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

Abstract

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.     

Increased Risk of Subarachnoid Hemorrhage in Patients With Systemic Lupus Erythematosus: A Nationwide Population‐Based Study

Objective

A relatively common occurrence of spontaneous subarachnoid hemorrhage (SAH) in patients with systemic lupus erythematosus (SLE) has been noted; however, the subsequent studies were conflicting. This nationwide population‐based study aimed to evaluate the risk of SAH in patients with SLE.

Methods

We identified 16,967 SLE patients from the Taiwan National Health Insurance (NHI) database between 2000 and 2006, and compared the incidence rate of SAH with 16,967 randomly selected age‐ and sex‐matched non‐SLE subjects. A Cox multivariable proportional hazards model was used to evaluate the risk factors of SAH in the SLE cohort.

Results

The SLE cohort had a higher risk of SAH, with an incidence rate ratio of 4.84 (P < 0.001). Despite a younger age, the mortality rate after SAH was significantly higher in the SLE cohort compared to all of the non‐SLE SAH patients identified from the 1 million NHI beneficiaries (60.0% versus 38.9%; P = 0.007). Age (hazard ratio [HR] 1.03, 95% confidence interval [95% CI] 1.01–1.05), platelet transfusion (HR 2.75, 95% CI 1.46–5.17), red blood cell transfusion (HR 7.11, 95% CI 2.81–17.97), and a mean daily steroid dose >10 mg of prednisolone or equivalent (HR 4.36, 95% CI 2.19–8.68) were independent risk factors for the new onset of SAH.

Conclusion

This study demonstrated that SAH is a rare but associated complication of SLE with a high mortality rate. Other than age, higher mean daily steroid use and a history of platelet or red blood cell transfusion were associated with the occurrence of SAH in patients with SLE.     

Subarachnoid hemorrhage and systemic lupus erythematosus

The frequency, clinical profile, treatment and outcome of subarachnoid hemorrhage (SAH) in patients with systemic lupus erythematosus (SLE) were assessed retrospectively, based on the case records of SLE of the Jichi Medical School Hospital over a 20 year period. Clinically defined SAH was found in 10 (3.9%) out of 258 SLE patients, which represented a frequency higher than previously assumed. Five patients had active SLE and lacked an apparent cause of SAH, other than SLE. A high mortality rate (5/5), no visible aneurysm on angiogram (3/4), and an onset during intractable SLE or after discontinued or no steroid therapy because of medical noncompliance (4/5) were characteristic of patients with active SLE, and thus an earlier successful suppression of SLE, if possible, might have prevented their SAH. In contrast, in the 5 patients with inactive SLE, 2 out of 3 saccular aneurysms were successfully clipped and small bleeding of one patient without aneurysms remitted spontaneously without the need for additional steroid therapy. When one death, which occurred outside of medical care, was excluded, the survival ratio of the hospitalized SAH patients with inactive SLE was significantly better than that with active SLE (3/4 versus 0/5, P=0.0476). In conclusion, the relatively common occurrence of SAH in SLE patients, and a significantly different clinical impact of SAH in respect to active and inactive SLE, were suggested from the results.     

系统性红斑狼疮并发蛛网膜下腔出血的临床特点

目的探讨系统性红斑狼疮(systemic lupus erythematosus,SLE)并发蛛网膜下腔出血(subarachnoid hemorrhage,SAH)患者的临床特点及预后。方法总结分析1983年1月至2012年1月就诊于北京协和医院的12例SLE并发SAH患者的临床资料。结果 SLE并发SAH患者住院期间的病死率高达42%(5/12)。SLE并发SAH的症状以头痛为主(75%)。系统性红斑狼疮疾病活动指数平均为(17.5±4.5)分。死亡患者在SAH发生早期即出现意识障碍者占80%(4/5),合并严重感染者占60%(3/5)。结论 SAH是SLE的少见且致命的并发症。对于出现意识障碍或合并感染的SLE患者,应当提高警惕,积极治疗SLE原发病及SAH,提高生存率。     

