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Risk of stroke in SLE: a systematic review and meta-analysis.

UNLABELLED: The association between SLE and composite stroke, ischaemic stroke and haemorrhagic stroke remains incompletely understood. This meta-analysis aims to assess the risk of stroke in patients with SLE. METHODS: Data sources included PubMed, Embase, the Cochrane Library and reference lists of included studies. This meta-analysis included cohort studies evaluating whether stroke risk is associated with SLE. The risk of bias was assessed using the Newcastle-Ottawa Quality Assessment Scale (NOS). Risk ratios (RRs) with 95% CIs were pooled using a random-effects model, and publication bias was assessed with funnel plots and Egger's test. RESULTS: A total of 25 cohort studies involving 5&#x2009;220&#x2009;837 individuals were included in this meta-analysis, which were published between 2001 and 2026. The pooled analysis demonstrated a significantly increased risk of stroke in patients with SLE (RR of 2.60, 95%&#x2009;CI 2.21 to 3.05, I&#xb2;=97.9%, p<0.001). The risk of composite stroke (RR of 2.83, 95%&#x2009;CI 2.25 to 3.57, I&#xb2;=98.0%, p<0.001), ischaemic stroke (RR of 2.34, 95%&#x2009;CI 1.75 to 3.12, I&#xb2;=97.6%, p<0.001) and haemorrhagic stroke (RR of 2.66, 95%&#x2009;CI 1.57 to 4.49, I&#xb2;=96.2%, p<0.001) was also increased in SLE. Despite the large heterogeneity, the sensitivity analysis indicated that the results were robust, and there was little evidence of publication bias. CONCLUSION: The risk of composite stroke, ischaemic stroke and haemorrhagic stroke is increased in SLE. PROSPERO REGISTRATION NUMBER: CRD420261294082.

Humans↗

Increased multiclonal antibody-forming cell activity in the peripheral blood of patients with SLE.

21 patients with criteria for systemic lupus erythematosus (SLE) and 12 normal controls were studied for their spontaneous circulating IgM and IgG plaque-forming cells (PFCs) reactive against sheep erythrocytes (SRBC) and against a panel of five haptens. Quantitatively defined active and mildly active SLE patients had significantly elevated IgM- and IgG-producing PFCs in their peripheral blood reactive with the panel of five chemically defined haptens. Those patients having inactive SLE also showed increased circulating IgM PFCs. Significant elevations in circulating hapten-reactive PFCs were found to correlate progressively with disease activity in the inactive, mildly active, and active SLE patient groups. Circulating IgM- and IgG-secreting PFC reactive against SRBC were both significantly elevated only in those patients with active SLE. The data support the concept that SLE patients have a generalized increase in B cell activity against a broad repertoire of determinants, even those ostensibly unrelated to natural tissue antigens.

Animals↗

Psychiatric disorder and cognitive impairment in SLE.

Poor performance on cognitive testing is common in SLE but it is not progressive in the majority of patients and may fluctuate or resolve without specific treatment. Cognitive impairment in patients without overt CNS-SLE may result from generalised disease activity or psychiatric disorder which reduce speed, concentration and motivation. This emphasises once again the importance of recognising and treating psychiatric disorder in these patients. Although mean cognitive scores are lower in SLE patients with overt CNS involvement than those without, an individual's cognitive score is a poor predictor of the presence of CNS involvement because of considerable overlap between groups. It has been suggested that the pattern of cognitive impairment, rather than simply whether it is present or absent, may be more helpful in identifying patients with CNS involvement but this requires further investigation in prospective studies. Cognitive impairment at one point in time is not predictive of future CNS events during 1 or 2 years of follow-up. Routine cognitive testing in SLE does not therefore appear to be helpful either for identifying patients with current CNS involvement or for identifying those at future risk of this complication. In the absence of double-blind randomised controlled trials, treatment of neuropsychiatric SLE is based on clinical experience and anecdotal case reports. Aggressive immunosuppression with high-dose corticosteroids in conjunction with either azathioprine or cyclophosphamide may be indicated in patients with life-threatening CNS-SLE but, on the basis of current evidence, is not justified in those with lone subtle cognitive abnormalities.

