Association of gut commensal translocation with autoantibody production in systemic lupus erythematosus.

OBJECTIVE: Bacterial translocation across the gut barrier has been implicated in the pathogenesis of systemic lupus erythematosus (SLE), though underlying mechanisms remain unclear. This study aimed to investigate the role of translocated bacteria in the context of molecular mimicry by utilizing lupus model mice and blood samples from untreated SLE patients. METHODS: Bacterial translocation was evaluated using nonselective cultured mesenteric lymph nodes (MLNs) from B6SKG mice, a lupus model characterized by impaired TCR signalling and gut dysbiosis. The relationships of detected pathobionts with autoantibody production were examined using in vivo experiments, enzyme-linked immunosorbent assay, immunoblotting, and epitope mapping. RESULTS: Culture-based bacterial profiling in MLNs demonstrated that Lactobacillus murinus was enriched in B6SKG mice with elevated anti-dsDNA IgG levels. Subcutaneous injection of heat-killed L. murinus induced anti-dsDNA IgG production without altering T- or B cell subset composition. Immunoblotting and mass spectrometry analysis identified a peptide ATP-binding cassette (ABC) transporter as a molecular mimicry antigen, with its cross-reactivity in lupus mice confirmed by serological assays and in vivo immunization. The L. murinus ABC transporter exhibited surface epitopes that were cross-reactive with sera from lupus mice and patients. The ABC transporter from R. gnavus, known for its pathogenic role in lupus patients, had a similar epitope sequence to that of the L. murinus ABC transporter and reacted with lupus sera. CONCLUSION: ABC transporters from gut bacteria can serve as cross-reactive antigens that may promote anti-dsDNA antibody production in genetically susceptible mice. These findings underscore the role of commensal-derived molecular mimicry and bacterial translocation in lupus pathogenesis.

Factors affecting discrepancies in disease activity evaluation between patients and physicians in systemic lupus erythematosus-The importance of symptoms such as fatigue.

OBJECTIVES: There are often discrepancies in the evaluation of disease activity between patients and physicians in systemic lupus erythematosus (SLE). In this study, we examined the factors that affect those evaluations. METHODS: Physician visual analogue scale (Ph-VAS), patient VAS (Pt-VAS), Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2k), glucocorticoid (GC) usage and dose, age, Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index, and three patient-reported outcomes (SLE symptom checklist [SSC], short-form 36 questionnaire [SF-36], and LupusPRO) were obtained from a study performed in 2019 using 225 SLE outpatients of the Kyoto Lupus Cohort at Kyoto University Hospital. Correlations among Ph-VAS, Pt-VAS, or dif (Pt-VAS-Ph-VAS) (Pt-VAS minus Ph-VAS) and other factors were examined. RESULTS: We found a significant discrepancy between Pt-VAS (median 38.0 mm) and Ph-VAS (median 18.7 mm) scores (p < 0.001). SSC score showed a significant correlation with Pt-VAS and dif (Pt-VAS-Ph-VAS) (p < 0.001). Among SSC items, fatigue showed the most significant correlation with dif (Pt-VAS-Ph-VAS). We also showed that higher dif (Pt-VAS-Ph-VAS) was associated with lower quality of life (QOL) evaluated by SF-36 and LupusPRO. CONCLUSIONS: Pt-VAS scores tended to be higher than Ph-VAS scores, and the discrepancy was influenced mainly by fatigue. Higher dif (Pt-VAS-Ph-VAS) was associated with lower patient QOL.

Risk factors for serious infections and infection-related mortality in patients with microscopic polyangiitis: Multicentre REVEAL cohort study.

