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Objectives This study aimed to develop clinical guidelines for the management of vascular Behçet’s disease (BD) by the Behçet’s Disease Research Committee of the Ministry of Health, Labour and Welfare of the Japanese Government. Methods A task force proposed clinical questions (CQs) concerning vascular BD based on a literature search. After screening, draft recommendations were developed for each CQ and brushed up in three blinded Delphi rounds, leading to the final recommendations. Results This study provides recommendations for 17 CQs concerning diagnosis and differential diagnoses, assessment of disease activity, and treatment. The guidelines recommend immunosuppressive treatments, for both arterial and venous involvement with active inflammation. Anticoagulation is also recommended for deep vein thrombosis except in high-risk patients. Surgical and endovascular therapies can be optional, particularly in patients with urgent arterial lesions undergoing immunosuppression. In addition, two sets of algorithms for diagnosis and treatment are shown for arterial and venous involvement. Conclusions These recommendations are expected to serve as useful tools in the daily clinical practice of BD. This content has already been published in Japanese in the Guideline for the Management of Behçet’s Disease 2020 and is submitted with permission from both the primary and secondary publishers.

Objectives Approximately 30–60% of Behçet’s disease patients exhibit joint symptoms. The aim of this study was to determine the clinical characteristics of such patients in Japan. Methods This study retrospectively analyzed 151 Behçet’s disease patients with joint symptoms who had been treated at seven cooperative medical institutions from 2007 to 2017. We investigated their clinical characteristics and treatments. Results The most commonly affected joints were the knee, ankle, and proximal interphalangeal joints. Of the cases with pain and swelling, 18 of 293 joints (11 cases) displayed narrowing of the cleft or deformity by X-ray analysis. Improvement in their arthritis was observed in 80% of the patients who received steroids as initial treatment; however, the rate of improvement was lower in patients who had received prednisolone (PSL) at Conclusions These results suggest that PSL is effective for remission induction for the treatment of joint symptoms of Behçet’s disease. Additionally, colchicine is effective in preventing the recurrence of joint symptoms in Behçet’s disease. Furthermore, joint damages like joint space narrowing or with any deformity can often be observed in Behçet’s disease.

Neuropsychiatric manifestations (NP) are common in systemic lupus erythematosus (SLE). However, the pathophysiological mechanisms are not completely understood. Neurofilament light protein (NfL) is part of the neuronal cytoskeleton. Increased NfL concentrations, reflecting neurodegeneration, is observed in cerebrospinal fluid (CSF) in several neurodegenerative and neuroinflammatory conditions. We aimed to explore if plasma NfL could serve as a biomarker for central nervous system (CNS) involvement in SLE. Sixty-seven patients with SLE underwent neurological examination; 52 underwent lumbar puncture, while 62 underwent cerebral magnetic resonance imaging (MRI). We measured selected auto-antibodies and other laboratory variables postulated to have roles in NP pathophysiology in the blood and/or CSF. We used SPM12 software for MRI voxel-based morphometry. Age-adjusted linear regression analyses revealed increased plasma NfL concentrations with increasing creatinine (β = 0.01, p

AIM Anti-ribosomal P protein antibodies (anti-ribo P) have been reported as one of the specific autoantibodies in patients with systemic lupus erythematosus (SLE) and has been demonstrated to bind and activate macrophages in vitro. Clinically, hyperferritinemia has been known to be a biomarker for macrophage activation. The aim of this study is to clarify the relationship of anti-ribo P and clinical characteristics and biomarkers including serum ferritin in patients with SLE. METHODS Clinical parameters and laboratory data were measured in patients with active SLE (N = 127) in our university hospital. The risk factors affected by anti-ribo P were retrospectively calculated by logistic regression analysis, and the correlation of anti-ribo P and clinical factors was demonstrated. RESULTS Anti-ribo P was significantly elevated in active SLE compared to non-SLE diseases (P

Objective Brain parenchymal involvement in Behçet's disease (BD) (neuro-Behçet's disease, NB) can be classified into acute type (ANB) and chronic progressive type (CPNB) based on differences in the clinical course and responses to corticosteroid treatment. The present study developed evidence-based recommendations for the management of NB. Methods The task force of the research subcommittee consisted of seven board-certified rheumatologists (one was also a board-certified neurologist) and three board-certified neurologists. First, several clinical questions (CQs) were established. A systematic literature search was performed by The Japan Medical Library Association in order to develop recommendations. The final recommendations for each CQ developed from three blind Delphi rounds, for which the rate of agreement scores [range 1(strongly disagree)-5(strongly agree)] was determined through voting by the task force. Results A flow chart of the algorithm was established for the management of ANB and CPNB. Thirteen recommendations were developed for NB (general 1, ANB 7, CPNB 5). The strength of each recommendation was established based on the evidence level as well as the rate of agreement. Conclusion The recommendations generated in this study are based on the results of uncontrolled evidence from open trials, retrospective cohort studies and expert opinions, due to the lack of randomized clinical trials. Nevertheless, these recommendations can be used for international studies, although verification by further properly designed controlled clinical trials is required.

