ObjectiveIschemic stroke is 2–3 times more common among SLE patients than in the general population, but it unknown if certain subtypes of stroke are more common in SLE patients, nor if stroke ...subtypes are associated with the susceptibility gene, STAT4, which we previously reported to be associated with stroke among patients with SLE. We investigated the distribution of ischemic stroke subtypes, classified according to the Trial of Org 10172 in Acute Stroke Treatment (TOAST) system,1 among patients with SLE. Genetic susceptibility in the signal transducer and activator of transcription factor 4 (STAT4) gene, defined by the single nucleotide polymorphism (SNP) rs10181656(G) was explored.MethodsWe identified 69/665 SLE patients with stroke in this multicenter study. Medical charts were retrieved and brain, cardiac and vascular imaging at the time of stroke were examined. Classification was performed according to TOAST: large-artery atherosclerosis (LAA), cardioembolism (CE), small-artery occlusion (SAO), stroke of other determined etiology (OC) and stroke of undetermined etiology (UE). Occurrence of the antiphospholipid syndrome (APS) was documented. Evaluators were blinded to genotypes. General population controls and SLE patients free from previous cerebrovascular disease were comparators.Results56/69 patients with ischemic stroke had charts with sufficient information for TOAST classification. Median age was 52 (Range 17–84) years, 91% were female. All strokes classified as OC were attributed to APS, and this group was younger at first stroke, 42 years (p= p=0.003). TOAST classification is presented in table 1. Stroke of OE/APS and CE origin were associated with the STAT4 risk genotype as presented in table 1, figure 1.ConclusionMost ischemic strokes among SLE patients were of APS or CE origin. These two subtypes were associated with genetic susceptibility in the STAT4 gene. Patients with APS associated strokes were remarkably young. STAT4 genotype could, in addition to antiphospholipid antibodies and echocardiography, add information about stroke risk and help identify patients who will benefit from prophylactic anticoagulation treatment.Reference Adams HP, et al. Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. TOAST. Trial of Org 10172 in Acute Stroke Treatment. Stroke. 1993;24(1):35–41.Abstract O10 Table 1Stroke subtypes and age at first stroke, and associations of STAT4 single nucleotide polymorphism (SNP) rs10181656 (G), in SLE patients with ischemic stroke and in stroke subtypes Stroke type Age at first stroke Median (range) STAT4 rs10181656 RAF% Controls, N=658 STAT4 rs10181656 RAF 22.1 % p-value vs. Controls Non-stroke SLE, N=517 STAT4 rs10181656 RAF 31.9 % p-value vs. Non-stroke SLE Any ischemic stroke N=56, 100 % 52 (17–84) 48.2 3.3 (2.2 - 4.9) <0.0001 2.0 (1.3 - 2.9) 0.0005 Small artery occlusion N=9, 16 % 63 (51–84) 27.8 1.4 (0.5–3.8) 0.57 0.8 (0.3–2.3) 0.71 Large artery occlusion N=7, 12 % 55 (34–67) 21.4 1.0 (0.3–3.5) 1.00 0.6 (0.2–2.1) 0.56 Cardioembolic stroke N=12, 21 % 57 (23–70) 70.8 8.6 (3.5 - 20.8) 1.8x10-8 5.1 (2.1 - 12.5) 6.7x10-5 Other determined etiology (all APS) N=1, 33 % 42 (18 -74) * 60.5 5.4 (2.8 - 10.5) 3.2x10-8 3.2(1.7 - 6.3) 0.0003 Undetermined etiology N= 9, 16 % 56 (25–73) 33.3 1.8 (0.7–4.7) 0.28 1.1 (0.4–2.8) 0.92 RAF = Risk Allele Frequency, N= number of patients. *Patients with OE/APS strokes were younger, as compared to all other stroke subtypes, p=0.003Abstract O10 Figure 1
Background In SLE, anti-dsDNA often exists together with autoantibodies against other chromatin components, like histones and nucleosomes. These antibodies can induce cytokines including ...interferon-alpha. Methods We have measured ANA specificities and investigated their associations to inflammatory biomarkers. We included 93 Sudanese and 480 Swedish SLE patients. Serum levels of autoantibodies against dsDNA, Sm, the Sm/U1RNP complex, U1RNP, SSA/Ro52, SSA/Ro60, SSB/La, ribosomal P, PCNA and histones were quantified with a bead-based multiplex immunoassay. In the Swedish cohort also anti-nucleosome antibodies were investigated. Relative levels of 73 plasma biomarkers were determined with Proximity Extension