OBJECTIVE: Infections are a critical concern for patients with microscopic polyangiitis (MPA). This study aimed to identify the risk factors associated with serious infections (SIs) and infection-related mortality in patients with MPA, as well as the effect of glucocorticoid (GC) dose tapering on these outcomes. METHODS: This multicentre, retrospective, and observational study utilised data from a cohort of patients with MPA in Japan [Registry of Vasculitis Patients to Establish REAL World Evidence (REVEAL) cohort]. Patients were categorised based on the occurrence of SIs or infection-related deaths, and various characteristics were compared among the groups. RESULTS: Among 182 patients, 66 (36.2%) experienced 129 SIs and 27 (14.8%) developed infection-related deaths. Advanced age, elevated C-reactive protein (CRP) levels, and higher ratio of the GC dose at 3 months to the initial dose were identified as independent risk factors for SIs. Older age was also associated with infection-related deaths. Furthermore, the cumulative incidence of infection-related deaths was significantly higher in patients with a higher ratio of the GC dose at 24 months to the initial dose. CONCLUSION: Older age, elevated CRP levels, and slower GC dose tapering predispose patients to SIs and infection-related deaths. Strategies, such as rapid GC dose tapering, are anticipated to mitigate the risk of infections.

Pathogenicity of IgG-Fc desialylation and its association with Th17 cells in an animal model of systemic lupus erythematosus.

OBJECTIVES: Decreased sialylation of IgG-Fc glycans has been reported in autoimmune diseases, but its role in systemic lupus erythematosus (SLE) is not fully understood. In this study, we examined the pathogenicity of IgG desialylation and its association with Th17 in SLE using an animal model. METHODS: B6SKG mice, which develop lupus-like systemic autoimmunity due to the ZAP70 mutation, were used to investigate the pathogenicity of IgG desialylation. The proportion of sialylated IgG was compared between B6SKG and wild-type mice with or without ß-glucan treatment-induced Th17 expansion. Anti-interleukin (IL)-23 and anti-IL-17 antibodies were used to examine the role of Th17 cells in IgG glycosylation. Activation-induced cytidine deaminase-specific St6gal1 conditionally knockout (cKO) mice were generated to examine the direct effect of IgG desialylation. RESULTS: The proportions of sialylated IgG were similar between B6SKG and wild-type mice in the steady state. However, IgG desialylation was observed after ß-glucan-induced Th17 expansion, and nephropathy also worsened in B6SKG mice. Anti-IL-23/17 treatment suppressed IgG desialylation and nephropathy. Glomerular atrophy was observed in the cKO mice, suggesting that IgG desialylation is directly involved in disease exacerbation. CONCLUSIONS: IgG desialylation contributes to the progression of nephropathy, which is ameliorated by blocking IL-17A or IL-23 in an SLE mouse model.

Rheumatoid factor recognizes specific domains of the IgG heavy chain complexed with HLA class II molecules.

OBJECTIVE: We previously reported that RF recognized the IgG heavy chain (IgGH)/RA-susceptible HLA class II molecule complex. In the present study, we investigated the molecular mechanisms underlying HLA binding to and the RF recognition of IgGH. METHODS: We synthesized various types of IgGH segments, including VH, CH1, CH2 and CH3, and transfected them with or without HLA class II molecules into the Human Embryonic Kidney 293T cell line. IgGH single domains linked with the HLA-Cw3 peptide, which binds to the binding groove of the HLA class II molecule, were also synthesized. The expression of IgGH domains on the cell surface and their recognition by RF were examined using flow cytometry. RESULTS: Flag-tagged IgGH segments containing CH1 (CH1, VH-CH1, CH1-CH2, VH-CH1-CH2, CH1-CH2-CH3 and VH-CH1-CH2-CH3) were clearly presented on the cell surface by HLA-DR4, while segments without the CH1 domain were expressed at a low level, and the CH3 single domain was only weakly detected on the cell surface, even with HLA-DR4. We then transfected IgGH single domains linked to the Cw3 peptide together with HLA-DR4 and showed that RF-containing sera from RA patients only recognized the CH3 domain and none of the other single domains. When various segments without the Cw3 peptide were transfected with HLA-DR4, only the CH1-CH2-CH3 segment and full-length IgGH were detected by the sera of RA patients. CONCLUSION: The CH1 domain of IgGH binds to the RA-susceptible HLA-DR molecule and is expressed on the cell surface. RF specifically recognizes the CH3 domain of the IgGH/HLA-DR4 complex.

