurrence of mortality and malignancy was collected. Results: CAM was identified in 32 patients with PM/DM-associated ILD (6.4%). Patients with CAM were older (64 vs 55 years, P < 0.001), presented with arthritis less frequently (24% vs 49%, P = 0.01), and showed a lower level of serum Krebs von den Lungen-6 (687 vs 820 IU/l, P = 0.03) than those without CAM. The distribution of myositis-specific autoantibodies, including anti-melanoma differentiation-associated gene 5, anti-aminoacyl tRNA synthetase, and anti-transcriptional intermediary factor 1-γantibodies, did not differ between the groups. Survival analysis demonstrated that CAM patients had a poorer survival than non-CAM patients (P = 0.006), primarily due to excess deaths by concomitant malignancy, while mortality due to ILD-related respiratory failure was similar between the groups (P = 0.51). Conclusion: Concomitant malignancy can occur in patients with PM/DM-associated ILD, and has significant impact on mortality. Older age, lack of arthritis, and a lower level of serum Krebs von den Lungen-6 at diagnosis are predictors of concomitant malignancy.

DOI： 10.1093/rheumatology/kez238

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Introduction: Dermatomyositis (DM) is characterized by skin lesions, such as heliotrope rash and Gottron's papules/sign, and skeletal myopathy. Patients with DM often have arthritis, cardiomyopathy, interstitial lung disease (ILD), and concomitant malignancy. Since clinical characteristics, treatment response, and prognosis are highly variable among patients, it is critical to predict future outcomes in DM patients before the initiation of management. Recently, a number of myositis-specific and -associated autoantibodies (MSAs/MAAs) have been identified and well characterized, and commercial assays for their detection have become available.Areas covered: There is accumulating evidence showing the utility of MSAs/MAAs in diagnosis of DM and in predicting clinical courses and outcomes in patients with DM as convenient biomarkers, i.e. an association of ILD with anti-ARS, anti-MDA5 and anti-SAE; and malignancy with anti-TIF1-γ, anti-NXP2, and anti-SAE in adults. This review describes available assays employed for the detection of MSAs/MAAs and how to integrate autoantibody results into clinical practice of DM patients, mainly adult patients. The relevant literature was searched on PubMed as of 2 November 2019.Expert opinion: MSAs/MAAs are convenient biomarkers that are useful in personalized medicine and thus should be adopted in routine clinical practice of patients with DM, but in a science-based manner.

DOI： 10.1080/1744666X.2019.1699059

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OBJECTIVE: Surfactant protein D (SP-D) is considered a serum biomarker of various forms of interstitial lung disease (ILD). In this study, we examined the utility of SP-D as a predictive biomarker for mortality in patients with ILD associated with polymyositis/dermatomyositis (PM/DM) using large-scale multicentre cohort data. METHODS: We enrolled 381 patients with incident PM/DM-associated ILD in a multicentre retrospective cohort based on the availability of serum SP-D at the baseline. Demographic and clinical characteristics as well as the presence of autoantibodies to melanoma differentiation-associated gene 5 (MDA5) and aminoacyl tRNA synthetase were measured at the time of diagnosis, and follow-up survival data were collected prospectively. RESULTS: Seventy-eight patients died during the median observation period of 18 months, and the majority of patients died of ILD. The SP-D levels at baseline were significantly lower (P = 0.02) in a non-survivor subset than in a survivor subset among the entire enrolled patients. However, the SP-D levels were higher in the non-survivor subset than in the survivor subset based on the stratification by anti-MDA5-positive, anti-ARS-positive and, double-negativity, although there was an only statistically significant difference (P = 0.01) in the double-negative group. Surprisingly, the SP-D levels were within the upper limit of normal, 110 ng/mL, in 54 (87%) of 62 anti-MDA5-positive patients who died. In the double-negative group, the mortality rates were significantly higher (P = 0.002) in a subset with SP-D ≥127.6 ng/mL, the cut-off value for mortality calculated by the receiver operating characteristic curve, than the other subset. All of patients with SP-D <127.6 ng/mL survived. CONCLUSION: Serum SP-D levels behave differently among patients with stratified by anti-MDA5 antibody, anti-ARS antibody and both negativity in PM/DM-associated ILD. Its use in clinical practice should be applied with caution on the basis of the presence or absence of anti-MDA5 antibody or anti-ARS antibody.

DOI： 10.1371/journal.pone.0234523

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The presence of anti-aminoacyl tRNA synthetase (ARS) or anti-melanoma differential-associated gene 5 (MDA5) is strongly related to interstitial lung disease (ILD) in patients with dermatomyositis (DM). Several studies suggest a potential relationship between ILD and anti-small ubiquitin-like modifier activating enzyme (SAE) antibody in DM patients, but detailed clinical characteristics of anti-SAE-associated ILD still remain unknown. We have experienced 2 cases who were positive for anti-SAE antibody, who presented with ILD in the context of clinically amyopathic DM. These 2 patients had the following common ILD characteristics: an insidious course with preserved pulmonary function; a limited extent of pulmonary lesions with subpleural peripheral-dominant small ground glass opacity/consolidation on high-resolution computed tomography; and a favorable treatment response. These findings suggest that anti-SAE-associated ILD is unique in terms of clinical and imaging features and differs from ILD associated with anti-ARS or anti-MDA5 antibody.

DOI： 10.1111/1756-185X.13593

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DOI： 10.12659/AJCR.915527

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We clarify clinical characteristics of patients with immune checkpoint inhibitor (ICI)-induced myositis.In 13 of 15 cases with ICI-induced myositis, the type of malignancy was melanoma. Eight, 4, and 3 patients received anti-PD-1 alone, anti-CTLA4 alone, and a combination of those, respectively. The mean period to the onset of ICI-induced myositis from the initiation of ICI was 4 weeks. Myocarditis was a complication in five patients. Seven of the patients died. The causes of death were myocarditis in three patients, respiratory muscle paralysis in two patients, and cancer progression in two patients. In patients without myocarditis or respiratory muscle paralysis, the prognosis for myositis was favorable with normalization of the CK levels occurring upon the cessation of ICI and the administration of immunosuppressive agents. Myocarditis and respiratory muscle paralysis are the major causes of death as immune-related adverse events in patients with ICI-induced myositis.

DOI： 10.1007/s11926-019-0811-3

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PURPOSE OF THE REVIEW: We clarify clinical characteristics of patients with immune checkpoint inhibitor (ICI)-induced myositis. RECENT FINDINGS: In 13 of 15 cases with ICI-induced myositis, the type of malignancy was melanoma. Eight, 4, and 3 patients received anti-PD-1 alone, anti-CTLA4 alone, and a combination of those, respectively. The mean period to the onset of ICI-induced myositis from the initiation of ICI was 4 weeks. Myocarditis was a complication in five patients. Seven of the patients died. The causes of death were myocarditis in three patients, respiratory muscle paralysis in two patients, and cancer progression in two patients. In patients without myocarditis or respiratory muscle paralysis, the prognosis for myositis was favorable with normalization of the CK levels occurring upon the cessation of ICI and the administration of immunosuppressive agents. Myocarditis and respiratory muscle paralysis are the major causes of death as immune-related adverse events in patients with ICI-induced myositis.

DOI： 10.1007/s11926-019-0811-3

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DOI： 10.1016/j.rmcr.2019.01.012

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DOI： 10.1097/RHU.0000000000000974

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DOI： 10.1080/14397595.2018.1452179

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DOI： 10.1093/rheumatology/key060

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BIOMED CENTRAL LTD  

Background: Some patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) also have positivity of rheumatoid factor (RF). However, the clinical significance of this occurrence remains unknown in AAV patients. The aim of this study was to clarify an association between the presence of RF and clinical features in patients with AAV.
Results: Forty-seven patients diagnosed with AAV who were not complicated with RA were enrolled in this study. We compared clinical manifestations of AAV between an RF-positive subset (n = 29) and an RF-negative subset (n= 18). The Birmingham Vasculitis Activity Score (BVAS) was higher (P = 0.026) in the RF-positive subset than in the RF-negative subset. The levels of CRP and ESR were higher in the RF-positive patients (P = 0.020 and P = 0.007, respectively) compared to the RF-negative subset. IgM-RF titers were significantly correlated with the BVAS (r = 0.50, P = 0.0004). In addition, the IgM-RF titers had significant correlations with the levels of CRP (r= 0.41, P = 0.004), ESR (r = 0.39, P = 0.016), IgM (r = 0.36, P = 0.016) and IgG (r = 0.37, P = 0.015). The frequency of commencement of dialysis therapy, usage of mechanical ventilation and mortality were higher in the RF-positive subset than in the RF-negative subset.
Conclusions: In patients with AAV, RF titers were significantly correlated with disease activity and the levels of inflammatory markers. The presence of RF could be a poor prognostic factor in patients with AAV.

DOI： 10.1186/s12865-017-0234-8

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER JAPAN KK  

Bortezomib-dexamethasone (BD) and high-dose melphalan (HDM) are effective for systemic light-chain (AL) amyloidosis, but have not been compared in detail. We retrospectively investigated patients treated with BD or HDM at our center between September 2001 and June 2016. Among 234 patients, 20 were treated with BD and 30 received HDM. With the exception of age, transplant eligibility, and previous history of other chemotherapy, there were no significant differences in most background parameters between the two groups. Median age was higher (63.2 vs. 55.8, P = 0.001), number of transplant-eligible patients was lower (60.0 vs. 96.7%, P = 0.002), and number of previously treated patients was higher (35.0 vs. 0.0%, P &lt; 0.001) in the BD group. The BD group showed trends toward lower treatment-related mortality (5.0 vs. 10.0%, P = 0.641), greater hematological response (partial response or better) (90.0 vs. 73.3%, P = 0.279), higher complete response (60 vs. 50%, P = 0.487), and similar survival with the HDM group (neither reached, P = 0.705). In conclusion, BD was as effective and safe as HDM. Notably, BD achieved this outcome among patients with poorer clinical backgrounds compared with HDM.

DOI： 10.1007/s12185-016-2128-6

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：JAPAN SOC INTERNAL MEDICINE  

We herein report a rare case of a 66-year-old woman who had synovitis-acne-pustulosis-hyperostosis-osteitis (SAPHO) syndrome with marked sternal osteitis and bilateral pleural effusions. SAPHO syndrome was diagnosed based on the characteristic features of a hyperostotic sternum and thoracic spine. The inflammatory changes of sternal osteitis and involvement of the adjacent soft tissue were assumed to be the cause of the pleural effusions. The effusions decreased during the natural course of the disease and resolved after methotrexate therapy. The pain dramatically decreased with oral tramadol. Physicians should consider the possibility of SAPHO syndrome in patients with anterior chest pain and pleural effusions.

DOI： 10.2169/internalmedicine.8250-16

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Interstitial lung disease is one of the most important causes of mortality in patients with polymyositis or dermatomyositis. Understanding the risk factors for development and progression of interstitial lung disease is crucial to improving clinical outcomes.

DOI： 10.1038/nrrheum.2016.120

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Objective. It has been reported that organizing pneumonia (OP) develops when patients with rheumatoid arthritis (RA) are treated with biologic disease-modifying antirheumatic drugs (bDMARD). However, the clinical characteristics and pathophysiology of OP in RA remain unknown in patients treated with bDMARD. We investigated the clinical characteristics and cytokine profiles of patients with RA-OP treated with bDMARD or conventional synthetic DMARD (csDMARD).
Methods. Twenty-four patients with RA who had developed OP were enrolled. These patients included 12 treated with bDMARD (bDMARD-OP subset) and 12 treated with csDMARD (csDMARD-OP subset). We compared the clinical characteristics and cytokine profiles between the patients with OP (OP subset, n = 24) and non-OP patients (non-OP subset, n = 29).
Results. There was no significant difference in clinical characteristics between the OP subset and the non-OP subset. Four patients developed OP within 2 months of bDMARD administration. In the other 8 patients, OP developed more than 1 year after the initiation of bDMARD. OP improved with corticosteroid treatment in all bDMARD-OP patients. After OP improved, bDMARD were readministered in 6 patients, and no OP recurrence was observed in any of these patients. Our multivariate analysis revealed that serum levels of interferon-alpha (IFN-alpha), interleukin (IL)-1 beta, IL-6, IL-8, and inter-feron-gamma-inducible protein 10 were significantly associated with the development of OP, although these cytokines tended to be lower in the bDMARD-OP subset than in the csDMARD-OP subset.
Conclusion. OP is unlikely to be fatal in patients treated with bDMARD or csDMARD. IFN-alpha and proinflammatory cytokines are associated with the pathophysiology of OP in RA.

DOI： 10.3899/jrheum.151019

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Objective. The physical function of PM/DM patients after remission induction therapy remains unknown adequately. The aim of our study was to evaluate the present status of physical dysfunction and to clarify the clinical manifestations and myositis-specific autoantibodies (MSAs) associated with physical dysfunction after treatment in PM/DM. Methods. We obtained clinical data including the age at disease onset, gender, disease duration, laboratory data prior to initial treatment, and the specific treatment administered. We evaluated disease activity and physical dysfunction after treatment using the core set provided by the International Myositis Assessment and Clinical Studies Group. Results. 57% of the 77 enrolled patients with PM/DMhad troubles in daily living after treatment. At the enrolment, disease activity evaluated by physicians was only revealed in 20% of patients. In a multivariate analysis, the age at disease onset, female gender, and CK levels before treatment were significantly associated with the severity of physical dysfunction after treatment. Anti-SRP positivity was associated with more severe physical dysfunction after treatment than anti-ARS or anti-MDA5. Conclusions. Half of the PM/DM patients showed physical dysfunction after treatment. Age at disease onset, gender, CK level before treatment, and anti-SRP were significant predictors associated with physical dysfunction after treatment in PM/DM.

