Safety of Tocilizumab on Rheumatoid Arthritis in Patients with Interstitial Lung Disease.

Purpose: The prognosis of rheumatoid arthritis (RA) with interstitial lung disease (ILD) is particularly poor. Although drugs that do not contribute to the progression of ILD should be used in RA treatment, none have been established. This study evaluated the safety of tocilizumab in terms of ILD activity. Patients and Methods: This study prospectively enrolled all 55 patients with RA complicated by ILD who were treated with tocilizumab at Dokkyo Medical University Saitama Medical Center from April 2014 to June 2022. The outcome measures were MMP-3 and KL-6 as biomarkers of RA and ILD activity, respectively, and the relationship between them was analyzed. Results: Both MMP-3 and KL-6 were significantly improved at 6 months of treatment (P < 0.001 and P < 0.05, respectively), and a weak correlation between MMP-3 and KL-6 was observed (R2 = 0.086, P = 0.087). The group with increased MMP-3 due to RA progression had significantly higher KL-6 at 6 months compared with the group with RA improvement (P < 0.05). Also, the group with ILD progression on computed tomography had significantly higher MMP-3 compared with the groups with improvement or no change of ILD (P < 0.05 and P < 0.01, respectively). The mortality rate was 0% at 6 months, 2.0% at 1 year, 16.7% at 2 years, and 32.4% at 3 years, and mortality from acute exacerbation of ILD due to respiratory infection increased over time. Conclusion: RA activity and ILD activity were found to be related at 6 months of treatment. Tocilizumab does not seem to affect the mechanism of ILD progression, as most patients showed improvement in both MMP-3 and KL-6 with tocilizumab within 6 months, when this drug would be expected to affect the lungs directly. However, respiratory infection exacerbated ILD from 1 year after the start of treatment. As immunosuppressive drugs, including tocilizumab, have a risk of respiratory infection, it is important to identify early signs of infection.

Changing patterns of pulmonary abnormalities in rheumatoid arthritis.

BACKGROUND: As a first step in identifying the developmental pathways of pulmonary abnormalities in rheumatoid arthritis (RA), we sought to determine the existing and changing patterns of pulmonary abnormalities. METHODS: We conducted a retrospective cohort study of consecutive patients with RA who underwent high-resolution computed tomography before and during biologic therapy. The presence of 20 pulmonary abnormalities and the changes in those abnormalities were recorded. Patterns of pre-existing and changing abnormalities were examined via cluster analysis, and their relationship was also assessed using the Kaplan-Meier method and log-rank test. RESULTS: A total of 208 subjects were included. Pulmonary abnormalities were observed in 70% of patients: 39% had interstitial lung disease, and 55% had airway disease (AD). Several different pulmonary abnormalities were commonly found to co-exist in several patterns in the same patient. In most patients with pulmonary abnormalities, AD was present alone or in combination with other abnormalities. During the observation period (mean 3.2 years), 172 pulmonary abnormalities had changed in 91 patients: 115 pulmonary abnormalities newly emerged, whereas 42 worsened and 25 demonstrated improvement. Pulmonary abnormalities changed in several patterns. Correlations were observed between pre-existing and new/worsening abnormalities at individual and regional levels, such as new ground-glass opacity (GGO) and pre-existing AD, small nodular patterns, and honeycombing. AD was a possible initial abnormality. CONCLUSIONS: Pulmonary abnormalities occurred and changed in several patterns, which suggests the existence of developmental pathways of pulmonary abnormalities. AD may play an important role in the development of these abnormalities, including GGO.

LAT1-specific inhibitor ameliorates severe autoimmune arthritis in SKG mouse.

L-type amino acid transporter 1 (LAT1, slc7a5) supplies large neutral amino acids to highly proliferative cells. LAT1 is an attractive therapeutic target for treating overactive T cell-mediated immune disorders due to its high expression in activated T cells, but not in resting T cells. Here, we demonstrate that LAT1 plays a crucial role in T helper (Th) 17-mediated autoimmune arthritis in SKG mice, an animal model of human rheumatoid arthritis (RA). Administration of JPH203, a LAT1-specific inhibitor, suppressed mannan-induced joint swelling, synoviocyte proliferation and inflammatory cell infiltration in SKG mice. A diminished metabolic reprogramming, including a decrease in oxidative phosphorylation that regulates Hif-1α expression and subsequent control of glycolysis enzymes, was involved in the downregulation of Th17 differentiation by LAT1 inhibition. Moreover, publicly released database analysis revealed facilitated expression of LAT1 in T cells with cytotoxic features in patients with RA. Our results demonstrate the essential contribution of LAT1 to the development of RA, proposing a potential therapeutic approach targeting amino acid transporters for treating hypersensitive immune diseases.