Transforming growth factor β activated kinase 1 (TAK1) has been found to mediate maladaptive tumour necrosis factor (TNF) signalling, leading to hyperactive downstream nuclear factor Kappa β (NF-κB) signalling. We explored the expression of TAK1 mRNA in bone marrow CD34+ cells in rheumatoid arthritis (RA) to delineate the mechanism for their abnormal response to TNF-α and differentiate into fibroblast-like cells.CD34+ cells were purified from bone marrow samples obtained from 47 RA patients and 27 osteoarthritis (OA) patients during joint operations via aspiration from the iliac crest. The expression of mRNAs for TAK1 and NFκB1 was examined by quantitative RT-PCR.TAK1 mRNA expression in bone marrow CD34+ cells was significantly higher in RA than in OA (TAK1/β-actin: [11.980 ± 2.380] x 10-3 and [5.593±1.307] x 10-3 [mean ± SEM], respectively; p=0.0238). TAk1 mRNA expression was not different depending on the type of operated joints or on the severity type of RA. Nor was it correlated with serum CRP or rheumatoid factor or with administration of methotrexate, other conventional synthetic disease-modifying anti-rheumatic drugs or oral glucocorticoid. TAK1 mRNA expression was significantly correlated with NFκB1 mRNA expression in RA bone marrow CD34+ cells.These results indicate that TAK1 mRNA expression is enhanced in bone marrow CD34+ cells independently of the clinimetrics or treatment in RA. It is also suggested that the upregulation of TAK1 mRNA expression might lead to the enhanced expression of NFκB1 mRNA in bone marrow CD34+ cells, but possibly not vice versa, resulting in their abnormal response to TNF-α.

Neuropsychiatric manifestations (NP) are common in systemic lupus erythematosus (SLE). However, the pathophysiological mechanisms are not completely understood. Neurofilament light protein (NfL) is part of the neuronal cytoskeleton. Increased NfL concentrations, reflecting neurodegeneration, is observed in cerebrospinal fluid (CSF) in several neurodegenerative and neuroinflammatory conditions. We aimed to explore if plasma NfL could serve as a biomarker for central nervous system (CNS) involvement in SLE.Sixty-seven patients with SLE underwent neurological examination; 52 underwent lumbar puncture, while 62 underwent cerebral magnetic resonance imaging (MRI). We measured selected auto-antibodies and other laboratory variables postulated to have roles in NP pathophysiology in the blood and/or CSF. We used SPM12 software for MRI voxel-based morphometry.Age-adjusted linear regression analyses revealed increased plasma NfL concentrations with increasing creatinine (β = 0.01, p 0.001) and Q-albumin (β = 0.07, p = 0.008). We observed higher plasma NfL concentrations in patients with a history of seizures (β = 0.57, p = 0.014), impaired motor function (β = 0.36, p = 0.008), increasing disease activity (β = 0.04, p = 0.008), and organ damage (β = 0.10, p = 0.002). Voxel-based morphometry suggested an association between increasing plasma NfL concentrations and the loss of cerebral white matter in the corpus callosum and hippocampal gray matter.Increased plasma NfL concentrations were associated with some abnormal neurological, cognitive, and neuroimaging findings. However, plasma NfL was also influenced by other factors, such as damage accrual, creatinine, and Q-albumin, thereby obscuring the interpretation of how plasma NfL reflects CNS involvement. Taken together, NfL in CSF seems a better marker of neuronal injury than plasma NfL in patients with SLE.

Neuro-Behçet's disease (NB) is classified into acute and chronic progressive types. Acute NB occurs as acute meningoencephalitis with focal lesions, presenting with high-intensity areas on T2-weighted images or flat images on magnetic resonance imaging (MRI). Chronic progressive NB is characterized by intractable, slowly progressive dementia and ataxia with progressive brain stem atrophy on MRI. The most important feature of chronic progressive NB is persistent elevation of cerebrospinal fluid (CSF) IL-6 levels. The progression rate of the brain stem atrophy has been shown to be closely correlated with integrated CSF IL-6. For the correct diagnosis of acute or chronic progressive NB, it is mandatory to confirm the diagnosis of Behçet's disease. Regarding treatment, all of corticosteroids, cyclophosphamide, and azathioprine are ineffective to treat chronic progressive NB. Low-dose methotrexate (MTX) is effective in decreasing CSF IL-6 levels without promoting the progression of neuropsychological manifestations. Infliximab has a beneficial effect in patients with inadequate response to MTX. Recently, clinical guidelines were established for the management of acute NB and chronic progressive NB, which is helpful for routine clinical practice.

Background To test the hypothesis that neurofilament light (NfL) in CSF is a biomarker of CNS involvement in patients with systemic lupus erythematosus (SLE) and primary Sjögren’s syndrome (pSS), we measured NfL in CSF from 52 patients with lupus and 54 with pSS and explored associations with clinical, structural, immunological and biochemical abnormalities. Methods In CSF, we measured NfL, anti-P antibodies, protein S100B and TWEAK by ELISA and anti-NR2 antibodies by electrochemiluminescence. Anti-phospholipid antibodies and routine immunological tests were performed in blood. IgG and albumin were measured in CSF and serum for assessment of the blood–brain barrier function (Q-albumin) and intrathecal IgG production (IgG index). Cerebral MRI and neuropsychological testing were performed. Results A multivariable regression model showed that increasing CSF anti-NR2 antibody levels were associated with increasing NfL levels in patients with SLE (B 1.27, 95% CI 0.88–1.65, p B 0.04, 95% CI 0.03–0.05, p Conclusions Increased concentration of NfL in CSF is a marker of cerebral involvement in patients with SLE and pSS, is strongly associated with the presence of anti-NR2 antibodies, and correlates with cognitive impairment in several domains.

Objectives: The aim of this study is to clarify the effect of various autoantibodies on overall mortality in patients with diffuse psychiatric/neuropsychological syndromes in SLE (diffuse NPSLE).Me...