Comparisons of SLE-DAS and SLEDAI-2K and classification of disease activity based on the SLE-DAS with reference to patient-reported outcomes.

OBJECTIVES: Although the SLE Disease Activity Score (SLE-DAS) and its definitions to classify disease activity have been recently developed to overcome the drawbacks of the SLE Disease Activity Index 2000 (SLEDAI-2K), the performance of the SLE-DAS for patient-reported outcomes (PROs) has not been fully examined. We aimed to compare SLE-DAS with SLEDAI-2K and validate the classifications of disease activity based on SLE-DAS in terms of PROs. METHODS: We assessed generic quality of life (QoL) using the Medical Outcome Survey 36-Item Short-Form Health Survey (SF-36), disease-specific QoL using the lupus patient-reported outcome tool (LupusPRO), burden of symptoms using the SLE Symptom Checklist (SSC), patient global assessment (PtGA) and physician global assessment (PhGA). RESULTS: Of the 335 patients with SLE, the magnitudes of the mean absolute error, root mean square error, Akaike information criterion, and Bayesian information criterion were comparable for most PROs between the SLE-DAS and SLEDAI-2K. In contrast, SLEDAI-2K had a higher predictive value for health-related QoL of LupusPRO and PtGA than SLE-DAS. Low disease activity, Boolean and index-based remission and categories of disease activity (remission, mild and moderate/severe activity) were significantly associated with health-related QoL in LupusPRO, SSC and PhGA, but not SF-36 or PtGA. CONCLUSION: No clear differences were identified in the use of the SLE-DAS over the SLEDAI-2K in assessing PROs in patients with SLE. The classification of disease activity based on the SLE-DAS was validated against several PROs. SLE-DAS and its categories of disease activity effectively explain some of the PROs.

Clinical profile and outcome of large-vessel giant cell arteritis in Japanese patients: A single-centre retrospective cohort study.

OBJECTIVES: Recent advances in imaging revealed that giant cell arteritis (GCA) is frequently associated with large vessel involvement (LVI), but they may also contribute to earlier diagnosis and treatment of LV-GCA. We aimed to compare the clinical characteristics of GCA with or without LVI and evaluate its association with clinical outcomes. METHOD: We retrospectively reviewed the medical records of 36 patients with GCA in Kyoto University Hospital. RESULTS: Eighteen patients each were assigned to the LVI(+) and LVI(-) groups. Five-year survival rates in the LVI(+) group were better than in the LVI(-) group (p = .034), while five-year relapse-free survival rates were similar between the groups (p = .75). The LVI(+) group required lower doses of glucocorticoid at month 6 (p = .036). Disease activity evaluated with the Birmingham Vasculitis Activity Score at disease onset was higher in the LVI(-) group (p = .014), and the Vasculitis Damage Index score examined at the last visit was higher in the LVI(-) group (p = .011). CONCLUSION: GCA without LVI had more active disease, severer vascular damage, and worse survival, possibly because of ophthalmic complications and their greater glucocorticoid requirement. Our results revisit the impact of cranial manifestations on disease severity and morbidity.

Factors associated with osteoporosis and fractures in patients with systemic lupus erythematosus: Kyoto Lupus Cohort.

OBJECTIVES: Osteoporosis and compression fractures of the lumbar spine are some of the major adverse effects of glucocorticoid therapy in patients with systemic lupus erythematosus (SLE). This study examined the association between bone mineral density, bone turnover markers, presence of vertebral fractures, and Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index in SLE patients. METHODS: This was a cross-sectional study of 246 outpatients with SLE at the Kyoto University Hospital. Lumbar and femoral bone mineral density was measured with dual-energy X-ray absorptiometry, and the presence of vertebral fractures was determined using X-ray, computed tomography, or magnetic resonance imaging. RESULTS: On multiple regression analysis, both high lumbar and femoral T-scores were associated with the concomitant use of hydroxychloroquine (P = .018 and P = .037, respectively), no use of bisphosphonate or denosumab (P = .004 and P = .038, respectively), high body mass index (P < .001), and low bone-specific alkaline phosphatase level (P = .014 and P = .002, respectively). Vertebral fractures showed a significant association with Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index score (P < .001) and femoral T-score (P < .001). CONCLUSION: Vertebral fracture was associated with SLE-associated organ damage, and serum bone-specific alkaline phosphatase level is a potentially useful marker for osteoporosis monitoring in SLE patients.

