Distribution of an anti-DNA idiotype among autoantibodies in patients with systemic lupus erythematosus (SLE) or rheumatoid arthritis (RA)

Autoantibodies from patients with systemic lupus erythematosus, rheumatoid arthritis, or other connective tissue disorders were probed for the presence of a cross-reactive idiotype (AM Id) originally defined on human anti-double-stranded DNA antibodies. The AM Id was distributed primarily among antibodies to double-stranded DNA, single-stranded DNA, or cardiolipin in patients with systemic lupus erythematosus and antibodies to single-stranded DNA or cardiolipin and rheumatoid factor in patients with rheumatoid arthritis, thus tending to codistribute with the predominant primary autoantibodies in both diseases. Strong associations were observed particularly between the AM Id and anti-single-stranded DNA antibodies in patients with systemic lupus erythematosus and the AM Id and anticardiolipin antibodies in patients with rheumatoid arthritis. Affinity absorption experiments with sera from individual lupus patients showed that up to 41% of the anti-single-stranded DNA antibodies were Id positive. The results indicate that the AM Id may be widely distributed among antibodies that have a potential for binding DNA.     

中国系统性红斑狼疮伴发骨坏死相关因素的Meta分析

背景：系统性红斑狼疮是一种异质性疾病,除长期应用激素可引起骨坏死外,有研究指出临床表现的差异性也有可能是骨坏死的危险因素。目前国内外学者对在系统性红斑狼疮患者中发生骨坏死的致病因素存在不同观点。 目的：对国内系统性红斑狼疮患者并发骨坏死的危险因素进行系统分析。 方法：检索中国学术期刊全文数据库(CNKI)、中国生物医学文献数据库(CBMdisc)、万方数据库获得已公开发表的国内系统性红斑狼疮并发骨坏死相关危险因素的病例对照研究文献,筛选出符合评价标准的文献,采用RevMan 5.0及Stata软件进行Meta分析,并计算各危险因素的合并比值比及95%置信区间。 结果与结论：共纳入10篇病例对照研究,累计病例组332例、对照组986例。系统性红斑狼疮并发骨坏死的各危险因素的比值比及95%置信区间分别为：雷诺现象3.28(1.69-6.38),口腔溃疡2.95(2.13-4.09),肾脏受累1.21(0.83-1.74),血管炎因素5.64(2.84-11.21),高脂血症5.11(3.10-8.42),抗磷脂抗体2.32(1.49-3.61),关节受累2.02(1.33-3.07)。提示激素应用明确为系统性红斑狼疮并发骨坏死的独立危险因素,但并非惟一因素,血管炎、高脂血症、雷诺现象、口腔溃疡、抗磷脂抗体阳性及关节受累均为需要重视的国内系统性红斑狼疮患者并发骨坏死的危险因素。     

Antihistones antibodies in systemic lupus erythematosus, comparison of three assays: Elisa, dot blot and immunoblot

AIMS: The purpose of our study is to determine and compare the sensitivity of an enzyme linked immunosorbent assay (ELISA), a dot blot assay and an immunoblot assay for the detection of the IgG class antihistones antibodies in a population of systemic lupus erythematosus. The correlation between antihistones antibodies and the main clinical features of SLE or between antihistones antibodies and the presence of anti-double-stranded-DNA antibodies were analysed. MATERIALS AND METHODS: Serum samples from 126 systemic lupus erythematosus patients, classified according to the criteria of the American College of Rheumatology, were analysed for the presence of antihistones antibodies using a dot blot assay and an ELISA. Antihistones subfractions antibodies were assessed using the immunoblot technique on 88 out of the 126 sera. Serum samples from 50 blood-donors were analyzed as negative controls. RESULTS: The sensitivity of antihistones antibodies assessed by dot blot assay and ELISA was 69% and 54% respectively, and was lower than that of anti-double-stranded-DNA antibodies (83%). The sensitivity of the immunoblot assay for the detection of antihistones antibodies was 72%. Incidence of autoantibodies against histones H1, H2 A, H2B, H3 and H4 was 60%, 53%, 48%, 36% and 29.5% respectively. We found a correlation between the presence of antihistones antibodies, detected by the dot blot assay and ELISA, and the presence of anti-double-stranded-DNA antibodies. Antihistones antibodies detected by ELISA were correlated with renal disease in systemic lupus erythematosus; they showed a specificity, a positive and a negative predictive value for renal disease in systemic lupus erythematosus higher than those of anti-double-stranded-DNA antibodies. CONCLUSIONS: The sensitivity of the dot blot assay for the detection of antihistones antibodies is better than that of ELISA, but the latter technique could detect some cases negative by ELISA. Antihistones antibodies detected by ELISA have an important predictive value in the renal complications in systemic lupus erythematosus, better than that of AdsDNA. Antibodies to histone H1 were the most frequent antihistones autoandibodies in systemic lupus erythematosus and they were highly correlated with anti-double-stranded-DNA antibodies and renal disease.     