IgG anti-DWEYS antibodies cross-reactive with DNA and the N-methyl-d-aspartate receptor subunits GluN2A and GluN2B are known to be associated with neuropsychiatric systemic lupus erythematosus (NPSLE). IgG anti-DWEYS have not been investigated in demyelinating NPSLE or in another demyelinating disorder, neuromyelitis optica spectrum disorder (NMOSD), which is a disease also found mainly in young women and associated with aquaporin 4 (AQP-4) or myelin oligodendrocyte glycoprotein (MOG) antibodies. This study was undertaken to investigate the frequency of all of these brain-reactive antibodies in patients with NPSLE, those with demyelinating NPSLE, and those with NMOSD.Serum samples from patients with NPSLE (n = 108), patients with SLE without neuropsychiatric manifestations (n = 38), patients with NMOSD (n = 33), and healthy controls (n = 106) were assessed for the frequency of IgG anti-brain antibodies as well as IgG antibodies to AQP-4, MOG, GluN2A/GluN2B, and double-stranded DNA (dsDNA).Sera were positive for IgG anti-AQP-4 antibodies in 27 (82%) of 33 patients with NMOSD and 3 (27%) of 11 patients with demyelinating NPSLE, whereas all sera from patients with non-demyelinating NPSLE, patients with SLE, and healthy controls were negative for IgG anti-AQP-4. IgG anti-MOG were detected at high titers in 3 (50%) of 6 patients with NMOSD who were negative for IgG anti-AQP-4, and at low titers in 2 (18%) of 11 patients with demyelinating NPSLE and 1 (1%) of 97 patients with non-demyelinating NPSLE. IgG antibodies to dsDNA were present in 11 (33%) of 33 patients with NMOSD. Only 4 (12%) of 33 patients with NMOSD were positive for IgG anti-DWEYS, compared to 11 (29%) of 38 patients with SLE and 59 (55%) of 108 patients with NPSLE. IgG anti-DWEYS antibodies were present in 56 (58%) of 97 patients with non-demyelinating NPSLE and 3 (27%) of 11 patients with demyelinating NPSLE. Serum IgG brain-reactive antibodies were present at a similar frequency in patients with non-demyelinating NPSLE (72 [75%] of 96), those with demyelinating NPSLE (9 [82%] of 11), and those with SLE (32 [84%] of 38), but were less frequent in patients with NMOSD (20 [61%] of 33).Patients with demyelinating NPSLE should be tested for IgG antibodies to AQP-4, MOG, and DWEYS. IgG anti-AQP-4 can be considered diagnostic for NMOSD, whereas none of these antibodies appear to be diagnostic for demyelinating NPSLE. Moreover, IgG anti-dsDNA are present in patients with NMOSD but are not cross-reactive with IgG anti-DWEYS, indicating that the antigenic stimulus and mechanisms of tissue damage are potentially different between demyelinating NPSLE and NMOSD.

Neuro-Behçet’s disease (NBD) is subcategorized into parenchymal-NBD (P-NBD) and non-parenchymal-NBD types. Recently, P-NBD has been further subdivided into acute P-NBD (A-P-NBD) and chronic progressive P-NBD (CP-P-NBD). Although an increasing number of studies have reported the various clinical features of A-P-NBD and CP-P-NBD over the last two decades, there was a considerable inconsistency. Two investigators systematically searched four electrical databases to detect studies that provided sufficient data to assess the specific characteristics of A-P-NBD and CP-P-NBD. All meta-analysis was carried out by employing the random-model generic inverse variance method. We included 11 reports consisted of 184 A-P-NBD patients and 114 CP-P-NBD patients. While fever (42% for A-P-NBD, 5% for CP-P-NBD, p 2 = 93%) was more frequently observed in A-P-NBD cases; sphincter disturbances (9%, 34%, P = 0.005, I2 = 87%), ataxia (16%, 57%, P 2 = 92%), dementia (7%, 61%, P 2 = 97%), confusion (5%, 18%, P = 0.04, I2 = 76%), brain stem atrophy on MRI (4%, 75%, P 2 = 98%), and abnormal MRI findings in cerebellum (7%, 54%, P = 0.02, I2 = 81%) were more common in CP-P-NBD. Cerebrospinal fluid cell count (94/mm3, 11/mm3, P = 0.009, I2 = 85%) was higher in A-P-NBD cases. We demonstrated that A-P-NBD and CP-P-NBD had clearly different clinical features and believe that these data will help future studies investigating P-NBD.

Objective Susceptibility genes that can account for characteristic features of SSc such as fibrosis, vasculopathy and autoimmunity remain to be determined. In mice, deficiency of Friend leukaemia integration 1 transcription factor (Fli1) causes SSc-like disease with these features. The human FLI1 gene contains (GA)n microsatellite, which has been shown to be associated with expression level. Because microsatellite polymorphisms are difficult to capture by genome-wide association studies, we directly genotyped FLI1 (GA)n microsatellite and examined its association with SSc. Methods Genomic DNA from 639 Japanese SSc patients and 851 healthy controls was genotyped for (GA)n microsatellite using the fragment assay. The cut-off repeat number for susceptibility to SSc was determined by receiver operating characteristics (ROC) analysis. Association with susceptibility and clinical characteristics was examined using logistic regression analysis. FLI1 mRNA levels were determined using quantitative RT-PCR. Results Based on the ROC analysis, (GA)n alleles with ≥22 repeats were collectively defined as L alleles and alleles with ≤21 repeats as S alleles. (GA)n L alleles were significantly associated with susceptibility to SSc (P = 5.0e-04, odds ratio 1.34, additive model). Significant association was observed both in diffuse cutaneous and limited cutaneous SSc. Among the SSc, (GA)n L alleles were significantly enriched in the patients with a modified Rodnan total skin thickness score ≥10 compared with those with a score Conclusion Extended repeat alleles of FLI1 (GA)n microsatellite may be associated with lower FLI1 mRNA levels and susceptibility to human SSc.