系统性红斑狼疮患者基因组DNA甲基化水平的初步研究

目的 研究系统性红斑狼疮(SLE)患者基因组DNA甲基化水平，分析影响基因组DNA甲基化水平的因素。方法 测定26例SLE患者和20名正常对照的同型半胱氨酸(Hcy)、S-腺苷蛋氨酸(SAM)和S-腺苷同型半胱氨酸(SAH)的水平和亚甲基四氢叶酸还原酶(MTHFR)基因677位的多态性。结果 ①SLE组与对照组相比，SAM明显降低。SAH明显升高，其差异有统计学意义：提示SLE患者基因组DNA甲基化水平明显降低；②SAM与同型半胱氨酸(Hcy)呈负相关，SAH与Hcy呈正相关，相关系数分别为-0．897、0．927，P＜0．01；③MTHFR基因677位C→T的突变不仅导致Hcy水平升高，同时使基因组DNA甲基化水平降低。结论 ①SLE患者普遍有基因组DNA甲基化水平降低：②基因组DNA低甲基化可能与MTHFR基因的突变和高Hcy血症有关。     

Lack of gene deletion for complement C4A deficiency in Japanese patients with systemic lupus erythematosus

The frequency of C4A gene deletion was studied in Japanese patients with systemic lupus erythematosus (SLE) and was compared with healthy controls. DNA preparations were extracted from peripheral blood leukocytes from 59 patients with SLE and from 166 healthy persons, and digested by restriction enzymes. They were hybridized with C4 complementary DNA by the Southern blotting method and the deletion of C4A gene was judged from restriction fragment length polymorphism. At the same time phenotypic C4A deficiency (C4AQ0) was measured. Our results showed that the frequency of phenotypic C4A deficiency was 44.1% in Japanese patients with SLE and this value was comparable with that (43.2%) in Caucasian patients. On the other hand the deletion of C4A gene was not found in Japanese patients with SLE (0%), or in healthy controls (0.6%). Our results indicate that C4AQ0 may contribute to the pathogenesis of SLE beyond the ethnical differences but Japanese patients with SLE have a different genetic background from Caucasian patients with the C4A gene deleted.     

Recognition and control of hypertension,diabetes, and dyslipidemia in patients with systemic lupus erythematosus

Systemic lupus erythematosus (SLE) patients have a high risk for cardiovascular events, but few studies have evaluated the recognition and none have evaluated the control of cardiovascular risk factors (RF) in SLE patients. The study aims to describe the recognition and control frequencies of systemic arterial hypertension (SAH), dyslipidemia, and diabetes mellitus (DM) in SLE patients. Of the female patients with SLE, 137 answered a questionnaire focused on general knowledge of the RF for coronary artery disease (CAD) and on recognition of the risk factors that they possess. The patient’s information collected on a structured medical record was reviewed to evaluate the RF control. The mean age was 29.1 (9.6) years. Seventy patients had SAH; 85.7% recognized their condition and 71.4% had desirable blood pressure (BP) control (<?140?×?90 mmHg). From a group of 63 patients with dyslipidemia, 68.3% recognized that they had dyslipidemia and 69.8% had desirable LDL-cholesterol (<?130 mg/dL). Sixteen patients had DM; 87.5% admitted being diabetic and 50.0% had desirable glycemic control (HbA1C <?7%). Most patients were aware of presenting SAH, DM, or dyslipidemia, and the recognition frequency was higher in comparison to general population. The SAH and dyslipidemia control frequencies were higher than that described for the general population.     

HLA antigens associated with systemic lupus erythematosus in Japan

We studied whether or not HLA-A,B,C and DR antigens were associated with clinical and immunological findings in 116 patients with systemic lupus erythematosus (SLE) in Japan. SLE patients tended to be associated with HLA-DR2, compared with 75 healthy individuals. Among the SLE patients, there was an association between HLA antigens and the presence or absence of certain clinical or immunological features. Different HLA antigens might have a predictive value for SLE and/or the same clinical and immunological abnormalities between Caucasian and Japanese SLE patients.     

Polymorphisms of the TAP1 and TAP2 transporter genes in Japanese SLE.

OBJECTIVE: To determine how polymorphism of transporter associated with antigen processing 1 and 2 (TAP1 and 2) alleles contributed to the pathogenesis of systemic lupus erythematosus (SLE) in Japanese patients. METHODS: TAP1 and TAP2 typing was carried out in 52 Japanese patients with SLE and 95 normal subjects by the PCR-RFLP (restriction fragment length polymorphism) method. HLA-DR typing and HLA-DRB1*15 genotyping were carried out by the PCR method and PCR-SSCP (single stranded DNA conformation polymorphism) method, respectively. RESULTS: No particular TAP 1 allele was associated with Japanese SLE or with immunological subgroup of SLE. TAP2H showed a tendency towards increased frequency in SLE (5.8% v 0% in control), but the corrected P value was not significant. No other particular association of TAP2 allele was observed. Furthermore, these was no evidence for linkage disequilibrium between any TAP1/TAP2 alleles and HLA-DRB1*1501--which is reported to be weakly but significantly association with Japanese SLE--in either the normal control or the SLE patient group. CONCLUSIONS: Neither the TAP1 nor the TAP2 gene appears to determine disease susceptibility to SLE in Japanese, and these results are in keeping with those reported in Caucasian SLE patients.     