Cell surface-expressed Ro52/IgG/HLA-DR complex is targeted by autoantibodies in patients with inflammatory myopathies.

Intracellular proteins are often targeted by autoantibodies in autoimmune diseases; however, the mechanism through which intracellular molecules are targeted remains unknown. We previously found that several intracellular misfolded proteins are transported to the cell surface by HLA class II molecules and are recognized by autoantibodies in some autoimmune diseases, such as rheumatoid arthritis, antiphospholipid syndrome, and microscopic polyangiitis. Ro52 is an intracellular Fc receptor that is a target antigen for myositis-associated autoantibodies. We analyzed the role of HLA class II molecules in the autoantibody recognition of Ro52. Ro52 alone was not transported to the cell surface by HLA class II molecules; however, it was transported to the cell surface in the presence of both IgG heavy chain and HLA class II molecules to form a Ro52/IgG/HLA-DR complex. The Ro52/IgG/HLA-DR complex was specifically recognized by autoantibodies from some patients with inflammatory myopathies. We then evaluated 120 patients with inflammatory myopathies with four types of myositis-specific antibodies and analyzed the autoantibodies against the Ro52/IgG/HLA-DR complex. The specific antibodies against the Ro52/IgG/HLA-DR complex were detected in 90% and 93% of patients who were positive for anti-MDA5 and anti-ARS antibodies, respectively. In individual patients with these two inflammatory myopathies, changes in serum titers of anti-Ro52/IgG/HLA-DR-specific antibodies were correlated with the levels of KL-6 (R = 0.51 in anti-MDA5 antibody-positive DM patients, R = 0.67 in anti-ARS antibody-positive PM/DM patients with respiratory symptoms) and CK (R = 0.63 in anti-ARS antibody-positive PM/DM patients with muscle symptoms) over time. These results suggest that antibodies against Ro52/IgG/HLA-DR expressed on the cell surface could be involved in the pathogenesis of inflammatory myopathy subgroups.

Autoantibody profiles associated with morbidity and mortality in scleroderma renal crisis.

OBJECTIVE: The aim of this study was to investigate association of autoantibodies with scleroderma renal crisis (SRC) among Japanese patients. METHODS: The clinical characteristics and mortality of 330 patients with sytemic screlosis (SSc) at Kyoto University Hospital were retrospectively analysed, focusing on possible association with anti-topoisomerase I (anti-topo I), anti-centromere (ACA), anti-RNA polymerase III (RNAPIII) and/or anti-U1-RNP. Logistic regression analyses were performed to reveal any association of these autoantibodies with the development and mortality of SRC. RESULTS: SRC was observed in 24 out of 330 SSc patients, including patients with anti-topo I (n = 12/24, 50%), anti-RNAPIII (n = 7/24, 29%), anti-U1-RNP (n = 5/24, 21%) and ACA (n = 3/24, 13%). Anti-U1-RNP [odds ratio (95% CI), 3.63 (1.11, 10.2)], anti-topo I [3.22 (1.37, 7.57)] and anti-RNAPIII (3.29 [1.16, 8.70]) were associated with the development of SRC. Furthermore, anti-topo I [6.00 (1.11, 41.1)] was associated with 1-year mortality of SRC. The 1-year survival rate after the onset of SRC among all patients and among those positive for anti-topo I was 54% and 33%, respectively. In contrast, the survival rate in patients negative for anti-topo I was 75%, of which the survival rate of patients positive for anti-RNAPIII and ACA was 83% and 100%, respectively. CONCLUSION: Specific SSc-related autoantibodies were associated with the morbidity and mortality of SRC.