DOI： 10.1155/2016/9163201

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OBJECTIVE: Neurocognitive impairment (NCI) has been intensively studied in patients with systemic lupus erythematosus (SLE). However, those studies have mostly included patients who were treated with corticosteroids, which may itself induce NCI. We investigated NCI in corticosteroid-naive people with SLE who did not exhibit any overt neuropsychiatric manifestations. METHODS: Forty-three inpatients with SLE who had no current or past neuropsychiatric history participated in the study. Patients and 30 healthy control subjects with similar demographic characteristics were given a 1-h battery of neuropsychological tests. NCI was defined as scores at least 2 SD below the mean of the healthy control group on at least 2 of the 7 neurocognitive domains. Results of clinical, laboratory, and neurologic tests were compared regarding the presence of NCI. RESULTS: NCI was identified in 12 patients (27.9%) with SLE and in 2 control subjects (6.7%). Patients with SLE showed a significant impairment compared with controls on tasks assessing immediate recall, complex attention/executive function, and psychomotor speed. We identified psychomotor speed (Digit Symbol Substitution Test) as the factor that best differentiated the 2 groups. Further, we identified the score of the SLE Disease Activity Index 2000 as an independent risk factor for NCI in patients with SLE. CONCLUSION: We conclude that reduced psychomotor speed is an SLE-specific pattern of NCI. Verbal-memory deficits that have been reported in patients with SLE were not evident among patients who were corticosteroid-naive. Our results indicate that impaired psychomotor speed may be added to the symptoms of early SLE.

DOI： 10.3899/jrheum.140659

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OBJECTIVE: PM and DM are often complicated by interstitial lung disease (ILD). In this study we aimed to evaluate various serum cytokines in patients with PM/DM with ILD so as to clarify the differences in pathophysiology between anti-melanoma differentiation-associated gene 5 antibody-associated ILD (anti-MDA5-ILD) and anti-aminoacyl tRNA synthetase antibody-associated ILD (anti-ARS-ILD). METHODS: We evaluated the serum cytokine profiles of 38 patients with PM/DM and compared the cytokine profiles of the non-ILD and ILD subsets as well as the anti-MDA5-ILD and anti-ARS-ILD subsets. RESULTS: The myositis intention-to-treat activity index score, which indicates whole disease activity, significantly correlated with serum IL-6, IL-8, TNF-α and IP-10. These cytokine levels were significantly higher in the ILD subset than the non-ILD subset and were lower in the ILD subset following treatment. By multivariate analysis, TNF-α was the most significant cytokine [P = 0.0006, odds ratio (OR) 1.4, CI 1.1, 2.2] associated with PM/DM with ILD. IL-8 levels were significantly higher in anti-MDA5-ILD than in anti-ARS-ILD, although IL-6, TNF-α and IP-10 levels were high in both subsets. IL-8 was the most significant cytokine (P = 0.0006, OR 1.5, CI 1.1, 3.0) associated with anti-MDA5-ILD by multivariate analysis. Moreover, the ratio of IL-4 to IFN-γ was lower in anti-MDA5-ILD than in anti-ARS-ILD. CONCLUSION: IL-6, IL-8, TNF-α and IP-10 are associated with global disease activity in PM/DM. These cytokine levels were high, especially in the ILD subset. Serum IL-8 levels and the balance between IL-4 and IFN-γ may contribute to the differences in pathophysiology between anti-ARS-ILD and anti-MDA5-ILD.

DOI： 10.1093/rheumatology/keu258

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The objective of this study was to clarify the incidence, clinical characteristics, and courses of new-onset psychiatric manifestations after corticosteroid therapy in patients with systemic lupus erythematosus (SLE), including possible ways of differentiating between corticosteroid-induced psychiatric disorders (CIPDs) and central nervous system manifestations of SLE (CNS-SLE). We prospectively followed for 8 weeks 139 consecutive episodes in 135 in-patients who had a non-CNS-SLE flare treated with corticosteroids. Psychiatric events were evaluated once a week using DSM-IV criteria. We then conducted a post hoc etiological analysis of any newly developed psychiatric events during this follow-up period. In the 8 weeks of corticosteroid administration, new psychiatric events occurred in 20 (14.4 %) of the 139 episodes. The mean dosage of corticosteroids administered was prednisolone at 0.98 (range 0.24-1.39) mg/kg/day. Of the 20 psychiatric events, 14 (10.1 %) were suitable for the strict definition of CIPDs, accompanied by mood disorders in 13 (depressive in 2, manic in 9, and mixed in 2) and psychotic disorder in one. Two (1.4 %), both presenting delirium, were diagnosed as CNS-SLE on the basis of evidence of abnormal CNS findings even before psychiatric manifestations, all of which improved in parallel with these patients' recoveries through augmentation of immunosuppressive therapy. The other four events (2.9 %) could not be etiologically identified. This study suggests that corticosteroid therapy triggers CIPDs and CNS-SLE in patients with SLE. Delirium may be suggestive of CNS-SLE, while mood disorders may be more suggestive of CIPDs. Electroencephalographic abnormalities may possibly be predictive of CNS-SLE.

DOI： 10.1007/s00415-014-7472-y

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ObjectiveAdult-onset Still's disease (AOSD) is a clinical entity with a heterogeneous etiology. We have encountered patients with AOSD who had severe polyarthritis and who fulfilled the classification criteria for rheumatoid arthritis (RA); however, most patients with AOSD typically exhibit mild arthritis. In this study, we proposed 2 clinical subsets of AOSD and investigated the clinically significant characteristics of the 2 subtypes.
MethodsWe retrospectively analyzed 71 consecutive patients with AOSD. We reviewed the medical records of all patients who were followed up for more than 2 years. We classified all of the patients with AOSD into the following 2 subsets: an RA subtype for patients who met the criteria for RA according to the American College of Rheumatology and a non-RA subtype for patients who did not meet the criteria for RA.
ResultsOur results indicated that the non-RA subtype was accompanied by severe inflammatory complications, including pleuritis and hemophagocytic syndrome. In addition, the serum ferritin and serum interleukin-18 (IL-18) levels were significantly higher in patients with the non-RA subtype than in those with the RA subtype. Interestingly, only 1 patient with the RA subtype had anti-cyclic citrullinated peptide antibodies and 1 patient with the non-RA subtype had rheumatoid factor. These findings distinguish these patients from patients with true RA.
ConclusionThere were 2 subsets of patients with AOSD in the examined population. Patients with high levels of IL-18 or ferritin presented with severe systemic inflammatory disorders (non-RA subtype) and patients with low levels of IL-18 or ferritin developed severe arthritis (RA subtype).

DOI： 10.1002/acr.22194

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Objective. Hyperferritinemia is frequently accompanied by rapidly progressive (RP) interstitial lung disease (ILD) with polymyositis (PM)/dermatomyositis (DM). To clarify the mechanism of RP-ILD with hyperferritinemia, we investigated the associations between serum ferritin levels and various cytokines in patients with PM/DM. Methods. This retrospective study included 38 patients admitted to our hospital with PM/DM. Levels of serum ferritin and cytokines (IL-1 beta, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12, IL-13, IL-17, IL-18, TNF-alpha, IFN-alpha, IFN-gamma, and IP-10) were measured. Disease activity was evaluated using the tool proposed by the International Myositis Assessment and Clinical Studies Group. We analyzed the associations between disease activity and levels of serum ferritin and cytokines. Results. The levels of serum ferritin, IL-8, IL-10, IL-18, and TNF-alpha, were significantly correlated with disease activity. In a multivariate analysis, IL-6 (t = 3.6, P = 0.0010), IL-8 (t = 4.8, P &lt; 0.0001), and IL-10 (t = 5.7, P &lt; 0.0001) significantly contributed to serum ferritin levels. The levels of serum ferritin, IL-6, IL-8, and IL-10, were higher in the RP-ILD subset than in the non-ILD subset or the chronic ILD subset. Conclusion. IL-6, IL-8, and IL-10 are significant contributors to hyperferritinemia in PM/DM. The regulation of these cytokines might offer a possible treatment strategy for RP-ILD with PM/DM.

DOI： 10.1155/2014/815245

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BACKGROUND: Accumulating evidence has shown that several non-HLA genes are involved in the susceptibility to polymyositis/dermatomyositis. This study aimed to investigate the involvement of C8orf13-BLK, one of the strongest candidate genes for autoimmune diseases, in susceptibility to polymyositis/dermatomyositis in the Japanese population. A possible gene-gene interaction between C8orf13-BLK and STAT4, which we recently showed to be associated with Japanese polymyositis/dermatomyositis, was also analyzed. METHODS: A single-nucleotide polymorphism in C8orf13-BLK (dbSNP ID: rs13277113) was investigated in the Japanese population using a TaqMan assay in 283 polymyositis patients, 194 dermatomyositis patients, and 656 control subjects. RESULTS: The C8orf13-BLK rs13277113A allele was associated with overall polymyositis/dermatomyositis (P<0.001, odds ratio [OR] 1.44, 95% confidence interval [CI] 1.19-1.73), as well as polymyositis (P = 0.011, OR 1.32, 95% CI 1.06-1.64) and dermatomyositis (P<0.001, OR 1.64, 95% CI 1.26-2.12). No association was observed between the C8orf13-BLK rs13277113A allele and either interstitial lung disease or anti-Jo-1 antibody positivity. The C8orf13-BLK rs13277113 A and STAT4 rs7574865 T alleles had an additive effect on polymyositis/dermatomyositis susceptibility. The strongest association was observed in dermatomyositis, with an OR of 3.07 (95% CI; 1.57-6.02) for the carriers of four risk alleles at the two SNP sites, namely, rs1327713 and rs7574865. CONCLUSIONS: This study established C8orf13-BLK as a new genetic susceptibility factor for polymyositis/dermatomyositis. Both C8orf13-BLK and STAT4 exert additive effects on disease susceptibility. These observations suggested that C8orf13-BLK, in combination with STAT4, plays a pivotal role in creating genetic susceptibility to polymyositis/dermatomyositis in Japanese individuals.

DOI： 10.1371/journal.pone.0090019

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Objectives. To evaluate the use of urinary free light chains (FLCs) as a biomarker for proliferative LN and the potential association between the intensity of plasma cell infiltration of the kidney and urinary FLC levels in LN.
Methods. Forty-three SLE patients were consecutively enrolled in the study. These patients were divided into an International Society of Nephrology and Renal Pathology Society (ISN/RPS) class III/IV LN subset (n = 18) and an ISN/RPS class I/II/V (class non-III/IV) LN subset (n = 25). The expression of kappa-LCs, lambda-LCs, CD19 and CD138 in kidney specimens was also evaluated with immunohistochemical staining. To measure FLC levels before and after treatment, an additional six patients with class III/IV LN were consecutively enrolled.
Results. Urinary FLCs were significantly higher in the class III/IV LN subset than in the class non-III/IV LN subset. Urinary lambda-FLC levels were significantly correlated with the urinary protein-creatinine ratio in the class III/IV LN subset (r(s) = 0.67, P &lt; 0.01). Moreover, the LC-secreting CD19(-)/CD138(+) cell counts in the kidney specimens were higher in the class III/IV LN subset than in the class non-III/IV LN subset. Total urinary FLC levels were correlated with the numbers of CD138(+) cells in the kidney (r = 0.71, P = 0.03). Following treatment, urinary lambda-FLCs could not be detected in any of the patients.
Conclusion. The intensity of plasma cell infiltration of the kidney is associated with urinary FLC levels. Urinary FLCs are potentially useful biomarkers in ISN/RPS class III/IV LN or proliferative LN.

DOI： 10.1093/rheumatology/ket108

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Systemic sclerosis (SSc) is a connective tissue disease characterized by thickening of the skin and tissue fibrosis of the internal organs. Ghrelin is primarily described as a gut hormone, and many studies currently indicate that ghrelin has protective effects in different organs, including the heart, pancreas, lung and liver, resulting from its anti-fibrotic properties. We found decreased levels of ghrelin in the plasma from patients with SSc compared with those from healthy controls. In skin fibroblast cultures, recombinant ghrelin diminished the production of collagen type I. In addition, the mRNA levels of COL1A2 and TGFB genes were significantly decreased by the stimulation of ghrelin. We showed that ghrelin may exert anti-fibrotic effects in the skin fibroblasts from patients with SSc. Because the plasma levels of ghrelin are low in SSc, the administration of ghrelin could be a new strategy for the treatment of SSc. © 2013 Elsevier Inc.

DOI： 10.1016/j.clim.2013.03.001

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OBJECTIVE: The complication of interstitial lung disease (ILD) in polymyositis/dermatomyositis (PM/DM) is associated with anti-aminoacyl-transfer RNA synthetase (anti-aaRS) antibody or anti-melanoma differentiation-associated gene 5 (anti-MDA-5) antibody positivity. Anti-MDA-5 antibody is associated with clinically amyopathic DM and fatal outcome due to rapidly progressive ILD in Asian populations. The association between genetic factors and anti-MDA-5 antibody-positive DM is unclear. This study was undertaken to investigate the HLA-DRB1 genotype in patients with anti-MDA-5 antibody-positive DM. METHODS: We examined genetic differences among 17 patients with anti-MDA-5 antibody-positive DM, 33 patients with anti-aaRS antibody-positive PM/DM, 33 patients with PM/DM without anti-aaRS antibody or ILD, and 265 healthy controls. RESULTS: The frequencies of HLA-DRB1*0101 and DRB1*0405 were 29% and 71%, respectively, in patients with anti-MDA-5 antibody-positive DM, which were higher than the frequencies in healthy controls (10% and 25%, respectively). Among the 17 patients with anti-MDA-5 antibody-positive DM, 16 (94%) harbored either the DRB1*0101 or DRB1*0405 allele. The combined frequency of the DRB1*0101 allele and the DRB1*0405 allele was significantly higher in patients with anti-MDA-5 antibody-positive DM than in patients with PM/DM without anti-aaRS antibody or ILD, with an odds ratio (OR) of 42.7 (95% confidence interval [95% CI] 4.9-370.2) (P = 1.1 × 10(-5)), or in patients with anti-aaRS antibody-positive PM/DM (OR 13.3 [95% CI 1.6-112.6], P = 4.5 × 10(-3)). CONCLUSION: Our findings indicate that HLA-DRB1*0101/*0405 is associated with susceptibility to anti-MDA-5 antibody-positive DM in the Japanese population.