The objective of this study is to explore the characteristics of brain MRI abnormalities in acute confusional state (ACS) in neuropsychiatric systemic lupus erythematosus (NPSLE).Thirty-six patients with ACS admitted to our institutions from 1992 to 2015 were exhaustively enrolled. Their medical charts and brain MRI scans were reviewed.Eighteen of 36 ACS patients had MRI abnormalities, mostly high-intensity lesions of various sizes in the cerebral white matter. MRI abnormalities improved after treatment in 12 of 14 patients in follow-up studies. MRI abnormalities were not correlated with ages at the onset of ACS, disease durations of SLE, the presence of anti-DNA, anti-phospholipid or anti-ribosomal P antibodies, or IL-6 levels in sera or cerebrospinal fluid. Notably, MRI abnormalities were significantly associated with the presence of serum anti-Sm antibodies (p = 0.0067). Finally, eight of the 18 patients with MRI abnormalities, but none of the other 18 patients without MRI abnormalities, died from active SLE. Thus, MRI abnormalities significantly increased the mortality in ACS (p = 0.0013, HR =10.36 [95% CI: 2.487-43.19]).These results demonstrate that patients with ACS with MRI abnormalities have more severe diseases, resulting in poorer prognoses. The data also indicate that anti-Sm is involved in the development of MRI abnormalities in ACS.

To explore the role of C5a in the pathogenesis of neuropsychiatric systemic lupus erythematosus (NPSLE) and lupus nephritis (LN).Sera were obtained from 29 patients with NPSLE, 25 with LN, 26 without NPSLE or LN [SLE alone], and 21 healthy donors. Cerebrospinal fluid (CSF) was obtained from 29 NPSLE patients. C5a and C5 were measured by ELISA. Blood-brain barrier (BBB) function was evaluated by Q albumin ([CSF albumin/serum albumin] × 10Serum C5a, but not C5, was significantly increased in SLE compared with healthy control. Serum C5a, but not C5, was significantly higher in NPSLE and in LN than in SLE alone. Serum C4, but not C3, was lower in LN than in NPSLE. Q albumin was significantly higher in diffuse NPSLE than in focal NPSLE, whereas there were no significant differences in CSF or serum C5a between both groups. Notably, CSF C5 and C5a were significantly correlated with Q albumin, whereas serum C5a, but not C5, appeared to be inversely correlated with Q albumin.These results disclosed that serum C5a was elevated not only in NPSLE but also in LN through different mechanisms. Moreover, it is suggested that C5a might be consumed during BBB damages.

Background Neuropsychiatric manifestation in systemic lupus erythematosus (NPSLE) is one of the most serious complications of the disease. The American College of Rheumatology (ACR) developed standardised nomenclature and case definitions for neuropsychiatric involvement in SLE (NPSLE) in 1999. Although myelopathy is included in the ACR nomenclature, no space is provided for the brainstem encephalitis. Moreover, it is still unclear whether the brainstem encephalitis is an independent clinical entity in NPSLE. Objectives The present study was designed in order to disclose the clinical characteristic features of the brainstem encephalitis in NPSLE. Methods We prospectively collected the patients who presented brainstem lesions from 2005 to 2015. The diagnosis of the brainstem encephalitis was made by the elevation of cerebrospinal fluid (CSF) IL-6, Magnetic Resonance Imaging and response to steroid. Serum autoantibodies, including anti-ribosomal P protein antibodies (anti-P), anti-NMDA receptor NR2 antibodies (anti-NR2), anti-Sm antibodies and anti-aquaporin 4 antibodies (anti-AQP4) and anti-cardiolipin antibodies (anti-CL), were measured by ELISA. Results Seven patients presented the brainstem encephalitis during the period of 10 years. All the patients showed the elevation of CSF IL-6 (8.3–2716 pg/ml, median 377 pg/ml), whereas CSF cell count was elevated in 6 patients. The most common clinical symptoms were headache (4 patients), vertigo (3patients) and consciousness disturbance (3 patients). All the patients showed high intensity lesions in FLAIR images on MRI. Notably, 5 of the 7 patients also showed the high intensities periventricular regions, including cerebral aqueduct and the 4th ventricle (figure 1). Anti-NR2 and anti-P were positive in 7 patients and 6 patients, respectively. By contrast, anti-CL, anti-Sm and anti-AQP4 were positive in 4 patients, 3 patients and 1 patient, respectively. Six patients recovered after steroid therapy, while 1 patient died due to severe brainstem damages at the onset. Conclusions These results indicate that the brainstem encephalitis is an independent clinical entity in NPSLE, characterised by reversible high intensity lesions, especially in periventricular areas. Moreover, the data demonstrate that anti-AQP4-related neuromyelitis optica disorder is a minor population within the brainstem encephalitis. By contrast, it is suggested that anti-NR2 and anti-P might play an important role in the pathogenesis of the brainstem encephalitis. Reference [1] ACR Ad Hoc Committee on Neuropsychiatric Lupus Nomenclature. The American College of Rheumatology nomenclature and case definitions for neuropsychiatric lupus syndromes. Arthritis Rheum1999;42:599–608. Disclosure of Interest None declared

