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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.

Neuropsychiatric syndromes of systemic lupus erythematosus (NPSLE) is a life-threatening disorder and early diagnosis and proper treatment are critical for the management of patients with this disease. Brain magnetic resonance imaging, electroencephalogram, neuropsychological tests and routine cerebrospinal fluid (CSF) examination are used clinically for the diagnosis of NPSLE. In addition to these tests, cytokine and chemokine levels in the CSF have been reported as useful diagnostic markers of NPSLE. This chapter provides an overview of the roles of cytokines and chemokines in NPSLE.

The current therapeutic approach to the difficult manifestations of neuropsychiatric systemic lupus erythematosus (NPSLE) remains empirical and is based on clinical experience. Available data on the use of rituximab in refractory NPSLE come from a large number of case reports and some open-label studies. Two patients with persistently active NPSLE, despite conventional therapy, responded dramatically to rituximab are described in this chapter. Current evidence on the therapeutic use of rituximab in this chapter is also analyzed through the English-language literatures. Evidence for the effectiveness of rituximab as induction therapy in NPSLE is based solely on several case reports and non-controlled trials. Although it is not yet possible to make definite recommendations, the global analysis of these cases supports the off-label use of rituximab in cases of severe refractory NPSLE. Furthermore, we present the blockade of new targets which may impact the future treatment of NPSLE.

Neuropsychiatric systemic lupus erythematosus (NPSLE) is a life-threatening disorder and early diagnosis and proper treatment are critical for the management of patients with this disease. NPSLE can manifest as a range of neurological and psychiatric features, which are classified using the ACR case definitions for 19 neuropsychiatric syndromes . Approximately one-third of all NPSLE events in patients with SLE are primary manifestations of SLE-related autoimmunity, with seizure disorders, cerebrovascular disease, acute confusional state and neuropathy being the most common. Such primary NPSLE events are a consequence either of autoantibodies and inflammatory mediators, or of microvasculopathy and thrombosis. Diagnosis of NPSLE requires the exclusion of other causes, and clinical assessment directs the selection of appropriate examinations. These examinations include measurement of autoantibodies, analysis of cerebrospinal fluid, electrophysiological studies, neuropsychological assessment and neuroimaging to evaluate brain structure and function. This chapter reviews the important key points for the correct diagnosis and the differential diagnosis.

The pathogenesis of neuropsychiatric syndromes of systemic lupus erythematosus (NPSLE) is multifactorial and can involve various inflammatory cytokines, autoantibodies such as anti-neuronal antibodies, anti-ribosomal P antibodies, anti-NR2 glutamate receptor binding antibodies, anti-Sm antibodies, anti-U1-RNP antibodies and anti-phospholipid antibodies, and immune complexes (IC). Disruption of the blood-brain barrier (BBB) is integral to the neuropathology of SLE. Recently the possibility has been reported that aforementioned autoantibodies in the circulation may be strongly associated with disruption of the BBB. Each of these mechanisms might contribute to the pathogenesis of focal NPSLE (for example, cerebrovascular disease, movement disorders, myelopathy, seizures and cranial neuropathy) or diffuse NPSLE (for example, acute confusional state, psychosis and cognitive dysfunction) to varying degrees. In this review we focus on how the aforementioned autoantibodies, the BBB, IC and cytokines as well as chemokines are associated with the appearance of NPSLE.

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

To investigate the influence of biologics on mortality and risk factors for death in rheumatoid arthritis (RA) patients. RA patients treated with at least one dose of biologics in daily practice in six large rheumatology institutes (“biologics cohort”) were observed until 15 May 2010 or death, whichever occurred first. Mortality of the biologics cohort and the “comparator cohort” (comprising patients among the IORRA cohort who had never been treated with biologics) was compared to that of the Japanese general population. Factors associated with mortality were assessed by a Cox model. Among 2683 patients with 6913.0 patient-years of observation, 38 deaths were identified in the biologics cohort. The probability of death in patients lost to follow-up, calculated using the weighted standardized mortality ratio (SMR), was 1.08 [95 % confidence interval (CI) 0.77–1.47] in the biologics cohort and 1.28 (95 % CI 1.17–1.41) in the comparator cohort. Pulmonary involvement was the main cause of death (47.4 %), and the disease-specific SMR of pneumonia was 4.19 (95 % CI 1.81–8.25). Risk factors for death included male gender [hazard ratio (HR) 2.78 (95 % CI 1.24–6.22)], advanced age (HR 1.07, 95 % CI 1.03–1.11), and corticosteroid dose (HR 1.08, 95 % CI 1.01–1.17). Mortality in RA patients exposed to biologics did not exceed that in patients not exposed to biologics, but death from pulmonary manifestations was proportionally increased in RA patients exposed to biologics.

We investigated the influence of antibodies against infliximab and etanercept on the serum trough levels of these agents and the influence of these antibodies on the effectiveness of treatment in patients with rheumatoid arthritis treated with these agents. Forty patients treated with infliximab for 54 weeks and 40 patients treated with etanercept for 32 weeks were enrolled. They were divided into responder and non-responder groups. Serum trough levels of and antibodies against these agents were measured by enzyme-linked immunosorbent assay or radioimmunoassay. Of the 40 patients treated with infliximab, 14 (35%) had anti-infliximab antibodies. Serum trough levels were significantly lower in the non-responder group (14 patients) than in the responder group (26 patients) 6 weeks after initiation of infliximab (p