DOI： 10.1002/art.34657

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Objectives To investigate associations between signal transducer and activator of transcription 4 (STAT4), one of the most commonly acknowledged genes for the risk of multiple autoimmune diseases, with susceptibility to adult-onset polymyositis/dermatomyositis among Japanese individuals.
Methods A single nucleotide polymorphism of STAT4, rs7574865, was genotyped using TaqMan assay in 1143 Japanese individuals. The first set comprised 138 polymyositis/dermatomyositis patients and 289 controls and the second set comprised 322 patients and 394 controls. 460 patients (273 polymyositis and 187 dermatomyositis patients) and 683 controls were genotyped.
Results rs7574865T conferred a risk of polymyositis/dermatomyositis with an OR of 1.37 (95% CI 1.16 to 1.64; p = 4x10(-4); p(corr) = 0.0012). Both polymyositis and dermatomyositis exhibited high associations with the rs7574865T allele (polymyositis: OR = 1.36, 95% CI 1.11 to 1.67; p = 0.0039; p(corr) = 0.012; dermatomyositis: OR = 1.40, 95% CI 1.10 to 1.78; p = 0.0054; p(corr) = 0.016). The association between this STAT4 polymorphism and interstitial lung disease (ILD) was also investigated in the first set of polymyositis/dermatomyositis patients (n = 138); those with ILD (n = 79) bore rs7574865T more frequently compared with controls (OR 1.59, 95% CI 1.10 to 2.28; p = 0.013; p(corr) = 0.039).
Conclusion This is the first study to show a positive association between a STAT4 polymorphism and polymyositis/dermatomyositis, suggesting that polymyositis/dermatomyositis shares a gene commonly associated with the risk of other autoimmune diseases.

DOI： 10.1136/annrheumdis-2011-200839

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OBJECTIVE: The aim of this study was to investigate the precise clinical characteristics and to analyse the association between the anti-MDA5 antibody (anti-MDA5ab) titre and disease status in patients with anti-MDA5ab-positive DM. METHODS: Twenty-seven patients who presented with DM and were positive for the anti-MDA5ab were enrolled. The association between the clinical manifestations and the clinical parameters, including the anti-MDA5ab, was analysed. RESULTS: The complication of rapidly progressive interstitial lung disease (RP-ILD) occurred in 20 (74%) patients. The frequencies of fatal outcome, relapse and malignancy were 33, 4 and 4%, respectively. Remarkably, a fatal outcome occurred within the first 6 months. Compared with six non-RP-ILD patients, elderly age at onset, severely involved pulmonary function and high levels of serum ferritin were present in 20 RP-ILD patients with anti-MDA5ab. Alveolar-arterial oxygen difference (AaDO(2)) ≥32 mmHg and ferritin ≥828 ng/ml at admission were poor prognostic factors in RP-ILD patients with anti-MDA5ab-positive DM. The median value of the anti-MDA5ab titre on admission was higher in patients who later died than in those who survived. The efficacy of treatment was indicated by the anti-MDA5ab, ferritin and IL-18 concentrations. The decline index of the anti-MDA5ab titre after treatment was lower in the subset of patients who died than in the subset of patients who lived. Sustained high levels of anti-MDA5ab, ferritin and IL-18 were present in the patients who died. CONCLUSION: Anti-MDA5ab titre and ferritin and IL-18 concentrations are useful for the evaluation of the response to treatment and the status of ILD in patients with anti-MAD5ab-positive DM.

DOI： 10.1093/rheumatology/kes102

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To assess the association between serum aquaporin-4 (AQP4) autoantibodies and neuromyelitis optica spectrum disorders (NMOSDs) associated with systemic autoimmune diseases.
We retrospectively studied 626 hospitalized patients with systemic lupus erythematosus (SLE) or Sjogren's syndrome (SS). We collected serum samples from those patients with suspected NMOSDs (i.e., myelitis or optic neuritis) at the time of onset and thereafter. AQP4 antibodies were measured by a cell-based indirect immunofluorescence assay using AQP4-transfected HEK-293 cells in a semi-quantitative manner.
Sera from 6 patients with suspected NMOSDs and SLE (n = 3) or SS (n = 3) were evaluated. Among these, 2 patients' sera samples, i.e., 1 with SLE and 1 with SS, were positive for AQP4 antibodies. There was an inverse relationship between disease amelioration and antibody titer in one NMOSD patient, whereas the antibody titer remained high in the other NMOSD patient, whose clinical manifestations of NMOSDs did not improve despite intensive immunosuppressive treatments.
These results indicate that serum AQP4 antibodies are present in some SLE/SS patients with myelitis/optic neuritis and might be associated with clinical outcomes. The semi-quantitative measurement of the AQP4 antibody might be a possible surrogate marker in patients with NMOSDs associated with systemic autoimmune diseases.

DOI： 10.1007/s10165-011-0572-y

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OBJECTIVES: To assess the association between serum aquaporin-4 (AQP4) autoantibodies and neuromyelitis optica spectrum disorders (NMOSDs) associated with systemic autoimmune diseases. METHODS: We retrospectively studied 626 hospitalized patients with systemic lupus erythematosus (SLE) or Sjogren&#039;s syndrome (SS). We collected serum samples from those patients with suspected NMOSDs (i.e., myelitis or optic neuritis) at the time of onset and thereafter. AQP4 antibodies were measured by a cell-based indirect immunofluorescence assay using AQP4-transfected HEK-293 cells in a semi-quantitative manner. RESULTS: Sera from 6 patients with suspected NMOSDs and SLE (n = 3) or SS (n = 3) were evaluated. Among these, 2 patients&#039; sera samples, i.e., 1 with SLE and 1 with SS, were positive for AQP4 antibodies. There was an inverse relationship between disease amelioration and antibody titer in one NMOSD patient, whereas the antibody titer remained high in the other NMOSD patient, whose clinical manifestations of NMOSDs did not improve despite intensive immunosuppressive treatments. CONCLUSIONS: These results indicate that serum AQP4 antibodies are present in some SLE/SS patients with myelitis/op

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DOI： 10.1016/j.psym.2011.08.010

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Objective. To determine the frequency of International Society of Nephrology/Renal Pathology Society (ISN/RPS) class HT or IV lupus nephritis in patients with systemic lupus erythematosus (SLE) without clinical renal involvement.
Methods. We investigated the renal pathology of 195 patients with SLE, including 86 patients without clinical renal involvement.
Results. Lupus nephritis other than class I was found in 58% of the patients without clinical renal involvement, and class III and IV nephritis was found in 15% of these patients. To reveal the predictive measures involved in class III or IV lupus nephritis, we explored the clinical measures in patients with SLE who did not have clinical renal involvement. Anti-dsDNA antibody titers were significantly higher (p = 0.0266) and C3 values were significantly lower (p = 0.0073) in patients with class III or IV lupus nephritis than in patients without class III or IV lupus nephritis. The sensitivity and specificity values were 77% and 73%, respectively, for cutoff levels of both 40 IU/ml for anti-dsDNA antibodies and 55 mg/dl for C3 (OR 8.8, p = 0.0011).
Conclusion. The frequency of nephritis, including ISN/RPS class III and IV, was unexpectedly high in SLE patients without clinical renal involvement. ISN/RPS class Ill or IV lupus nephritis could be hidden in patients with SLE who present both a high titer of anti-dsDNA antibody and a low concentration of C3,;wen when they have clinically normal urinary findings and renal function. (First Release Nov 15 201 I; J Rheumatol 201239:79-85; doi:10.3899/jrheum.110532)

DOI： 10.3899/jrheum.110532

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OBJECTIVE: Anti-N-methyl-D-aspartate (anti-NMDA) receptor subunit NR2-reactive antibody may play a crucial role in neuronal manifestations of systemic lupus erythematosus (SLE). However, how NR2-reactive antibody acts as a critical modulator of the NMDA receptor is unknown. This study was undertaken to investigate the biologic function of NR2-reactive antibody in patients with SLE. METHODS: The study included 14 patients with SLE, 9 of whom had NR2-reactive antibody. We analyzed the effects of NR2-reactive antibody on cell viability and intracellular Ca(2+) level. We also investigated the efficacy of zinc as a modulator of the intracellular Ca(2+) level in the presence of NR2-reactive antibody. RESULTS: There was a significant inverse correlation between the NR2-reactive antibody titer and cell viability (R(2) = 0.67, P < 0.0001; n = 23), and there was a significant association between the NR2-reactive antibody titer and the intracellular Ca(2+) level in NR1/NR2a-transfected HEK 293 cells (R(2) = 0.69, P < 0.0001). Intracellular Ca(2+) levels were significantly higher in cells incubated with IgG derived from NR2-reactive antibody-positive SLE patients than in those incubated with IgG derived from NR2-reactive antibody-negative SLE patients (P = 0.0002). The addition of zinc decreased the intracellular Ca(2+) level in a dose-dependent manner. NR2-reactive antibody-positive SLE IgG weakened the efficacy of zinc as a negative modulator of the intracellular Ca(2+) level. CONCLUSION: Our findings indicate that NR2-reactive antibody decreases cell viability by Ca(2+) influx in SLE through inhibition of the binding capacity of zinc.

DOI： 10.1002/art.30616

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Objective. The aim of this study is to establish a detection method for anti-N- methyl-D-aspartate receptor subunit 2A (NR2A) antibody and to evaluate the relationship between anti-NR2A antibody and various organ involvement in SLE.
Methods. Serum anti-NR2A antibody was measured by ELISA using a peptide with a core of either DWEYS or DWDYS as autoantigen. Additionally, clinical characteristics were compared between 27 anti-NR2A antibody-positive (P group) and 80 antibody-negative (N group) SLE patients using DWDYS peptide.
Results. The optical density (OD) values of anti-NR2A antibody using DWDYS and DWEYS peptides correlated significantly (r = 0.94, P &lt; 0.0001). The median OD value was significantly higher (P &lt; 0.0001) with DWDYS. Additionally, the SLEDAI was significantly higher (P = 0.023) in the P group. The frequency of neuropsychiatric SLE (NPSLE) was significantly higher (P = 0.0002) in the P group, although the frequencies of serositis and nephritis were not statistically significant. Significant correlations were found between anti-NR2A antibody and leucocyte count (r(s) = -0.31, P = 0.001) and haemoglobin (r(s) = -0.42, P &lt; 0.0001), although no correlation was found between anti-NR2A antibody and the titre of anti-dsDNA antibody. NPSLE was the most significant independent variable (P = 0.0008) associated with anti-NR2A antibody positivity, as estimated by multiple linear regression analysis.
Conclusion. Serum anti-NR2A antibody can be associated with the complication of NPSLE and may indicate the involvement of non-nervous tissue. The use of peptides that include DWDYS is preferable to detect anti-NR2A antibody in ELISA.

DOI： 10.1093/rheumatology/keq408

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

Objective. Several studies have shown that anti-C1q antibodies correlate with the occurrence and activity of nephritis in systemic lupus erythematosus (SLE). However, the significance of anti-C1q antibodies in SLE has not been fully characterized. The aim of this study was to investigate associations between anti-C1q antibodies and clinical and serologic parameters of SLE.
Methods. An enzyme-linked immunosorbent assay kit was used to measure anti-C1q antibodies in the sera of 126 consecutive patients with active SLE who were admitted to our university hospital from 2007 through 2009. Sera obtained from patients with high titers of anti-C1q antibodies at the initial evaluation (n = 20) were reevaluated following treatment. Control sera were obtained from patients with other autoimmune diseases and from normal healthy control subjects (n = 20 in each group). Associations between anti-C1q antibodies and clinical and serologic parameters of SLE were statistically analyzed.
Results. Anti-C1q antibodies were detected in the sera of 79 of 126 patients with SLE. The prevalence and titers of anti-C1q antibodies were significantly (P &lt; 0.0001) higher in SLE patients than in patients with rheumatoid arthritis, patients with systemic sclerosis, and normal healthy control subjects. The prevalence and titers of anti-C1q antibodies were not significantly associated with active lupus nephritis (P = 0.462 and P = 0.366, respectively). Anti-C1q antibody titers were significantly correlated with SLE Disease Activity Index 2000 scores and the levels of anti-double-stranded DNA antibodies, C3, C4, CH50, and C1q (P &lt; 0.0001 for all comparisons). Moreover, anti-C1q antibody titers significantly decreased as clinical disease was ameliorated following treatment (P = 0.00097).
Conclusion. These findings indicate that anti-C1q antibodies are associated with SLE global activity but not specifically with active lupus nephritis.

DOI： 10.1002/art.30401

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER  

Interstitial lung disease (ILD) is a noteworthy condition in the treatment of systemic sclerosis (SSc) because of its associated mortality and morbidity; however, the efficacy of various treatments for ILD has been controversial in previous reports. In this study, we examined the efficacy and safety of intravenous cyclophosphamide (IVCY) pulse therapy with prednisolone (PSL) for the treatment of ILD with SSc. A total of 121 patients with SSc were screened and evaluated for ILD, using high-resolution computed tomography of the chest, pulmonary function testing, and bronchoalveolar lavage. Thirteen patients with active ILD were enrolled in this study. The treatment protocol for ILD was 0.4 g/m(2) of body surface area of IVCY monthly plus 0.8 mg/kg of body weight of PSL daily. Two to six doses of IVCY were administered, depending on the remission of ILD. Initial PSL doses were maintained for a month and then gradually tapered to 10 mg daily. An activity index of ILD showed improvements in all patients in the 12 months after the initial intervention; however, four patients experienced recurrence of ILD after 24 months, and one additional patient had recurrence of ILD after 36 months. Seven patients reached the 48-month point with no recurrence of ILD. This long observational study for 48 months showed the efficacy of IVCY with PSL for active alveolitis in the first year. However, because five patients had recurrence of ILD more than 1 year after the treatment, it would be necessary to consider maintenance therapy for ILD beyond 1 year.