Neutrophil count reduction 1 month after initiating tocilizumab can predict clinical remission within 1 year in rheumatoid arthritis patients.

Neutropenia is a common adverse event of tocilizumab (TCZ) in rheumatoid arthritis (RA) patients; however, the association between the decrease in neutrophil counts and the TCZ clinical efficacy remains inconclusive. This study aimed to examine whether TCZ-induced neutrophil decrease at 1 month predicts clinical remission within 1 year. We reviewed medical records of RA patients initiating TCZ between May 2011 and September 2019 in our hospital. The Clinical Disease Activity Index (CDAI) was evaluated at baseline (before initiating TCZ) and 1, 3, 6, and 12 months after administration. Clinical remission was defined when CDAI decreased ≤ 2.8. The ratio of neutrophil counts 1 month after initiating TCZ to those at baseline (neutrophil ratio) was also calculated. Among 255 TCZ-treated patients, 169 with valid CDAI and neutrophil counts were enrolled (with median age of 60 years and 79% females). Rheumatoid factor and anti-cyclic citrullinated peptide antibody were positive in 75% and 83%, respectively, and 56% of the patients had concomitant methotrexate (median dose: 8 mg/week). Multivariate logistic regression analysis suggested baseline CDAI (odds ratio (OR) 0.96, p = 0.045), concomitant PSL (OR 0.42, p = 0.030), and the neutrophil ratio (OR 0.19, p = 0.011) as predictors of CDAI remission. Neutrophil ratio ≤ 0.8 was associated with achieving remission (Fisher's exact test, p = 0.02) with no apparent increase of severe infection. More than 20% reduction of neutrophil count 1 month after initiating TCZ predicts clinical remission within 1 year at an early treatment phase.

Phenotypic landscape of systemic lupus erythematosus: An analysis of the Kyoto Lupus Cohort.

OBJECTIVES: The present study aimed to clarify comprehensive relationships among the clinical variables of systemic lupus erythematosus (SLE). METHODS: We retrospectively surveyed 32 clinical variables in 581 patients and conducted comprehensive association studies among SLE clinical phenotypes. A univariate analysis of all possible combinations was performed, and the results of phenotypic correlations were reduced into two dimensions. We also created a regression formula using L1 regularisation (LASSO) to calculate the probability of exhibiting each phenotype. RESULTS: The univariate analysis identified 26 correlations, including multiple phenotypes with low complement. Some unpredicted correlations were identified, including fever and the anti-Sm antibody (odds ratio; OR = 2.3, p = 1.6 × 10-5) or thrombocytopenia and psychosis (OR = 3.7, p = 3.2 × 10-5). The multivariate analysis accurately estimated the probability of exhibiting each phenotype (area under the curve > 0.7) in 10 out of 20 phenotypes. CONCLUSIONS: The present results show the phenotypic architecture of SLE and represent a model for estimating the probability of exhibiting each phenotype. They also offer insights into the pathology of SLE and estimating the probability of the onset of new phenotypes in clinical practice.

Validation and verification of the Japanese version of the systemic lupus erythematosus symptom checklist for patient quality of life.

OBJECTIVE: The systemic lupus erythematosus (SLE) symptom checklist (SSC) is a patient-reported outcome measure consisting of 38 queries. We translated SSC into Japanese and attempted to validate its usefulness for evaluating the quality of life (QOL) of SLE patients and identify factors that affect QOL. METHODS: Data from the Medical Outcomes Study Short-form 36 questionnaire (SF-36), Japanese LupusPRO, the Japanese version of the SSC (SSC-J) questionnaire, SLEDAI-2k, and the physician global assessment (PGA) were obtained on the same day from 226 SLE outpatients of the Kyoto Lupus cohort at Kyoto University Hospital. Relationships between the total scores or each item of SSC-J and SF-36, Japanese LupusPRO, SLEDAI-2k, or PGA were analyzed by Spearman's rank test. RESULTS: The total scores of SSC-J correlated with the scores of SF-36 and Japanese LupusPRO. In each item of SSC-J, all 38 items correlated with the physical component summary and mental component summary of SF-36 as well as the Health-Related QOL (HRQOL) scores of Japanese LupusPRO, but not with the non-HRQOL of LupusPRO. SSC-J scores correlated with age, PGA, and corticosteroid doses, but not with SLEDAI-2k. CONCLUSIONS: SSC-J is suitable as a disease-specific QOL assessment tool for SLE.