Several literatures have reported that the elimination of autoantibodies by immunoadsorption (IA) therapy induced short- and long-term improvements in cardiac function of patients with dilated cardiomyopathy (DCM). We assessed whether reduction in oxidative stress was related to the mechanism underlying left ventricular functional benefit from IA. We studied 7 patients with DCM (New York Heart Association (NYHA) functional class III/IV). Autoantibodies were removed with IA by passing patients’ plasma over tryptophan columns. The level of anti-β1-adrenoreceptor (AR) autoantibodies was measured by enzyme- linked immunosorbent assay. The level of diacron- reactive oxygen metabolite (d-ROM) was determined as a marker of oxidative stress. During IA, the anti- β1-AR autoantibodies titers of all the patients decreased significantly from 27.8 ± 5.0 to 18.7 ± 5.5 U/ml (p < 0.01). IA induced the following hemodynamic improvements: cardiac index increased from 1.71 ± 0.40 to 1.97 ± 0.41 l/min/m2 and left ventricular ejection fraction (LVEF) increased from 22.8 ± 6.1 to 29.1±9.1% (p < 0.05). d-ROM level decreased significantly from 392.7 ±17.0 to 314.1 ± 22.0 Carratelli units (p < 0.05), and was negatively correlated with LVEF before and after IA therapy (r = －0.601, p < 0.05). The anti-β1-AR autoantibodies, LVEF and d- ROM returned to the baseline levels at 12 months after IA. In conclusion, oxidative stress reduction may be responsible for the beneficial effect of IA therapy in patients with DCM.

Although TNF inhibitors have dramatically improved the outcome of patients with rheumatoid arthritis, 30-40% of patients do not respond well to them and treatment needs to be changed. In an effort to discriminate good and poor responders, we focused on the change in serum and synovial fluid levels of interleukin (IL-) 33 before and after treatment with TNF inhibitors. They were also measured in synovial fluids from 17 TNF inhibitor-naïve patients, and fibroblast-like synoviocytes (FLS) in-culture from 6 patients and correlated with various pro-inflammatory cytokines. Serum levels of IL-33 at 6 months after treatment decreased significantly in responders, while they did not change in non-responders. Synovial fluid levels of IL-33 in 6 patients under treatment with TNF inhibitors stayed high in 3 who were refractory and slightly elevated in 2 moderate responders, while they were undetectable in one patient under remission. Among inflammatory cytokines measured in 17 synovial fluids from TNF inhibitor-naïve patients, levels of IL-33 showed a significant positive correlation only to those of IL-1β. IL-1β increased IL-33 expression markedly in FLS in vitro, compared to TNF-α. IL-1β might be inducing RA inflammation through producing pro-inflammatory IL-33 in TNF inhibitor-hypo-responders. Sustained elevation of serum and/or synovial levels of IL-33 may account for a poor response to TNF inhibitors, although how TNF inhibitors affect the level of IL-33 remains to be elucidated.

Objective Rheumatoid arthritis (RA) is the most common systemic autoimmune disease and is characterized mainly by symmetric polyarticular joint disorders. The pathologic processes are mediated by a number of cytokines, chemokines, cell adhesion molecules, and matrix metalloproteinases. The expression of most of these molecules is controlled at the transcriptional level. In addition, activation of NF-κB is involved in RA pathogenesis. This study was performed to explore the role of a novel serine/threonine kinase inhibitor, fasudil, in the control of the NF-κB activation pathway and to investigate the therapeutic effects of fasudil on arthritis development in a rat model of RA. Methods Fibroblast-like synoviocytes (FLS) from RA patients and human endothelial cells (ECs) were established and maintained. To study the role of fasudil on cytokine expression, various cytokines expressed in the RA FLS and human ECs were measured by enzyme-linked immunosorbent assay following stimulation of the cells with interleukin-1β (IL-1β) in the presence of various concentrations of fasudil. The role of fasudil on NF-κB activation was studied using a reporter gene assay, Western blotting of IκBα, immunofluorescence analysis of the p65 subunit of NF-κB, and electrophoretic mobility shift assay. The in vivo effects of fasudil on arthritis were studied in a rat adjuvant-induced arthritis (AIA) model. Results Fasudil inhibited cytokine expression in RA FLS and human ECs and also inhibited the activation of ECs, in a dose-dependent manner. Fasudil inhibited IL-1β–induced activation of NF-κB independent of the inhibition of IκBα degradation and nuclear translocation of NF-κB, and inhibited IL-1β–induced DNA binding of NF-κB. Finally, in vivo, fasudil ameliorated arthritis in rats with AIA, without any adverse effects. Conclusion Serine/threonine kinase inhibitor fasudil inhibits the development of arthritis in a rat model of RA, and also inhibits the NF-κB signaling required for binding of NF-κB to specific DNA sequences through, for example, the phosphorylation of p65, suggesting that a specific target of fasudil might be a novel NF-κB kinase. Thus, fasudil serves as a novel strategy for the treatment of RA.

Neuropsychiatric disease in systemic lupus erythematosus (NPSLE) is a poorly understood, but potentially fatal, disease manifestation. A pathogenetic role for autoantibodies is suspected, but the mechanism is unclear. Since immune complexes in SLE can stimulate IFN-α and there is strong evidence in humans and in mice that IFN-α can cause neuropsychiatric manifestations, we asked whether NPSLE patient serum and/or cerebrospinal fluid (CSF) contain abnormally high IFN-α-inducing activity. In a bioassay containing plasmacytoid dendritic cells and a source of Ag, NPSLE CSF induced significantly higher IFN-α compared with CSF from patients with multiple sclerosis or other autoimmune disease controls. When normalized for IgG concentration, NPSLE CSF was 800-fold more potent at inducing IFN-α compared with paired serum due to inhibitors present in serum. Analysis of Ig-deficient patient serum, depletion of IgG from normal serum, as well as addition of purified IgG to NPSLE CSF and serum in the bioassays revealed that one inhibitor was contained within the IgG fraction itself. In addition to IFN-α, immune complexes formed by CSF autoantibodies produced significantly increased levels of IFN-γ-inducible protein 10 (IP-10/CXCL), IL-8, and MCP-1, all of which have been reported to be elevated in CSF from NPSLE patients. Taken together, these findings are consistent with a two-step model of NPSLE whereby CSF autoantibodies bind to Ags released by neurocytotoxic Abs or other brain cell injury, and the resulting immune complexes stimulate IFN-α and proinflammatory cytokines and chemokines.