DOI： 10.1007/s10165-010-0403-6

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD  

Systemic sclerosis (SSc) is a chronic disease of unknown etiology that is characterized by multiple tissue fibrosis. Transforming Growth Factor-beta (TGF-beta) is thought to be the most important mediator that induces fibrosis. However, the molecular mechanisms by which fibrosis is induced have not been fully elucidated. In this study, the role of activin, a member of the TGF-beta superfamily, was investigated in the pathogenesis of fibrosis in SSc. Serum activin A levels in patients with SSc were measured by ELISA, and the expression of the activin receptor type IB (ACVRIB/ALK4) and the activity of the signaling pathway via ACVRIB/ALK4 were investigated using western blotting. To evaluate a potential therapeutic strategy for SSc, we also attenuated the ACVRIB/ALK4 pathway using an inhibitor. Serum activin A levels were significantly higher in SSc patients than in normal controls. Activin A and ACVRIB/ALK4 expression were also higher in cultured SSc fibroblasts. Activin A stimulation induced phosphorylation of Smad2/3 and CTGF expression in SSc fibroblasts. Procollagen production and Col1 alpha mRNA also increased upon stimulation by activin A. The basal level of Smad2/3 phosphorylation was higher in cultured SSc fibroblasts than in control cells, and treatment with the ALK4/5 inhibitor SB431542 prevented phosphorylation of Smad2/3 and CTGF expression. Furthermore, production of collagen was also induced by activin A. Activin A-ACVRIB/ALK4-Smad-dependent collagen production was augmented in SSc fibroblasts, suggesting the involvement of this signaling mechanism in SSc. Inhibition of the activin A-ACVRIB/ALK4-Smad pathway would be a new approach for the treatment of SSc. (C) 2010 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.jaut.2010.09.004

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Systemic sclerosis (SSc) is a chronic disease of unknown etiology that is characterized by multiple tissue fibrosis. Transforming Growth Factor-beta (TGF-beta) is thought to be the most important mediator that induces fibrosis. However, the molecular mechanisms by which fibrosis is induced have not been fully elucidated. In this study, the role of activin, a member of the TGF-beta superfamily, was investigated in the pathogenesis of fibrosis in SSc. Serum activin A levels in patients with SSc were measured by ELISA, and the expression of the activin receptor type IB (ACVRIB/ALK4) and the activity of the signaling pathway via ACVRIB/ALK4 were investigated using western blotting. To evaluate a potential therapeutic strategy for SSc, we also attenuated the ACVRIB/ALK4 pathway using an inhibitor. Serum activin A levels were significantly higher in SSc patients than in normal controls. Activin A and ACVRIB/ALK4 expression were also higher in cultured SSc fibroblasts. Activin A stimulation induced phosphorylation of Smad2/3 and CTGF expression in SSc fibroblasts. Procollagen production and Col1alpha mRNA also increased upon stimulation by activin A. The basal level of Smad2/3 phosphoryl

DOI： 10.1016/j.jaut.2010.09.004

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Dermatomyositis (DM) is occasionally complicated by interstitial lung disease. Acute/subacute interstitial pneumonia (A/SIP) with DM is intractable and life threatening. Clinically amyopathic dermatomyositis (C-ADM) is also reported to be complicated with A/SIP, especially in those patients with anti-melanoma differentiation-associated gene 5 (MDA5) antibody. In the present cases, we indicate that serum ferritin level correlated with activity of A/SIP with DM. Two patients, a 65-year-old woman and a 30-year-old woman, were diagnosed with anti-MDA5 antibody-associated A/SIP with DM. Serum ferritin was high, 1600 and 770 mg/dl, respectively, on admission. Immunosuppressive therapy ameliorated A/SIP in both cases. Similarly, serum ferritin was also decreasing. However, A/SIP was recurrent and progressive, and serum ferritin was also increasing again in one case. In conclusion, serum ferritin correlates with disease activity of anti-MDA5 antibody-associated A/SIP with DM. Intensity of treatment may be decided according to serum ferritin level.

DOI： 10.1007/s10165-010-0371-x

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER LONDON LTD  

The aim of this study was to evaluate neurological manifestations of primary Sjogren's syndrome (pSS) and investigate the etiology and pathogenesis of peripheral and central nervous complications in pSS. Thirty-two patients with pSS were enrolled in the present study, 20 of whom had neurological involvement plus sicca symptoms. The clinical features were evaluated by neurological examinations including nerve conduction study, magnetic resonance imaging, cerebrospinal fluid, and electroencephalogram. The frequency of fever was significantly higher (P = 0.006) in pSS with neurological involvement than in pSS without neurological involvement. There was no statistical significance in other factors between the two groups. Peripheral nervous system (PNS), central nervous system (CNS), and both PNS and CNS involvements were revealed in 14, 3, and 3 patients, respectively. Optic neuritis and trigeminal neuralgia were revealed frequently in cranial neuropathy. Anti-aquaporin 4 antibody was detected in one patient with optic neuritis. Of the nine patients with polyneuropathy, eight patients presented pure sensory neuropathy including small fiber neuropathy (SFN). pSS with SFN appeared to have no clinically abnormal features, including muscle weakness and decreasing deep tendon reflex. Skin biopsy revealed epidermal nerve fiber degenerated in one pSS patient with pure sensory neuropathy who was diagnosed as having SFN. Our observations suggest that a number of mechanisms can be attributed to neurological involvements in pSS rather than just the mechanisms previously described (i.e., vasculitis and ganglioneuronitis). Presumably, specific autoantibodies may directly induce injury of the nervous system.

DOI： 10.1007/s10067-010-1458-7

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BIOMED CENTRAL LTD  

Background: The risk for amenorrhea following treatment of systemic lupus erythematosus (SLE) patients with low-dose intravenous cyclophosphamide (IVCY) has not been fully explored. Our objective was to ascertain the incidence of amenorrhea following treatment with low-dose IVCY and the association between amenorrhea and the clinical parameters of SLE.
Methods: A case-control retrospective study of premenopausal women &lt;= 45 years old who had been treated for SLE with low-dose IVCY (500 mg/body/pulse) plus high-dose glucocorticoids (0.8-1.0 mg/kg/day of prednisolone; IVCY group) or glucocorticoids alone (0.8-1.0 mg/kg/day of prednisolone; steroid group) in our hospital from 2000 through 2009 was conducted using a questionnaire survey and medical record review.
Results: Twenty-nine subjects in the IVCY group and 33 subjects in the steroid group returned the questionnaire. A multivariate analysis revealed that age at initiation of treatment &gt;= 40 years old was significantly associated with amenorrhea [p = 0.009; odds ratio (OR) 10.2; 95% confidence interval (CI) 1.8-58.7]. IVCY treatment may display a trend for association with amenorrhea (p = 0.07; OR 2.9; 95% CI 0.9-9.4). Sustained amenorrhea developed in 4 subjects in the IVCY group and 1 subject in the steroid group; all of these patients were &gt;= 40 years old. Menses resumed in all subjects &lt; 40 years old, irrespective of treatment.
Conclusions: Although low-dose IVCY may increase the risk for amenorrhea, our data suggest that patients &lt; 40 years old have a minimum risk for sustained amenorrhea with low-dose IVCY treatment. A higher risk for sustained amenorrhea following treatment with IVCY is a consideration for patients &gt;= 40 years old.

DOI： 10.1186/1472-6874-11-28

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：OXFORD UNIV PRESS  

Objective. To determine whether IL-18 is involved in the inflammation of DM and PM.
Methods. Thirty-three patients with DM were enrolled in this study, including 25 with interstitial lung disease (ILD). In addition, 16 patients with PM were enrolled, including 6 with ILD. All patients were admitted to our hospital as a result of their condition requiring treatment, and clinical laboratory data including serum IL-18 were recorded on admission.
Results. Serum IL-18 was significantly (P &lt; 0.0001) higher in both DM and PM patients than in healthy controls (n = 30). Serum ferritin and IL-18 were significantly (P = 0.003 and 0.0044, respectively) higher in DM than in PM patients. Additionally, ferritin and IL-18 were significantly (P = 0.023 and 0.034, respectively) higher in DM patients with ILD than in DM patients without ILD. Significant positive correlations were found between creatine kinase (CK) and ferritin (r(s) = 0.39, P = 0.024); CK and IL-18 (r(s) = 0.48, P = 0.005); and IL-18 and ferritin (r(s) = 0.54, P = 0.0012) in the DM group as a whole. These findings were different for the DM plus ILD subgroup: significant positive correlations were found between CK and ferritin (r(s) = 0.40, P = 0.047); CK and IL-18 (r(s) = 0.63, P = 0.0008); and IL-18 and ferritin (r(s) = 0.41, P = 0.042).
Conclusion. Serum IL-18 was strikingly elevated in patients with DM and was associated particularly with disease activity and ILD complication in DM.

DOI： 10.1093/rheumatology/keq196

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The objective of this study was to explore the association of single nucleotide polymorphisms (SNPs) of the CD244 gene with several clinical features of systemic lupus erythematosus (SLE). Two hundred and forty-three patients with SLE and 369 healthy controls were enrolled. Two SNPs (rs6682654 and rs3766379) in the CD244 gene were determined by allelic discrimination using a specific TaqMan probe. Only SNP rs3766379 was significantly associated with susceptibility to SLE [P = 0.009; odds ratio (OR) 1.28; 95% confidence interval (CI) 1.04-1.57]. The association was preferentially observed in subsets of SLE patients with nephritis and neuropsychiatric lupus. The frequency of the rs6682654 C allele was strongly associated with nephritis and neuropsychiatric lupus (P = 0.00065; OR 1.99; 95% CI 1.34-2.95, and P = 1.6 x 10(-7); OR 3.47; 95% CI 2.12-5.70, respectively), as was the frequency of the rs3766379 T allele (P = 0.0014; OR 1.86; 95% CI 1.27-2.71, and P = 2.6 x 10(-7); OR 3.15; 95% CI 2.00-4.96, respectively). In this study, an SNP of the CD244 gene was associated with susceptibility to SLE. There was a strikingly strong association in SLE patients with nephritis and neuropsychiatric lupus, suggesting that this genetic marker could predict involvement of those severe complications.

DOI： 10.1007/s10165-010-0302-x

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The aim of the present study was to evaluate whether the interferon-induced helicase (IFIH1) Ala946Thr (rs1990760 A &gt; G) polymorphism is associated with susceptibility to systemic lupus erythematosus (SLE) and dermatomyositis (DM) or polymyositis (PM) in the Japanese population. The study population consisted of 243 SLE patients, 125 DM/PM patients, and 268 healthy controls from Japan. A Taqman single nucleotide polymorphism genotyping assay was designed for rs1990760 by Applied Biosystems. There were no significant differences between SLE and DM/PM patients and healthy controls regarding the frequency of each genotype and allele. However, the frequency of the AA genotype and the A allele tended to be higher in PM patients with interstitial lung disease (ILD). Additionally, when comparing the AA and AG + GG genotypes at rs1990760, the AA genotype was significantly more frequent in PM patients with ILD than in healthy controls [odds ratio, 3.23 (95% confidence interval, 1.06-9.81); P = 0.04] or in PM patients without ILD [odds ratio, 5.40 (95% confidence interval, 1.37-21.26); P = 0.027]. Our observations suggest that the G allele protects against the onset of ILD and that the AA genotype is a risk factor for lung injury in PM patients.

DOI： 10.1007/s10165-010-0311-9

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OBJECTIVE: The aim of this study is to evaluate the clinical manifestation and prognostic factors of anti-melanoma differentiation-associated gene 5 (MDA5) antibody-associated interstitial lung disease (ILD) with DM. METHODS: Fourteen patients who presented with anti-MDA5 antibody and 10 patients with anti-aminoacyl-tRNA synthetase (ARS) antibody were enrolled. All patients were diagnosed as having DM with ILD. Clinical manifestations in the patients with anti-MDA5 antibody were compared with those in the patients with anti-ARS antibody. RESULTS: The frequencies of acute/subacute interstitial pneumonia (A/SIP) and fatal outcome were significantly higher in the subset with anti-MDA5 antibody. The creatine kinase (CK) value was significantly lower and the gamma-glutamyl transpeptidase and ferritin values were significantly higher in the subset with anti-MDA5 antibody. Significant correlations were found between PaO(2)/F(i)O(2) and ferritin (r(s) = -0.59, P = 0.035), alveolar-arterial oxygen difference (A-aDO(2)) and KL-6 (r(s) = 0.73, P = 0.016) and A-aDO(2) and ferritin (r(s) = 0.66, P = 0.013) in the subset with anti-MDA5 antibody. The most significant prognostic factor was ferritin. The cumulative survival rate was significantly lower (P < 0.0001) in the subset with ferritin >or=1600 ng/ml than that in the subset with ferritin <1600 ng/ml in anti-MDA5 antibody-associated ILD. CONCLUSION: Both serum ferritin and anti-MDA5 antibody are powerful indicators for the early diagnosis of A/SIP with DM. Ferritin also predicts disease severity and prognosis for patients with anti-MDA5 antibody. Intensive treatment should be administered to cases that have anti-MDA5 antibody-associated ILD with DM showing hyperferritinaemia, especially if the ferritin level is >or=1600 ng/ml.