The role of anti-elastin antibodies in a mouse model of asthma.

BACKGROUND: The role of anti-elastin antibody (Ab) in the lung is unclear, although they may be involved in chronic obstructive pulmonary disease (COPD). Recently, increased anti-elastin Ab levels were reported in asthma. OBJECTIVE: To elucidate the role of anti-elastin Ab in asthma, we created a murine asthma model. Anti-elastin Ab in the airway was neutralized by intratracheal administration of elastin peptide, and the inhibitory effects of anti-elastin Ab on airway remodeling were evaluated. METHODS: BALB/c mice were immunized with ovalbumin (OVA) on days 0 and 14. After immunization, the mice received booster OVA via inhalation twice per week for 9 weeks, and bronchoalveolar lavage fluid (BALF) and lung tissues were evaluated. RESULTS: In lung tissues, airway remodeling occurred after 9 weeks of OVA sensitization. Peak levels of anti-elastin Ab and eosinophils in BALF were detected after 3 weeks of OVA sensitization. Anti-elastin Ab and eosinophil levels in BALF were significantly reduced after 3 weeks by the neutralization of anti-elastin Ab. Peak transforming growth factor-ß1 levels in BALF were detected at 3 weeks after OVA sensitization and were significantly reduced by the neutralization of anti-elastin Ab. Airway remodeling in lung tissues was also significantly inhibited by the neutralization of anti-elastin Ab. CONCLUSIONS: In our murine asthma model, anti-elastin Ab was recruited to the airway by OVA-induced allergic inflammation. Airway remodeling was inhibited by the neutralization of anti-elastin Ab. Anti-elastin Ab may contribute to the progression of airway remodeling.

Elevation of anti-elastin antibody in patients with asthma.

BACKGROUND: It is often difficult to differentiate between asthma and chronic obstructive pulmonary disease (COPD), and useful biomarkers are needed for accurate diagnosis. OBJECTIVE: We evaluated anti-elastin antibody to identify useful biomarkers for differentiating between a diagnosis of asthma and COPD. METHODS: Patients with asthma (male to female ratio = 10/13; mean age, 67.3 years), COPD (16/0; 74.8 years) and controls (8/4; 72.3 years) were enrolled. Samples from sputum and serum were collected and levels of anti-elastin Ab were measured. RESULTS: The levels of anti-elastin Ab in sputum were significantly higher in asthma (11.4 ± 7.16 µg/mL) than in COPD (5.82 ± 5.16 µg/mL; P < 0.01), and serum levels in asthma (67.4 ± 29.7 µg/mL) were also significantly higher than in COPD or controls (45.0 ± 12.8 µg/mL; P < 0.05, 38.6 ± 10.4 µg/mL; P < 0.01, respectively). Anti-elastin Ab in sputum showed a positive correlation with smoking in asthma (r2 = 0.218, P < 0.05). However, no significant differences were observed in the levels of anti-elastin Ab and eosinophils, asthma phenotypes, inhaled corticosteroids, or severity in patients with asthma. Elastin was strongly expressed under the airway basement membrane in asthma compared with COPD or the healthy control. CONCLUSIONS: Anti-elastin Ab in sputum could be a useful biomarker for COPD and asthma in ever-smokers. In asthma, anti-elastin Ab was recruited to the airways by both airway allergic inflammation and smoking, and it may contribute to the progression of airway remodeling via autoimmune inflammation, but not emphysema, in COPD.

Tofacitinib for refractory interstitial lung diseases in anti-melanoma differentiation-associated 5 gene antibody-positive dermatomyositis.