Background and purpose Migraine is frequent in patients with systemic lupus erythematosus (SLE), but the pathogenesis and pathophysiology are poorly understood. Migraine is assumed to be a consequence of abnormal neuronal excitability. Based on the hypothesis that the threshold for migraine is lower in SLE patients due to cerebral disturbances, whether structural abnormalities of the brain or relevant biomarkers are associated with headaches in SLE was investigated. Methods Sixty-seven SLE patients and age- and gender-matched healthy subjects participated. Volumes of grey matter (GM) and white matter (WM) were estimated from cerebral magnetic resonance images with SPM8 software. Anti-NR2 and anti-P antibodies and protein S100B were measured in cerebrospinal fluid. Results In regression analyses, larger GM volumes in SLE patients reduced the odds for headache in general [odds ratio (OR) 0.98, P = 0.048] and for migraine in particular (OR 0.95, P = 0.004). No localized loss of GM was observed. Larger WM volumes in patients increased the odds for migraine (OR 1.04, P = 0.007). These findings could not be confirmed in healthy subjects. Neither anti-NR2 and anti-P antibodies nor S100B were associated with headaches in SLE patients. Conclusions Systemic lupus erythematosus patients with migraine have a diffuse reduction in GM compared to patients without migraine. This finding was not observed in healthy subjects with migraine, and selected biomarkers did not indicate specific pathophysiological processes in the brain. These findings indicate that unknown pathogenic processes are responsible for the increased frequency of migraine in SLE patients.

A variety of neuropsychiatric manifestations are observed in patients with SLE. The American College of Rheumatology (ACR) developed standardized nomenclature and case definitions for neuropsychiatric involvement in SLE (NPSLE) in 1999. One of the problems in the 1999 ACR classification is the inclusion of milder, less specific and more subjective manifestations such as headache, mild cognitive dysfunction and mood disorders, which resulted in an enormous variation in the prevalence between studies. Another critical point of the ACR classification is the lack of a number of other neurological manifestations, such as neuromyelitis optica spectrum disorders and reversible focal neurological deficits mimicking cerebrovascular disease. Steroid psychosis is sometimes a difficult differential diagnosis, but not necessarily an exclusion, of lupus psychosis. CSF IL-6 might be one of the surrogate markers to detect patients with headache, cognitive dysfunction and mood disorders, requiring immunosuppressive therapy.

The diagnosis of neuropsychiatric manifestations in systemic lupus erythematosus (NPSLE) is challenging. Neuroimaging is very important technique for the evaluation of abnormalities occurred in the central nervous system (CNS). Computed tomography (CT) scan is one of the common techniques and is very useful to detect a large lesion such as ischemic stroke, hemorrhage and tumor, providing help to rule out CNS diseases other than SLE. Magnetic resonance imaging (MRI) is the best tool at present to detect parenchymal lesions in the CNS. Conventional MRI figures out exact abnormalities in the CNS causing neurologic or psychiatric symptoms. However, it should be remembered that MRI abnormalities in patients with NPSLE are not always specific for NPSLE. New MRI techniques can give us more detailed information in patients with NPSLE in addition to findings by conventional MRI. Functional analysis of the CNS by imaging system would be promising.

There are at least 2 separate and probably complementary pathogenetic mechanisms for NPSLE. One is the predominant ischemic-vascular involvement in large and small blood vessels, mediated mainly by anti-phospholipid antibodies (aPL), leading to focal NPSLE, such as stroke, seizures, movement disorders and myelopathy. The other is the inflammatory process with complement activation, the dysfunction of the blood-brain barrier (BBB), transudation of autoantibodies into the central nervous system (CNS) and local production proinflammatory cytokines such as IFN-α, leading to diffuse NPSLE such as psychosis, mood disorders, cognitive dysfunctions and acute confusional state. In the latter process, autoantibodies, such as anti-ribosomal P antibodies, anti-NMDA receptor NR2 antibodies and anti-Sm antibodies, play a pivotal role. Greater attention is now paid to the role of microglia in the pathogenesis.

Small vessel non-inflammatory vasculopathy, microvessel occlusion, multifocal microinfarcts, microhaemorrhages and cortical atrophy were most frequently observed pathological changes in NPSLE. Although vasculitis in the brain is rather uncommon, it might be detected in about 10% of patients with NPSLE. It has been revealed that activation of complement appears to play an important role in the development of microvasculopathy in NPSLE. Autoantibodies, including anti-phospholipid antibodies, causing direct injury of endothelial cells would be involved in the deposition of complements. Since anti-NMDA receptor NR2 antibodies have been demonstrated to react with endothelial cells to induce the production of inflammatory cytokines, it is possible that these antibodies might also result in the microvascular changes in the brain. Recent studies have shed light on the roles of microglia in relation with type I interferons in the pathogenesis of NPSLE.

To compare the effects of certolizumab pegol (CZP) and infliximab (IFX) on human monocytes.Highly purified monocytes from healthy donors were cultured with CZP, IFX, control IgG1, or polyethylene glycol (PEG) at pharmacological attainable concentrations in culture medium with 10% autologous normal human serum (NHS) or with fetal bovine serum (FBS) for 24 h, after which the supernatants were replaced by fresh culture medium containing LPS. After additional 24 h of incubation, the supernatants were assayed for TNF-α and IL-6. In some experiments, the cells were harvested after 1 h of stimulation with LPS for analysis of mRNA for TNF-α by quantitative PCR.Pre-incubation of monocytes with CZP or IFX reduced the production of TNF-α in subsequent cultures stimulated by LPS in a dose-dependent manner. The suppressive effects of IFX on the TNF-α production were significantly diminished, but those of CZP were rather enhanced, in cultures with autologous NHS compared with in cultures with FBS. Addition of IgG, but not IgG F(ab')These results indicate that the mechanism of action of CZP is different from that of IFX. Thus, CZP suppresses the production of proinflammatory cytokines independently of Fc receptors, whereas the suppressive effects of IFX on human monocytes are almost totally dependent on the interaction with Fc receptors.