Assay technique or ELISA. Adjusted p values were considered significant when <0.05. Results Among Sudanese patients, levels of 5/73 biomarkers showed significant associations to ANA-associated antibodies. Anti-histone antibodies showed the strongest positive correlations with interferon-inducible factors MCP-1 and IP-10, and with MCP-3 and S100A12, and negative correlation with stem cell factor. Also anti-dsDNA antibodies associated with MCP-3, IP-10 and S100A12, but when combined in the same regression model, anti-dsDNA associations but not anti-histone lost significance. Validation analyses among Swedish patients for MCP-1, IP-10, SA100A12 also demonstrated significantly stronger associations to anti-histone and anti-nucleosome antibodies respectively, compared to anti-dsDNA and other ANA specificities, and in combined regression models, anti-histone/nucleosome showed the strongest associations. When excluding anti-histone or anti-nucleosome positive patients, the associations between interferon-inducible factors MCP-1/IP-10 and anti-dsDNA and were lost. In contrary, when excluding anti-dsDNA positive patients, associations with anti-histone and anti-nucleosome respectively remained significant. SA100A12 associations with anti-dsDNA antibodies remained significant after exclusion of anti-histone positive patients but lost significance when excluding anti-nucleosome positive patients. Conclusions Levels of mainly IFN-induced inflammatory biomarkers correlate stronger with anti-histone and anti-nucleosome antibodies compared to other ANA specificities including anti-dsDNA. Our results suggest that autoantibodies against DNA-complexes or DNA-associated proteins rather than anti-dsDNA induce the interferon signature in SLE.
Abstract Objectives The main objectives of this study were to calculate total costs of illness and cost-driving disease features among patients with systemic lupus erythematosus (SLE) in Sweden. ...Methods Five cohorts of well-defined SLE patients, located in different parts of the country were merged. Incident and prevalent cases from 2003 through 2010 were included. The American College of Rheumatology (ACR) classification criteria was used. From the local cohorts, data on demographics, disease activity (SLEDAI 2K), and organ damage (SDI) were collected. Costs for inpatient care, specialist outpatient care and drugs were retrieved from national registries at the National Board of Health and Welfare. Indirect costs were calculated based on sickness leave and disability pensions from the Swedish Social Insurance Agency. Results In total, 1029 SLE patients, 88% females, were included, and approximately 75% were below 65 years at the end of follow-up, and thus in working age. The mean number of annual specialist physician visits varied from six to seven; mean annual inpatient days were 3.1–3.6, and mean annual sick leave was 123–148 days, all per patient. The total annual cost was 208,555 SEK ($33,369 = 22,941€), of which direct cost was 63,672kr ($10,188 = 7004€) and the indirect cost was 144,883 SEK ($23,181 = 15,937€), all per patient. The costs for patients with short disease duration were higher. Higher disease activity as measured by a SLEDAI 2K score > 3 was associated with approximately 50% increase in both indirect and direct costs. Damage in the neuropsychiatric and musculoskeletal domains were also linked to higher direct and indirect costs, while organ damage in the renal and ocular systems increased direct costs. Conclusion Based on this study and an estimate of slightly more than 6000 SLE patients in Sweden, the total annual cost for SLE in the country is estimated at $188 million (=129.5 million €). Both direct (30%) and indirect costs (70%) are substantial. Medication accounts for less than 10% of the total cost. The tax paid national systems for health care and social security in Sweden ensure equal access to health care, sick leave reimbursements, and disability pensions nationwide. Our extrapolated annual costs for SLE in Sweden are therefore the best supported estimations thus far, and they clearly underline the importance of improved management, especially to reduce the indirect costs.