Vaccination against meningococcus in complement-deficient individuals

Autoantibodies to CRP were reported previously in patients suffering from toxic oil syndrome. This syndrome resembles autoimmune diseases such as systemic lupus erythematosus (SLE) or systemic scleroderma. We therefore examined the prevalence of antibodies to CRP and other acute-phase proteins in autoimmune diseases, including SLE, subacute cutaneous lupus erythematosus (SCLE), systemic scleroderma (SSc), and primary biliary cirrhosis (PBC), as well as in bone marrow transplantation-induced chronic graft-versus-host disease and eosinophilia–myalgia syndrome. IgG antibodies to CRP were found in 78% of SLE and in 30% of SCLE patients, while 16% of patients with PBC were positive. In up to 45% of patients with SSc predominantly IgG antibodies to ceruloplasmin were detectable. Lack of systemic involvement as in discoid lupus erythematosus and localized scleroderma (morphea) correlated with low or absent antibody formation. However, no correlation was found between anti-acute-phase protein antibodies with liver disease or other organ involvement. Adsorption studies revealed that non-native epitopes on the CRP molecule, termed modified CRP, are the main target of antibodies. Chronic inflammatory tissue injury in systemic autoimmune disease might increase the presentation of cryptic epitopes of CRP to the threshold required for T cell activation.     

组织多普勒成像技术对系统性红斑狼疮心脏功能评价的研究进展

目的 探讨组织多普勒成像技术(TDI)对系统性红斑狼疮心脏功能的评价及其进展。方法 通过pubmed数据库、中国知网数据库查阅2009年1月—2015年2月国内外关于组织多普勒成像技术在系统性红斑狼疮心脏病变中的应用有关文献,进行总结归类。结果 发现系统性红斑狼疮心脏病变表现是多方面的,包括心肌、心包、瓣膜以及冠脉等不同程度的损害。这些损害2D超声早期难以判断;而运用TDI相关指标Sm、e′/a′值、e′值、E/e′比值不仅可以对其进行早期评估,还可以对其严重程度及预后可做出准确的判断,从而为临床及时处置提供决策信息。结论 TDI不但能够早期并较好的评价系统性红斑狼疮心脏功能改变,而且对心脏损害的系列病变的检测也具有重要价值。     

An updated review of anti-Ro52 (TRIM21) antibodies impact in connective tissue diseases clinical management

Anti-Ro52 (or anti-TRIM21) antibodies are part of the family of anti-Ro/SSA antibodies, historically markers of Sjögren syndrome and systemic lupus erythematosus. Anti-Ro52 antibodies represent one the most frequently encountered autoantibodies in patients with connective tissue disease (primary Sjögren syndrome, systemic lupus erythematosus, systemic sclerosis and idiopathic inflammatory myopathies). Because of their lack of specificity and detection in patients with non-autoimmune disorders, the usefulness of anti-Ro52 testing in connective tissue diseases is still matter of debate among clinicians and immunologists. Autoantibodies are mainly diagnostic markers for autoimmune diseases but some of them can also be directly involved in the generation of tissue damage. Over the past decade several authors reported associations of anti-Ro52 antibodies with some clinical features – especially interstitial lung disease – and survival in patients with connective tissue diseases. There is also a growing evidence of the role of anti-Ro52 antibodies in the pathogenesis of connective tissue diseases. In this review, we comprehensively discuss the clinical associations of anti-Ro52 antibodies in the different connective tissue diseases and the recent advances on their potential role in the inflammatory response.     