FcgammaRIIa polymorphism in Japanese patients with systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is an immune complex-mediated disease and organ damage is caused by the deposition of immune complex. Receptors which recognize the Fc portion of immunoglobulin G (FcgammaR) play a key role in the phagocytosis of immune complexes. As the gene encoding for FcgammaR of class IIa (FcgammaRIIa) has two allelic forms, H131 and R131, which differ in their affinity to IgG2, this polymorphism might have implications in handling immune complex. We studied the distribution of the FcgammaRIIa polymorphism in 90 Japanese patients with SLE. We also examined the association between FcgammaRIIa polymorphism and the disease activity of SLE and the histopathological findings of lupus nephritis. FcgammaRIIa polymorphism was determined by PCR and dot blot analysis. The allelic frequency of H131 in patients with SLE was significantly lower (H131/R131 = 0.44/0.56) than that of normal controls (H131/R131 = 0.62/0.38; P < 0.05). No significant association was observed between FcgammaRIIa polymorphism and the clinical parameters for the activity of SLE. There was no association between FcgammaRIIa polymorphism and the histological findings in lupus nephritis. The difference in the distribution of FcgammaRIIa alleles between patients with SLE and normal subjects indicates that this polymorphism is a candidate of susceptibility gene for SLE in Japanese.     

Association of the TAP2*Bky2 allele with presence of SS-A/Ro and other autoantibodies in Japanese patients with systemic lupus erythematosus

We previously reported that a new allele of transporter associated with antigen processing (TAP) 2 gene, TAP2*Bky2 (Val577), was significantly increased in Japanese patients with Sj?gren's syndrome (SS) and had a strong association with SS-A/Ro antibody production. In the present study, it was investigated whether the association of TAP2*Bky2 with SS-A/Ro antibody production was also found in Japanese patients with systemic lupus erythematosus (SLE). Polymorphisms of the TAP1 and TAP2 genes were determined in 114 Japanese SLE patients by the polymerase chain reaction-single-stranded conformation polymorphism (PCR-SSCP) method. The allele frequencies of the TAP1 and TAP2 genes in SLE patients were not significantly different from those in controls, although the allele frequency of TAP2*Bky2 was slightly higher in SLE patients than in healthy control subjects (9.2% vs 5.5%, P = 0.126). The allele frequency of TAP2*Bky2 was significantly higher in SLE patients with oral ulcers than in those without. It was noteworthy that TAP2*Bky2 was significantly associated with the appearance of not only SS-A/Ro antibody but also SS-B/La, nRNP, and Sm antibodies in the patients. The association of TAP2*Bky2 was found with the antibody production to both 60 and 52kDa SS-A/Ro antigens. As TAP2*Bky2 had a strong linkage disequilibrium with DRB1*08032, TAP2*Bky2 or its haplotype with DRB1*08032 may be involved in SS-A/Ro antibody production not only in SS but also SLE patients, indicating that TAP2*Bky2 may be a susceptible gene not only to the disease of SS but also to the SS-A/Ro autoantibody production.     

Prevalence and risk factors of vertebral fracture in female Japanese patients with systemic lupus erythematosus

Abstract

Objective We examined the prevalence and risk factors of vertebral fracture in female Japanese patients with systemic lupus erythematosus (SLE).

Methods We performed lateral radiographs of the thoracic and lumbar spine and bone mineral density (BMD) measurements and collected demographic, lifestyle, clinical, and treatment characteristics of 52 SLE patients. Vertebral fractures were defined as a >20 % reduction of vertebral body height. Odds ratios (ORs) and their 95 % confidence intervals (CIs) were computed to assess the strength of associations between vertebral fractures and selected factors among SLE patients.

Results At least one vertebral fracture was detected in 50 % of SLE patients. A history of previous bone fracture was significantly associated with an increased risk of vertebral fractures among SLE patients (adjusted OR = 14.8, 95 % CI = 1.62–134; P = 0.017). Daily use of tea or coffee was marginally associated with a decreased risk of vertebral fractures among SLE patients (adjusted OR = 0.11, 95 % CI = 0.01–1.01; P = 0.051).

Conclusion The high prevalence of vertebral fracture in SLE patients (50 %) indicates that we need to assess the lateral spine radiograph in more female Japanese SLE patients regardless of BMD and use of corticosteroids, although additional studies are warranted to confirm the findings suggested in this study.     