DOI： 10.1093/rheumatology/keq149

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ACADEMIC PRESS INC ELSEVIER SCIENCE  

We investigated the expression of hepatocyte growth factor (HGF), which has mitogenic and anti-fibrotic activities, in muscle tissue of polymyositis/dermatomyositis (PM/DM) patients, as well as its functional roles in cultured myoblasts. Immunohistochemistry in muscle from PM/DM patients revealed that HGF was expressed predominantly on infiltrating mononuclear cells and that muscle cells expressed the receptor c-met. Cultured myoblasts produced HGF; which was increased by IL-1 alpha but suppressed by TGF-beta and dexamethasone. Exogenous HGF induced myoblast proliferation and reduced procollagen type I production. Furthermore, HGF enhanced the gene expression of muscle regulatory factors MyoD and Myf5, while suppressing expression of fibrosis-related genes, connective tissue growth factor and alpha-smooth muscle actin. Although dexamethasone showed contrasting effects to HGF on the expression of these genes, co-treatment with HGF ameliorated the effects of dexamethasone. Taking the beneficial roles of HGF into consideration, administration of HGF might contribute to muscle regeneration in PM/DM especially under corticosteroid treatment. (C) 2010 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.clim.2010.04.015

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：OXFORD UNIV PRESS  

Objectives. Acute/subacute interstitial pneumonia (A/SIP) is an intractable and fatal complication of DM. Since a useful indicator predicting the complication of A/SIP has not been found, the aim of this study was to determine whether serum ferritin is a potential predictive indicator of the occurrence of A/SIP in 64 patients with DM.
Methods. Of the total patients enrolled, 19 had A/SIP, 24 had chronic interstitial pneumonia and 21 were without interstitial lung disease (ILD). Clinical manifestations and laboratory data were obtained from medical records on admission.
Results. Serum ferritin levels were extremely high in patients with DM with A/SIP. It was significantly higher in DM with A/SIP than that in DM without A/SIP (median 790 vs 186 ng/ml; P&lt;0.0001). The cumulative survival rate for 6 months was 62.7% in patients with DM with A/SIP. Moreover, the cumulative survival rate was significantly (P = 0.016) lower in the group with ferritin levels &gt;= 1500 ng/ml than the rate in the group with ferritin levels &lt; 1500 ng/ml.
Conclusions. Serum ferritin can be useful as a predictor of the occurrence of A/SIP and correlates with the prognosis of A/SIP in DM. The intensive treatment using combination therapy with various immunosuppressant agents should be chosen for patients with ILD with DM showing hyperferritinaemia, especially levels &gt; 1500 ng/ml.

DOI： 10.1093/rheumatology/keq073

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Neurological involvement occurs in approximately 20% of patients with primary Sjogren's syndrome. Although neurological symptoms can affect the peripheral nervous system and the central nervous system, the most frequent symptom is polyneuropathy. Small fiber neuropathy (SFN) is a form of painful peripheral polyneuropathy that is common in patients with diabetic neuropathy, but may also occur in toxic, infectious, or immune-mediated neuropathy. We show here a patient with Sjogren's syndrome who developed SFN and was treated with intravenous immunoglobulin (IVIG) therapy, which was immediately and extremely effective. Because of the efficacy of IVIG therapy, we propose that direct immune-mediated mechanisms may be involved in the pathogenesis of SFN complicated by Sjogren's syndrome.

DOI： 10.1007/s10165-009-0180-2

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Sympathetic storms (SyS) are characterized by hyperactivity of autonomic functions, resulting in episodes of hyperthermia, hypertension, tachycardia, and hyperhidrosis. We show here a patient with neuro-Behcet&apos;s disease (NBD) complicated by SyS. Although SyS is well known to occur with brain tumors, trauma, and hydrocephalus, this is the first report to show that SyS is a manifestation of central nervous system involvement in a patient with NBD. High concentrations of norepinephrine (NE) and IL-8 in cerebrospinal fluid reflected the activity of SyS. The patient&apos;s symptoms showed almost complete improvement after treatment with corticosteroids and intravenous cyclophosphamide. Also, the concentrations of NE and IL-8 were decreased to normal levels. An awareness of the potential for SyS and adequate immunosuppressant therapy are of importance when dealing with patients with NBD.

DOI： 10.1007/s10067-008-1070-2

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Language：Japanese   Publisher：(一社)日本神経学会  

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Objective. Clinical pictures of polymyalgia rheumatica (PMR) and remitting seronegative symmetrical synovitis with pitting edema (RS3PE) are often indistinguishable from those of early rheumatoid arthritis (RA). To investigate whether there is a difference in immunological aspects among these 3 disorders, we performed a phenotypic analysis of peripheral blood lymphocytes. Patients and methods. Eleven patients with early RA, 14 with PMR and 11 with RS3PE were enrolled in this study. After separation of mononuclear cells from peripheral blood using the Ficoll-Hypaque method, surface markers and intracellular cytokines of lymphocytes were analyzed by 2- or 3-color flow cytometry. Results. Both PMR and RS3PE showed a significant decrease in CD8+CD25+ cells (p&lt
0.05), and significant increases in CD4+IFN-γ+IL-4- (p&lt
0.05), CD8+IFN-γ+IL-4 (p&lt
0.05 and p&lt
0.01, respectively) and CD4+TNF-α+ cells (p&lt
0.05) compared with early RA. CD3+CD4+ cells were higher in PMR than in RS3PE (p&lt
0.01), but there were no significant differences in any other phenotypes between these disorders. Conclusions. A decrease in activated cytotoxic/suppressor T cells and increases in circulating Th1 and Tc1 cells may be common characteristics of PMR and RS3PE in comparison with early RA. Both disorders are clearly different from early RA, and probably belong to the same disease entity with regard to phenotypes of peripheral blood lymphocytes. © Copyright Clinical and Experimental Rheumatology 2008.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：INFORMA HEALTHCARE  

We describe a 69-year-old woman who developed subacute onset cognitive decline after hitting the left side of her head. Cerebral spinal fluid showed yellowish discoloration with highly elevated protein content. FLAIR MRI revealed diffuse high signal intensity in all cortical sulci, and leptomeningeal enhancement in the left cerebral hemisphere was seen in the T1 image after contrast administration. She was treated with a corticosteroid. Consciousness disturbance was temporarily relieved but again worsened, resulting in an apathetic state due to communicating hydrocephalus. A shunt tube was placed in her right lateral ventricle. A brain biopsy disclosed multiple cortical microbleeds and heavy deposition of A beta-immuoreactive amyloid on vascular walls. Inflammatory mononuclear cells surrounded a few leptomeningeal vessels. After the operation her condition further deteriorated and she fell into a coma. MRI showed diffuse swelling of the right cerebral white matter. She again received high-dose corticosteroid and gradually recovered during the following 2 months. On MRI the vast majority of abnormal signals in the right cerebral white matter disappeared. An initial manifestation of this patient was possibly caused by multiple microhemorrhages from fragile cortical and subarachnoid vessels with A beta-amyloid deposition, which was triggered by head trauma. CAA-related inflammation possibly worsened this condition. Additionally, surgical intervention for communicating hydrocephalus might have induced cerebral amyloid angiopathy (CAA)-related leukoencephalopathy in her right cerebral hemisphere. These CAA-derived manifestations are unusual and high-dose corticosteroids seems to be useful for vascular events in CAA patients.

DOI： 10.1080/13506120701815589

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：JAPAN SOC INTERNAL MEDICINE  

We report a 28-year-old woman patient suffering from refractory subcutaneous abscess. Stimuli-induced microbicidal reactive oxygen metabolites formation test of the patient's neutrophils revealed that only 9.6% of the neutrophils produced H2O2. DNA analysis of the CYBB that encodes gp91(phox) demonstrated that she was heterozygous for a nonsense mutation, (206)Trp(TGG)/stop(TGA) and therefore, a diagnosis of adult onset X-linked chronic granulomatous disease was made. Our molecular biological study revealed that her disease was caused by a de novo mutation in the CYBB gene on the paternal-origin X-chromosome and a skewed inactivation of the normal maternal X-chromosome.

DOI： 10.2169/internalmedicine.47.0919

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：TAYLOR & FRANCIS LTD  

We report a 67-year-old male patient who suffered from nephrotic syndrome and progressive renal dysfunction with monoclonal gammopathy (IgM kappa). Renal biopsy demonstrated amyloid deposition in glomeruli. Immunohistochemical studies of the renal amyloid using a number of antibodies, including anti-lambda and anti-kappa light chains, AA, beta(2)-microglobulin, and transthyretin, showed negative findings. Biochemical analysis of the deposited amyloid fibrils in gastroduodenal mucosa revealed that the amyloid fibrils were composed of an immunoglobulin heavy chain variable region (VH) fragment belonging to the VH1 subgroup, and a diagnosis of AH amyloidosis was made. In our institute, three patients with AH amyloidosis including the present one have been identified during the past 2 years, so AH amyloidosis seems to be by no means a rare disorder.

DOI： 10.1080/13506120802006229

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Objective To investigate the clinical usefulness of measuring diameters of spinal nerve roots on magnetic resonance imaging (MRI) in patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) with regard to the diagnosis and estimation of neurofunctional impairment.
Patients and Methods Fourteen patients with CIDP (mean age, 38.9 +/- 19.2 years) and 10 controls were enrolled in this study. Diameters of cervical and lumbosacral spinal nerve roots were determined on the short tau inversion recovery image of MRI. Correlations between these diameters and clinical indices, including the conduction velocity of median and tibial nerves, were examined.
Results Mean diameters of cervical and lumbosacral spinal nerve roots in CIDP patients were 6.0 to 6.8 mm and 7.3 to 10.4 mm, respectively. CIDP patients showed higher values of the diameter in C5 (p &lt; 0.05), C6 (p &lt; 0.05), C7 (p &lt; 0.005) and C8 (p &lt; 0.01) than controls. C7 and C8 showed significantly negative correlations between diameters of spinal nerve roots and the F-wave conduction velocity (FWCV) (p &lt; 0.05). In the lumbosacral region, L3, L4 and S1 showed significantly negative correlations between diameters of spinal nerve roots and FWCV (p &lt; 0.005, p &lt; 0.0005 and p &lt; 0.005, respectively). The latency-time difference between F- and M-waves increased with diameters of spinal nerve roots, and there were significantly positive correlations between them in L3 (p &lt; 0.05) and L4 (p &lt; 0.005).
Conclusion Hypertrophy of spinal nerve roots shown on MRI may be useful as a clue to the diagnosis of CIDP and also as a clinical marker suggesting impairment of peripheral nerve conduction, particularly FWCV.

DOI： 10.2169/internalmedicine.47.1272

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We report three patients with AL amyloidosis manifesting as systemic lymphadenopathy, mainly in the cervical and supraclavicular regions. Histopathology of lymph nodes showed massive deposition of AL amyloid with no abnormal findings suggestive of lymphoproliferative disorders. Two of the patients were considered to be classifiable as primary systemic AL amyloidosis based on the presence of M-protein in serum and abnormal plasma cells or lymphoplasmacytoid cells in the bone marrow probably producing the precursor immunoglobulin, although no visceral organs were affected. The size of the involved lymph nodes in these two patients increased gradually, and one was treated with rituximab and VAD (vincristine, doxorubicin and dexamethasone) followed by high-dose melphalan with autologous peripheral blood stem cell transplantation (auto-PBSCT). The remaining patient showed no obvious change in the size of lymph nodes or detectable M-protein in serum. The prognosis of AL amyloidosis manifesting as lymphadenopathy is usually good as long as there are no hematological malignancies or rapid increases in the size of lymph nodes, but in cases of the systemic type, intensive chemotherapy, such as high-dose melphalan with auto-PBSCT, should be actively considered in order to avoid possible involvement of visceral organs.

DOI： 10.1080/13506120802006047

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：JAPAN SOC INTERNAL MEDICINE  

Objective Intensive chemotherapy targeting plasma cell dyscrasia has been recently employed for the treatment of primary systemic AL amyloidosis. We prospectively studied the clinical usefulness of cyclic VAD (vincristine, doxorubicin and dexamethasone) in patients with primary systemic AL amyloidosis who were ineligible for high-dose melphalan with autologous stem cell support.
Patients and Methods Eight patients (mean age, 60.4+/-8.8 years) were treated with cyclic VAD until the disappearance of M-protein from both serum and urine. Of these, seven showed nephrotic syndrome before the start of VAD irrespective of a decrease in creatinine clearance. Serial follow-up studies after VAD evaluated hematological status and organ function.
Results Four patients (50%) showed a marked decrease in abnormal plasma cells in the bone marrow and normalized kappa/lambda ratios of serum free light chain in conjunction with disappearance of M-protein after 1 to 3 courses of VAD. There were no serious adverse events, and nephrotic syndrome gradually improved with no hematological relapse in the follow-up period of 3 to 5 years. The remaining 4 patients showed worsening of congestive heart failure and/or systemic edema ascribable to dexamethasone, resulting in cessation of cyclic VAD before disappearance of M-protein. All of these patients died of multiple organ failure or required permanent hemodialysis within 1 year after the start of cyclic VAD.
Conclusion Cyclic VAD is a potent therapeutic option in primary systemic AL amyloidosis, but in patients with renal or cardiac dysfunction careful management for adverse events, especially body fluid retention, is necessary.

DOI： 10.2169/internalmedicine.47.0949

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Objective Primary systemic AL amyloidosis arises from immunoglobulin light chains produced by plasma cell dyscrasia. To prospectively investigate the production of M-protein and plasma cells in bone marrow before and after chemotherapy, we performed flow cytometry and analysis of serum free light chains (FLCs).
Patients and Methods Fifty-nine patients with primary systemic AL amyloidosis (mean age, 59.9 +/- 8.8 years) were enrolled in this study, and of these 31 were serially studied before and after chemotherapy. Complete hematological remission was defined as normalization of the FLC kappa/lambda ratio.
Results MPC-1-CD45 (p&lt;0.05) and MPC-1(+)CD45 CD49e (p&lt;0.005) were significantly higher, and MPC-1-CD45(+)(p&lt;0.05), MPC-1(+)CD45(+)CD49e (p&lt;0.0001) and MPC-1(+)CD45(+)CD49e(+) (p&lt;0.0005) were significantly lower in the patients with AL amyloidosis than in controls. There was a significantly positive correlation between the serum predominant FLC/serum creatinine ratio and MPC-1(+)CD45CD49e (p&lt;0.05). After chemotherapies, such as high-dose melphalan with autologous stem cell support, 20 of 31 patients with AL amyloidosis achieved complete hematological remission. There were no significant differences in any subtype of plasma cells before treatment between the remission and non-remission groups, but in the former group MPC-1(+)CD45CD49e and MPC-1-CD45(+) were significantly decreased and increased after chemotherapy compared with before, respectively.
Conclusion Abnormal plasma cells in the bone marrow, particularly the MPC-1+CD45CD49e subset, may be important as a follow-up marker before and after chemotherapy in primary systemic AL amyloidosis. These cells maintain low levels as long as no relapse occurs.