Background Neuropsychiatric manifestation in systemic lupus erythematosus (NPSLE) is one of the most serious complications of the disease. We have recently demonstrated that the breakdown of blood brain barrier (BBB) plays a crucial role in the development of diffuse psychiatric/neuropsychological manifestations (diffuse NPSLE), allowing influx of neuron-reactive autoantibodies from systemic circulation into the brain. However, the mechanism of BBB damages remains unclear. On the other hand, although CSF interleukin-6 (IL-6) has been shown to be elevated in NPSLE, there has been no report on serum IL-6 in NPSLE. Objectives The present study was designed in order to elucidate the roles of serum IL-6 in the pathogenesis, especially in development of BBB damages, In NPSLE. Methods Paired serum and cerebrospinal fluid (CSF) samples were obtained from 101 SLE patients when they presented active neuropsychiatric manifestations (69 patients with diffuse psychiatric/neuropsychological syndromes [diffuse NPSLE] and 32 patients with neurologic syndromes or peripheral nervous system involvement [focal NPSLE]) and from 22 non-SLE control patients with non-inflammatory neurological diseases. The levels of albumin and IL-6 in CSF and sera were measured by ELISA. Results Serum IL-6 as well as CSF IL-6 was significantly elevated in acute confusional state (ACS) compared with non-ACS diffuse NPSLE (anxiety disorder, cognitive dysfunction, mood disorder and psychosis) or focal NPSLE (figure). Q albumin (CSF/serum albumin quotient) was also significantly higher in ACS than in the other 2 groups of NPSLE. Of note, serum IL-6 (r=0.2801, p=0.0207), but not CSF IL-6 (r=0.1602, p=0.1918), was significantly correlated with Q albumin in patients with diffuse NPSLE, including ACS and non-ACS, although serum IL-6 was significantly correlated with CSF IL-6 in this population (r=0.3205, p=0.082). Conclusions These results indicate that serum IL-6 as well as IL-6 is involved in the pathogenesis of NPSLE. The data also confirm that the severity of BBB damages plays a crucial role in the development of ACS, the severest form of diffuse NPSLE. Finally, it is suggested that serum IL-6 might play a most important role in BBB breakdown in NPSLE, whereas CSF IL-6 might be involved in subsequent central nervous system inflammation. Disclosure of Interest None declared

Background Central nervous system involvement is one of the most serious complications in Behcet9s disease (BD). This condition is referred to as neuro-Behcet9s disease (NB) and can be classified into acute type (ANB) and chronic progressive type (CPNB) based upon differences in the clinical course and responses to corticosteroid treatment. Cerebellar ataxia, such as gait disturbances and dysarthria, is one of the representative manifestations in CPNB. Accordingly, brainstem atrophy is frequently observed in CPNB, but not in ANB. Notably, progressive neurobehavioral changes mimicking those in Alzheimer9s disease (AD) are also frequently observed in CPNB, but these changes cannot be accounted for by brainstem atrophy. Objectives In the present study, volumes of the hippocampus were examined to identify the responsible lesions for neurobehavioral changes in CPNB, and patterns of atrophy in the hippocampus and brainstem were compared between patients with CPNB and AD. Methods The subjects were 32 patients, including 13 with CPNB (11 males and 2 females, age 51.2±12.1 years old [mean ± SD]), 13 with Behcet9s disease without NB (non-NB) (10 males and 3 females, age 54.4±11.4 years old), and 6 with AD (5 males and 1 female, age 78.8±7.5 years old). All patients with BD satisfied the international classification criteria for BD. CPNB was defined as intractable, slowly progressive neurobehavioral changes and/or cerebellar ataxia accompanied by persistent elevation of interleukin-6 of >20 pg/mL in cerebrospinal fluid on two different occasions at an interval of at least 2 weeks. All patients with AD satisfied Diagnostic and Statistical Manual of Mental Disorders (DSM)-IV criteria. Brain magnetic resonance imaging (MRI) was obtained from each subject. The areas of the midbrain tegmentum and pons were measured on mid-sagittal sections of T1-weighted images using image analysis software (Image J ver.1.45: NIH, USA). Severity of gray matter loss in the hippocampal region and whole brain were investigated using Voxel-Based Specific Regional Analysis System for Alzheimer9s Disease (VSRAD) software (Eisai Co., Ltd) to determine the degrees of hippocampal region atrophy (Z score) and whole-brain atrophy (WBAI). Thus, the 1/Z score is positively correlated with the hippocampus volume. The ratio of the degree of brainstem atrophy to that of hippocampal atrophy was evaluated by the brainstem area value divided by the 1/Z score (BA/H score) in each patient. Results The brainstem area was significantly decreased in CPNB (461.8±87.3 [mean ± SD]) compared with that in AD (661.9±56.1) and non-NB (666.1±50.6) (Figure A). VSRAD analysis showed that Z score was significantly increased in CPNB (1.46±0.70) and AD (3.13±1.21) compared with that in non-NB (0.77±0.40) (Figure B). Of note, the BA/H score, reflecting the brainstem/hippocampus volume ratio, was much lower in CPNB than in AD [663.5±311.8 vs 2018±667.6, p=0.001] (Figure C). Conclusions These results indicate that the hippocampus, in addition to the brainstem, is a common target lesion in CPNB, and this accounts for the progressive neurobehavioral dysfunction in this disease. Moreover, the data emphasize that brainstem atrophy is disproportionately greater than hippocampal atrophy in CPNB, in contrast to AD. Disclosure of Interest None declared