Antinuclear Antibodies and Anti-DNA Antibodies in Scleroderma

Antinuclear antibodies (ANA), including anti-DNA antibodies, and rheumatoid factors (RAT, Waaler-Rose) were determined prospectively during a 3-year period in 40 patients with localized scleroderma (LS) compared with 77 patients with generalized scleroderma (GS). ANA were increased in 26% of patients with LS, and in 47% with GS, anti-DNA antibodies in 23% of patients with LS, and in 34% with GS. Thus, the anti-DNA antibody level was lower compared with the known level in systemic lupus erythematosus. Rheumatoid factors were present in 6-7% of patients with LS, and in 14-15% of patients with GS. Increased antinuclear antibodies were not associated with any specific type of localized scleroderma, nor with internal disorders, and no case of clinical overlap to discoid or systemic lupus erythematosus was observed. However, six patients with localized scleroderma and complaints of arthralgia all presented increased antibodies, and one patient showed overlap to rheumatoid arthritis. It is suggested that increased ANA and anti-DNA antibodies in localized scleroderma, associated with joint manifestations, represents a systemic component in this type of scleroderma, with activation of the immune system and similarities with generalized collagen diseases.     

The Crithidia luciliae and Farr assays for the detection of systemic lupus erythematosus

The specificity and sensitivity of two commercial systems for the detection of anti-native deoxyribonucleic acid (DNA) antibodies in the diagnosis of active systemic lupus erythematosus were evaluated. Sera containing antinuclear antibodies from 64 patients were tested by an indirect immunofluorescent antibody technique employing the protozoan Crithidia luciliae as substrate and immunoradioassay based on the Farr technique. Twenty one patients had active systemic lupus erythematosus, 21 had other collagen vascular diseases, and 22 had miscellaneous non-collagen vascular diseases. The immunofluorescence test was 100 percent specific and 66.7 percent sensitive for systemic lupus erythematosus, whereas the radioimmunoassay was 90.7 percent specific and 80.9 percent sensitive. There was agreement between methods in 57 of the 64 (89.1 percent) sera tested.     

Placental pathology in systemic lupus erythematosus with antiphospholipid antibodies

Systemic lupus erythematosus (SLE) is associated with a poor pregnancy outcome. Antiphospholipid antibodies (APL), which include lupus anticoagulant (LAC) and anticardiolipin antibodies (aCL), are frequently found in patients with SLE, and their presence has been associated with fetal loss. To examine placental pathologic features of SLE patients with APL, we performed a pathologic study on 47 placental tissue samples from 47 pregnant SLE patients with APL (15 patients; four LAC single-positive patients, seven aCL single-positive patients, four LAC and aCL double-positive patients) and without APL (32 LAC and aCL double-negative patients). The incidence of extensive infarction, decidual vasculopathy, decidual thrombosis and perivillous fibrinoid change, which have been thought to be characteristic lesions of APL placenta, was significantly higher in the LAC and aCL double-positive patients than in the patients without APL. Conversely, the above-mentioned lesions between the LAC or aCL single-positive patients and the APL negative patients did not differ significantly. Among the 15 patients with APL, two of the three patients with both decidual vasculopathy and thrombosis had extensive infarction associated with fetal death. Moreover, the patients having fetal death showed LAC and aCL double-positivity. In conclusion, this study indicated that the LAC and aCL double-positivity is an important factor for extensive infarction resulting from decidual vasculopathy and decidual thrombosis in the SLE placenta. Moreover, it was indicated that LAC and aCL double-positivity is an important risk factor for fetal death in the SLE patient.     

Multimodality imaging and the emerging role of cardiac magnetic resonance in autoimmune myocarditis

Autoimmune responses and inflammation are involved in the excess cardiovascular risk observed in patients with systemic inflammatory diseases. Autoimmune myocarditis is a presentation of an inflammatory reaction of the heart during the course of autoimmune disorders, with most cases seen in systemic lupus erythematosus. Early diagnosis is of great significance because of the likelihood of progression to severe and potentially fatal complications such as arrhythmias, heart block, and heart failure. The clinical presentation of the disease is silent leading to delayed diagnosis when dilated cardiomyopathy or heart failure has already advanced. Therefore, a major issue is whether the diagnosis of myocarditis will continue to require invasive procedures such as endomyocardial biopsy or can be achieved with non-invasive methods. There is increasing evidence that noninvasive cardiac imaging, including tissue Doppler echocardiography and cardiac magnetic resonance (CMR), is able to detect subclinical cases and aid in the initiation of specific treatment when it is more likely to be effective. CMR in particular, has emerged as an important technique in the evaluation of myocarditis using three types of images: T2-weighted (T2-W), early T1-weighted (EGE) images taken after 1 min, and delayed enhanced images (LGE) taken 15 min after the injection of contrast agent. If 2/3 of the imaging sequences are positive, myocardial inflammation can be predicted or ruled out with a diagnostic accuracy of 78%. As our understanding of disease mechanisms improves, multimodality imaging may aid in the development of new diagnostic and therapeutic strategies for this potentially devastating complication of systemic inflammation, but further studies are needed to formally evaluate this.     