DOI： 10.2169/internalmedicine.47.0966

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We report 3 patients with nephrotic syndrome ascribed to primary systemic AL amyloidosis that were successfully treated with VAD (vincristine, doxorubicin and dexamethasone) alone. M-protein in serum disappeared soon after VAD, and nephrotic syndrome gradually improved in parallel with a decrease in daily protein excretion in urine. Long-term follow-up of these patients showed neither relapse of nephrotic syndrome nor reappearance of M-protein. High-dose melphalan followed by autologous stem cell support is a standard therapy for primary systemic AL amyloidosis, but in high-risk cases for this treatment, such as elderly patients and those with multiple organ involvement, VAD might be a therapeutic option.

DOI： 10.2169/internalmedicine.47.0709

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：CHURCHILL LIVINGSTONE  

We report a patient with multiple sclerosis (MS) who developed subcutaneous nodules on the face, shoulders and extremities while being treated with interferon (IFN)-beta-1b. These nodules fluctuated in parallel with myelopathy, and were diagnosed as lupus erythematosus profundus (LEP) based on histopathological findings. The patient showed no relapse of either neurological symptoms or subcutaneous nodules after cessation of (IFN)-beta-1b. This agent can cause induration and necrosis in the sites of injection but also systemic skin lesions such as LEP ascribable to its immunomodulatory effects. (c) 2006 Elsevier Ltd. All rights reserved.

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We report a young female patient with Henoch-Schonlein purpura (HSP) nephritis complicated by reversible posterior leukoencephalopathy syndrome (RPLS). The patient suddenly showed generalized seizures and cortical blindness with severe hypertension due to renal insufficiency approximately 1 year after cessation of corticosteroid treatment for HSP nephritis. Magnetic resonance imaging (MRI) demonstrated bilateral abnormal signals mainly in the cerebellum and white matter of the occipital lobe. Clinical symptoms quickly improved in conjunction with disappearance of abnormal signals on brain MRI after starting control of hypertension and continuous hemodiafiltration with steroid pulse therapy and plasmapheresis. RPLS may be caused by vasculitis and also by hemodynamic change due to severe hypertension in HSP, particularly in patients with nephropathy. In such cases intensive treatment should be performed as soon as possible to avoid neurological sequelae.

DOI： 10.1007/s10067-006-0502-0

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Familial amyloid polyneuropathy (FAP) is a form of hereditary generalized amyloidosis. Liver tissue explanted from FAP patients has normal structure and function, except for the production of amyloidogenic variant transthyretin (TTR), and domino liver transplantation (DLT) using grafts from FAP patients was first performed in 1995. FAP symptoms usually develop in genetically determined individuals after the age of 20, but it is difficult to estimate when FAP symptoms will appear in domino recipients. Concerning this problem, histological findings showing amyloid deposition have recently been obtained in a few domino recipients of FAP livers. This study investigated the presence of de novo amyloid deposition in the gastroduodenal mucosa of domino recipients transplanted at our institution. Biopsy of gastroduodenal mucosa was carried out in 5 recipients of FAP livers and TTR-derived amyloid deposits were detected in 2 patients, both of whom had undergone DLT 47 months previously. In FAP liver recipients, de novo systemic amyloid deposition may begin much sooner than previously supposed. Therefore, careful follow-up of domino recipients of FAP livers is required. © 2007 AASLD.

DOI： 10.1002/lt.20954

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We report a patient with rheumatoid arthritis (RA) who showed bicytopenia with hyperferritinemia and hepatic dysfunction ascribable to hemophagocytic syndrome (HPS) 2 weeks after commencement of bucillamine. Pathology of the bone marrow showing infiltration of macrophages confirmed the diagnosis of HPS. On the basis of renal dysfunction with an increase in fibrin degradation products, disseminated intravascular coagulation was considered to be concurrent with HPS. Oral prednisolone and cyclosporine A were started right after cessation of bucillamine, and yielded complete normalization of hepatic and renal function and hematology. As there was neither disease activity of RA nor associated infection throughout the clinical course, bucillamine was suspected of being the cause of HPS in our patient. HPS is a very rare complication in RA, but should be actively considered when abnormalities in laboratory data, especially pancytopenia and hepatic dysfunction, quickly worsen.

DOI： 10.2169/internalmedicine.46.0396

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DOI： 10.1007/s10067-005-0119-8

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We report an 85-year-old man with Hashimoto&apos;s encephalopathy (HE) who showed spontaneous complete remission. The autoantibody against the amino (NH(2)) terminal region of alpha-enolase was positive in our patient. Neuropsychological manifestations, such as personality change and progressive cognitive impairment, gradually improved over approximately 6 weeks after onset of disease without corticosteroid treatment in parallel with a decrease in the anti-thyroglobulin antibody in the cerebrospinal fluid. HE should be considered as a possible diagnosis even in elderly patients with neuropsychiatric symptoms, particularly when a previous history of thyroid disease is present.

DOI： 10.2169/internalmedicine.46.0266

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PARTHENON PUBLISHING GROUP  

Previously, we reported a case of localized plasma cell type Castleman's disease with severe hepatomegaly and reactive systemic AA amyloidosis. The amyloid deposits were demonstrated in both the hepatic tissue and in the gastric mucosa. Surgical resection of an isolated extra-hepatic tumor was performed. The laboratory findings, including SAA and IL-6, remained within normal limits and the patient's hepatomegaly subsequently showed regression. Nine years after the operation, no amyloid deposition was seen in the gastric mucosa and the patient's liver was of normal size. Our findings with long-term follow up in this case indicated that the cessation of SAA production was the probable cause of histopathological regression of AA amyloid deposits in this patient.

DOI： 10.1080/13506120600876930

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：CHURCHILL LIVINGSTONE  

We report a patient with chronic inflammatory, demyelinating polyradiculoneuropathy (CIDP) who showed high titers of anti-sulfated glucuronyl paragloboside (SGPG) IgM antibody without M-protein in serum. The patient was resistant to corticosteroids and immunosuppressants, but after administration of rituximab, clinical symptoms improved and the patient remained in a stable state for approximately 10 months. Rituximab may be a potent therapeutic option for refractory cases of CIDP irrespective of detectable M-protein in either serum or urine. (c) 2006 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.jocn.2005.09.008

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We report a patient with severe cranial polyneuropathy as well as sensory limb neuropathy. Biclonal serum IgM-κ/IgM-λ gammopathy was found and serum anti-myelin-associated glycoprotein (MAG)/sulfoglucuronyl paragloboside (SGPG) IgM antibody was also detected. Immunofluorescence analysis of a sural nerve biopsy specimen revealed binding of IgM and λ-light chain on myelin sheaths. No amyloid deposition was detected in biopsied tissues except for the hard palate, suggesting that the amyloidosis was of the localized type and had no relation to the pathogenesis of cranial neuropathy. Our observations indicate that the anti-MAG/SGPG IgM antibody may be responsible for this patient's cranial polyneuropathy, which is a rare manifestation in anti-MAG/SGPG-associated neuropathy. © 2006 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.jns.2006.01.018

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To date, the presence of amyloidosis associated with immunoglobulin heavy chain (AH amyloidosis) was reported in only 7 cases. Although AH amyloidosis is caused mainly by plasma cell dyscrasia, as in AL amyloidosis, we report a 61-year-old patient who presented with nephrotic syndrome caused by AH amyloidosis associated with lymphoplasmacytic lymphoma. Biochemical and molecular analyses of the deposited amyloid fibrils and heavy-chain genes of lymphocytes showed that proliferative lymphoma cells produced a γ heavy chain, not a μ heavy chain, which carried an unusual truncated diversity (D) segment of the variable region. Our results indicate that production of the abnormal heavy chain caused by the partially deleted D segment gene is responsible for γ heavy-chain-related amyloid fibril formation in this patient. © 2006 National Kidney Foundation, Inc.

DOI： 10.1053/j.ajkd.2006.02.174

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DOI： 10.1016/j.jocn.2004.12.008

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DOI： 10.2169/internalmedicine.45.1587

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We report a patient with polymyalgia rheumatica (PMR) who showed a relapse soon after tapering of oral prednisolone. C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) were quickly normalized after the re-increase in oral prednisolone, and muscle pain and stiffness gradually improved in parallel with a decrease in serum amyloid A (SAA). Flow cytometry simultaneously demonstrated an increase in CD8+CD25+ cells and a decrease in CD4+CD25+ cells and CD4+CD45RA+ cells. When clinical symptoms remain with negative results for CRP and ESR even after the start of corticosteroid treatment, SAA might be a potent therapeutic marker for disease activity in PMR. Copyright © 2005 by The Japanese Society of Internal Medicine.

DOI： 10.2169/internalmedicine.44.1009

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Neuropsychiatric symptoms are often seen in patients with systemic lupus erythematosus (SLE). To investigate the relationship between involvement of the nervous system and clinical factors, including autoantibodies and the activity of SLE, we retrospectively reviewed 25 patients with neuropsychiatric SLE (NPSLE, mean age: 35.2±12.2 years). As controls 37 SLE patients without neuropsychiatric manifestations (mean age: 31.8±15.8 years) were employed in this study. At the onset no significant differences were seen in any clinical factors between the patients and the controls except for serum antinuclear antibodies. In relapse, the patients with NPSLE showed significantly lower levels of Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) scores without neuropsychiatric evaluation (p&lt
0.0001), erythrocyte sedimentation rate (ESR, p&lt
0.005), and antinuclear and anti-double-stranded DNA antibodies (p&lt
0.005) and higher WBC values (p&lt
0.05) than at the onset. Also in the patients with relapsing NPSLE similar significant differences were seen in these parameters between onset and relapse (p&lt
0.005). Despite a lack of significant differences, the cerebrospinal fluid showed lower values in cell counts, total protein, and IgG in relapse than at onset. These results suggest that there are no clinical factors that predict the development of NPSLE and that relapse can occur with low disease activity in the nervous system even with an inactive state of other organ involvement. Since NPSLE may suddenly relapse with a slight change in common disease activation markers, including inflammatory reactions, autoantibodies, and complements in serum and CSF findings, adequate corticosteroid and/ or immunosuppressive agents should be given at the onset and gradually be tapered after recovery, while looking out for recurrence. © Clinical Rheumatology 2005.

DOI： 10.1007/s10067-004-1060-y

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Objective: Immunoglobulin-related free light chains (FLCs) in serum have recently become quantitatively detectable using the nephelometric assay in plasma cell disorders, including multiple myeloma and AL amyloidosis. To investigate whether FLCs are useful as a diagnostic and therapeutic marker in Japanese patients with primary systemic AL amyloidosis, we determined these values in serum before and after chemotherapy. Patients and methods: The serum FLC analysis was carried out in 25 patients with primary systemic AL amyloidosis (mean age, 60.1±8.4 years). All of the patients were shown to have either ALκ- or ALλ-immunoreactive amyloid deposits on biopsied tissues. Thirteen patients were treated with VAD (vincristine, doxorubicin and dexamethasone) alone (n=6) or VAD and subsequent high-dose melphalan followed by autologous stem cell support (n=7), and serum FLCs were serially determined before and after the chemotherapy. Results: Before chemotherapy the amyloidogenic FLC was elevated in serum with or without abnormal κ/λ ratios in 24 patients, including 5 with undetectable M-protein in both serum and urine on immunofixation. After chemotherapy the amyloidogenic FLC in serum was significantly decreased irrespective of high-dose melphalan (p&lt
0.05), and all the patients with normalized κ/λ ratios showed a good prognosis. Conclusions: With respect to sensitivity and quantification serum FLCs will be a key marker for diagnosis and therapeutic effects in primary systemic AL amyloidosis. The prognosis of patients with this disease may be improved if the κ/λ ratio in serum can be normalized by intensive chemotherapy.

DOI： 10.2169/internalmedicine.44.428

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This report concerns a patient with systemic lupus erythematosus (SLE) who died of acute respiratory distress syndrome (ARDS) 1 day after the onset of pulmonary symptoms. Autopsy demonstrated severe hemophagocytosis in the bone marrow and histopathology indicating a marked increase in vascular permeability in both lungs and kidneys. In this patient, active SLE and associated hemophagocytic syndrome may have induced an increase in the production of inflammatory cytokines, which immediately induced ARDS. Since fatal ARDS can occur as a life-threatening complication of SLE, careful observation is necessary, particularly when there are clinical findings suggestive of associated hemophagocytic syndrome. © Clinical Rheumatology 2004.

DOI： 10.1007/s10067-004-0985-5

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To investigate whether there is a correlation between subtypes of plasma cells in the bone marrow and the production of M-protein, flow cytometry and serum free light chain (FLC) analyses were carried out in 17 patients with primary systemic AL amyloidosis (mean age, 59.9 ± 8.8 years) and controls with M-protein (MGUS controls, n = 6) and without it (negative controls, n = 9). The patients showed a significantly higher value in the serum predominant FLC:serum creatinine ratio (43.8 ± 63.2) and CD38++ CD19 -CD56+ subpopulation (monoclonal plasma cells) (2.57 ± 5.35%) than either the negative (p &lt
0.0005 and p &lt
0.001, respectively) or MGUS controls (p &lt
0.05). With respect to maturation of plasma cells in the bone marrow, the intermediate (MPC-1+CD45 -CD49e-) and mature (MPC-1+CD45 +CD49e-) subtypes were significantly higher (49.2 ± 23.2%, p &lt
0.005) and lower (27.6 ± 21.3%, p &lt
0.005) in the patients than in the negative controls, respectively. The serum predominant FLC:serum creatinine ratio was elevated in parallel with an increase in CD38++CD19-CD56+ and MPC-1+CD45 +CD49e- cells and a decrease in mature subtypes (MPC-1+CD45-CD49e- and MPC-1 +CD45+CD49e+ cells), There was a significantly positive correlation between the serum predominant FLC:serum creatinine ratio and either CD38++CD19-CD56+ (r=0.510, p &lt
0.05) or MPC-1+CD45-CD49e- cells (r = 0.481, p &lt
0.05). In primary AL amyloidosis M-protein is probably produced by increased monoclonal plasma cells in the bone marrow, particularly by the intermediate subpopulation with a phenotype of MPC-1+CD45 -CD49e-. © 2005 Taylor &amp
Francis Group Ltd.

