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1.
  • Bolin, Karin, et al. (författare)
  • Association of STAT4 Polymorphism with Severe Renal Insufficiency in Lupus Nephritis
  • 2013
  • Ingår i: PLOS ONE. - : Public Library of Science. - 1932-6203. ; 8:12, s. 84450-
  • Tidskriftsartikel (refereegranskat)abstract
    • Lupus nephritis is a cause of significant morbidity in systemic lupus erythematosus (SLE) and its genetic background has not been completely clarified. The aim of this investigation was to analyze single nucleotide polymorphisms (SNPs) for association with lupus nephritis, its severe form proliferative nephritis and renal outcome, in two Swedish cohorts. Cohort I (n = 567 SLE cases, n = 512 controls) was previously genotyped for 5676 SNPs and cohort II (n = 145 SLE cases, n = 619 controls) was genotyped for SNPs in STAT4, IRF5, TNIP1 and BLK. Case-control and case-only association analyses for patients with lupus nephritis, proliferative nephritis and severe renal insufficiency were performed. In the case-control analysis of cohort I, four highly linked SNPs in STAT4 were associated with lupus nephritis with genome wide significance with p = 3.7x10(-9), OR 2.20 for the best SNP rs11889341. Strong signals of association between IRF5 and an HLA-DR3 SNP marker were also detected in the lupus nephritis case versus healthy control analysis (pless than0.0001). An additional six genes showed an association with lupus nephritis with pless than0.001 (PMS2, TNIP1, CARD11, ITGAM, BLK and IRAK1). In the case-only meta-analysis of the two cohorts, the STAT4 SNP rs7582694 was associated with severe renal insufficiency with p = 1.6x10(-3) and OR 2.22. We conclude that genetic variations in STAT4 predispose to lupus nephritis and a worse outcome with severe renal insufficiency.
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2.
  • Diaz-Gallo, Lina-Marcela, et al. (författare)
  • Four Systemic Lupus Erythematosus Subgroups, Defined by Autoantibodies Status, Differ Regarding HLA-DRB1 Genotype Associations and Immunological and Clinical Manifestations
  • 2022
  • Ingår i: ACR Open Rheumatology. - : Wiley. - 2578-5745. ; 4:1, s. 27-39
  • Tidskriftsartikel (refereegranskat)abstract
    • Objective: The heterogeneity of systemic lupus erythematosus (SLE) constitutes clinical and therapeutical challenges. We therefore studied whether unrecognized disease subgroups can be identified by using autoantibody profiling together with HLA-DRB1 alleles and immunological and clinical data.Methods: An unsupervised cluster analysis was performed based on detection of 13 SLE-associated autoantibodies (double-stranded DNA, nucleosomes, ribosomal P, ribonucleoprotein [RNP] 68, RNPA, Smith [Sm], Sm/RNP, Sjögren's syndrome antigen A [SSA]/Ro52, SSA/Ro60, Sjögren's syndrome antigen B [SSB]/La, cardiolipin [CL]-Immunoglobulin G [IgG], CL-Immunoglobulin M [IgM], and β2 glycoprotein I [β2 GPI]-IgG) in 911 patients with SLE from two cohorts. We evaluated whether each SLE subgroup is associated with HLA-DRB1 alleles, clinical manifestations (n = 743), and cytokine levels in circulation (n = 446).Results: Our analysis identified four subgroups among the patients with SLE. Subgroup 1 (29.3%) was dominated by anti-SSA/Ro60/Ro52/SSB autoantibodies and was strongly associated with HLA-DRB1*03 (odds ratio [OR] = 4.73; 95% confidence interval [CI] = 4.52-4.94). Discoid lesions were more common for this disease subgroup (OR = 1.71, 95% CI = 1.18-2.47). Subgroup 2 (28.7%) was dominated by anti-nucleosome/SmRNP/DNA/RNPA autoantibodies and associated with HLA-DRB1*15 (OR = 1.62, 95% CI = 1.41-1.84). Nephritis was most common in this subgroup (OR = 1.61, 95% CI = 1.14-2.26). Subgroup 3 (23.8%) was characterized by anti-ß2 GPI-IgG/anti-CL-IgG/IgM autoantibodies and a higher frequency of HLA-DRB1*04 compared with the other patients with SLE. Vascular events were more common in Subgroup 3 (OR = 1.74, 95% CI = 1.2-2.5). Subgroup 4 (18.2%) was negative for the investigated autoantibodies, and this subgroup was not associated with HLA-DRB1. Additionally, the levels of eight cytokines significantly differed among the disease subgroups.Conclusion: Our findings suggest that four fairly distinct subgroups can be identified on the basis of the autoantibody profile in SLE. These four SLE subgroups differ regarding associations with HLA-DRB1 alleles and immunological and clinical features, suggesting dissimilar disease pathways.
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3.