The autoantibodies stimulate the beta1-adrenoreceptors on cardiac myocytes similar to norepinephrine, and are associated with reduced cardiac function. Iodine-123 metaiodobenzylguanidine ((123)I-MIBG) is metabolized similarly to norepinephrine. This study was undertaken to investigate the relationship between cardiac stimulation by anti-beta1-adrenoreceptor autoantibodies and myocardial sympathetic nervous activity in patients with chronic heart failure.We screened for the anti-beta1-adrenoreceptor autoantibodies in 52 patients with chronic heart failure by conducting an enzyme-linked immunosorbent assay, and underwent (123)I-MIBG scintigraphy in 27 of the patients. Anterior planar images of (123)I-MIBG were obtained 15 min and 3 h after the injection. We determined the heart to mediastinum radioactivity ratio (H/M), and calculated the rate of washout of (123)I-MIBG from the heart.Patients with New York Heart Association functional class III or IV had higher levels of anti-beta1-adrenoreceptor autoantibodies than those with class I or II (p0.01). The autoantibody level was significantly correlated with delayed H/M (r=-0.65, p0.001) and washout rate (r=0.65, p0.001). Sixteen patients with a cardiac event showed higher levels of the autoantibodies (p0.05). Cardiac event-free survival was poorer in patients with the autoantibody levels10 U/ml than that10 U/ml (log-rank=12.1, p0.001).The anti-beta1-adrenoreceptor autoantibodies are closely associated with cardiac sympathetic nervous activity assessed by (123)I-MIBG and cardiac event in patients with chronic heart failure.

Objective To determine whether the intrathecal concentrations of cytokines/chemokines are associated with, or influenced by, serum concentrations in patients with central neuropsychiatric systemic lupus erythematosus (NPSLE), and to ascertain whether the increased production of cytokines/chemokines intrathecally relative to serum levels is associated with the presence of central NPSLE. Methods 52 SLE patients (30 with central NPSLE and 22 with non-NPSLE), for whom the CSF and serum samples were obtained at the same time, were enrolled. 27 kinds of cytokine/chemokine concentrations other than IFN-α in the cerebrospinal fluid (CSF) and serum samples were measured by Bio-Plex Pro Assays. IFN-α concentration and anti-ribosomal P protein antibody (anti-P) titres in CSF and serum samples were measured by ELISA. Results The mean concentrations of IL-6, IL-8, IP-10, MCP-1, G-CSF and GM-CSF were higher in the CSF than in the sera, respectively, while the mean concentrations of other 22 cytokines/chemokines, including RANTES and IFN-α, in the CSF were much lower than those in the sera, respectively. Furthermore, the concentrations of IL-6, IL-8, IP-10, MCP-1 and G-CSF in the CSF of the 30 patients with NPSLE were significantly higher than in the 22 patients with non-NPSLE ( p = 6.82 × 10−5, p = 0.00037, p = 0.0028, p = 0.00065, and p = 0.0001, respectively), while the concentration of GM-CSF in the CSF of the 30 patients with NPSLE was not significantly higher than in the 22 patients with non-NPSLE. Most importantly, the largest difference occurred in CSF IL-6 concentrations. A significant positive correlation between CSF anti-P titres and serum anti-P titres in 52 patients with SLE ( r = 0.6316, p = 6.44 × 10−6) was found, while no significant positive correlation was observed between CSF levels and serum levels of each cytokine/chemokine in the 52 SLE patients. Conclusion In central NPSLE the production of IL-6, IL-8, IP-10, MCP-1 and G-CSF might take place in the central nervous system (CNS). These increased CSF cytokines/chemokines along with anti-P might have a prerequisite role in the pathogenesis of central NPSLE.

Introduction: Neuropsychiatric manifestation in systemic lupus erythematosus (NPSLE) is one of the most serious complications of the disease. Previous studies revealed the strong association between serum anti-Sm and organic brain syndrome, consisting mainly of acute confusional state (ACS) of diffuse psychiatric/neuropsychological syndromes (diffuse NPSLE). However, the precise mechanism by which anti-Sm causes diffuse NPSLE remains unclear. Of note, recent studies demonstrated that anti-U1 RNP antibodies (anti-RNP) in cerebrospinal fluid (CSF) are associated with NPSLE. The present study was designed to explore the association of anti-Sm antibodies in CSF with NPSLE. Methods: Paired serum and CSF specimens were obtained from 72 patients with NPSLE (49 with diffuse NPSLE, 23 with neurological syndromes or peripheral neuropathy (focal NPSLE) and from 22 control patients with non-SLE neurological diseases. Sera were also obtained from 41 patients with active SLE without neuropsychiatric manifestations (non-NPSLE). Anti-Sm and anti-RNP were measured by enzyme-linked immunosorbent assay (ELISA). Blood-brain barrier (BBB) function and intrathecal anti-Sm production were evaluated by Q albumin and CSF anti-Sm index, respectively. Binding of anti-Sm to neuroblastoma cell lines SK-N-MC and Neuro2a was examined by flow cytometry and by cell ELISA. Results: Anti-Sm and anti-RNP in CSF and sera were elevated in NPSLE compared with non-SLE control. CSF anti-Sm, but not CSF anti-RNP, was significantly elevated in ACS compared with non-ACS diffuse NPSLE or with focal NPSLE. By contrast, there were no significant differences in serum anti-Sm or anti-RNP among subsets of NPSLE and non-NPSLE. Whereas there were no significant differences in CSF anti-Sm index, Q albumin was elevated in ACS compared with non-ACS or with focal NPSLE. Notably, CSF anti-Sm was correlated with Q albumin (r = 0.2373, P = 0.0447) or with serum anti-Sm (r = 0.7185, P