Objective: We aimed to determine the outcome of combination therapy with tofacitinib (TOF) in a case series of refractory rapidly progressive interstitial lung disease (ILD) associated with anti-melanoma differentiation-associated 5 gene (MDA5) antibody-positive (Ab+) DM. Patients who had poor prognostic factors and failed to respond to immunosuppressive therapy were selected for TOF treatment. Methods: Five patients with anti-MDA5 Ab+ DM-ILD who failed to respond to triple therapy with high dose glucocorticoids, CSA and CYC were given additional TOF (10 mg/day). To identify the poor prognostic factors, data from 15 consecutive patients (seven survived and eight died) with anti-MDA5 Ab+ DM-ILD before induction of TOF were analysed. Results: Three poor prognostic factors were identified: serum ferritin level >1000 ng/ml before therapy; ground-glass opacities in all six lung fields before therapy; and worsening of pulmonary infiltrates during therapy. All six patients who had all of the three factors and received triple therapy died before TOF therapy. There were five patients who had all of the three prognostic factors and failed to respond to triple therapy, but were able to receive the combination therapy with TOF; among them, three survived and two died. The survival rate of patients who received TOF was significantly better than that of the historical controls with immunosuppressive therapy before TOF. The patients who received TOF experienced complicated adverse events, particularly viral infection. Conclusion: Combination therapy with TOF might have the potential to control refractory anti-MDA5 Ab+ DM-ILD.

Intensive immunosuppressive therapy for endogenous lipoid pneumonia associated with rheumatoid arthritis.

Endogenous lipoid pneumonia is an uncommon inflammatory pulmonary disease that is caused by lipids from an endogenous source, the treatment for which has not been established. We report the first case of endogenous lipoid pneumonia presenting as lung consolidation and which was associated with rheumatoid arthritis. Treatment was successful with intensive immunosuppressive therapy. When a physician finds lung consolidation in a patient with active rheumatic disease, lipoid pneumonia should be considered.

Clinical features of organizing pneumonia associated with rheumatoid arthritis.

OBJECTIVES: To clarify the clinical features of organizing pneumonia (OP) associated with rheumatoid arthritis (RA) and to determine whether development of OP is related to RA activity. METHODS: A cross-sectional study was conducted, in which medical records of 499 consecutive RA patients who visited our hospital during one month were reviewed. OP was diagnosed by pathological findings by trans-bronchial biopsy or by clinical features (typical computed tomography findings, no causative agents, good response to glucocorticoids, and lack of response to antibiotics). RESULTS: Among 499 patients, OP was found in 19 patients and the estimated prevalence was 1.9-4.8%. No differences in clinical features were noted between the OP and non-OP groups. The mean age of OP development was 57.2 years and the period from the onset of RA to OP ranged from -4 to +34 years. Although 14 patients presented OP after the onset of RA, two developed OP before RA and three developed OP simultaneously with RA. Patients receiving tumor necrosis factor inhibitors also developed OP. RA disease activity just before onset of OP was low in 8 of 14 RA cases. At the onset of OP, only two patients showed exacerbations of arthritis, whereas most patients presented with fever and serum C-reactive protein (CRP) elevations. Glucocorticoids were effective for OP in all patients who received them. Relapse occurred in 4 of 19 cases. CONCLUSIONS: OP develops in approximately 4% of RA patients, which occurs independently from arthritis activity and at any time in RA patients.

B and T lymphocyte attenuator inhibits LPS-induced endotoxic shock by suppressing Toll-like receptor 4 signaling in innate immune cells.

Although innate immune responses are necessary for the initiation of acquired immune responses and the subsequent successful elimination of pathogens, excessive responses occasionally result in lethal endotoxic shock accompanied by a cytokine storm. B and T lymphocyte attenuator (BTLA), a coinhibitory receptor with similarities to cytotoxic T-lymphocyte antigen (CTLA)-4 and programmed death (PD)-1, is expressed in not only B and T cells but also dendritic cells (DCs) and macrophages (Mϕs). Recently, several studies have reported that BTLA-deficient (BTLA(-/-)) mice show enhanced pathogen clearance compared with WT mice in early phase of infections. However, the roles of BTLA expressed on innate cells in overwhelming and uncontrolled immune responses remain unclear. Here, we found that BTLA(-/-) mice were highly susceptible to LPS-induced endotoxic shock. LPS-induced TNF-α and IL-12 production in DCs and Mϕs was significantly enhanced in BTLA(-/-) mice. BTLA(-/-) DCs also produced high levels of TNF-α on stimulation with Pam3CSK4 but not poly(I:C) or CpG, suggesting that BTLA functions as an inhibitory molecule on Toll-like receptor signaling at cell surface but not endosome. Moreover, BTLA(-/-) DCs showed enhanced MyD88- and toll/IL-1R domain-containing adaptor inducing IFN (TRIF)-dependent signaling on LPS stimulation, which is associated with impaired accumulation of Src homology 2-containing protein tyrosine phosphatase in lipid rafts. Finally, we found that an agonistic anti-BTLA antibody rescued mice from LPS-induced endotoxic shock, even if the antibody was given to mice that had developed a sign of endotoxic shock. These results suggest that BTLA directly inhibits LPS responses in DCs and Mϕs and that agonistic agents for BTLA might have therapeutic potential for LPS-induced endotoxic shock.

