Effect of Infliximab on Chronic Progressive Neuro-Behçet's Disease: Influence of the Timing of Introduction on the Patient Outcome.

Objectives Chronic progressive neuro-Behcet's disease (CPNB) is characterized by progressive deterioration leading to disability. Methotrexate (MTX) has been shown to have beneficial effects on CPNB. However, while infliximab has been found to be effective for patients with inadequate responses to MTX, the appropriate timing for the introduction of infliximab remains unclear. We explored the effects of intervals before the introduction of infliximab on the functional outcome. Methods A retrospective analysis was performed for patients with CPNB who received infliximab and were followed up until October 2015. Functional disability was rated by the Steinbrocker functional classification as used in rheumatoid arthritis. Correlations between the outcomes and intervals before the introduction of infliximab were then analyzed by Spearman's rank correlation test. Patients Eleven patients with CPNB [8 men, 3 women, age 35.2±9.3 years old (mean±standard deviation)] who met the international classification criteria for Behcet's disease were included. Results All 11 patients had received MTX prior to infliximab. The intervals from the onset to the introduction of infliximab and the follow-up periods were 26.6±35.1 months and 65.2±43.6 months [mean±standard deviation], respectively. Among the 11 patients, 2 still showed progression after the introduction of infliximab. The functional disability grades after infliximab treatment were significantly correlated with the intervals from the onset of CPNB to the introduction of infliximab (r=0.6177, p=0.0476). Conclusion The results indicate that the delayed introduction of infliximab leads to irreversible functional disability in CPNB. Thus, it is recommended that infliximab be administered as soon as possible for CPNB patients with inadequate responses to MTX.

Recommendations for the management of the vascular involvement in Behçet's disease by the Japanese National Research Committee for Behçet's disease-secondary publication.

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.

Histopathology of pulmonary thromboembolism in a patient with Behçet's disease.

Pulmonary involvement in vascular Behçet's disease (BD) (VBD) is a serious manifestation. Among the pulmonary manifestations, pulmonary embolism is considered a rare manifestation because deep vein thrombosis (DVT) has been thought to detach from the vessel wall, whereas pulmonary thrombus has been suggested to result from in situ pulmonary arteritis.In this case report, we present histopathological evidence of pulmonary embolism derived from DVT in an autopsy case of VBD. This observation emphasises that DVT causes pulmonary embolism in BD, indicating that anticoagulants are required for its prevention.

Enhanced expression of mRNA for transforming growth factor ß activated kinase 1 in CD34+ cells of the bone marrow in rheumatoid arthritis.

OBJECTIVES: Transforming growth factor ß activated kinase 1 (TAK1) has been found to mediate maladaptive tumour necrosis factor (TNF) signalling, leading to hyperactive downstream nuclear factor Kappa ß (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. METHODS: 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. RESULTS: TAK1 mRNA expression in bone marrow CD34+ cells was significantly higher in RA than in OA (TAK1/ß-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. CONCLUSIONS: 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.

Anti-ribosomal P protein antibodies in patients with systemic lupus erythematosus is associated with hyperferritinemia.

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 < .0001). Sensitivity and the specificity of anti-ribo P in patients with SLE were 32.0% and 99.3%, respectively. Patients positive for anti-ribo P had the highest risk for elevated serum ferritin (odds ratio: 8.432). Accordingly, anti-ribo P positive patients had significantly elevated serum ferritin compared to negative patients (P = .024). A significant positive correlation was observed between the anti-ribo P titer and the serum ferritin level (r2  = .07, t = 5.22, P = .0081), but not serum interleukin (IL)-6 in SLE patients. CONCLUSION: The presence of anti-ribo P is a risk factor for higher ferritin levels that is independent of systemic inflammation regulated by IL-6. We speculate that anti-ribo P could be directly associated with macrophage activation leading to hyperferritinemia in patients with SLE.

Clinical features of Behçet's disease patients with joint symptoms in Japan: A national multicenter study.

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 <10 mg/day. The recurrence of joint symptoms was significantly less common in the colchicine group than in the PSL group. 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.

Neurofilament light in plasma is a potential biomarker of central nervous system involvement in systemic lupus erythematosus.

BACKGROUND: 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. METHODS: 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. RESULTS: Age-adjusted linear regression analyses revealed increased plasma NfL concentrations with increasing creatinine (ß = 0.01, p < 0.001) and Q-albumin (ß = 0.07, p = 0.008). We observed higher plasma NfL concentrations in patients with a history of seizures (ß = 0.57, p = 0.014), impaired motor function (ß = 0.36, p = 0.008), increasing disease activity (ß = 0.04, p = 0.008), and organ damage (ß = 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. CONCLUSION: 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.