Efficacy of mycophenolate mofetil in Japanese patients with systemic lupus erythematosus

Clinical Rheumatology - To assess the renal and non-renal efficacy of mycophenolate mofetil (MMF) in Japanese patients with systemic lupus erythematosus (SLE). We conducted a retrospective study to...     

The association of a nonsynonymous single‐nucleotide polymorphism in TNFAIP3 with systemic lupus erythematosus and rheumatoid arthritis in the Japanese population

Objective

Genome‐wide association (GWA) studies in systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) in Caucasian populations have independently identified risk variants in and near the tumor necrosis factor α (TNFα)–induced protein 3 gene (TNFAIP3), which is crucial for the regulation of TNF‐mediated signaling and Toll‐like receptor signaling. The aim of this study was to assess the role of TNFAIP3 in the development of SLE and RA in Japanese subjects.

Methods

We selected 2 single‐nucleotide polymorphisms (SNPs) from previous GWA studies. Rs2230926 is a nonsynonymous SNP in TNFAIP3 and is associated with SLE, while rs10499194 is an intergenic SNP associated with RA. We then performed 2 independent sets of SLE case–control comparisons (717 patients and 1,362 control subjects) and 3 sets of RA case–control comparisons (3,446 patients and 2,344 control subjects) using Japanese subjects. We genotyped SNPs using TaqMan assays.

Results

We observed a significant association between rs2230926 and an increased risk of SLE and RA in the Japanese population (for SLE, odds ratio [OR] 1.92, 95% confidence interval [95% CI] 1.53–2.41, P = 1.9 × 10⁻⁸; for RA, OR 1.35, 95% CI 1.18–1.56, P = 2.6 × 10⁻⁵). The intergenic SNP rs10499194 was also associated with SLE and RA, while the risk allele for RA in Caucasians was protective against the diseases in our population.

Conclusion

We demonstrated a significant association between the nonsynonymous variant in TNFAIP3 and the risk for SLE and RA in the Japanese population. TNFAIP3, similar to STAT4 and IRF5, may be a common genetic risk factor for SLE and RA that is shared between the Caucasian and Japanese populations.

     

Systemic lupus erythematosus flare up manifestation as cerebral and spinal subarachnoid hemorrhage

Subarachnoid hemorrhage (SAH) is an uncommon complication of systemic lupus erythematosus (SLE). Here we report a 52-year-old woman with flare up of lupus activity, manifesting as spontaneous cerebral and spinal SAH due to central nervous system vasculitis. The patient received external ventricular drainage for hydrocephalus and pulse steroid and intravenous cyclophosphamide therapies. Her neurological deficits gradually improved with only minimal gait unsteadiness at discharge. Although very rare, cerebral and spinal SAH related to vasculitis could be one of the presentations of SLE flare up.     

A novel mutation (T61I) in the gene encoding tumour necrosis factor receptor superfamily 1A (TNFRSF1A) in a Japanese patient with tumour necrosis factor receptor-associated periodic syndrome (TRAPS) associated with systemic lupus erythematosus

OBJECTIVE: To identify potential mutations in the tumour necrosis factor receptor superfamily 1A gene (TNFRSF1A) in a Japanese female patient with recurrent fever complicated by systemic lupus erythematosus (SLE), and in her family members. METHODS: DNA sequencing of exons 1-10 of the TNFRSF1A gene was performed to determine mutations that might be associated with the tumour necrosis factor receptor-associated periodic syndrome (TRAPS). Moreover, the TNFRSF1A gene was examined in Japanese patients with autoimmune diseases, including SLE, rheumatoid arthritis (RA), mixed connective tissue disease (MCTD) and Beh?et's disease, and in healthy Japanese controls. Enzyme-amplified sensitivity immunoassay (EASIA) analysis was used to assess serum levels of TNF, the 55-kDa TNF receptor (TNFRSF1A) and the 75-kDa TNF receptor (TNFRSF1B). Membrane TNFRSF1A expression was analysed on the surface of peripheral blood mononuclear cells by flow cytometry. RESULTS: A novel mutation, a heterozygous C to T transition in exon 3 which substitutes an isoleucine for a threonine at position 61 (T61I) was detected in the TNFRSF1A gene derived from the genomic DNA of a Japanese female TRAPS patient. Two nieces and one nephew, all with a similar clinical phenotype, also possessed the same TNFRSF1A mutation. We further demonstrated the same mutation in five of 60 SLE patients (8.3%) and in five of 120 healthy individuals (4.2%), with no significant differences. Although high titres of serum TNF and soluble TNFRSF1B protein were observed in this patient, low titres of soluble TNFRSF1A protein were detected. However, a defect in TNFRSF1A shedding in vitro was not observed in monocytes derived from this patient. CONCLUSION: This is the first report of a TRAPS patient associated with SLE with a novel TNFRSF1A mutation (T61I).     