ObjectivesAdverse pregnancy outcomes (APOs) are more common among women with SLE compared to the general population and the underlying immunopathological mechanisms are largely unknown. The type I ...interferon (IFN) signature persists in complicated SLE pregnancies, while it is downregulated in uncomplicated SLE pregnancies. Moreover, IFNα protein concentrations are higher in SLE compared to healthy pregnancies, but whether IFNα protein levels are associated with APOs in SLE is unknown. The aim of this study was to evaluate whether APOs are more common in Swedish women with SLE compared to healthy controls, and if this associates with circulating IFNα protein or autoantibodies.MethodsWe included 83 births from 77 women with SLE and 58 births from 58 healthy controls (HC). Repeated peripheral blood samples were collected and IFNα protein levels were quantified with Simoa. Anti-nuclear antibody (ANA) specificities and anti-phospholipid antibodies (aPL) during pregnancy was analysed using multiplexed bead technology. APOs were defined as an infant small for gestational age (SGA), preterm birth, low birth weight (LBW) and/or preeclampsia. Multivariate orthogonal partial least squares analysis (OPLS) was used to examine SGA, LBW and/or preterm (combined outcomes, Y-variable) in relation to mean IFNα protein level, IFNα positivity, ANA specificity and aPL positivity during pregnancy.ResultsAPOs were more common in women with SLE compared to healthy women (33% compared to 12%, p=0.005). The most common outcome was SGA, which was present in 17% of women with SLE compared to 3% of HC (p=0.01). In OPLS, SGA, LWB and/or preterm birth was most positively associated to mean IFNα protein level and IFNα positivity in plasma during pregnancy. Preeclampsia was unrelated to IFNα and autoantibody positivity in women with SLE. In univariate analysis, the mean IFNα protein level was significantly higher in women with SLE who had an infant who was SGA, LBW and/or preterm compared to women without these APOs.ConclusionIFNα protein level in plasma is a potential risk factor for giving birth to an infant who is small for gestational age, has low birth weight and/or is delivered preterm in SLE.
ObjectiveAdverse pregnancy outcomes are more common among women with systemic lupus erythematosus (SLE) compared to healthy women, but there is limited understanding on how pregnancy affects the ...immune system and what specific immunopathological processes that precede these complications. Lymphopenia, autoantibodies and activation of the type I interferon (IFN) system are common features SLE. We aimed to investigate the impact of pregnancy on lymphocyte subset counts in SLE and their associations with autoantibody profiles and IFNα concentrations.MethodsRepeated blood samples were collected from 80 pregnant women with SLE and 51 healthy controls (HC), with additional samples from 19 women with SLE postpartum. Flow cytometry was used to measure CD4+ and CD8+ T cells, B cells, and NK cells. Positivity for anti-nuclear antibodies (ANA) fine specificities and anti-phospholipid antibodies was assessed using multiplexed bead assay. IFNα concentration was quantified with Single molecule array (Simoa) immune assay. Clinical data were retrieved from medical records.ResultsWomen with SLE had lower counts of all lymphocyte subsets compared to HC throughout pregnancy, but counts did not differ during pregnancy compared to postpartum. Principle component analysis revealed that low lymphocyte subset counts differentially related to autoantibody profiles, cluster one (anti-dsDNA/anti-Sm/anti-RNP/anti-Sm/RNP/anti-chormatin), cluster two (anti-SSA/anti-SSB) and cluster three (anti-CL/anti-β2GPI), IFNα protein levels and disease activity. CD4+ T cell counts were lower in women positive to all ANA fine specificities in cluster one compared to those who were negative, and B cell numbers were lower in women positive for anti-dsDNA and anti-Sm compared to negative women. Moreover, CD4+ T cell and B cell counts were lower in women with moderate/high compared to no/low disease activity, and CD4+ T cell count was lower in IFNα protein positive relative to negative women. Finally, CD4+ T cell count was unrelated to treatment.ConclusionLymphocyte subset counts are lower in SLE compared to healthy pregnancies, which seems to be a feature of the disease per se and not affected by pregnancy. Our results also indicate that low lymphocyte subset counts relate differentially to autoantibody profiles, IFNα protein levels and disease activity, which could be due to divergent disease pathways.
Abstract
Objectives
Studies on repeat renal biopsies in membranous LN (MLN) are limited, and evaluation of treatment response is mainly based on proteinuria. EM of renal biopsies from rituximab ...(RTX)-treated MLN patients has revealed resorption of sub-epithelial ICs. Whether resorption phenomena are useful for treatment evaluation, or differs between treatment regimens is not known. We studied EM findings and clinical treatment response in MLN patients after RTX vs conventional immunosuppressive treatment.