[Chronic Progressive Neuro-Behçet's Disease].

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.

Role of Serum IL-6 in Neuropsychiatric Systemic lupus Erythematosus.

OBJECTIVE: The present study was designed in order to elucidate the roles of serum interleukin 6 (IL-6) in the pathogenesis in neuropsychiatric systemic lupus erythematosus (NPSLE). METHODS: Paired serum and cerebrospinal fluid (CSF) samples were obtained from 101 patients with SLE 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 control patients without SLE with noninflammatory neurological diseases. The levels of albumin and IL-6 in CSF and sera were measured by enzyme-linked immunosorbent assay. RESULTS: Serum IL-6 and CSF IL-6 were elevated in NPSLE compared with non-SLE controls. Among NPSLE, serum IL-6 and CSF IL-6 were significantly elevated in acute confusional state (ACS) compared with non-ACS diffuse NPSLE (anxiety disorder, cognitive dysfunction, mood disorder, and psychosis) or focal NPSLE. Q albumin (CSF/serum albumin quotient) was also significantly higher in ACS than in the other two 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. CONCLUSION: These results indicate that serum IL-6 as well as CSF IL-6 is involved in the pathogenesis of NPSLE. Moreover, it is suggested that serum IL-6 might play a most important role in blood-brain barrier breakdown in NPSLE.

Neurofilament light is a biomarker of brain involvement in lupus and primary Sjögren's syndrome.

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 < 0.001). Age contributed significantly in the model (B 0.04, 95% CI 0.03-0.05, p < 0.001). Similar findings were observed in the pSS group. Adjusted for age and sex, no associations were found between NfL levels and any MRI data. In SLE patients, higher NfL concentrations were associated with impairments in psychomotor speed and motor function, and in pSS with motor dysfunction. These associations remained in multivariable regression models. 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.

Recommendations for the Management of Neuro-Behçet's Disease by the Japanese National Research Committee for Behçet's Disease.

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.

Association of functional (GA)n microsatellite polymorphism in the FLI1 gene with susceptibility to human systemic sclerosis.

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 <10. FLI1 mRNA levels were significantly decreased in healthy controls carrying (GA)n L alleles as compared with non-carriers. CONCLUSION: Extended repeat alleles of FLI1 (GA)n microsatellite may be associated with lower FLI1 mRNA levels and susceptibility to human SSc.

Differential expression of antibodies to NMDA receptor in anti-NMDA receptor encephalitis and in neuropsychiatric systemic lupus erythematosus.

OBJECTIVE: Anti-NMDA receptor encephalitis is the most prevalent autoimmune encephalitis having characteristic clinical features with autoantibodies against tetrameric transmembrane channels composed of combinations of NR1 subunits of NMDA receptors with NR2 subunits, which are detected by cell-based assay (anti-NR1/NR2). On the other hand, antibodies against the linear epitope in NR2 subunit (anti-NR2) have been shown to be expressed in patients with diffuse psychiatric/neuropsychological syndromes of neuropsychiatric SLE (diffuse NPSLE). However, it has not been explored whether anti-NR1/NR2 might be detected in NPSLE, nor has it been clear whether anti-NR2 might have cross-reactivity with anti-NR1/NR2. The current study was therefore performed to explore the prevalence of anti-NR1/NR2 in NPSLE. METHODS: Serum specimens were obtained from 31 patients with NPSLE (22 with diffuse NPSLE and 9 with neurological syndromes or polyneuropathy) and from 18 normal healthy subjects. Anti-NR2 and anti-NR1/NR2 were measured by ELISA and cell-based assay, respectively. The positivity for anti-NR2 was defined by a value exceeding mean+2 SD of normal healthy subjects. RESULTS: Anti-NR2 was positive in the sera of 19 of 31 patients with NPSLE (in 15 of 22 patients with diffuse NPSLE). By contrast, anti-NR1/NR2 was positive only in 2 of 31 patients with NPSLE (in 2 of 22 patients with diffuse SLE). The positivity for anti-NR1/NR2 was not correlated with anti-NR2 values. CONCLUSIONS: These results demonstrate that the prevalence of anti-NR1/NR2 is extremely low in NPSLE. Moreover, the data also confirm that anti-NR2 antibodies do not have cross-reactivity with anti-NR1/NR2.