Cognition Disorders↗

TNF microsatellites in systemic lupus erythematosus-a high frequency of the TNFabc 2-3-1 haplotype in multicase SLE families.

TNFa, TNFb and TNFc microsatellites were analyzed in 102 SLE patients recruited from a defined area in Southern Sweden. Furthermore we studied 27 SLE patients belonging to 10 multiplex families in which a majority of the members were living within the same area in Southern Sweden. As a control population 98 healthy blood donors from the same region was used. The TNFa2 allele was found more often in the SLE patients (48%) than in the normal controls (33%) (P < 0.01). A low frequency of the TNFa4 allele (10%) vs 16% in controls was observed. The family study showed that the TNFabc haplotype 2-3-1 was more common in SLE associated haplotypes than in non-SLE haplotypes (P < 0.001). The 2-3-1 haplotype was associated with the extended haplotype MHC haplotype [HLA-B8,SC01,DR17]. The results suggest that TNF haplotypes do not constitute special markers of susceptibility to SLE but reflect the increased frequencies of specific intact haplotypes already known to be associated with the disease.

Adolescent↗

IgA deficiency and SLE: prevalence in a clinic population and a review of the literature.

An association between systemic lupus erythematosus (SLE) and immunoglobulin A (IgA) deficiency has been reported previously and may have therapeutic consequences for patients who require treatment with intravenous immunoglobulin. We report the prevalence of IgA deficiency in a clinic population of 96 patients with SLE. Five patients were found to be consistently IgA deficient. These patients were more likely to be West Indian, to have anti-Sm and anti-La antibodies and to have a speckled pattern of antinuclear antibody. There were no significant differences in clinical features between IgA deficient and other SLE patients, nor in SLE-related HLA alleles. We thus confirm the increased prevalence of IgA deficiency in patients with SLE. A review of the literature is presented and we speculate on the nature of the link between IgA deficiency and SLE.

Adult↗

Mild presentation of systemic lupus erythematosus in elderly patients assessed by SLEDAI. SLE Disease Activity Index.

OBJECTIVE: Systemic lupus erythematosus (SLE) predominantly affects young patients. SLE starting in later life has a clinical presentation different than in younger patients. We have used the SLE Disease Activity Index (SLEDAI) to explore the relationship between age of onset and disease activity. METHODS: We selected all patients controlled in our hospital at the moment of clinical diagnosis of SLE (100 patients; 85 females and 15 males). They were classified in two groups: those with early onset (>50 y) and those with late onset (>50 y) based on their age at the moment of clinical diagnosis of SLE. RESULTS: In 12 patients the onset of SLE was >50 y (10 females and two males; mean age 59 y). The early onset patients had significantly higher SLEDAI values at the presentation and during the first year of disease with respect to elderly patients. Antibodies to DNA and hypocomplementemia were detected more often in younger patients. CONCLUSION: Our results confirm using SLEDAI, that the lupus of the elderly patients is a distinct clinical subgroup with a milder course of disease.

Adolescent↗

Cluster analysis of antinuclear autoantibodies in the prognosis of SLE nephropathy: are anti-extractable nuclear antibodies protective?

To investigate the possible role of anti-ENA autoantibodies in the pathogenesis of SLE nephropathy, we performed a cross sectional clustering study of 91 SLE patients using 75 clinical and laboratory variables examining the presence of anti-dsDNA and ENA autoantibodies by ELISA and Western blot. We applied principal component, hierarchical cluster, multiple correspondence and logistical regression analysis. Two polar forms of SLE nephropathy and five clinical groups were identified: group 1 without overt nephropathy (n = 37), group 2 with nephropathy and only proteinuria (n = 19), group 3 nephropathy and only hematuria (n = 11), group 4 with hematuria and proteinuria (n = 14) and group 5 on renal failure (n = 10). When analyzed individually, levels of anti-dsDNA and single anti-ENA antibodies did not allow us to differentiate between renal and non-renal groups. However, when the anti-ENA autoantibodies were analyzed as a cluster, a high predictive value for clinical nephropathy was obtained. Thus, the absence of ENA antibodies (ENA ve or Venezuelan cluster) increased eleven-fold the odds ratio to develop SLE nephropathy. We suggested that the ENA ve cluster may predict development of the most severe forms of renal lupus while the ENA Sm/RNP and the ENA Ro/La/Sm/RNP clusters could be associated with the absence and the most benign form of SLE nephropathy. It must be interesting to apply similar cluster methodology in an SLE population with different ethnic background.