Correlation between irreversible organ damage and the quality of life of patients with systemic lupus erythematosus: The Kyoto Lupus Cohort survey.

OBJECTIVES: It is important to clarify the relationship between irreversible organ damage and the quality of life (QOL) by considering the unique factors of patients with systemic lupus erythematosus (SLE). We aimed to clarify their correlation using SLE-specific QOL assessment tools. We also aimed to identify which type of organ damage is adversely correlated with the QOL. METHODS: We conducted a questionnaire-based survey of outpatients with SLE at Kyoto University Hospital and evaluated irreversible organ damage using the SLICC/ACR damage index (SDI). LupusPRO and the SLE symptom checklist (SSC) were employed as SLE-specific QOL tools, and the SF-36v2 was used as a conventional QOL tool. Multiple linear regression analyses were performed to examine the correlations between the total SDI score and each QOL score, and between each SDI item/system score and each QOL score. RESULTS: We analyzed the data of 265 patients. The total SDI score was significantly correlated with physical (PCS) and role/social component summary (RCS) of the SF-36v2, health-related QOL (HRQOL) of LupusPRO, and SSC (p < 0.001). Among the SDI items, atrophy/weakness and osteoporosis with fracture/vertebral collapse were negatively correlated with PCS (ß = -0.40, p < 0.001/ß = -0.28, p < 0.001), RCS (ß = -0.30, p < 0.001/ß = -0.35, p < 0.001), and HRQOL (ß = -0.34, p < 0.001/ß = -0.31, p < 0.001), respectively. Among the SDI systems, musculoskeletal damage had higher negative correlations with PCS (ß = -0.51, p < 0.001), RCS (ß = -0.29, p < 0.001), and HRQOL (ß = -0.40, p < 0.001). CONCLUSION: We demonstrated the QOL of patients with SLE is negatively correlated with irreversible organ damage. We also revealed musculoskeletal damage is adversely correlated with the health-related QOL, especially the physical and role/social QOL.

Long-term outcomes of refractory Takayasu arteritis patients treated with biologics including ustekinumab.

OBJECTIVES: Biologics have been used to treat refractory Takayasu arteritis (TAK), but their efficacy and safety have not been sufficiently evaluated. METHODS: We extracted clinical information from medical records for TAK patients who were treated with biologics including ustekinumab (UST) at Kyoto University Hospital. We also analysed the patient's genetic backgrounds. RESULTS: Of 163 cases, 12 (7.4%) were treated with infliximab, tocilizumab, or UST (n = 3). Erythrocyte sedimentation rate (ESR), C-reactive protein levels (CRP), and prednisolone (PSL) dose were significantly decreased 12 months after the initiation of biologics. When compared with the 15 patients who were only treated with immunosuppressants (IS group), the change in ESR from baseline was significantly lower in the biologics group than in the IS group (-2 mm/h, p = .005). The proportion of patients with HLA-B*52 and the risk-type alleles of the SNP were similar in both groups. Among the biologics, TCZ showed the highest continuation rate. UST exhibited marginal effects on reducing ESR, CRP levels, and PSL dose. No adverse events were observed in patients with UST for approximately 3 years. CONCLUSIONS: Biological treatments resulted in a reduction in inflammatory markers and PSL dose in refractory TAK patients.

Efficacy of plasma exchange in anti-MDA5-positive dermatomyositis with interstitial lung disease under combined immunosuppressive treatment.