Objective To examine the incidence of hepatitis B virus (HBV) reactivation in patients with rheumatoid arthritis (RA) receiving biological disease-modifying antirheumatic drugs (DMARDs). Methods We retrospectively reviewed RA patients treated with biological DMARDs at our institution from July 2010 to December 2012. Patients with antibodies for hepatitis B core antigen and/or hepatitis B surface antigen were regarded as having prior HBV infection. Clinical data on these patients, including HBV-DNA levels, were retrieved from the medical records. Results During the study period, 251 patients were administered various biological DMARDs. Six patients with a history of HBV vaccination and one patient with positive HBV surface antigen were excluded from the study. Fifty-seven of the remaining 244 patients (23.4%) had prior HBV infection. These patients were followed for a median of 18 months (range: 2–27 months) and HBV-DNA was examined a median of seven times (range: 2–27). HBV-DNA was detected in three patients (5.3%), comprising two receiving tocilizumab and one receiving etanercept. However, HBV-DNA levels were below the quantitation limit (

We report on five patients with dermatomyositis (DM) and cutaneous necrosis. Patients presented with classic DM skin eruptions, mild myositis, and a high incidence (4/5) of interstitial pneumonia. Cutaneous necrosis developed independently of steroid therapy, with the majority of lesions being cured following several months of sterilization treatment. In addition, one patient with accompanying cancer presented with multiple necrotic lesions. Topical treatment using gentiana violet against local infection was considered to have been essential in accelerating healing.

Clinical profiles and the treatment process of three female patients with systemic sclerosis (cases 1, 2, and 3) complicated by thrombotic microangiopathic hemolytic anemia (TMHA) were described. Thrombocytopenia preceded renal damage and hypertension in cases 1 and 2, although the chronological relationship between these parameters were unknown in case 3. Plasma exchange therapy using fresh frozen plasma was beneficial in cases 1 and 2. Cases land 3 presented with delirium and fluctuating psychosis, respectively. Early detection of thrombocytopenia and insidious hemolysis might be essential for starting effective plasmapheresis treatment in a part of patients with scleroderma kidney who present with thrombotic thrombocytopenic purpura (TTP) like disorder.

In extravasation of T cells, little is known about the mechanisms of transendothelial migration subsequent to the T cells' tight adhesion to endothelium. To investigate these mechanisms, we developed a monoclonal antibody (mAb), termed anti-4C8, that blocks transmigration but not adhesion in a culture system in which high CD26-expressing (CD26(hi)) T cells preferentially migrate through human umbilical vein endothelial cell (HUVEC) monolayers cultured on collagen gels. Anti-4C8 reacted with all CD3(+) T cells and monocytes but not neutrophils or HUVECs. The structure defined by this antibody was an 80-kD molecule. The mAb at 1 mug/ml inhibited 80-90% of migration of CD3(+) T cells through unstimulated and interferon gamma-stimulated HUVEC monolayers without interfering with adhesion and cell motility. When added to the cultures after the adhesion, anti-4C8 completely blocked subsequent transmigration of adherent T cells. Phase-contrast and electron microscopy revealed that T cells are arrested at the intercellular junctions of HUVECs in the presence of anti-4C8. Anti-4C8 exhibited agonistic effects on resting T cells without other stimuli under culture conditions in which anti-4C8 can stimulate T cells. First, in the checkerboard assay using collagen gels, the antibody promoted chemokinetic migration of the cells in a dose-dependent manner from 0.1 to 10 mug/ml. The predominant population of T cells that migrated into collagen gels with impregnated anti-4C8 were CD26(hi). Second, solid-phase-immobilized anti-4C8 induced adhesion of T cells to the substrate, often with polarizations in cell shape and large pseudopods rich in filamentous (F-) actin. Third, soluble anti-4C8 augmented F-actin content preferentially in CD26(hi) T cells when added to T cells at a high dose of 10 mug/ml. Finally, both anti-4C8-induced chemokinetic migration and transendothelial migration were inhibited by pretreatment of T cells with pertussis toxin. These findings suggest that stimulation via the 4C8 antigen increases cell motility of CD26(hi) cells with profound cytoskeletal changes through signaling pathways including G proteins. The 4C8 antigen may be involved in preferential transmigration of CD26(hi) cells adherent to HUVECs.

Proinflammatory cytokines increase in concentration in the cerebrospinal fluid (CSF) of patients with neuropsychiatric syndromes of systemic lupus erythematosus (NPSLE), and some reports have shown that cytokines are elevated intrathecally.1–3 Recently, levels of Th1 chemokines, monocyte chemotactic protein 1 (MCP-1; CCL2) and interferon inducible protein-10 (IP-10; CXCL10) have been reported to be raised in the CSF of patients with NPSLE, implicating important roles for these chemokines in the pathogenesis of NPSLE.4,5 Here we study the role of soluble fractalkine (CX3CL1) in NPSLE. A total of 165 patients (161 women and 4 men, aged 16–58 years; mean age 32.4 years) fulfilling the criteria of the American College of Rheumatology for systemic lupus erythematosus (SLE) classification were selected. NPSLE was diagnosed under the American College of Rheumatology criteria for neuropsychiatric lupus syndromes.1 In all, 84 patients were diagnosed with NPSLE and 81 patients did not fulfill our criteria …

One hundred thirty-two patients with various connective tissue disorders, including 60 with rheumatoid arthritis (RA), had antibodies against human as well as Escherichia coli hsp60 in titers significantly higher than those of normal controls. There was a correlation between titers of antibody to human hsp60 and those to E. coli hsp60. Levels of antibodies against human and E. coli hsp60 were lower in joint fluids than in sera, indicating little production of antibodies in the joint. Antibodies affinity-purified with E. coli hsp60 bound strongly with the homologous hsp60, but weakly with human hsp60. However, antibodies affinity-purified with human hsp60 bound comparably with both E. coli hsp60 and human hsp60. Antibodies affinity-purified with Mycobacterium tuberculosis hsp65 bound to human hsp60 with a reactivity similar to the reactivity of those affinity-purified with human hsp60. The reactivity to the three hsp60 species was lost when sera were absorbed with E. coli hsp60, while the reactivity to E. coli hsp60 remained after extensive absorption with M. tuberculosis hsp65 or human hsp60. These results indicate that anti-hsp60 antibodies in patients with RA and other connective tissue disorders are raised by infection with intestinal microorganisms such as E. coli. They may represent another example of autoimmune responses triggered by antigenic mimicry of host proteins to microbes and suggest that the reactivity of antibodies from RA patients with M. tuberculosis hsp65 might have been a cross-reaction with the E. coli homologue.