Adolescent↗

Fas expression on peripheral blood lymphocytes in systemic lupus erythematosus (SLE): relation to lymphocyte activation and disease activity.

Levels of apoptotic lymphocytes have been found to be increased in SLE and persistence of apoptotic cells has been associated with autoantibody production. Increased lymphocyte Fas (CD95) expression due to lymphocyte activation may account for increased susceptibility to Fas-mediated apoptosis in SLE. Flowcytometry was performed to evaluate membrane expression of Fas in combination with the activation markers CD25, HLA-DR and CD38 on, respectively, CD4+, CD8+ and CD19+ lymphocytes of SLE patients with inactive (n = 20) and with active disease (n = 13). SLEDAI-scores were calculated. Healthy volunteers (n = 14) served as controls. Percentages of CD4+ T-cells expressing CD25 and CD19+ B-cells expressing CD38 were increased in patients with active disease compared to controls (P = 0.03, P = 0.04, respectively). In contrast to CD4+ and CD8+ cells, percentages of CD19+ cells expressing Fas were increased in SLE patients with active disease (P = 0.0002 vs controls). In these patients percentages of cells double positive for both CD38 and Fas were increased compared to patients with inactive disease (P = 0.006) and controls (P = 0.0007). Percentages of CD19+ cells expressing Fas correlated with SLEDAI-scores. In SLE patients, percentages of Fas-expressing B-lymphocytes are increased, are related to the state of lymphocyte activation, and correlate to disease activity. Increased Fas expression results in a higher susceptibility for Fas-mediated apoptosis, which might contribute to the increased levels of apoptotic lymphocytes in SLE patients.

Adult↗

SLE/myositis overlap: are the manifestations of SLE different in overlap disease?

Myositis is a rare but recognized complication of systemic lupus erythematosus (SLE). This study compares clinical and laboratory features in patients with SLE complicated by myositis with patients with SLE who do not have myositis. Thus we reviewed the notes of 10 patients with an overlap of biopsy-proven myositis and SLE and compared their clinical, serological and immunogenetic features with 290 patients with SLE without myositis. Our data suggests that patients with SLE associated with myositis are more likely to have alopecia, oral ulcers, erosive joint disease and pulmonary disease but less likely to have renal disease. Our SLE/myositis patients were likely to die at a younger age. The overall disease process seems to be influenced by the presence of anti-RNP autoantibodies.

Adult↗

Anti-dsDNA antibody avidity determination by a simple reliable ELISA method for SLE diagnosis and monitoring.

High avidity anti-dsDNA antibodies are more specific for SLE diagnosis, and more closely associated with renal involvement than intermediate or low-affinity anti-dsDNA antibodies. ELISA methods are largely used to detect anti-dsDNA, but their high sensitivity is inversely related to specificity because they also detect low avidity antibodies. We developed an ELISA assay based on the law of mass action and the competitive binding of dsDNA in solution and coated to microwells with anti-dsDNA antibodies. A simplified Scatchard plot analysis system was used to measure anti-dsDNA antibody avidity which was expressed as apparent affinity constant (Kaa), and quantified in liters per unit (I/U). We prospectively studied 101 consecutive SLE patients, who were followed for 3 years; three serum samples were sequentially collected from each patient during follow-up for determination of IgG anti-dsDNA antibody concentration, and anti-dsDNA avidity. SLE disease activity was estimated using the European Consensus Lupus Activity Measure (ECLAM) index. Sera from 100 healthy subjects and 133 patients with other connective tissue diseases or infectious diseases were also assayed as controls. The mean Kaa in SLE patients was 65.2 +/- 47.3 l/U, with no variations over time. Anti-dsDNA-positive SLE patients had higher Kaa values (79.1 +/- 46.8) than anti-dsDNA negative patients (27.2 +/- 20.1; P < 0.001). No correlation emerged between anti-dsDNA avidity and the ECLAM activity index score. Avidity was significantly higher in patients with renal involvement vs patients without this complication (78.2 +/- 50 vs 59.9 +/- 45.6 l/U; P = 0.0013). This simple ELISA method could be very useful in the diagnostic phase to differentiate high avidity anti-dsDNA autoantibodies that are characteristically found in SLE patients from low avidity antibodies that can also be found in other inflammatory diseases. Moreover, our data confirm the predictive value of high avidity anti-dsDNA antibodies for the development of lupus nephritis.