Methods
Twenty-four patients with MLN and renal biopsies performed before and after treatment were included in this retrospective observational study. Laboratory data were collected at both biopsy occasions. Seven patients had received RTX and 17 had received conventional treatment (CYC, MMF or AZA). Electron micrographs of renal tissue were scored using an arbitrary scale (0–3) for the level of sub-epithelial ICs, resorption of ICs and podocyte fusion.
Results
Sub-epithelial ICs decreased after treatment, however not significantly and with no difference between treatments. The resorption phenomena increased after RTX (P = 0.028), but not after conventional therapy (P = 0.29). Six out of seven (86%) RTX-treated patients had increased resorption vs 7/17 (41%) after conventional therapies (P = 0.047). Clinical responders had more pronounced resorption of ICs vs non-responders (P = 0.022).
Conclusions
We report increased resorption of ICs in repeat renal biopsies in MLN, especially after RTX treatment. Increased resorption phenomena were associated with clinical response, suggesting that EM findings may be useful for treatment evaluation in MLN. Although of limited size, the study indicates that RTX is effective both clinically and at a tissue level.
Abstract
Objectives
We investigated the cell adhesion molecules (CAMs) Vascular CAM 1 (VCAM-1) and Activated Leucocyte CAM (ALCAM) as urinary biomarkers in SLE patients with and without renal ...involvement.
Methods
Female SLE patients (n = 111) and non-SLE population-based controls (n = 99) were enrolled. We measured renal activity using the renal domain of the BILAG index and urine (U) and plasma (P) concentrations of soluble (s)VCAM 1 and U-sALCAM using ELISA. U-sCAM levels were next corrected by U-creatinine.
Results
U-sVCAM-1/creatinine and U-sALCAM/creatinine ratios were higher in SLE patients vs non-SLE controls (P < 0.001 for both), as well as in patients with active/low-active (BILAG A–C; n = 11) vs quiescent (BILAG D; n = 19) LN (P = 0.023 and P = 0.001, respectively). U-sALCAM/creatinine but not U-sVCAM-1/creatinine ratios were higher in patients with nephritis history (BILAG A–D; n = 30) vs non-renal SLE (BILAG E; n = 79) (P = 0.014). Patients with baseline U-sVCAM-1/creatinine ratios ≥75th percentile showed a 23-fold increased risk of a deterioration in estimated glomerular filtration rate by ≥25% during a 10-year follow-up (odds ratio: 22.9; 95% CI: 2.8, 189.2; P = 0.004); this association remained significant after adjustments for age, disease duration and organ damage. Traditional markers including anti-dsDNA antibodies did not predict this outcome.
Conclusion
While high U-sVCAM-1 levels appear to reflect SLE disease activity, sALCAM might have particular importance in renal SLE. Both U-sVCAM-1 and U-sALCAM showed ability to distinguish SLE patients with active renal involvement from patients with quiescent or no prior nephritis. High U-sVCAM-1 levels may indicate patients at increased risk for long-term renal function loss.
Introduction
Kidney biopsy is the reference tool for diagnosing and guiding treatment strategies in inflammatory renal diseases, such as lupus nephritis (LN).
We investigated the histopathological ...findings in first-time kidney biopsies from a large cohort of SLE patients. We focused on the occurrence and type of histopathological findings other than LN, and fulfillment of renal criteria in established SLE classification systems were analyzed.
Methods
We retrospectively included SLE patients (
n
= 139) who underwent a first kidney biopsy between 1995 and 2021, upon clinical suspicion of renal involvement. Based on histology, two groups were defined, LN and non-LN, for which clinical and laboratory features were compared.
Results
Findings consistent with LN according to ISN/RPS classification system were present in 123/139 patients (88.5%) and findings not consistent with LN were present in 16 /139 (11.5%).
Non-LN patients were older at SLE diagnosis compared to LN patients (M, years 38.0 vs. 30.1,
p
=0.013) and had longer disease duration (M, years 11.9 vs 0.5) (
p
=0.027).
Among non-LN patients 85.7% met the SLICC criteria item for renal SLE, seen in 94.7% in the LN group (ns). For the ACR/EULAR criteria, 66.7% of the non-LN group fulfilled the criteria compared to 74.8% in LN patients (ns). Proteinuria below the criteria cut-off level (< 0.5 g/24 h) was seen in 20% of patients with class III/IV LN.