Positivity for anti-RNP antibody is a risk factor for adverse effects caused by trimethoprim-sulfamethoxazole, a prophylactic agent for P. jiroveci pneumonia, in patients with connective tissue diseases.

OBJECTIVES: Trimethoprim-sulphamethoxazole (TMP-STX), an agent used for prophylaxis against pneumocystis pneumonia (PCP) in immunocompromised hosts, causes serious adverse effects (AEs) in some patients. The objective of this study was to identify the risk factors for AEs caused by TMP-STX in connective tissue disease (CTD) patients and to describe the clinical features of the AEs. METHODS: The medical records of 539 patients (CTDs 312, pulmonary diseases 227) receiving TMP-STX for prophylaxis against PCP were reviewed retrospectively. Patients with human immunodeficiency virus were excluded. Univariate and multivariate analyses were conducted to identify the risk factors. RESULTS: Adverse events caused by TMP-STX occurred in 22 of 312 (7.05 %) CTD patients, while only six of 227 (2.64 %) pulmonary disease patients developed AEs. The incidence of AEs was significantly higher in systemic lupus erythematosus (SLE) (11.0 %) and mixed connective tissue disease (MCTD) (33.3 %) patients than in other CTD patients. AEs occurred in 25 % of patients with anti-RNP antibody. Univariate analysis revealed that SLE, MCTD, and anti-RNP antibody were risk factors for AEs in CTD patients. Further multivariate analyses demonstrated that only anti-RNP antibody positivity was a risk factor for AEs. Systemic inflammation, including fever, was a characteristic manifestation of the AEs in CTD patients, particularly those with anti-RNP antibody. CONCLUSIONS: Positivity for anti-RNP antibody is a risk factor for AEs caused by TMP-STX in CTD patients. Systemic inflammation, including fever, might be a characteristic feature of the AEs in CTD patients, particularly those with anti-RNP antibody.

Marked increase in serum KL-6 and surfactant protein D levels during the first 4 weeks after treatment predicts poor prognosis in patients with active interstitial pneumonia associated with polymyositis/dermatomyositis.

OBJECTIVE: The aim of this study is to determine whether serum KL-6 and surfactant protein D (SP-D) levels predict the prognosis of patients with interstitial pneumonia (IP) in cases of polymyositis (PM) and dermatomyositis (DM). PATIENTS AND METHODS: Fifty consecutive patients with PM (n = 17) or DM (n = 33) and active IP, 6 of whom died of respiratory failure, were enrolled in this study. Serum KL-6 and SP-D levels were measured every 2-4 weeks. Medical records were reviewed retrospectively. Univariate analyses and multivariate analyses with a logistic regression model were conducted. RESULTS: Serum KL-6 and SP-D levels were elevated in patients with active IP. At the time of diagnosis of active IP, the serum KL-6 level was within the normal range in 28 % of patients and the SP-D level was within the normal range in 46 % of patients. Serum KL-6 level increased up to 3 months after starting treatment and then decreased gradually to baseline, whereas SP-D level peaked within the first 4 weeks after treatment and decreased rapidly to normal levels. Patients with poor prognosis showed increases in KL-6 and SP-D levels during the first 4 weeks after treatment, which was confirmed by uni- and multivariate analyses. Comparing the marker levels at 2-4 weeks after treatment with those at 0 weeks, an increase in the ratio over 1.70 for KL-6 and over 1.75 for SP-D, and an increase in KL-6 over 850 U/ml during the first 4 weeks after treatment, were poor prognostic factors. CONCLUSIONS: Increases in serum KL-6 and SP-D levels during the first 4 weeks after starting therapy, but not their levels at any one time point, predict poor prognosis in patients with PM/DM. When marked increases of KL-6 and SP-D levels during the first 4 weeks are found or are predicted by serial measurement of the markers, patients have risks of poor prognosis and additional therapy should be considered.