Background Central nervous system involvement is one of the most serious complications in Behcet9s disease (BD). This condition is referred to as neuro-Behcet9s disease (NB) and can be classified into acute type (ANB) and chronic progressive type (CPNB) based upon differences in the clinical course and responses to corticosteroid treatment. Diagnostic criteria were generated in 2013 based on a multicenter clinical survey performed by the Behcet9s Disease Research Committee of the Ministry of Health, Labor and Welfare of the Japanese Government. Although “Guidelines for Treatment of NB” was also proposed based on the survey, it is still preliminary. Objectives The aim of the current study is to develop evidence-based recommendations for the management of NB supplemented by expert opinions where necessary. Methods First, clinical questions (CQs) on NB were extracted from a literature search for problem areas and related keywords, and draft CQs and a flow chart were prepared. The expert committee, a task force of the research subcommittee for NB, consisted of 7 board-certified rheumatologists (one was also a board-certified neurologist) and 3 board-certified neurologists. A systematic literature search was performed using Medline and the Japan Medical Abstract Society databases from 1997 to 2016. A total of 15 initial CQs were generated. These yielded the final recommendations developed from 3 blind Delphi rounds, in which the rate of agreement scores on CQs (range 1 [disagree]–5 [strongly agree]) was determined though voting by the whole committee. Results Thirteen recommendations were developed for the management of NB (general 1, ANB 7, CPNB 5). The strength of each recommendation was established based on the evidence level as well as rate of agreement. There was excellent concordance between the level of agreement of rheumatologists and that of neurologists. Based on these recommendations, a flow chart was established for the management for ANB and CPNB (Figure). Conclusions The recommendations generated in this study are mainly based not only on expert opinions but on the results of uncontrolled evidence from open trials and retrospective cohort studies. Guidelines that can be used for international studies are needed, for which verification by further properly designed controlled clinical trials is required. Disclosure of Interest None declared

To investigate the influences of various factors on the relapse of acute neurological attacks in patients with Behçet's disease (BD).Sixty-one patients, who met the international classification criteria for BD, had attacks of acute neuro-Behçet's disease (NBD) and could be followed up at least for 2 months, including 60 patients in our multicenter retrospective survey on BD patients in 2011. The factors associated with relapse of acute neurological attacks were assessed.Twenty-one of 61 patients had been taking cyclosporine A (CyA) at the onset of acute NBD. All the 21 patients with CyA and 33 of the 40 patients without CyA had eye involvement. There were no significant differences in demographic features, clinical symptoms, MRI findings, the need for, and responses to corticosteroid therapy including pulse therapy between patients with CyA and those without CyA. CyA was withdrawn in 19 of 21 patients with CyA. Of note, patients with CyA showed significantly lower relapse rates than those without CyA (HR 0.1283, 95% CI: 0.0788-0.7836, p = 0.0186 as calculated by log-rank test). Moreover, colchicine was found to reduce the relapse rates in patients with acute NBD without CyA (HR 0.2771, 95% CI: 0.0827-0.9422, p = 0.0450 [log-rank test]).These results indicate that CyA-related acute neurological manifestations are almost identical with CyA-unrelated acute events of NBD, except for the paucity of relapse on withdrawal of CyA. The data also demonstrate that colchicine is effective to prevent relapses of acute neurological attacks especially in patients with CyA-unrelated acute NBD.

Objectives To examine whether quantitative analysis of the brainstem areas on magnetic resonance imaging (MRI) scans is useful for diagnosis as well as evaluation of disease activity in chronic progressive neuro-Behcet's disease (CPNB). Methods MRI scans in patients with acute neuro-Behcet's disease (ANB) (n = 10), CPNB (n = 10), Behcet's disease with neurological manifestations non-attributable to NB (non-NB) (n = 8), and control patients with non-inflammatory neurological diseases (NID) (n = 10) were studied. The areas of midbrain tegmentum and pons were measured on mid-sagittal sections of T1-weighted images of MRI using software NIH Image J ver.1.45. Results The areas of midbrain tegmentum as well as those of pons were significantly decreased in CPNB compared with those in the other three groups. On receiver operating characteristic (ROC) analysis, the sensitivity and specificity of the areas of brainstem combining midbrain tegmentum and pons for diagnosis of CPNB against non-CPNB (ANB + non-NB) were 80.0% and 94.4%, respectively, at cut-off value of 614.9 mm2. Brainstem atrophy progressed most markedly during the first 2 years during the course of CPNB. Moreover, the progression rate of atrophy was closely correlated with the elevation of cerebrospinal fluid interleukin-6. Conclusion These results indicate that quantitative analysis of the brainstem areas on MRI scans is effective for diagnosis as well as for evaluation of the disease activity in CPNB. Moreover, it is suggested that an appropriate therapeutic intervention to reduce CSF IL-6 would be required as early as possible upon diagnosis of CPNB.