Adult↗

A study of 20 SLE patients with intravenous immunoglobulin--clinical and serologic response.

OBJECTIVE: To test the clinical response of systemic lupus erythematosus (SLE) patients to intravenous immunoglobulins (IVIg), and whether the clinical response of IVIg treatment in SLE is accompanied by modification of SLE-associated autoantibodies/antibodies (Abs) and complement levels. METHODS: Twenty SLE patients were treated with high-dose (2 g/kg) IVIg monthly, in a 5-d schedule. Each patient received between 1-8 treatment courses. They were evaluated for the clinical response, Systemic Lupus Activity Measure (SLAM) score before and after IVIg, levels of antinuclear antibody (ANA), dsDNA (double-stranded DNA), SS-A or SS-B, ENA (extractable nuclear antigens), C3 and C4 levels before and after the treatment, and before and after each treatment course. RESULTS: A beneficial clinical response following IVIg treatment was noted in 17 out of 20 patients (85%). Few clinical manifestations responded more to treatment: arthritis, fever, thrombocytopenia, and neuropsychiatric lupus. In 9 patients evaluated before and after IVIg, mean SLAM score decreased from 19. 3+/-4.7 to 4+/-2.9 (P<0.0001). There was a tendency towards abnormal levels of complement and Abs before IVIg courses among the treatment responders compared with the non-responders, and similarly the former tended to have normalization of their abnormal levels more than the latter. These differences were found statistically significant only with respect to C4 and SS-A or SS-B levels before IVIg courses. CONCLUSION: IVIg has a high response rate among SLE patients. A combination of clinical manifestations, Abs and complement levels may aid in the future in predicting who among SLE patients will benefit more from IVIg treatment.

Adult↗

CD4 TCRBV CDR3 analysis in prevalent SLE cases from two ethnic groups.

We examined CD4+ T cell TCRBV-CDR3 transcripts from 19 lupus patients and 16 controls to test the hypothesis that CD4+ TCRBV-CDR3 expression in SLE differs from normals. Within the disease group we also performed exploratory analyses to determine the association between risk of oligoclonality and HLA-DRB specificities and the duration of the CDR3 patterns. Oligoclonal patterns consistent with CDR3 restriction were three times more likely in SLE than in controls (OR = 3.7). TCRBV1, BV4, BV5.1, BV7, BV9, BV18 and BV22 gene segment CDR3 patterns of oligoclonality were seen exclusively among lupus patients. HLA-DRB3 increased the risk of oligoclonal expression in SLE. In four patients studied over time, the pattern of TCRBV-CDR3 expression was stable in a second sample obtained 6-14 months later. The increased frequency of CD4+ T cell TCRBV-CDR3 oligoclonal expression in SLE when compared to controls and the persistence of these patterns are consistent with an expanded pool of autoreactive CD4 T cells in SLE which recognize peptides derived from autoantigens. The association of HLA-DRB3 genes with increased risk of CDR3 oligoclonality among the SLE subjects is compatible with the hypothesis that molecules encoded by HLA-DRB3 may facilitate autoantigen recognition by CD4 T cells.

Adult↗

Systemic lupus erythematosus (SLE)-like syndromes associated with carbamazepine therapy.