Conclusion
Our data confirm the importance of kidney biopsy for ruling out the presence of renal pathology other than LN. Patients with low-grade proteinuria may exhibit severe types of LN, which reinforces the need for early biopsies to detect LN.
Key Points
•
Our findings show that histopathology changes other than lupus nephritis may occur in a significant number of patients with clinical and laboratory signs of novel kidney involvement.
•
Low-grade proteinuria does not exclude findings of active lupus nephritis that require the start of immunosuppressive therapy.
•
The study stresses the importance of performing kidney biopsies also in the presence of low-grade proteinuria or when signs of kidney function abnormalities occur.
•
This is crucial as early detection and prompt initiation of therapy may improve outcomes in lupus nephritis.
The study aims to increase the understanding regarding the role of regulatory T cells (Tregs) in lupus nephritis (LN) and ANCA-associated vasculitis (AAV) by comparing their localization in renal ...tissue and changes following immunosuppressive therapy. Kidney biopsies from 12 patients with LN and 7 patients with AAV were examined. Kidney biopsies had been performed both at active disease and following immunosuppressive treatment. Clinical data was collected at both biopsy occasions. Expression of Forkhead Box P 3 (Foxp3) in renal tissue was assessed by immunohistochemistry. An arbitrary scale was used to estimate the number of Foxp3+ cells. In LN, 8/12 (67%) had positive tissue staining for Foxp3 at baseline, most pronounced in inflammatory infiltrates, but also interstitially and in a peri-glomerular pattern. At second biopsies, after immunosuppressive treatment, 4/12 (33%) still had detectable Foxp3+ cells, found in persisting inflammatory infiltrates and some in the interstitium. Patients with a good clinical response to treatment had high grade of Foxp3+ cells in first biopsies. In AAV, only 2/7 (29%) had positive staining for Foxp3 at baseline, in inflammatory infiltrates and to a lesser extent in the interstitium, despite large areas of inflammatory infiltrates in all patients. At follow-up, 2/7 (29%) biopsies were positive for Foxp3. Our data show a higher presence of Foxp3+ cells in renal tissue from LN patients compared to AAV, suggesting that Tregs may be differently involved in the control of inflammatory mechanisms in these diseases. These findings could have further implication for therapeutic approaches aiming at restoring the immunological tolerance.
Key Points
• Foxp3+-cells are present in larger amount in renal tissue in lupus nephritis vs. ANCA-associated vasculitis.
• Our data suggest that Foxp3+ regulatory T cells are involved in the control of inflammatory processes in lupus nephritis.
Abstract Objectives Belimumab is the first biologic drug approved for Systemic Lupus Erythematosus (SLE). Here, we aimed to investigate the effects of belimumab on clinical and serologic outcomes, ...and sought to identify predictors of treatment response in three Swedish real-life settings. Methods Fifty-eight patients were enrolled at initiation of belimumab and followed longitudinally for up to 53 months. Surveillance outcomes included the SLE Disease Activity Index 2000 (SLEDAI-2K), 100 mm Visual Analogue Scales for Physician's Global Assessment (PGA), fatigue, pain and general health, and the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI). Assessment of treatment response included the SLE responder index (SRI). B lymphocyte stimulator (BLyS) levels were determined using ELISA. Results SLEDAI-2K (median baseline score: 8.0; IQR: 4.0–13.8), PGA and corticosteroid use decreased during therapy, and patients reported improvements on fatigue, pain, and general health ( p < 0.0001 for all). SDI scores remained stable ( p = 0.08). Patients with baseline SDI scores > 1 showed decreased probability and prolonged time to attain SRI response (HR: 0.449; 95% CI: 0.208–0.967), as did current smokers compared with non-smokers (HR: 0.103; 95% CI: 0.025–0.427). In contrast, baseline BLyS levels ≥ 1.2 ng/mL predicted increased probability and shorter time to attain SRI response (HR: 2.566; 95% CI: 1.222–5.387). Conclusions Disease activity and corticosteroid usage decreased, patient-reported outcomes improved, and no significant organ damage was accrued during follow-up. Smoking and organ damage predicted reduced treatment efficacy. These findings might contribute to a better selection of patients who are likely to benefit from belimumab.
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