DOI： 10.1080/02772240500032515

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Patients with AL amyloidosis were treated with VAD (vincristine, doxorubicin and dexamethasone) with or without high-dose melphalan followed by auto-PBSCT according to eligibility criteria based on disease severity, and prospectively investigated the therapeutic benefits and complications. Thirty-one patients were enrolled in this study. VAD and subsequent high-dose melphalan with auto-PBSCT were performed only in patients who met all of the eligibility criteria. Among patients ineligible for this treatment, VAD alone was performed in those with satisfactory general status. Eleven patients met the eligibility criteria, and of these, 7 were treated with VAD and subsequent high-dose melphalan with auto-PBSCT. Seven patients received VAD alone, and the remaining 17 were treated with the supportive therapy. Among the 14 patients treated with chemotherapy, 9 (5 of the 7 treated with VAD and high-dose melphalan, and 4 of the 7 treated with VAD alone) showed complete hematological response with apparent improvement of amyloidosis-related clinical symptoms. Serious complications of chemotherapy were cytomegalovirus infection and pneumocystis carinii pneumonia seen in 1 and 2 patients, respectively. These chemotherapies may be effective for reduction of M-protein and are also useful in improving of amyloidosis-induced organ dysfunction. In patients who cannot tolerate high-dose melphalan, VAD alone is a potent therapeutic option, although there are possible harmful effects on the heart and peripheral nerve.

DOI： 10.1080/13506120412331336907

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To investigate the therapeutic efficacy of cyclosporin A (CyA) in the treatment of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), a microemulsion form of this drug (Neoral®) was orally given to seven patients with the disease who were unresponsive or resistant to conventional therapies. The daily dose of CyA was carefully controlled in order to keep the plasma trough concentration between 100 and 150 ng/ml. Within 1 month of initiation of CyA, all patients subjectively showed improvement of clinical symptoms, while both modified Rankin and INCAT disability scores were significantly decreased (p&lt
0.05) and grip strength was significantly increased (p&lt
0.05) 3 months after initiation compared with before. Total protein in the cerebrospinal fluid was significantly decreased 3 and 6 months after starting CyA (p&lt
0.05). Although the maximal motor nerve conduction velocity showed a significant improvement in the median nerve 1 to 1.5 years after commencement of CyA (p&lt
0.05), there were no significant changes in any other neurophysiological parameters. One patient with anti-sulphoglucuronyl paragloboside IgM antibodies gradually became resistant to CyA, but the rest have since been in good neurological condition without complications ascribable to this drug. These results suggest that oral CyA may be effective even for refractory cases with CIDP. CyA should be actively considered as a therapeutic option when patients with CIDP are resistant to conventional treatment. © 2004 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.jns.2004.05.014

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We report a patient with polymyositis (PM) associated with myasthenia gravis (MG). Both disorders had been controlled for around 15 years by oral prednisolone and a cholinesterase inhibitor following surgical removal of invasive thymoma and radiotherapy, but muscular weakness due to myalgia and an increase in serum levels of myogenic enzymes, mainly ascribable to the recurrence of PM, reappeared immediately after cessation of these drugs, which was done because the patient had multiple bone fractures and severe osteoporosis due to the long-term corticosteroid therapy. Oral tacrolimus was therefore tried, and produced an improvement in muscular symptoms in association with normalization of myogenic enzymes. PM associated with MG as in this patient might be the best indication for tacrolimus, considering its efficacy in MG, but this drug should also be actively considered as a therapeutic option in refractory cases of PM alone, particularly when either corticosteroids or other immunosuppressive agents are not usable. © Clinical Rheumatology 2004.

DOI： 10.1007/s10067-004-0865-z

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We report a patient with systemic lupus erythematosus (SLE) who developed fulminant pulmonary hemorrhage. This patient also showed liver dysfunction, bicytopenia and hyperferritinemia, with an increase in serum levels of interleukin (IL)-1β, IL-6 and tumor necrosis factor-α (TNF-α) at the onset of pulmonary symptoms, probably indicating an associated hemophagocytic syndrome. Despite an acute progressive course temporarily requiring mechanical ventilation the patient was successfully treated with continuous drip infusion of tacrolimus, plasmapheresis and intravenous high-dose immunoglobulin and corticosteroid. In this patient increased inflammatory cytokines ascribable to activation of macrophages and/or helper T cells were considered to play an important role in the pathogenesis of the pulmonary hemorrhage. Because this complication is frequently fatal in SLE, intensive therapy, including immunosuppressants and plasmapheresis, should be actively considered as early as possible after onset. © Clinical Rheumatology 2004.

DOI： 10.1007/s10067-003-0859-2

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This report concerns a patient with IgM AL amyloidosis due to a B cell lymphoproliferative disorder who was successfully treated with VAD and subsequent high-dose melphalan followed by autologous stem cell support. After this chemotherapeutic regimen, the patient showed complete hematological remission and improvement in nephrotic syndrome. These findings suggest that high-dose melphalan may also be effective for lymphoplasmacytoid cells producing monoclonal IgM which are phenotypically distinct from plasma cells. Myeloablative therapies, such as high-dose melphalan, should definitely be considered as a treatment option for AL amyloidosis, irrespective of the type of precursor immunoglobulin.

DOI： 10.1080/13506120410001725994

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Language：English   Publisher：The Japanese Society of Internal Medicine  

We report a patient with rheumatoid arthritis (RA) who developed malignant lymphoma of the diffuse large B-cell type in the right submandibular region shortly after initiation of oral methotrexate (MTX). Despite cessation of MTX, the lymphadenopathy did not regress, and only reached complete remission after 3 courses of CHOP therapy followed by irradiation. In this patient highly active RA itself was considered to be the main cause of malignant lymphoma, and MTX might have contributed to the development by modifying the immune system. When RA is highly active, MTX should be used carefully because of the possible development of malignant lymphoma as well as other serious complications.

DOI： 10.2169/internalmedicine.43.135

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Language：Japanese   Publishing type：Research paper (scientific journal)  

We report a 46-year-old woman who extensively showed intracranial calcifications possibly due to neuropsychiatric systemic lupus erythematosus (NPSLE) and antiphospholipid syndrome (APS). She had been treated with oral prednisolone for SLE since age 15, and experienced two abortions due to APS at ages 28 and 35 respectively. After a convulsion attack due to NPSLE at age 30, she had been suffering from dysarthria and choreic movement in her extremities. On admission to our hospital brain CT demonstrated extensive and symmetrical calcifications bilaterally in basal ganglia, subcortical white matter of the frontal lobe and dentate nuclei. She was shown to have neither metabolic nor congenital disorders causing these intracranial abnormalities. In this patient both NPSLE and APS, therefore, might have contributed to the remarkable intracranial calcifications in a long clinical course.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Japanese Society of Internal Medicine  

Primary AL amyloidosis involves vital organs from the early phase of illness, resulting in a poor prognosis. We report a patient with nephrotic syndrome due to this type of amyloidosis, who was successfully treated with two courses of VAD (vincristine, doxorubicin and dexamethasone) and subsequent high-dose melphalan (140 mg/m2) with autologous stem cell support. Following the serial chemotherapy his proteinuria improved, and M protein became undetectable in both serum and urine. To avoid the progression of primary AL amyloidosis, intensive chemotherapy should be actively used when the general status and vital organ functions are well preserved.

DOI： 10.2169/internalmedicine.42.72

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Informa Healthcare  

To investigate whether monoclonal plasma cells in the bone marrow are useful as a therapeutic marker in AL amyloidosis, serial flow cytometry was performed in five patients with this disorder before and after chemotherapy. Four patients were treated with 2 or 3 courses of VAD (vincristine, doxorubicin and dexamethazone) and subsequently with high-dose melphalan followed by auto-PBSCT. The remaining one patient was treated with two courses of VAD alone. Before treatment all patients exhibited a CD19-CD56+ subpopulation, which indicated monoclonal plasma cells, in varying degrees. After treatment all patients showed a decrease in monoclonal plasma cells in accordance with the disappearance of M-protein in serum and/or urine. In two patients treated with VAD followed by auto-PBSCT, polyclonal (CD19 +CD56-) and total plasma cells gradually increased in the follow-up study, while monoclonal plasma cells stayed at less than 0.3% nine months after treatment. No apparent correlation was found between altered maturation of plasma cells and disappearance of M-protein. With respect to easy detection of monoclonal plasma cells producing amyloidogenic M-protein, flow cytometry of bone marrow aspirates is useful and reliable in the follow-up of patients with AL amyloidosis and in the evaluation of the effects of chemotherapy.

DOI： 10.3109/13506120309041742

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Parthenon Publishing Group Ltd  

AL amyloidosis is an intractable disease resulting from a plasma cell dyscrasia which has a wide clinical spectrum. To investigate the phenotype of plasma cells in the bone marrow, a flow cytometric analysis was carried out in 10 patients with this disease (mean age, 57. 8±7.9 years) and controls with M-protein (positive controls, n=4) and without it (negative controls, n=8). All patients were shown to have either Aκ- or Aλ-immunoreactive amyloid deposits on the biopsied tissues. On flow cytometry CD38--CD19-CD56- cells (polyclonal plasma cells) showed no significant difference between patients (0.59±0.37%) and either negative (2.25±2.84%) or positive controls (0.38±0.20%), while CD38+-CD19-CD56+ cells (monoclonal plasma cells) showed a significantly higher level in the patients (1.34±1.54%) than in either negative (0.041±0.004%, p&lt
0.005) or positive controls (0.11±0.09%, p&lt
0.05). With respect to maturation of plasma cells, five of the patients (50%), three of the positive controls (75%) and all of the negative controls showed a dominant proliferation of mature subtype (CD45+MPC-1+CD49e- or CD45-MPC-1+CD49e-. Immature (CD45+MPC-1- or CD45-MPC-1-) and intermediate (CD45-MPC-1+CD49e-) subtypes were dominantly present in the bone marrow in 2 and 3 patients, respectively. In AL amyloidosis monoclonal plasma cells producing M-protein can be easily and reliably detected in the bone marrow by flow cytometry. This analysis might provide plasma cell phenotypic markers useful for assessing the prognosis and for monitoring the response to treatment.

DOI： 10.3109/13506120309041732

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Parthenon Publishing Group Ltd  

A 74-year-old woman who had developed numbness in both hands was diagnosed as having bilateral carpal and right cubital tunnel syndrome and underwent bilateral carpal and right cubital tunnel release. Transthyretin immunoreactive amyloid deposits were seen on specimens and were also detected in gastric, duodenal and ileal mucosal biopsies. The transthyretin gene analysis showed no mutation. This is a rare case of senile systemic amyloidosis presenting as carpal tunnel syndrome.

DOI： 10.3109/13506120209114102

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Language：Japanese   Publisher：(一社)日本リウマチ学会  

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＜文献概要＞Point ◎筋炎患者の大半では,疾患特異的な自己抗体(筋炎特異自己抗体:MSA)が血清から検出される.◎筋炎関連間質性肺疾患でみられるMSAの大半は,抗ARS抗体と抗MDA5抗体である.◎抗ARS抗体陽性例では筋炎症状に乏しく,肺病変が主体となる症例が存在する.◎抗MDA5抗体陽性間質性肺疾患は,1年以内の死亡率が約30%と予後不良である.◎抗ARS抗体陽性間質性肺疾患は,ステロイド薬の減量で再燃を繰り返す傾向にある.