Infliximab was introduced along with methotrexate 8 mg/week to a female patient with intractable rheumatoid arthritis. Although a dramatic improvement of her arthritic symptoms was achieved immediately, a small nodular shadow developed in the right middle field of her lung, visible on chest X-ray at the third injection. Because the nodular shadow rapidly increased its size in a week, transbronchial fiberoptic examination was performed and lavage fluid was obtained. The polymerase chain reaction was positive for Mycobacterium avium and the bacterial growth in culture confirmed the diagnosis. Although tuberculosis is a well-known adverse reaction to infliximab, development of nontuberculous mycobacteriosis is quite rare and no such report has so far been published in the context of infliximab usage. We should be alert to the fact that nontuberculous mycobacteriosis of slow progression in a usual clinical setting progresses quite rapidly, thus treatment should not be delayed, especially in patients on infliximab.

Infliximab was introduced along with methotrexate 8 mg/week to a female patient with intractable rheumatoid arthritis. Although a dramatic improvement of her arthritic symptoms was achieved immediately, a small nodular shadow developed in the right middle field of her lung, visible on chest X-ray at the third injection. Because the nodular shadow rapidly increased its size in a week, transbronchial fiberoptic examination was performed and lavage fluid was obtained. The polymerase chain reaction was positive for Mycobacterium avium and the bacterial growth in culture confirmed the diagnosis. Although tuberculosis is a well-known adverse reaction to infliximab, development of nontuberculous mycobacteriosis is quite rare and no such report has so far been published in the context of infliximab usage. We should be alert to the fact that nontuberculous mycobacteriosis of slow progression in a usual clinical setting progresses quite rapidly, thus treatment should not be delayed, especially in patients on infliximab.

A 59-year-old woman developed edema of the face and eyelids during interferon (IFN)-alpha-2b therapy for chronic hepatitis C with a cumulative dose of 6 million × 47 units. Despite cessation of the therapy, the edema progressed and was followed by exophthalmos, pyrexia, liver dysfunction, pancytopenia, and disseminated intravascular coagulation. Two months after initial presentation, she died of hemorrhagic shock and was diagnosed with histiocytic cytophagic panniculitis at autopsy. This may be a hitherto unrecognized adverse effect of therapeutic IFNα.(Internal Medicine 35: 115-118, 1996)

OBJECTIVES--To clarify the pathophysiological role of endothelin-1 (ET-1) in the vascular injury associated with systemic lupus erythematosus (SLE) by investigating the effect of sera from patients with SLE on ET-1 release from cultured human umbilical vein endothelial cells. METHODS--Confluent monolayers of cultured human umbilical vein endothelial cells were incubated with serum samples (diluted 1:10) from 25 patients with SLE and 16 normal controls for two hours at 37 degrees C and ET-1 concentration in the culture supernatant was measured by enzyme immunoassay. RESULTS--The mean release of ET-1 from endothelial cells in the presence of serum from SLE patients was greater than in the presence of serum from normal controls (p < 0.005). ET-1 release from endothelial cells significantly correlated with the titre of IgM anti-endothelial cell antibodies (IgM-AECA) and immune complex concentration in sera from SLE patients (p < 0.05 and p < 0.01, respectively). After gel chromatography of the serum from an SLE patient, those fractions containing IgM-AECA or immune complex were shown to stimulate ET-1 release from endothelial cells. Heat aggregated IgG also stimulated ET-1 release from endothelial cells in a concentration dependent manner. CONCLUSIONS--IgM-AECA and immune complexes may stimulate ET-1 release from endothelial cells and ET-1 may play an important role in the initiation and development of vascular injury, such as pulmonary hypertension and lupus nephritis, in SLE.

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 (ref). Notably, C5a, a split product of C5, has been recently shown to cause BBB damages. Moreover, association of C5a with some forms of glomerulonephritis has been implicated. Objectives The present study therefore explored the levels of C5a in sera from patients with NPSLE and lupus nephritis (LN). Methods Serum specimens were obtained from 29 patients with NPSLE including 18 patients with diffuse NPSLE and 9 patients with neurologic syndromes (focal NPSLE), 25 patients with LN, 26 patients without NPSLE or LN (SLE alone), and from 21 healthy individuals. Cerebrospinal fluid (CSF) specimens were obtained from 29 patients with NPSLE on the same day of the collection of serum specimens. The levels of C5a, C5, C3 and C4 were measured by enzyme-linked immunosorbent assay. The BBB function was evaluated by CSF /serum albumin ratio (Q albumin). Results Serum C5a was significantly increased in 80 SLE patients compared with that in healthy individuals. Serum C5a was significantly elevated in NPSLE as well as in LN compared with that in SLE alone (figure), whereas there were no significant differences in serum C5 among these 3 groups. Serum C4, but not serum C3, was significantly lower in LN than that in NPSLE (figure), indicating the activation of complement classical pathway in LN, but not in NPSLE. Q albumin was significantly elevated in diffuse NPSLE compared with that in focal NPSLE, whereas there were no significant differences in CSF C5a and in serum C5a between these 2 groups. Notably, Both CSF C5 and CSF C5a were significantly correlated with Q albumin, whereas serum C5a, but not serum C5, was inversely correlated with Q albumin in NPSLE patients. Conclusions These results have disclosed that serum C5a was elevated in NPSLE as well as in LN through different mechanisms. Moreover, the data indicate that CSF C5a and C5 were elevated in NPSLE due to BBB damages. Finally, it is suggested that C5a might be consumed during the process of BBB damages. References Hirohata S, Arinuma Y, Yanagida T, Yoshio T. Arthritis Res Ther 16:R77, 2014 Disclosure of Interest None declared