Investigations into Ro-specific antibody-associated congenital cardiac conduction defects

Summary Forty-two babies with different congenital cardiac conduction defects, and in 12 cases the mothers, were tested for autoantibodies to Ro, La, U₁RNP and Sm. Ro-specific antibodies were detected most frequently. They were to be found in 16 sera from infants and in 8 maternal serum samples. The occurrence of anti-Ro was associated preferentially with several atrioventricular conduction blocks. The sex relation of anti-Ro associated congential heart block did not show a typical preference (6 male/10 female). At the time of giving birth, 5 anti- Ro-positive mothers did not have any clinical symptoms of rheumatic autoimmune diseases. Three of them had a first degree atrioventricular block. Our findings indicate that all pregnant women at risk for anti-Ro like connective tissue disease or cardiac conduction defects should be tested for these autoantibodies because of the suspicion of cardiac conduction abnormalities in the offspring. Anti-Ro-positive infants should be examined for structural heart disease by echocardiography.Abbreviations anti-EBV VCA IgG anti-viral capsid antigens immunoglobulin G - AV atrioventricular - CHB congenital heart block - CIE counter immunoelectrophoresis - EBV Epstein-Barr virus - NLE neonatal lupus erythematosus - SLE systemic lupus erythematosus     

The prevalence of antiphospholipid antibody syndrome among systemic lupus erythematosus patients

Systemic lupus erythematosus (SLE) is an autoimmune disease characterised by excess autoantibody production. It typically affects women of childbearing age. Antiphospholipid antibody syndrome (APLAs) is associated with serious co-morbidity to mother and child characterized by recurrent vascular thrombosis and/or pregnancy associated morbidity. We reviewed SLE patients attending a specialist connective tissue disease clinic both to assess the occurrence of APLAs and its clinical presentations and to audit the effectiveness of screening for APL antibodies in a specialist clinic. 204 patients attended the newly established connective tissue disease outpatient clinic over a twenty-seven month period; 42 (34 female, 8 male) with a diagnosis of SLE. Ten patients (24%), eight female and 2 male with a median age of 38.5 years (range 20 to 64 years) fulfilled the ACR criteria for secondary APLAs (Table 2). The commonest clinical presentation was pulmonary embolus (five patients). Overall 37 patients (88%) with SLE were screened for APLAs during the study period: 94% of females and 62.5% of males were screened (for anticardiolipin antibodies, lupus anticoagulant or both), 27% had evidence of APLAs, 24% had positive antibodies but were asymptomatic. There is a significant occurrence of APLAs among SLE patients. Given the important clinical implications of this disorder including substantial risk of fetal loss and patient morbidity or mortality, routine screening of all SLE patients for APL antibodies is recommended.     

The Ro 60 kDa autoantigen: insights into cellular function and role in autoimmunity

An RNA-binding protein, the Ro 60 kDa autoantigen, is a major target of the immune response in patients suffering from two systemic rheumatic diseases, systemic lupus erythematosus and Sjogrens syndrome. In lupus patients, anti-Ro antibodies are associated with photosensitive skin lesions and with neonatal lupus, a syndrome in which mothers with anti-Ro antibodies give birth to children with photosensitive skin lesions and a cardiac conduction defect, third degree heart block. In vertebrate cells, the Ro protein binds small RNAs of unknown function known as Y RNAs. Although the cellular function of Ro has long been mysterious, recent studies have implicated Ro in two distinct processes: small RNA quality control and the enhancement of cell survival following exposure to ultraviolet irradiation. Most interestingly, mice lacking the Ro protein develop an autoimmune syndrome that shares some features with systemic lupus erythematosus in patients, suggesting that the normal function of Ro may be important for the prevention of this autoimmune disease. In this review, we summarize recent progress towards understanding the role of the Ro 60 kDa protein and discuss whether the cellular function of Ro could be related to certain manifestations of lupus in patients.Abbreviations RNP Ribonucleoprotein - RRM RNA recognition motif - SCLE Subacute cutaneous lupus erythematosus - SLE Systemic lupus erythematosus - snRNP Small nuclear ribonucleoprotein - SS Sjogrens syndrome - UV Ultraviolet - VWFA von Willebrand factor A     