OBJECTIVES: Rapidly progressive interstitial lung disease (RP-ILD) with poor prognosis often accompanies anti-melanoma differentiation-associated gene 5 (MDA5)-positive DM. Combined immunosuppressive therapy, including glucocorticoids, calcineurin inhibitors and intravenous cyclophosphamide (IVCY) is reportedly effective in DM with RP-ILD, but some patients remain resistant to therapy. We examined the utility of plasma exchange (PE) in such intractable cases and investigated the prognostic factors of the disease. METHODS: Thirty-eight anti-MDA5-positive DM-ILD patients who received the combined immunosuppressive therapy were retrospectively reviewed. Their serum cytokines were evaluated by multiplex assay before treatment. The patients were divided into two groups: those who achieved remission without exacerbation of respiratory dysfunction (n = 25, group A) and those who progressed to hypoxemia during the treatment (n = 13, group B). RESULTS: PE was carried out in eight group B patients, but none of group A. Five of the eight treated with PE survived, while the five untreated patients died (P =0.04). Higher neutrophil lymphocyte ratio, higher serum ferritin, hypoxemia, high-resolution computed tomography (HRCT) score before treatment and increase of Krebs von Lungen-6 (KL-6) in the first 4 weeks of the treatment were the prognostic factors for disease progression. Serum cytokines such as IL-1, IL-6, IL-8, IL-10, IL-12p70, IL-18 and sCD163 levels were higher in group B than group A. CONCLUSION: PE should be an effective adjuvant treatment in anti-MDA5-positive DM with RP-ILD. Assessment of basal laboratory tests or monocyte/macrophage-derived cytokines and the increase of KL-6, HRCT score and hypoxemia may help us to predict intractable cases and to make early treatment decisions regarding PE in anti-MDA5-positive DM.

Thigh muscle MRI findings in myopathy associated with anti-mitochondrial antibody.

INTRODUCTION: Myopathy associated with anti-mitochondrial antibody (AMA) has recently been characterized as a distinct type of idiopathic inflammatory myopathy. The purpose of this study is to evaluate the pattern of involvement in thigh muscles in AMA myopathy using MRI. METHODS: Six patients with AMA myopathy were identified and their muscle MRI findings evaluated. RESULTS: On thigh muscle MRI, all six patients showed high signal intensity with short-tau inversion recovery that reflected disease activity mostly in the adductor magnus, called a "cuneiform sign." Fatty degeneration was also prominent in the adductor magnus, as well as the semimembranosus muscles. DISCUSSION: These characteristic changes on MRI contrast with those of other inflammatory myopathies. From these observations, we concluded that the localization pattern of the inflammatory changes in muscle MRI can contribute to the diagnosis of AMA myopathy.

Association of anti-NR2 and U1RNP antibodies with neurotoxic inflammatory mediators in cerebrospinal fluid from patients with neuropsychiatric systemic lupus erythematosus.

BACKGROUND: Autoantibodies (auto Abs) and inflammatory mediators (IMs) in cerebrospinal fluid (CSF) may be involved in the pathogenesis of neuropsychiatric systemic lupus erythematosus (NPSLE). It is suggested that anti-N-methyl D-aspartate receptor NR2 subunit (NR2) Ab can develop NP manifestation after blood-brain barrier (BBB) abruption. We also reported the association between NPSLE and CSF anti-U1RNP Ab. In the present study, combined effects of CSF anti-NR2 and anti-U1RNP Abs on IMs in patients with NPSLE were examined. METHODS: CSF samples were collected from 69 patients with NPSLE and 13 non-NPSLE controls. CSF anti-NR2 and anti-U1RNP Abs were determined using ELISA. Levels of IL-6, IL-8, and monokine induced by IFN-γ (MIG) in CSF were measured by quantitative multiplex cytokine analysis. RESULTS: CSF IL-6 levels were higher in CSF anti-NR2-positive than in CSF anti-NR2-negative patients (p = 0.003) and non-NPSLE controls (p = 0.015) and were positively correlated with anti-NR2 titer (r = 0.42). CSF IL-8 levels were higher in CSF anti-U1RNP-positive than in CSF anti-U1RNP-negative patients (p = 0.041). CSF MIG levels were more elevated in CSF anti-NR2-positive (p = 0.043) and anti-U1RNP-positive patients (p = 0.029) than in non-NPSLE controls. Additionally, in double positive (DP; both anti-NR2 and U1RNP Ab positive) group, CSF IL-6 and MIG levels were significantly higher than in the double negative (DN; both anti-NR2 and U1RNP Ab negative) group. However, combined effect of both Abs on IM elevation and clinical manifestation was not clear. CONCLUSIONS: CSF anti-NR2 and anti-U1RNP Abs have different effects on the elevation of CSF IM levels in patients with NPSLE. Additional effect of anti-U1RNP Abs on anti-NR2 Ab-mediated NP manifestation, however, was not recognized in our study.