Detection of inflammatory lesions by f-18 fluorodeoxyglucose positron emission tomography in patients with polymyositis and dermatomyositis.

OBJECTIVE: To evaluate the usefulness of F-18 fluorodeoxyglucose positron emission tomography (FDG-PET) imaging in the management of patients with inflammatory myopathy. We examined whether FDG-PET scanning detects myositis or extramuscular lesions in patients with polymyositis (PM) and dermatomyositis (DM). METHODS: FDG-PET imaging was performed in 24 patients with active inflammatory myopathy (PM, 11; DM, 13). The images were read by radiologists in a blinded manner. FDG uptake into muscles was judged positive when the intensity of muscles was higher than or equal to that of the liver. As controls, FDG imaging findings of patients with a lung mass and without muscle diseases were used. To investigate associations between FDG-PET findings and clinical/laboratory findings, the patients' medical records were reviewed retrospectively. RESULTS: Increased FDG uptake in muscles was found in 8 of 24 (33%) patients. In 67 of 69 (97%) controls without muscle diseases, no muscle FDG uptake was detected. The sensitivity of FDG-PET to detect myositis was lower than that of electromyogram (EMG), magnetic resonance imaging, and muscle biopsy. There were no significant differences in clinical manifestations between patients with and without increased FDG uptake in muscles, although patients with FDG muscle uptake had a tendency to have extended myositis with endomysial cell infiltration. FDG-PET detected neoplasms in patients with associated malignancy. FDG uptake in lungs was found in 7 of 18 patients with interstitial lung disease. CONCLUSION: FDG-PET imaging has limited usefulness for the evaluation of myositis in patients with PM/DM because of its low sensitivity, although it might be useful for detection of malignancy in these patients.

Lack of B and T lymphocyte attenuator exacerbates autoimmune disorders and induces Fas-independent liver injury in MRL-lpr/lpr mice.

MRL/Mp-Fas (lpr) (MRL-lpr) mice develop a systemic autoimmune disease and are considered to be a good model for systemic lupus erythematosus in humans. We have recently shown that mice lacking B and T lymphocyte attenuator (BTLA), an inhibitory co-receptor expressed mainly on lymphocytes, on a 129SvEv background spontaneously develop lymphocytic infiltration in multiple organs and an autoimmune hepatitis (AIH)-like disease. In this study, we investigated the role of BTLA in the pathogenesis of autoimmune diseases in MRL-lpr mice. We found that BTLA-deficient (BTLA(-/-)) MRL-lpr/lpr mice developed severe lymphocytic infiltration in salivary glands, lungs, pancreas, kidneys and joints as compared with BTLA-sufficient (BTLA(+/+)) MRL-lpr/lpr mice. In addition, although AIH-like disease was not found in BTLA(+/+) MRL-lpr/lpr mice, AIH-like disease was exacerbated in BTLA(-/-) MRL-lpr/lpr mice as compared with that in BTLA(-/-) 129SvEv mice. These results suggest that BTLA plays a protective role in autoimmune diseases in MRL-lpr mice and that AIH-like disease develops in BTLA(-/-) mice even in the absence of Fas-dependent signaling.

A functional polymorphism in B and T lymphocyte attenuator is associated with susceptibility to rheumatoid arthritis.

Inhibitory coreceptors are thought to play important roles in maintaining immunological homeostasis, and a defect in the negative signals from inhibitory coreceptors may lead to the development of autoimmune diseases. We have recently identified B and T lymphocyte attenuator (BTLA), a new inhibitory coreceptor expressed on immune cells, and we suggest that BTLA may be involved in the development of autoimmune diseases using BTLA-deficient mice. However, the role of BTLA in the pathogenesis of autoimmune diseases in humans remains unknown. We, therefore, examined the possible association between BTLA and rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and Sjögren's syndrome (SS) by conducting a case-control genetic association study. We found that 590C single-nucleotide polymorphism (SNP) of BTLA gene was significantly associated with susceptibility to RA, but not to SLE or SS. Furthermore, RA patients bearing this 590C SNP developed the disease significantly earlier than the patients without this allele. We also found that BTLA with 590C allele lacked the inhibitory activity on concanavalin A- and anti-CD3 Ab-induced IL-2 production in Jurkat T cells. These results suggest that BTLA is an RA-susceptibility gene and is involved in the protection from autoimmunity in humans.