Prospects for the assessment of cardiac rhythm variability in patients with rheumatoid arthritis and systemic lupus erythematosus

Rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) are chronic autoimmune diseases associated with confirmed high risk of cardiovascular pathology. Most low-risk patients develop cardiovascular complications (CVC) with the involvement of traditional factors of limited diagnostic value which requires introduction of new efficacious methods for CVC prognostication. Reduced cardiac rhythm variability (CRV) along with increased levels of inflammation markers is an independent predictor of unfavourable outcome in patients with coronary heart disease, chronic cardiac insufficiency, diabetes mellitus, arterial hypertension, and metabolic syndrome; it may be a consequence of joint contribution of sympatic activation and inflammation to the development of atherothrombotic complications. This review is focused on the methods of CRV evaluation, possible mechanisms of mutual potentiation of autonomous nervous system disturbances and inflammatory process, factors responsible for cardiac autonomous dysfunction in RA and SLE. Much attention is given to the possibilities of correction of vegetative dysregulation of cardiac activity in patients with autoimmune diseases.     

Anti-chromatin (anti-nucleosome) antibodies: diagnostic and clinical value

Anti-chromatin (nucleosome) autoantibodies were one of the first autoantibodies ever detected since they make up the majority of antibodies causing LE Cell formation. The prevalence of anti-chromatin antibodies in systemic lupus erythematosus (SLE) varies from 50% to 100%, being similar to that of the classical positive LE cell. The presence of these antibodies can be used, in conjunction with clinical findings and other laboratory tests, to help in the diagnosis of SLE and drug-induced lupus. Anti-chromatin antibodies have also been found in a lesser percentage of other autoimmune disorders such as primary Sj?gren's syndrome and primary antiphospholipid syndrome. The presence of anti-chromatin antibodies has also been linked to glomerulonephritis and disease activity in SLE patients. Recent studies demonstrated the induction of anti-chromatin (anti-nucleosome) antibodies after an anti-tumour necrosis factor (TNF)-alpha agent treatment.     

Analysis of antibodies to RNA in patients with systemic lupus erythematosus and other autoimmune rheumatic diseases.

The frequency and clinical associations of anti-RNA antibodies measured by ELISA were assessed in 138 patients with systemic lupus erythematosus (SLE). Of the sera from these patients 9.4% had anti-RNA antibodies but no distinguishing features, clinical, serological or immunogenetic, between those with or without these antibodies could be identified. However, investigations of patients with other autoimmune rheumatic diseases did not reveal any anti-RNA positivity, which indicates a marked disease specificity for anti-RNA antibodies in SLE. The initial anti-RNA antibody screen used a soluble yeast extract as test antigen. The positive sera were further tested against a range of RNAs from 10 different types of rat tissue. In essence few differences were observed, suggesting that the anti-RNA response is directed against common, highly conserved epitopes.     

Methods for detecting lupus anticoagulants and their relation to thrombosis and miscarriage in patients with systemic lupus erythematosus.

AIMS: To examine the sensitivity and specificity to past thrombotic events of four different coagulation tests, which screen for lupus anticoagulant (LA), and of anticardiolipin antibodies in patients with systemic lupus erythematosus. METHODS: Fifty three consecutive patients with systemic lupus erythematosus were studied of whom three males and 21 females, aged 21-60 years, had a history of venous and arterial thrombosis, or miscarriage, or both. Activated partial thromboplastin time (aPTT), dilute Russell's viper venom time (dRVVT), kaolin clotting time (KCT), dilute aPTT and the circulating titre of anticardiolipin antibodies were investigated in the two groups of patients and in 20 healthy control subjects. RESULTS: The prolonged dilute aPTT was more sensitive to thromboses or miscarriages, or both than dRVVT (p less than 0.05), KCT (p less than 0.01), and aPTT (p less than 0.001). No significant differences in specificity were found among aPTT (100%), dRVVT (93%), KCT (93%) and dilute aPTT (86.2%); but aPTT and dRVVT were significantly more specific (p less than 0.01, p less than 0.05, respectively) than anticardiolipin antibodies. CONCLUSIONS: The study shows a strong association between lupus anticoagulant and thrombosis when a very sensitive test such as the dilute aPTT is used. The combination of this assay with a very specific test such as dRVVT might enable patients with SLE at high risk of thrombosis to be identified.     