The aim of this study was to elucidate the characteristics, pathogenesis and treatment strategy of hypertrophic pachymeningitis that is associated with myeloperoxidase anti-neutrophil cytoplasmic antibody (ANCA). We retrospectively investigated clinical, radiological, immunological and pathological profiles of 36 patients with immune-mediated or idiopathic hypertrophic pachymeningitis, including 17 patients with myeloperoxidase-ANCA, four patients with proteinase 3-ANCA, six patients with other immune-mediated disorders, and nine patients with 'idiopathic' variety. Myeloperoxidase-ANCA-positive hypertrophic pachymeningitis was characterized by: (i) an elderly female predominance; (ii) 82% of patients diagnosed with granulomatosis with polyangiitis (previously known as Wegener's granulomatosis) according to Watts' algorithm; (iii) a high frequency of patients with lesions limited to the dura mater and upper airways, developing headaches, chronic sinusitis, otitis media or mastoiditis; (iv) a low frequency of patients with the 'classical or generalized form' of granulomatosis with polyangiitis involving the entire upper and lower airways and kidney, or progressing to generalized disease, in contrast to proteinase 3-ANCA-positive hypertrophic pachymeningitis; (v) less severe neurological damage according to the modified Rankin Scale and low disease activity according to the Birmingham Vasculitis Activity Score compared with proteinase 3-ANCA-positive hypertrophic pachymeningitis; (vi) increased levels of CXCL10, CXCL8 and interleukin 6 in cerebrospinal fluids, and increased numbers of T cells, neutrophils, eosinophils, plasma cells and monocytes/macrophages in autopsied or biopsied dura mater with pachymeningitis, suggesting TH1-predominant granulomatous lesions in hypertrophic pachymeningitis, as previously reported in pulmonary or renal lesions of granulomatosis with polyangiitis; and (vii) greater efficacy of combination therapy with prednisolone and cyclophosphamide compared with monotherapy with prednisolone. Proteinase 3-ANCA may be considered a marker for more severe neurological damage, higher disease activity and a higher frequency of the generalized form compared with myeloperoxidase-ANCA-positive hypertrophic pachymeningitis. However, categorization into 'granulomatosis with polyangiitis' according to Watts' algorithm and immunological or pathological features were common in both proteinase 3- and myeloperoxidase-ANCA-positive hypertrophic pachymeningitis. These data indicate that most patients with myeloperoxidase-ANCA-positive hypertrophic pachymeningitis should be categorized as having the central nervous system-limited form of ANCA-associated vasculitis, consistent with the concept of ophthalmic-, pulmonary- or renal-limited vasculitis.

We determined the characteristic features of synovial tissues of rheumatoid arthritis (RA) patients treated by TNF inhibitors in order to delineate their mechanism of action. Synovial tissues were obtained during the joint surgical operations from 12 RA patients who had been treated with TNF inhibitors in addition to disease modifying antirheumatic drugs (DMARDs) for at least 5 months (5-25 months) (RA-TNFinh), and from 12 RA patients who had been treated with DMARDs alone (RA-DMARD), and were evaluated under light microscopy. There were no significant differences in disease duration, serum CRP levels, DAS28, Steinbrocker's stages on X-ray and treatment regimen except for TNF inhibitors between RA-TNFinh and RA-DMARD. The most prominent changes in the synovium from RA-TNFinh were discoid fibrosis in the subliming layers of the synovium with degeneration and detachment of synoviocytes and marked decrease in vasculatures. There was no significant difference in these synovial features between RA patients with infliximab and those with etanercept. Interestingly, appearance of osteoclasts was observed in RA-TNFinh (3 out of 12 patients) and in RA-DMARD (1 out of 12 patients). These results indicate that not only infliximab, but etanercept might have direct actions on synovial cells in the deep lining layers of the synovium, leading to the discoid fibrosis thereof. Moreover, the data confirm that the deep lining or sublining layers of the synovium are the most important portions that steer the disease process of RA synovitis.

SH2D1A, also known as signaling lymphocytic activation molecule (SLAM)-associated protein (SAP), is an adaptor protein. Recently, it was reported that SAP deficient mice were protected from systemic lupus erythematosus (SLE). In this study, we postulated SH2D1A gene to be a candidate susceptibility gene for SLE and analyzed its association with SLE. A case-control association study was conducted on 5 tag single nucleotide polymorphisms (SNPs) in SH2D1A region in 506 Japanese female SLE patients and 330 healthy female controls. The luciferase assay was performed to determine the functional role of the SNP associated with SLE. One SNP in the intron 2, rs2049995, showed association with SLE ( p = 0.0110, odds ratio (OR) 1.97, 95% confidence interval (CI) 1.16–3.34, under the dominant model). The association of rs2049995 seemed to be stronger in the subset with the age of onset less than 20 years ( p = 0.0067, OR 2.65, 95% CI 1.28–5.46). Functional evaluation of rs2049995 showed that reporter gene activity was increased 1.9-fold for the susceptible allele compared with the resistant allele. An intronic SNP of SH2D1A is associated with SLE.

Although quotient of alpha2 macroglobulin (Qα2MG) was previously reported to be useful for the evaluation of blood-brain barrier (BBB) function, it is not commonly used. We therefore evaluated BBB function among the various subsets of neuropsychiatric systemic lupus erythematosus (NPSLE) using quotient Q α2MG. Furthermore, we determined the correlation between Q α2MG and cerebrospinal (CSF) interleukin (IL)-6 level and quotient complement component 3 (Q C3). To determine intrathecal production of C3, the C3 index (Q C3/Q α2MG) was also calculated. Fifty-six patients with SLE were included in this study. Of these, 48 were diagnosed with NPSLE, consisting of 30 diffuse NPSLE patients (acute confusional state (ACS): n = 14, non-ACS: n = 16) and 18 patients with focal NPSLE. CSF IL-6 concentration, and paired serum and CSF levels of α2MG and C3, were measured by enzyme-linked immuno solvent assay (ELISA). The Q α2MG, Q C3, and C3 index were then calculated. Q α2MG, Q C3, and IL-6 concentrations in the CSF were significantly elevated in NPSLE compared with non-NPSLE. Among the subsets of NPSLE, significant increases in Q α2MG, CSF IL-6, and Q C3 were observed in ACS compared with non-ACS or focal NPSLE. There was a positive correlation between CSF IL-6 level and Q α2MG, as well as between Q C3 and Q α2MG, in diffuse NPSLE. There were no significant differences in C3 index between NPSLE and non-NPSLE, as well as among the subgroups of NPSLE. Our study suggests that BBB disruption is present in ACS, and elevated levels of IL-6 and C3 in CSF in diffuse NPSLE, especially in ACS, might result from their entry to the CSF from the systemic circulation through the damaged BBB, as well as increased intrathecal production. Furthermore, Q α2MG might be useful for the evaluation of BBB integrity.