Autoantibodies against platelet-derived growth factor receptor alpha in patients with systemic lupus erythematosus.

Autoantibody against platelet-derived growth factor receptors (PDGFRs) has been reported in scleroderma (SSc). However, it remains unknown whether anti-PDGFRs antibody exists in collagen vascular diseases other than SSc. To answer the question, we developed an ELISA system and examined sera from patients with SLE (n = 75), SSc (n = 31), RA (n = 25) and control individuals. We also reviewed medical records to clarify clinical features of patients with anti-PDGFRα antibody. To examine the functions of anti-PDGFRα antibody in patients, fibroblasts were cultured and stimulated in the presence of purified IgG from patients, and their cell numbers were counted. Anti-PDGFRα antibody was detected in 29% of patients with SLE and in 21% of patients with SSc. Anti-PDGFRα antibody was found in 36% with active SLE, but in 10% in an inactive phase. Immunosuppressive therapy decreased the titer of the antibody. Patients with anti-PDGFRα antibody frequently developed a rash and hematological abnormalities, particular hemolytic anemia. Moreover, anti-PDGFRα antibody in SLE failed to demonstrate agonistic or antagonistic activities on PDGFR signaling. These findings indicate that nonfunctional anti-PDGFRα autoantibody exists in patients with SLE as well as those with scleroderma, and that the antibody could be a marker of disease activity and may be a marker of a subgroup of SLE.

Protective roles of B and T lymphocyte attenuator in NKT cell-mediated experimental hepatitis.

Although B and T lymphocyte attenuator (BTLA) was originally identified as an inhibitory coreceptor selectively expressed on Th1 cells and B cells, recent studies have revealed that BTLA is expressed on a variety of cells, including macrophages, dendritic cells, and NK cells, and modulates their functions. However, the role of BTLA in the regulation of NKT cell function remains unknown. In this study, we found that BTLA was expressed on NKT cells at the levels similar to those on T cells and that BTLA-deficient (BTLA(-/-)) NKT cells produced larger amounts of IL-4 and IFN-gamma upon alpha-glactosylceramide stimulation as compared with wild-type (WT) NKT cells. In vivo, BTLA(-/-) mice produced larger amounts of IL-4 and IFN-gamma upon Con A injection and were more susceptible to Con A-induced hepatitis than WT mice. In addition, the augmentation of Con A-induced hepatitis in BTLA(-/-) mice was not observed in BTLA/NKT-double deficient mice. Moreover, NKT(-/-) mice reconstituted with BTLA(-/-) NKT cells were significantly more susceptible to Con A-induced hepatitis as compared with NKT (-/-) mice reconstituted with WT NKT cells. These results suggest that BTLA functions as the inhibitory coreceptor of NKT cells and plays a critical role in the prevention of NKT cell-mediated liver injury.

Activation-induced accumulation of B and T lymphocyte attenuator at the immunological synapse in CD4+ T cells.

BTLA, a recently cloned coreceptor expressed on lymphocytes, negatively regulates cell activation by recruiting SHP-1/SHP-2. However, the mechanisms that regulate the intracellular localization of BTLA and its trafficking to the cell surface in T cells are still unknown. To determine the mechanisms that regulate the expression of BTLA on the surface of T cells, we examined the subcellular localization of BTLA in mouse T cells in a steady state, as well as upon activation by using a confocal laser-scanning microscopy. We found that BTLA was localized mainly in the Golgi apparatus and secretory lysosomes in resting CD4(+) T cells. We also found that intracellular BTLA was translocated to the cell surface and accumulated at the immunological synapse upon TCR stimulation. Furthermore, we found that the BTLA-HVEM interaction was required for the association of BTLA with lipid rafts. These results indicate that the surface expression of BTLA and its accumulation at the immunological synapse are tightly regulated by TCR and HVEM stimulation to deliver efficient inhibitory signals in the regulation of CD4(+) T cell activation.

Subarachnoid hemorrhage in systemic lupus erythematosus in Japan: two case reports and a review of the literature.

We report 51- and 43-year-old Japanese female patients with systemic lupus erythematosus (SLE) associated with subarachnoid hemorrhage (SAH) due to rupture of intracranial saccular aneurysms. We also review the literature of Japanese SLE patients with SAH. SAH in Japanese SLE patients is more frequent than in patients from Western countries, has different features from the general population, and can occur regardless of SLE disease activity. Clinicians must pay attention to SAH in all SLE patients.