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by widespread immunologic abnormalities and multiorgan involvement including the skin, joints, and kidney as well as the peripheral and central nervous systems. The clinical course of SLE is usually dependent on the organ involved such as neuropsychiatric syndromes of systemic lupus erythematosus (NPSLE), lupus nephritis (LN), lupus pancreatitis (LP), and pulmonary hypertension (PH). Early diagnosis and epoch-making therapeutic strategies are prerequisites for improved prognosis of patients with SLE. To fulfill this medical need, a better understanding of the pathogenesis of SLE is required. Research over the course of several years has yielded a basic scientific understanding of SLE pathogenesis. This includes understanding the role of various cytokines and chemokines in disease progression, the chronic activation of plasmacytoid dendritic cells by circulating immune complexes, and the expression of neutrophil-specific genes.

Objective To investigate the possibility that IgG anti–NR2 glutamate receptor antibodies (anti-NR2) derived from patients with systemic lupus erythematosus (SLE) cause an immunologic interaction with endothelial cells (ECs) in the blood–brain barrier, resulting in inflammation of the blood–brain barrier, allowing the entrance of these autoantibodies into the cerebrospinal fluid. Methods Purified IgG anti-NR2 antibodies from 14 patients with SLE were tested for their ability to bind to double-stranded DNA (dsDNA) and ECs, to modulate endothelial adhesion molecule expression and cytokine production by ECs, and to activate the NF-κB pathways in the ECs. Purified IgG from 5 normal subjects was used as a negative control. Results Purified IgG anti-NR2 antibodies bound to dsDNA in an IgG-dose–dependent manner. This interaction up-regulated the expression of endothelial leukocyte adhesion molecule 1, vascular cell adhesion molecule 1, and intercellular adhesion molecule 1 on the EC surface and increased the production of interleukin-6 (IL-6) and IL-8, but not tumor necrosis factor α or IL-1β, by ECs. Purified IgG anti-NR2 also activated the degradation of cytoplasmic IκB, indicating the activation of NF-κB in the ECs. Conclusion EC activation through the NF-κB signaling pathway induced by IgG anti-NR2 antibodies in the central nervous system of SLE patients may lead to inflammation of the blood–brain barrier, initiating the pathogenesis of neuropsychiatric SLE.

A 57-year-old Japanese woman developed skin eruption, pleuritis, pancytopenia, parotid gland swelling and glomerulonephritis after 7-month treatment with pegylated interferon-α and ribavirin for chronic hepatitis C. Disease-specific autoantibodies such as anti-SSA, anti-SSB, anti-Sm and anti-dsDNA antibodies became positive. The diagnosis of systemic lupus erythematosus and Sjögren’s syndrome was made and treatment with glucocorticoid pulse followed by oral glucocorticoid was started. It is highly probable that interferon-α-induced systemic lupus erythematosus and Sjögren’s syndrome in this case. Interferon-α might be important pathogenically in these diseases. Lupus (2010) 19, 753—755.

Objective.To determine levels of interleukin 33 (IL-33) in serum and synovial fluid (SF) and their clinical associations in patients with rheumatoid arthritis (RA). To evaluate the ability of activated peripheral blood mononuclear cells (PBMC) and fibroblast-like synoviocytes (FLS) from RA patients to release IL-33.Methods.Sera were obtained from 59 patients with RA, 10 patients with infectious diseases, and 42 healthy volunteers. SF samples were obtained from 15 patients with RA and 13 with osteoarthritis. IL-33 levels were measured using a sandwich ELISA after removal of rheumatoid factor with protein A-Sepharose beads. FLS were stimulated with IL-1ß and tumor necrosis factor, and treated with or without chemical damage. PBMC were stimulated with anti-CD3/CD28 antibodies. The levels of IL-33 were measured in the culture supernatants and cell lysates by ELISA or immunoblotting.Results.Serum IL-33 levels were significantly higher in RA patients, especially in the high disease activity group compared to the moderate or low activity group. IL-33 levels in SF were elevated in all 15 RA patients measured. IL-33 levels were higher in SF samples than in sera in 7 RA patients measured simultaneously. The 30-kDa IL-33 precursor was detected in the culture supernatants of damaged FLS but was not detected in those of activated PBMC and non-damaged FLS.Conclusion.IL-33 levels were elevated in sera and SF samples from patients with RA, and correlated with disease activity. IL-33 was produced mainly in inflamed joints; IL-33/ST2L signaling might play an important role in joint inflammation of human RA.

The objective of this study is to investigate the clinical markers of life-threatening Pneumocystis pneumonia (PCP) in patients with collagen vascular diseases (CVD). The patients who contracted Pneumocystis jeroveccii were retrospectively selected from our medical charts and conditions related to the patients’ death were reviewed. The findings indicated that lower levels of serum albumin and cholinesterase, increased alveolar–arterial oxygen gradient, intratracheal intubation, and necessity to treat in the intensive care unit were significantly related to deaths associated with PCP in CVD. A special attention should be paid to decreased serum albumin and cholinesterase as ominous predictors in PCP occurred in patients with CVD.

Systemic lupus erythematosus (SLE) is often complicated by pericarditis with effusion, which generally responds well to glucocorticoid. We report herein a Japanese patient with SLE who showed a sign of cardiac tamponade and severe chest and back pain because of massive intractable pericardial effusion. Pulse glucocorticoid and pulse cyclophosphamide gained marginal effects. Pericardial effusion accumulated again soon after ultrasound-guided pericardiocentesis and drainage. Pericardial fenestration performed surgically as a last resort, for draining pericardial fluid into the pleural space, was very effective, and only a much smaller amount of fluid was observed in the space thereafter in comparison with the volume before the surgery. Pathological examination of the retrieved pericardium unfolded intense hyperplasia of small vessels and capillaries. Levels of IL-6 and TNF-α in pericardial effusion were extremely higher than those in serum. Pericardial effusion with extensive capillary hyperplasia in SLE would be resistant to medical treatment and require surgical fenestration.