Association of PHRF1-IRF7 region polymorphism with clinical manifestations of systemic lupus erythematosus in a Japanese population

Interferon regulatory factor 7 (IRF7) has an essential role in the production of type I interferon. Although recent studies detected association of a single nucleotide polymorphism (SNP) rs4963128 in PHD and ring finger domains 1 (PHRF1)/KIAA1542, located closely to IRF7, and IRF7 rs1131665 (glutamine (Gln) 412 arginine (Arg)) with systemic lupus erythematosus (SLE), causal variants have not been established. In this study, we resequenced exons and introns of IRF7 to screen for all common polymorphisms, and examined whether they were associated with SLE in 416 Japanese patients with SLE and 505 healthy controls. We also tested whether the association of PHRF1 rs4963128 with SLE was replicated in a Japanese population. None of the IRF7 polymorphisms was associated with SLE. PHRF1 rs4963128T was not significantly associated with occurrence of SLE either; however, this allele was significantly increased in SLE with anti-Sm antibodies (6.8%) as compared with healthy controls (3.1%, P?=?0.014, odds ratio [OR] 2.31) and SLE without anti-Sm antibodies (3.3%, P?=0.041, OR 2.12). This allele was also increased in SLE with renal disorder (5.1%) as compared with those without renal disorder (2.4%, P?=?0.047, OR 2.17). These results confirmed recently reported association of PHRF1 rs4963128T with anti-Sm antibody positive SLE in African-American populations, and supported the role of PHRF1-IRF7 region in the genetics of SLE.     

Lack of association between tyrosine kinase 2 (TYK2) gene polymorphisms and susceptibility to SLE in a Japanese population

Tyrosine kinase 2 (TYK2) is a type I interferon (IFN) signaling pathway gene and was previously reported to be a risk factor for systemic lupus erythematosus (SLE) in Caucasian populations. In order to test for its genetic association with SLE in a Japanese population, TYK2 single nucleotide polymorphisms (SNPs), rs2304256, rs12720270 and rs280519, were genotyped. A case–control association study was performed in a total of 411 Japanese SLE patients and 467 healthy controls. Linkage disequilibrium (LD) among TYK2 SNPs was examined. According to the data from 94 healthy controls, non-synonymous rs2304256 resulting in Val → Phe substitution was revealed to be in a LD with rs12720270 and rs280519. Therefore, we further genotyped rs2304256 as a tag SNP in the full sample sets. As a result, no differences in genotype distribution and allelic frequencies of rs2304256 were found between SLE patients and healthy controls. In conclusion, TYK2 is not a genetic risk factor for SLE in a Japanese population. Our result suggests that there is an ethnic difference in the susceptibility genes for SLE.     

Two medium-chain acyl-coenzyme A synthetase genes, SAH and MACS1, are associated with plasma high-density lipoprotein cholesterol levels, but they are not associated with essential hypertension

BACKGROUND AND OBJECTIVES: SAH has been proposed as a candidate gene for essential hypertension (EH) because elevated expression of SAH was observed in the kidneys of spontaneously hypertensive rats. Recently, a homology search of SAH in the human genome revealed the presence of the SAH gene family, which includes SAH, MACS1, MACS2, and MACS3. SAH and MACS1 are located within a 150-kb region on human chromosome 16p13.11. SAH and MACS1 are thought to function as acyl-coenzyme A synthetases, which are involved in fatty acid metabolism. In the present study, we analyzed six single nucleotide polymorphisms (SNPs) in the SAH and MACS1 genes in a Japanese population, and examined whether these SNPs contribute to EH and multiple risk factors. METHODS AND RESULTS: We performed association studies of six SNPs in 287 EH patients and 259 normotensive subjects. Multiple logistic linear regression analysis revealed that the allele frequencies of these six SNPs in SAH and MACS1 genes were not significantly different between EH patients and normotensives. SNP in exon 8 of the A/G polymorphism of the MACS1 gene and the G/T SNP in intron 3 of the SAH gene were associated with plasma levels of plasma high-density lipoprotein cholesterol. CONCLUSIONS: SNPs in the MACS1 and SAH genes contribute to plasma levels of high-density lipoprotein cholesterol.