Records of 80 cases of systemic lupus erythematosus (SLE)-like syndromes associated with use of carbamazepine entered in the single case files of Central Drug Monitoring, Ciba-Geigy, Basel, were reviewed. Included in these were 11 cases reported in the literature. These were assessed in light of the current concepts of both idiopathic and drug-induced forms of SLE. Even allowing for under-reporting of adverse drug reactions, the number of such cases is far below the prevalence rates for SLE. This adverse drug reaction remains allocated to the category 'isolated cases' i.e. frequency is less than 0.001% of the cases treated. Antinuclear antibody (ANA) and anti-double-stranded DNA (anti-dsDNA) tests were not helpful in differentiating between idiopathic and drug-induced SLE. IgG antihistone antibodies in the absence of high titres of dsDNA antibodies is the only reliable test. Symptoms of SLE-like syndromes which manifest after carbamazepine therapy usually subside after discontinuation of the drug. Persistence of symptoms support the diagnosis of idiopathic SLE.

Antibodies, Antinuclear↗

Type I interferon as a target of treatment in SLE.

Systemic lupus erythematosus (SLE) is a multi-organ autoimmune disease characterized by the production of antibodies against a spectrum of autoantigens. Recent evidence suggests that type-I interferons (IFN-I) are critically involved in the pathogenesis of SLE. Initially recognized for their anti-viral properties, IFN-I play important roles in immunity and autoimmunity by promoting DC maturation, T cell survival, and antibody production. Onset of SLE has been reported in patients with hepatitis or neoplastic diseases undergoing treatment with recombinant IFN-I while elevated serum IFN-I and IFN-stimulated gene expression are found in approximately 2/3 of SLE patients. This interferon signature is clinically important as it correlates with disease activity and renal as well as CNS involvement. Supporting these findings, genetic abnormalities resulting in increased IFN-I production and/or signaling are associated with SLE. In view of the accumulating evidence linking IFN-I to the pathogenesis of SLE, targeting of IFN-I may be beneficial therapeutically while avoiding the side effects associated with conventional immunosuppressive therapy. To this end, IFN-I and IFN-producing cells as well as IFN-inducers and molecules of the IFN signaling pathway may all serve as potential therapeutic targets. Several anti-IFN-I approaches have already shown promising effects in animal studies and clinical trials will likely begin in the near future.

Animals↗

Oral contraceptives in systemic lupus erythematosus: side-effects and influence on the activity of SLE.

The risk of a disease flare-up and the side-effects experienced during the use of oral contraceptives (OCs) were studied in 85 female SLE patients, 18-44 years old, regularly attending two specialist rheumatological clinics. Thirty-one patients had used combined oral contraceptives (cOCs) during or after the onset of SLE. Initial manifestations or exacerbations of SLE were noted in 4 (13%) of these patients during the first six months after starting cOCs and three of these four patients had major renal involvement. The incidence of disease flare-ups was the same as in patients not using cOCs. Two patients developed deep venous thrombosis during cOCs, and they both had antiphospholipid antibodies. Thirty-two patients had used progestagen-only contraceptives (PCs) and they were discontinued in 25 (78%) of the patients because of minor side-effects, mainly reflecting poor gynaecological tolerance. Albeit there is no definitive proof that cOCs actually precipitate or exacerbate SLE some patients may be more likely to have adverse effects while taking cOCs. It appears best to avoid cOCs in SLE patients with high levels of antiphospholipid antibodies and in patients with active nephritis. PCs cause many side-effects in SLE patients, but do not seem to activate the disease.

Adolescent↗

Production of IL-1beta, IL-1 receptor antagonist and IL-10 by mononuclear cells from patients with SLE.