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Language：Japanese   Publisher：(株)先端医学社  

多発性筋炎や皮膚筋炎(polymyositis:PM/dermatomyositis:DM)では、約半数の症例に間質性肺疾患(interstitial lung disease:ILD)を併発する。2020年4月に、日本呼吸器学会・日本リウマチ学会合同にて、「膠原病に伴う間質性肺疾患診断・治療指針2020」が発刊されPM/DM関連ILD(PM/DM-ILD)の治療アルゴリズムが提唱された。PM/DM-ILDは、個々の症例で進行速度、重症度、治療反応性がさまざまであり、個々の患者に対して適切な治療戦略を十分に勘案する必要がある。筋炎特異自己抗体をはじめとする予後不良因子によるアウトカムのリスク評価法を確立させ、PM/DM-ILDにおける治療の層別化をより緻密に構築していくことが、PM/DM患者のQOLおよび生命予後の改善を図るうえで重要と考えられる。(著者抄録)

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60歳男性。咳嗽、呼吸困難、発熱、手指疼痛を主訴に当院救急搬送となった。入院時、発熱、炎症反応上昇、動脈閉塞による両側手指壊疽、肺胞出血(びまん性間質性肺病変)、縦隔気腫・気胸、胃壁のびまん性肥厚を認めたことから、結節性多発性動脈炎を考え、メチルプレドニゾロン、エンドキサンパルス療法、ヘパリン投与、胸腔ドレナージを行い、気管挿管による人工呼吸管理を開始した。その後は全身状態が改善傾向にあり、第12病日の内視鏡検査と皮膚生検で胃癌併発抗ARS抗体陽性が明らかになった。悪性腫瘍の根治術目的にステロイド漸減を目指したが、第35病日に死亡した。

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DOI： 10.18888/se.0000000539

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DOI： 10.2169/naika.106.1433

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&lt;p&gt;【目的】MESACUP&lt;sup&gt;TM&lt;/sup&gt; anti-MDA5テストが保険収載され，抗MDA5抗体が広く診療で測定可能になった．本キットはこれまで我々の研究室で測定していた測定系（以下in-house ELISA）と抗体価の算出法が異なるため，両測定法における抗体陽性・陰性結果と抗体価の相関を検討する．【方法】72例（筋炎70例と健常者2例）を対象にMESACUP&lt;sup&gt;TM&lt;/sup&gt; anti-MDA5テスト及びin-house ELISAで抗MDA5抗体を同時に測定．MESACUP&lt;sup&gt;TM&lt;/sup&gt; anti-MDA5テストで32 index以上を，in-house ELISAで8 unit以上を陽性とした．5例で抗体価の推移も検討した．両測定法で結果に解離がみられた際には免疫沈降–免疫ブロット法（IP-IB）で抗体の存在を確認した．【成績】両測定法の陽性一致率96％，陰性一致率92％，判定一致率97％と良好な結果で，抗体価は有意な相関（r = 0.73, P &lt; 0.0001）を認めた．抗MDA5抗体陽性例の抗体価範囲は，MESACUP&lt;sup&gt;TM&lt;/sup&gt; anti-MDA5テストで106-197 indexで，37/46例で定量上限の150 indexを超えていたが，in-house ELISAで15-816 unitと多くが定量範囲内に分布した．抗体価は治療後に低下し，両測定法で概ね同じ傾向を示した．全5例でin-house ELISAで陰性化したのに対してMESACUP&lt;sup&gt;TM&lt;/sup&gt; anti-MDA5テストで3例は陰性化せず，IP-IBで抗体陽性が確認された．【結論】両測定法による陽性・陰性の判定は概ね一致したが，抗体価の算出法が異なるため，従来法で報告された抗体価を用いた治療効果判定の解釈には注意を要する．&lt;/p&gt;

DOI： 10.2177/jsci.40.299c

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DOI： 10.2177/jsci.40.314a

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Language：Japanese   Publisher：日本臨床免疫学会  

<p>【目的】抗KS抗体陽性患者の臨床特徴を検討する．【方法】2006年9月から2017年4月に当院を受診し，多発性筋炎（PM）/皮膚筋炎（DM）/筋力低下の乏しい皮膚筋炎（CADM）または間質性肺疾患（ILD）と診断された症例のうち，RNA免疫沈降法によって抗aminoacyl tRNA synthetase（ARS）抗体が血清中に検出された43例を対象とした．診断時の臨床背景と転帰について後ろ向きに解析し，臨床特徴がまだ十分明らかでない抗KS抗体陽性例（KS例）と非KS例に層別化して比較検討した．【結果】抗ARS抗体陽性43例（女性31例）の発症年齢は62.7±13.4歳，発症後の観察期間は4.2±4.2年であった．臨床診断はPM 3例，DM 4例，CADM 6例，ILD 30例であった．抗ARS抗体の内訳は，KS 12例，EJ 11例，PL-7 8例，Jo-1 7例，PL-12 4例，OJ 2例だった．KS 12例を非KS 31例と比較したところ，筋力低下を伴う筋病変は0例（0％），7例（23％）と少ない傾向にあった（p = 0.1）．肺病変は12例（100％），29例（94％）に見られ，胸部CT所見ではUIP/NSIPパターンは両群で差はなかったが，KS例で嚢胞性病変が有意に多かった（p = 0.001）．ヘリオトロープ疹，ゴットロン徴候，メカニックハンドは両群で差は見られず，関節炎はKS例で少ない傾向にあった（p = 0.09）．観察期間中に0例，4例が死亡したが，累積生存率に差は見られなかった（p = 0.2）．【結論】抗KS抗体陽性例は，筋病変が乏しく，嚢胞性病変を伴う肺病変が多い特徴を有し，比較的経過が良好であった．</p>

DOI： 10.2177/jsci.40.314a

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Language：Japanese   Publisher：The Japanese Society of Internal Medicine  

DOI： 10.2169/naika.105.2251

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Language：Japanese   Publisher：The Japanese Society of Internal Medicine  

&lt;p&gt;多発性筋炎（polymyositis：PM）/皮膚筋炎（dermatomyositis：DM）は，自己組織に対して過剰な免疫応答が生じる結果，筋肉，皮膚，関節，肺などに炎症を来たす膠原病である．皮疹を認めない場合はPM，特徴的な皮疹を伴う場合はDMと診断する．PM/DMでは間質性肺炎や悪性腫瘍の併発が比較的多い．モデルマウスを用いた病態機序の解明，自己抗体の発見とその測定法の開発，間質性肺炎を併発したPM/DMの診断・治療のマネジメントなど，ここ10年で日本より世界へ多くの研究成果が発信された．2015年には厚生労働省自己免疫疾患に関する調査研究班内PM/DM分科会により治療ガイドラインが作成された．これらの成果により，日常診療を行う上で非常に有用なノウハウが，医療従事者や患者を含め世の中へ示された．今後，PM/DM患者の機能予後・生命予後のさらなる改善をめざし，具体的な個別化医療の確立が求められる．&lt;/p&gt;

DOI： 10.2169/naika.105.2251

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Language：English   Publishing type：Book review, literature introduction, etc.   Publisher：Libertas Academica Ltd.  

Interstitial lung disease (ILD) is a prognostic factor for poor outcome in polymyositis (PM)/dermatomyositis (DM). The appropriate management of ILD is very important to improve the prognosis of patients with PM/DM. ILD activity and severity depend on the disease subtype. There-fore, clinicians should determine therapeutic strategies according to the disease subtype in each patient with PM/DM. Anti–melanoma differentiation-associated gene 5 antibody and hyperferritinemia predict the development and severity of rapidly progressive (RP) ILD, particularly in East Asian patients. Combination therapy with corticosteroids, intravenous cyclophosphamide pulse, and calcineurin inhibitors should be administered in RP-ILD. In contrast, patients with anti–aminoacyl-tRNA synthetase (ARS) show better responses to corticosteroids alone. However, ILDs with anti-ARS often display disease recurrence or become refractory to corticosteroid monotherapy. Recent studies have demonstrated that the administration of tacrolimus or rituximab in addition to corticosteroids may be considered in ILD patients with anti-ARS. Large-scale, multicenter randomized clinical trials should be conducted in the future to confirm that the aforementioned agents exhibit efficacy in ILD patients with PM/DM. The pathophysiology of ILD with PM/DM should also be elucidated in greater detail to develop effective therapeutic strategies for patients with ILD in PM/DM.

DOI： 10.4137/CCRPRPM.S23313

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Language：Japanese   Publisher：東京女子医科大学学会  

第349回東京女子医科大学学会例会 平成26年2月22日(土) 総合外来センター5階大会議室

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Idiopathic inflammatory myopathies (IIMs) are a group of inflammatory muscle disorders of unknown etiology
these include polymyositis (PM), dermatomyositis (DM), and inclusion body myositis. Extra-muscular manifestations such as dermatitis, arthritis, interstitial lung disease (ILD), cardiomyopathy, and enteropathy are occasional complications in patients with PM/DM. Several myositis-specific autoantibodies (MSAs) have been discovered in IIMs
these can help predict clinical characteristics, response to treatment, and prognosis. For example, anti-aminoacyl-tRNA synthetase (ARS) antibodies, including Jo-1 antibody (Ab) and anti-melanoma differentiation-associated gene 5 (MDA-5) Ab, have been associated with the manifestation of ILD in PM and DM. Anti-MDA5 Ab-associated ILD has a 1-year survival rate of 50-60%
however, short-term prognosis is relatively good in anti-ARS Ab-associated ILD. Fatal outcome occurs remarkably often within the first 6 months of anti-MDA5 Ab-associated ILD. Therefore, intensive treatment should be administered to patients harboring anti-MDA-5 Ab or showing hyperferritinemia in ILD with DM. In addition, corticosteroid occasionally induces myopathy, which is an issue arising in PM/DM treatment. Some experts recommend combination therapy of corticosteroid and an immunosuppressive agent as a first-line treatment for myositis in PM/DM. Methotrexate and azathioprine are commonly used immunosuppressive agents for myositis in western countries. Immunosuppressive agents are steroid-sparing, serving to mitigate corticosteroid-related side effects, thus making combination therapy an effective treatment option. Preventing the progression of physical dysfunction is of prime importance to patients with PM/DM. Dermatologists, neurologists, and rheumatologists should therefore work together to care for these patients before muscular and extra-muscular involvement develop progressively and irreversibly.

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N-Methyl-D-aspartate (NMDA) receptors are ligand-gated ion channels with crucial roles in synaptic transmission and central nervous system plasticity. Systemic lupus erythematosus (SLE) is a multi-system inflammatory disorder characterized by the presence of autoantibodies directed against double-stranded (ds) DNA. The pathophysiology of neuropsychiatric (NP) SLE is diverse and complicated. In SLE, anti-dsDNA antibody (Ab) cross-reacts with NMDA receptors. Serum anti-NMDA receptor Ab was found in -30% of SLE patients. We demonstrated the relationship between anti-NMDA receptor Ab and each organ's involvement in SLE, and the biological function of anti-NMDA receptor Ab. The frequency of NP-SLE was significantly higher in the anti-NMDA receptor Ab positive subset than the negative subset, although the frequencies of serositis and nephritis were not significant. Anti-NMDA receptor Ab titer inversely correlated with leukocyte counts and hemoglobin levels. Moreover, regarding to the effects of anti-NMDA receptor Ab on NMDA receptor-transfected cell viability and intracellular Ca2+ level, there was a significant inverse correlation between anti-NMDA receptor Ab titer and cell viability, and a significant association between anti-NMDA receptor Ab titer and intracellular Ca 2+ level. In conclusion, anti-NMDA receptor Ab is associated with NP-SLE and cytopenia. Anti-NMDA receptor Ab could cause the injury of NMDA receptor-expressed cells by increasing Ca2+ influx.

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Systemic lupus erythematosus (SLE) is characterized by the presence of several autoantibodies, including anti-dsDNA. Among types of SLE, neuropsychiatric (NP)-SLE accounts for significant morbidity and mortality. Cerebrovascular disease, which could account for most of the serious permanent neurological damage, is a common presentation of NP-SLE. The pathophysiology of NP-SLE involves several factors, including vasculitis, thrombosis, and inflammation and/or apoptosis of neuronal and glial cells. The current treatment strategy is immunosuppressive therapy, which is occasionally insufficient for patients with NP-SLE. Recent studies have revealed that autoantibodies, such as anti-NR2, pass from the peripheral blood to the brain through the blood-brain barrier, cross-react with human brain tissue and cause increased intracellular Ca2+ in SLE. Regulating blood-brain barrier permeability, inhibiting autoantibody deposition in tissues and modulating intracellular Ca2+ may be new concepts for the treatment with NP-SLE. © 2013 Future Medicine Ltd.

DOI： 10.2217/ijr.13.48

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：WILEY-BLACKWELL  

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DOI： 10.15106/J00974.2013227262

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Systemic lupus erythematosus (SLE) is a multi-system inflammatory disorder characterized by the presence of several autoantibodies, including anti-double-stranded DNA. Neuropsychiatric (NP)LE contributes to the prognosis of SLE, and is divided into 19 NPLE syndromes. Its mechanisms are mediated through autoantibodies, complement components, and cytokines. The pathophysiology and diagnosis of NPLE are diverse and complicated. Recent studies have shown that several autoantibodies cross-react with human brain tissue and cause NPLE symptoms in SLE. It is known that in mice, depression and hippocampus-related memory impairment are induced by anti-ribosomal P antibody and anti-NR2 antibody, respectively. In a BMC Medicine research article, Kivity et al. demonstrated novel work showed that the 16/6 Id antibody impaired visual memory and spatial memory by causing hippocampal injury in mice. Given differences in the cross-reactivity of each autoantibody with the nervous system, the clinical features might be different and diverse in NPLE. Identification of autoantibody targets could lead to the development of novel therapies. Investigators and clinicians should consider not only the inhibition of autoantibody synthesis but also the protection of neuronal cells in the treatment strategy for NPLE.

DOI： 10.1186/1741-7015-11-91

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Language：Japanese   Publisher：日本臨床免疫学会  

&amp;emsp;全身性エリテマトーデス（SLE）は，自己抗原に対して過剰反応する樹状細胞やリンパ球が活性化し，抗二本鎖DNA抗体をはじめとする自己抗体の産生，補体及びサイトカインを介して，皮膚炎，関節炎，血球減少，腎炎，神経障害など全身の諸臓器に障害をきたす自己免疫疾患である．一卵性双生児におけるSLEの発症一致率は25%であり，その病因に遺伝的要因が強く関与している．SLEは，20-40歳代の若年女性に発症する頻度が高く，日光暴露にて病状の増悪を認めることから，性ホルモン，紫外線などの環境的要因もSLEの発症に関わっている．個々の症例においてSLEの病状は異なり，その臨床像は多彩である．例えば，SLEに起因する腎炎（ループス腎炎）といっても，メサンギウムの増殖と上皮下や内皮下に免疫複合体の沈着を伴う腎炎と，基底膜の肥厚が主体となる膜性腎症に分けられる．また，SLEに起因する精神・神経障害を呈するneuropsychiatric (NP) SLEでは，アメリカリウマチ学会により19の精神・神経症候に分類され，その病態は複雑で治療もしばしば難渋する．このセッションでは，SLEの予後規定因子であるループス腎炎とNP-SLEを中心に，SLEにおける基本的な病態を踏まえつつ，近年，新たに明らかとなったSLEの病態に関する研究成果をレビューし，その病態の理解を深めていきたい．&lt;br&gt;

DOI： 10.2177/jsci.36.346

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J-GLOBAL

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J-GLOBAL

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DOI： 10.2177/jsci.35.327a

J-GLOBAL

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DOI： 10.2177/jsci.35.373b

J-GLOBAL

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CiNii Books

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Language：Japanese   Publisher：医学出版  

CiNii Books

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Language：English   Publishing type：Rapid communication, short report, research note, etc. (scientific journal)   Publisher：OXFORD UNIV PRESS  

DOI： 10.1093/rheumatology/kes012

Web of Science

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J-GLOBAL

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J-GLOBAL

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