Various autoantibodies had been detected in patients with dilated cardiomyopathy (DCM). Among them, anti-beta 1 adrenoreceptor antibody (ARAb) had been proven to act as agonist on beta 1 adrenoreceptor and cause DCM. Cardiomyopathy is also serious problem in progressive muscular dystrophy (PMD). Because cardiac dysfunction is quite variable even in siblings sharing identical mutations, it is highly possible that there are some modifier factors. Thus, we measured ARAb in 93 patients with PMD and 11 patients with DCM to clarify immune function for cardiac impairment of PMD. The titer was abnormally elevated in 30.1% of PMD, 72.7% of DCM and 75.0% (9/12) of PMD patients with symptomatic cardiac failure. ARAb was weakly correlated to fractional shortening, brain natriuretic peptide, noradrenalin and severity of premature ventricular contractions (Lown grade). During the study period, four patients developed cardiac failure and ARAb was increased in all these patients. In DMD, although the patients receiving both beta blocker and angiotensin converting enzyme inhibitor showed worst cardiac function, the titers were rather low compared to patients with angiotensin converting enzyme inhibitor alone. Four of five patients initiating beta blocker showed decrease of ARAb. Autoantibodies for myocardium actually exist in PMD in certain ratio as is the case with DCM. It is highly possible that immune system plays some role in cardiac impairment even in PMD. We should pay enough attention to immune system to elucidate the mechanism of cardiac dysfunction and refine strategy of cardiac treatments.

Objective. CD34-positive bone marrow mononuclear cells (MNCs) have been successfully used for regeneration of small arteries in Buerger’s disease. The objective of this study is to examine the angiogenetic potential of autologous MNCs from bone marrow and peripheral blood implanted into the ischaemic digits from patients with connective tissue diseases. Methods. Three patients with systemic sclerosis, two with mixed connective tissue disease, and one with CREST syndrome were enrolled who had painful ischaemic digits with necrosis refractory to several vasodilators including intravenous prostaglandins. MNCs obtained from 7 ml/kg bone marrow blood and 400ml peripheral blood were implanted into 20 different sites in palms and/or soles. The study was performed open-labelled. Results. Pain in the numeric rating scale improved remarkably up to 1 month after implantation of bone marrow or peripheral MNCs to the same extent, although no significant differences were found in transcutaneous oxygen pressure and thermogram before and after the implantation. Bone marrow MNCs increased blood flow of the hand determined by intra-arterial digital subtraction angiography, while peripheral MNCs did not. Conclusions. Implantation of autologous MNCs from peripheral and bone marrow into the ischaemic digits was so effective in pain-relief and more clinical trials would be warranted to see whether this could be a new treatment modality for angiogenesis in connective tissue diseases as in Buerger’s disease. KEY WRODS: Connective tissue disease, Bone marrow mononuclear cell, Peripheral mononuclear cell, CD34-positive cell, Angiogenesis.

A 27-year-old woman with systemic lupus erythematosus (SLE) was found to have acute acalculous cholecystitis. At the time of admission, the patient was not under corticosteroid or immunosuppressive therapy. Computed tomography (CT) and ultrasonography revealed findings in the gall bladder consistent with acute acalculous cholecystitis. Her abdominal pain completely disappeared following corticosteroid therapy, with dramatic improvement in the images of CT and ultrasonography. Six similar cases of SLE complicated with acute acalculous cholecystitis have been reported in the literature and they were all treated surgically by cholecystectomy or cholecystostomy. This is the first case report in which acute acalculous cholecystitis accompanying SLE was treated successfully by corticosteroid without surgical intervention.

Objective To clarify whether mouse monoclonal antibodies (mAb) against human thrombomodulin (TM), which react with human TM present on the endothelial cell (EC) surface, have anti–endothelial cell antibody (AECA) activity and influence antiinflammatory properties of human TM expressed on the EC surface in vitro. Methods Three preparations of mouse mAb against human TM that react with different sites of the human TM epidermal growth factor–like domain were tested for their ability to 1) bind to ECs, 2) modulate cytokine secretion from ECs, EC adhesion molecule expression, and neutrophil adhesion to ECs, and 3) stimulate nuclear translocation of NF-κB through the degradation of cytoplasmic IκB in ECs. Recombinant human interleukin-1β (IL-1β) was used as a positive control, and mouse IgG1 and mouse IgG2a were used as negative controls. Results The 3 preparations of mouse mAb against human TM that bind to unfixed EC monolayers enhanced IL-6 and IL-8 secretion from ECs, up-regulated expression of endothelial leukocyte adhesion molecule 1, vascular cell adhesion molecule 1, and intercellular adhesion molecule 1 on EC monolayers, and enhanced neutrophil adhesion to ECs to a degree similar to that observed with IL-1β stimulation, but they did not induce the secretion of tumor necrosis factor α or IL-1β from ECs throughout the incubation period. The 3 preparations stimulated nuclear translocation of NF-κB through the degradation of cytoplasmic IκB. Mouse IgG1 and mouse IgG2a did not exhibit such effects. Conclusion These results suggest the possibility that AECA can react with antigens such as TM that are present on the EC surface and activate ECs. Such events on ECs may lead to vascular inflammation and damage in patients with connective tissue diseases and vasculitis in which AECA are present.