Depositions of immune-complexes are responsible for many of the pathological features of systemic lupus erythematosus (SLE). For example, immune-complex-induced tissue damage in glomerulonephritis has been shown to be mediated, at least in part, by interleukin (IL)-1. Inappropriate production or function of IL-1 may therefore contribute to disease manifestations in SLE. We investigated lipopolysaccharide (LPS)- and adherent IgG-stimulated release of IL-1beta, IL-1 receptor antagonist (IL-1ra) and IL-10, a potent modulator of IL-1, by blood mononuclear cells from patients with SLE. Mediator production was measured as ng cytokines/10(6) monocytes and compared with clinical parameters. Release of IL-1beta was only detectable in LPS-stimulated cultures and substantially reduced in patients with both active and inactive disease (P < 0.001). LPS-stimulated IL-1ra release was normal and the IL-1ra/IL-1beta ratio was therefore increased (P < 0.05) and correlated inversely to prednisolone dosage (P = 0.009). IgG-stimulated release of IL-1ra was reduced in patients with active disease compared to those with inactive disease and controls (P = 0.002). IL-10 release was similar in patients and controls. We conclude that monocytes from patients with active SLE are deficient in Fc gamma-R-mediated production of IL-1ra, whereas LPS-stimulated IL-1beta release by SLE monocytes is reduced regardless of disease activity. The former may contribute to immune-complex-mediated tissue damage in SLE.

Adult↗

[Asymptomatic bacteriuria in women diagnosed with systemic lupus erythematosus (SLE)].

The aims of our research were: estimation of asymptomatic bacteriuria (a.b.) incidence in population of women with systemic lupus erythematodes (SLE), evaluation its clinical significance and examination of bacterial colonisation of nostrils and pharynx in SLE patients with a.b. 85 women aged 24-77 (mean 49.3) with mean SLE duration 7.8 (range 1-32) years were examined. All of them fulfilled ARA criteria for the classification of SLE. Among group of patients with a.b. were counted women who had significant bacteriuria > or = 10(4) in ml urine in two cultures. Asymptomatic bacteriuria was found in 14 cases of 85 women with SLE (16.5%). In two following urine cultures bacteria from family Enterobacteriaceae were dominated: the same types of bacteria were in 85.7%--bacteriuria persistens, in others 14.3% were observed change of bacteria--bacteriuria transistens. In 9 from 14 patients with (64.3%) a.b. very massive growth of Staphylococcus aureus in culture from vestibulae of the nose swab was, in other cultures very massive growth of physiological flora was seen. All patients with a.b. were in clinical remission of SLE and they had no clinical symptoms of infection in urinary tract in 5 months of observation. However clinical significance of asymptomatic bacteriuria and pathogenic bacteria colonisation of nostrils as a precedence to symptomatic infections needs further investigations.

Adult↗

High levels of antibodies against Clq are associated with disease activity and nephritis but not with other organ manifestations in SLE patients.

OBJECTIVE: Serum concentration of antibodies to C1q (C1qAb) has been reported to be elevated in a high percentage of patients with systemic lupus erythematosus (SLE). The associations of high C1qAb levels with different clinical manifestations and the activity of the disease, however, are not definitely understood. METHODS: We measured the levels of IgG type C1qAb in the sera of 137 patients with SLE using an ELISA method. RESULTS: Serum concentrations of C1qAb were found to be higher (p < 0.0001) in SLE patients than in healthy controls. High titer (> 66 AU/ml) C1qAb was found in 40/137 (29.2%) SLE patients, and 4/192 (2.1%) healthy controls (p < 0.0001). A strong negative correlation (R = -0.4, p < 0.0001) between the age of the patients and the C1qAb titers could be detected. C1qAb levels in clinically active SLE patients significantly (p < 0.0001) exceeded those measured in the sera of patients in the inactive stage of the disease. A significant positive correlation was detected between C1qAb levels and the laboratory activity markers (anti-DNA, low C3 level) of the disease. We found a significant negative correlation between levels of C1qAb and a negative acute phase protein, alpha2-HS-glycoprotein. Renal involvement was present in 11/40 (27.5%) and 11/97 (11%) of the patients with high and low titers of C1qAb, respectively (p = 0.038). The prevalence of other organ manifestations was, however, the same in the patients with or without high titer C1qAb. CONCLUSION: These findings indicate that C1qAb measurement is a useful method for detecting the activity of SLE and predicting renal manifestations, but not other organ involvement in the disease.

Adult↗