Clinical features of anti-chromo antibodies associated with anti-centromere antibodies

Anti-chromo antibodies (AChA) are autoantibodies accompanying anti-centromere antibodies (ACA). We determined the frequency and clinical significance of AChA in autoimmune rheumatic diseases. Serum samples from 252 patients with rheumatic diseases were examined by immunoblotting with HeLa nuclear extract and with recombinant N-terminus of 25-kD chromo protein (p25). AChA were detected in 28 (36%) of 77 sera with ACA. AChA were found only in ACA-positive sera. Twenty-two (79%) of 28 recognized a recombinant N-terminal portion of p25, including the chromo domain which is conserved among species. AChA were related to leucopenia, thrombocytopenia, elevated erythrocyte sedimentation rate, and existence of Sjögren*s syndrome (SS). In ACA-positive patients, AChA might be a serologic indicator of systemic sclerosis (SSc), having features of systemic lupus erythematosus and/or SS or diseases other than SSc.     

Congenital heart block associated with maternal anti SSA/SSB antibodies :a report of four cases

Congenital heart block (CHB) associated with maternal anti-SSA/SSB antibodies: a report of four cases. CHB detected in utero is strongly associated with maternal antibodies to SSA (Ro) and SSB (La). Their pathogenic role in the development of CHB has been established in several studies. The mothers of affected infants frequently had autoimmune disease (systemic lupus erythematosus, Sj?gren's syndrome) or were entirely asymptomatic. It is very difficult to identify pregnant asymptomatic mothers carrying anti-SSA/SSB antibodies. We report four cases of infants born to asymptomatic mothers with anti-SSA/SSB antibodies, three of them developed isolated congenital cardiac heart block and one with no evidence of CHB. All three CHB are detected during pregnancy between 16 and 24 weeks of gestation. All maternal sera contained antibodies to SSA alone or the both SSA and SSB. Three of four subsequent pregnancies were complicated by heart block. One child affected died in utero. While the two other newborns with CHB required pacemaker insertion during the first 3 months of life. Although the association of anti-SSA/SSB with CHB is widely accepted, the precise mechanism by which these antibodies cause cardiac conduction abnormalities remains to be defined. Antibodies to SSA/SSB have been proposed to be a serologic marker for neonatal lupus syndrome and CHB. Fetal and neonatal diseases are presumed to be due to the transplacental passage of these IgG autoantibodies from the mother into the fetal circulation. Since these antibodies may have a pathogenic role in CHB, screening of infants with isolated CHB or neonatal lupus and their mothers for the presence of anti-SSA and anti-SSB is strongly recommended.     

ANA negative (Ro) lupus erythematosus with multiple major organ involvement: a case report

Anti-nuclear antibody (ANA) negative systemic lupus erythematosus (SLE) occurs in about 4-13% of SLE cases. A small group of ANA negative SLE patients with positive anti-Ro antibodies usually present with typical vasculitic skin lesions which can be associated with photosensitivity, renal disease, congenital heart block or neonatal lupus. We present a case of a persistently ANA negative patient who presented with joint pain, rashes, mouth ulcer and alopecia. Clinical diagnosis of systemic lupus erythematosus was made even though ANA was negative. She was started on steroids and went into remission. Later, she developed several episodes of convulsions associated with fever and prominent vasculitic lesions. The patient was also found to have microscopic hematuria, proteinuria, anemia and thrombocytopenia. Renal biopsy showed lupus nephritis class 1B. Due to the prominent skin lesions, we performed anti-extractable nuclear antigens (ENA) antibodies test and anti-Ro turned out to be positive. The final diagnosis was ANA negative SLE (Ro lupus) with cutaneous, renal, musculoskeletal, hematological and cerebral Involvement.