Activated neutrophil carbamylates albumin via the release of myeloperoxidase and reactive oxygen species regardless of NETosis.

Objective: An anti-carbamylated albumin antibody was detected in rheumatoid arthritis (RA) patients, and its presence was associated with serum myeloperoxidase (MPO) levels, as we reported previously. Since MPO is a key enzyme for carbamylation and is released by neutrophil extracellular traps (NETs), we aimed to demonstrate that NETosis induces carbamylation.Methods: Human neutrophils were isolated from a healthy donor, pre-treated with or without diphenyleneiodonium (DPI, an inhibitor for the generation of reactive oxygen species (ROS)), Cl-amidine (a peptidylarginine deiminase inhibitor), 4-aminobenzoic acid hydrazide (4-ABAH, an MPO inhibitor), or GW311616A (a neutrophil elastase (NE) inhibitor), and incubated for 8 h with or without phorbol 12-myristate 13-acetate (PMA). Proteins in the medium were collected and the carbamylation of albumin was evaluated by Western blotting.Results: The carbamylation of albumin was detected in the culture medium of activated neutrophils. NETosis was observed under the stimulation by PMA. DPI and 4-ABAH inhibited the carbamylation of albumin and NETosis. GW311616A inhibited NETosis, but not carbamylation. Neither carbamylation nor NETosis was inhibited by Cl-amidine.Conclusion: Activated neutrophils may carbamylate ambient albumin, and this is dependent on ROS and MPO, but does not require NETosis.

Predicting factors for disappearance of anti-mutated citrullinated vimentin antibodies in sera of patients with rheumatoid arthritis.

Objectives: We aimed to determine the predicting factors for disappearance of anti-mutated citrullinated vimentin antibody (anti-MCV Ab) in sera from rheumatoid arthritis (RA) patients.Methods: In 2013, 95 RA patients whose Disease Activity Score with erythrocyte sedimentation rate were moderate to severe (DAS28-ESR ≥3.2) at baseline were enrolled. Titers of anti-MCV Ab and anti-cyclic citrullinated peptide (anti-CCP) Ab for 2013 and 2014 were measured. The association of anti-MCV disappearance with disease activity, treatment, interstitial lung disease (ILD), and serum markers of ILD were retrospectively examined. Predicting factors of anti-MCV disappearance were determined by multivariable analysis.Results: While anti-CCP positivity rate did not change during the year, anti-MCV Ab changed from positive to negative in 18 patients (=19.0%). Continuous biological disease-modifying anti-rheumatic drug use, prednisolone dose (≥5.0 mg daily), and low KL-6 level (<191 U/mL) were determined as predicting factors of anti-MCV disappearance by multivariable analysis. In our cohort, anti-MCV Ab disappearance was not linked to clinical and radiological improvement.Conclusion: Different from anti-CCP Ab, anti-MCV Ab in sera from RA patients can disappear in a year. Some predicting factors for such negative seroconversion were found, whereas clinical significance of anti-MCV Ab disappearance was undetermined.