Anti-ribosomal P protein antibodies influence mortality of patients with diffuse psychiatric/neuropsychological syndromes in systemic lupus erythematous involving a severe form of the disease.

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). Methods: Fifty-five patients with diffuse NPSLE admitted from 1992 to 2017 had met inclusion criteria and were recruited for this study. The relationship of various serum autoantibodies with mortality was retrospectively analyzed based on the medical charts. Results: Of 55 patients, 14 patients [25.5%] had died during the observation period (2728 [22-8842] days (median [range])). The 5-year, 10-year, 15-year and 20-year mortality rates were 18.8%, 21.9%, 36.9% and 47.4%, respectively. Among various serum autoantibodies at the onset of diffuse NPSLE, only the presence of anti-ribosomal P protein antibodies (anti-ribo P) significantly increased the risk for death (relative risk 2.262, 95% confidence interval 1.276-4.417, p = 0.005). Of 14 fatal patients, 10 patients had died within 1 y after the onset of diffuse NPSLE. Remarkably, 7 of 10 patients with positive anti-ribo P had died of the severe complication primarily attributed to SLE except for one patient. Conclusions: The presence of anti-ribo P is a significant risk factor for overall poor prognosis in patients with diffuse NPSLE, involving a fatal complication by SLE.

Nurse-like cells in rheumatoid arthritis: Formation of survival niches cooperating between the cell types.

Nurse-like cells (NLCs) established from bone marrow and synovial tissue of rheumatoid arthritis (RA) patients were found to promote maturation and differentiation of B lineage cells as well as T cells. In co-culture of RA-NLCs and B cells, tight physical interactions (pseudoemperipolesis) developed, which resulted in activation of both cell types. RA-NLCs also supported myeloid cell maturation, promoting their differentiation into tartrate-resistant acid phosphatase-positive mononuclear cells, which are precursor cells of osteoclasts. In RA synovial tissue, the characteristic dendritic-shaped cells (the DCs) were electron microscopically found to form direct physical interactions with adjacent plasma cells (PCs) suspecting to be pseudoemperipolesis. The numbers of PCs accumulating in various areas tended to correlate with the numbers of the DCs, which appeared to have RA-NLC functions forming survival niches for PCs. Immunohistochemical staining analysis indicated that CD14+ cells including the DCs formed survival niches for CD138+ PCs by RA-NLC functions. Quantitative dual immunofluorescence staining studies of these areas indicated that the majority of CD14+ cells were of myeloid lineage. These survival niches promoted by RA-NLCs appear to play important roles in supporting immunological functions in RA bone marrow and synovial tissues.

Synergistic enhancement of production of proinflammatory cytokines of human peripheral blood monocytes by anti-Sm and anti-RNP antibodies.

The present study was performed to elucidate the roles of serum anti-Sm antibodies in the pathogenesis of systemic lupus erythematosus (SLE). Highly purified peripheral blood monocytes obtained from healthy donors were cultured in the presence of monoclonal anti-Sm antibody (anti-Sm mAb), monoclonal anti-U1-RNP antibody (anti-RNP mAb) or control murine IgG1 or IgG3. After various periods of incubation, levels of IL-6 and TNF-α in the culture supernatants were measured by ELISA and the expression of mRNA for various molecules in monocytes was determined using RT-PCR. Flow cytometry analysis confirmed the bindings of anti-Sm mAb and anti-RNP mAb on viable human monocytes. Both anti-Sm mAb and anti-RNP mAb significantly increased the production of IL-6 and TNF-α of human monocytes in a dose-dependent manner, although the latter was more potent than the former. Of note, anti-Sm mAb synergistically enhanced the production and mRNA expression of IL-6 and TNF-α of human monocytes in the presence of anti-RNP mAb. Notably, anti-RNP mAb, but not anti-Sm mAb, significantly enhanced the mRNA expression of RelA in human monocytes. Finally, anti-Sm mAb still up-regulated the IL-6 production of monocytes in the presence of anti-RNP mAb under the influence of N-acetyl cysteine or pyrrolidine dithiocarbamate that totally abrogated the IL-6 production provoked by anti-Sm mAb alone in the absence of anti-RNP mAb. These results demonstrate that anti-Sm and anti-RNP antibodies synergistically up-regulate the expression of IL-6 and TNF-α in human monocytes. The data also suggest that the effect of anti-Sm in the synergy with anti-RNP might not involve NFkB activation.