An imbalance in cytokine homoeostasis is thought to have a key role in the neuropsychiatric syndromes of systemic lupus erythematosus (NPSLE), and recently, a role for chemokines has been noted.To compare concentrations of monocyte chemotactic protein-1 (MCP-1)/CCL2 in cerebral spinal fluid (CSF) of patients with SLE, and with and without neuropsychiatric symptoms.CSF was obtained from 185 patients with SLE: 96 with NPSLE and 89 patients with SLE without neuropsychiatric symptoms (non-NPSLE patients). MCP-1/CCL2 concentrations were measured with an ELISA.The average concentration of CSF MCP-1/CCL2 in patients with NPSLE was 1959 pg/ml, and in non-NPSLE patients 712 pg/ml. The average MCP-1/CCL2 concentration was significantly higher in the NPSLE group than in the non-NPSLE group (p0.001). In one representative patient with NPSLE, MCP-1/CCL2 levels in the CSF decreased in parallel with a decline in neuropsychiatric symptoms.CSF MCP-1/CCL2 levels are higher in patients with NPSLE than in non-NPSLE patients. MCP-1/CCL2 may have an important role in the expression of NPSLE. These results indicate that CSF MCP-1/CCL2 reflects an inflammatory activity in the brain, suggesting that it might be used as a diagnostic tool and a monitor for therapeutic responses in patients with NPSLE.

Objective To quantitatively evaluate the diagnostic accuracy of antibodies to ribosomal P proteins (anti-P) for neuropsychiatric systemic lupus erythematosus (NPSLE) in general, for psychosis, mood disorder, or both, and for other diffuse manifestations. Methods This international meta-analysis combined standardized data from 1,537 lupus patients contributed by 14 research teams. Weighted estimation of sensitivity and specificity with fixed-effects and random-effects models, as well as summary receiver operating characteristic (SROC) curve analysis, was used to summarize test performance. The robustness of the overall estimates was examined in sensitivity analyses that included additional studies published up to November 1, 2004 in the Medline, EMBase, and Cochrane databases. Results Combining the data from the 14 teams, the weighted sensitivity and specificity estimates for the diagnosis of NPSLE were 26% (95% confidence interval [95% CI] 15–42%) and 80% (95% CI 74–85%), respectively. For psychosis, mood disorder, or both, the sensitivity and specificity were 27% (95% CI 14–47%) and 80% (95% CI 74–85%), respectively. For other diffuse manifestations, the sensitivity was 24% (95% CI 12–42%), and the specificity was 80% (95% CI 73–85%). The proportion of patients with anti-P antibodies did not vary markedly across different presentations of NPSLE. Between-study heterogeneity was substantial, but the SROC curves were consistent with the weighted estimates. In further analyses that included another 24 published studies, only the sensitivity for psychosis and/or mood disorder was slightly improved, but it was still suboptimal (42% [95% CI 30–53%]); the specificity remained essentially the same (81% [95% CI 76–85%]). Conclusion Anti-P antibody testing has limited diagnostic value for NPSLE, and it is not helpful in differentiating among various disease phenotypes.

Although the development of pulmonary arterial hypertension (PAH) in mixed connective tissue disease (MCTD) is now recognised as the most important life threatening factor, an effective treatment for PAH has not been established. The response to steroid treatment of PAH related to MCTD varies. Furthermore, Raynaud’s phenomenon is the most common symptom of MCTD and one symptom of the 1996 revised criteria for MCTD in Japan.1 However, a reliable and consistently effective treatment for Raynaud’s phenomenon in MCTD has not been established. Sildenafil is reportedly effective for PAH and Raynaud’s phenomenon in systemic sclerosis (SSc) and systemic lupus erythematosus (SLE).2–4 However, the effect of sildenafil on PAH and Raynaud’s phenomenon in MCTD has not been reported. We describe a case of PAH and Raynaud’s phenomenon in a 39 year old female patient with MCTD, in …

To investigate whether antiribosomal P protein antibodies (anti-P) are present in the cerebrospinal fluid (CSF) of patients with systemic lupus erythematosus (SLE), and if presence of anti-P in CSF is more strongly related to the appearance of neuropsychiatric SLE (NPSLE) than anti-P in serum.CSF and serum samples from 70 patients with SLE were used. Patients were divided into 4 groups: 21 patients with neurologic syndromes of the central nervous system (CNS); 19 patients with diffuse psychiatric/neuropsychological syndromes; 10 patients with complex presentations (neurologic syndromes of the CNS plus diffuse psychiatric/neuropsychological syndromes); and 20 patients without NPSLE based on diagnostic criteria for 19 NPSLE syndromes proposed by the American College of Rheumatology. IgG anti-P in CSF and serum samples were detected by Western blotting using rat liver ribosomes. Inhibition assay was performed using 5 anti-P-positive CSF samples preincubated with synthetic ribosomal P peptide. Western blotting results were compared with those from ELISA with synthetic ribosomal P peptide as antigen. The association of CSF and serum anti-P with NPSLE was analyzed.CSF and serum IgG anti-P by Western blotting were detected, respectively, in 20 (28.6%) and 32 (45.7%) of 70 patients. The presence of IgG anti-P by Western blotting in the CSF was supported by positive results in the inhibition assay and significant association with CSF IgG anti-P titers by ELISA. The frequency of CSF anti-P by Western blotting in SLE patients with serum anti-P was significantly higher than in SLE patients without serum anti-P (18/32 vs 2/38; p0.001). The frequency of CSF anti-P by Western blotting in patients with NPSLE was significantly higher than in patients without NPSLE (19/50 vs 1/20; p0.01). The frequency of CSF anti-P by Western blotting in the group with complex presentations (10/10) was significantly higher than in the other 3 groups [neurologic syndromes of CNS (5/21); diffuse psychiatric/neuropsychological syndromes (4/19); and patients without NPSLE (1/20)] (p0.001). The frequency of serum anti-P by Western blotting in patients with NPSLE was not significantly higher than in patients without NPSLE (25/50 vs 7/20; p = 0.192).These results suggest that the presence of IgG anti-P in CSF of SLE patients may be involved in the appearance of NPSLE, especially in complex presentations. Measurement of IgG anti-P in CSF by Western blotting may be more useful for diagnosis of NPSLE than measurements in serum.