  • Jönsen, Andreas, et al. (författare)
  • Direct and indirect costs for systemic lupus erythematosus in Sweden. A nationwide health economic study based on five defined cohorts
  • 2016
  • Ingår i: Seminars in Arthritis & Rheumatism. - : Elsevier BV. - 0049-0172 .- 1532-866X. ; 45:6, s. 684-690
  • Forskningsöversikt (refereegranskat)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(sic)), of which direct cost was 63,672kr ($10,188 = 7004(sic)) and the indirect cost was 144,883 SEK ($23,181 = 15,937(sic)), 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 (sic)). 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. (C) 2016 Elsevier Inc. All rights reserved.
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4.
  • Jönsen, Andreas, et al. (författare)
  • Mutations in genes encoding complement inhibitors CD46 and CFH affect the age at nephritis onset in patients with systemic lupus erythematosus
  • 2011
  • Ingår i: Arthritis Research & Therapy. - : Springer Science and Business Media LLC. - 1478-6354 .- 1478-6362. ; 13, s. R206-
  • Tidskriftsartikel (refereegranskat)abstract
    • INTRODUCTION: Inherited deficiencies of several complement components strongly predispose to systemic lupus erythematosus (SLE) while deficiencies of complement inhibitors are found in kidney diseases such as atypical hemolytic uremic syndrome (aHUS). METHODS: The exons of complement inhibitor genes: CD46 and CFH (factor H) were fully sequenced using Sanger method in SLE patients with nephritis originating from two cohorts from southern and mid Sweden (n = 196). All identified mutations and polymorphisms were then analyzed in SLE patients without nephritis (n = 326) and healthy controls (n = 523). RESULTS: We found non-synonymous, heterozygous mutations in CFH in 6.1% patients with nephritis in comparison to 4.0% and 5.4% in patients without nephritis and controls, respectively. No associations of SLE or nephritis with common variants in CFH (V62I/Y402H/E936D) were found. Furthermore, we found two non-synonymous heterozygous mutations in CD46 in SLE patients but not in controls. The A353V polymorphism, known to affect function of CD46, was found in 6.6% of nephritis patients vs 4.9% and 6.1% of the non-nephritis SLE patients and controls. The presence of mutations in CD46 and CFH did not predispose to SLE or nephritis but was associated with earlier onset of nephritis. Furthermore, we found weak indications that there is one protective and one risk haplotype predisposing to nephritis composed of several polymorphisms in non-coding regions of CD46, which were previously implicated in aHUS. CONCLUSION: SLE nephritis is not associated with frequent mutations in CFH and CD46 as found in aHUS but these may be modifying factors causing earlier onset of nephritis.
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5.
  • Lundström, Emeli, et al. (författare)
  • HLA-DRB1*04/*13 alleles are associated with vascular disease and antiphospholipid antibodies in systemic lupus erythematosus
  • 2013
  • Ingår i: Annals of the Rheumatic Diseases. - : BMJ. - 0003-4967 .- 1468-2060. ; 72:6, s. 1018-1025
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND AND OBJECTIVES:Vascular disease is common in systemic lupus erythematosus (SLE) and patients with antiphospholipid antibodies (aPL) are at high risk to develop arterial and venous thrombosis. Since HLA class II genotypes have been linked to the presence of pro-thrombotic aPL, we investigated the relationship between HLA-DRB1 alleles, aPL and vascular events in SLE patients.METHODS:665 SLE patients of Caucasian origin and 1403 controls were included. Previous manifestations of ischaemic heart disease, ischaemic cerebrovascular disease (ICVD) and venous thromboembolism (together referred to as any vascular events (AVE)) were tabulated. aPL were measured with ELISA. Two-digit HLA-DRB1 typing was performed by sequence-specific primer-PCR.RESULTS: HLA-DRB1*04 was more frequent among SLE patients with ICVD compared to unaffected patients. This association remained after adjustment for known traditional cardiovascular risk factors. HLA-DRB1*13 was associated with AVE. All measured specificities of aPL—cardiolipin IgG and IgM, β2-glycoprotein-1 IgG, prothrombin (PT) IgG and a positive lupus anticoagulant test were associated with HLA-DRB1*04—while HLA-DRB1*13 was associated with IgG antibodies (β2-glycoprotein-1, cardiolipin and PT). In patients with the combined risk alleles, HLA-DRB1*04/*13, there was a significant additive interaction for the outcomes AVE and ICVD.CONCLUSIONS:The HLA-DRB1*04 and HLA-DRB1*13 alleles are associated with vascular events and an aPL positive immune-phenotype in SLE. Results demonstrate that a subset of SLE patients is genetically disposed to vascular vulnerability.
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6.
  • Parodis, Ioannis, et al. (författare)
  • Autoantibody and cytokine profiles during treatment with belimumab in patients with systemic lupus erythematosus
  • 2020
  • Ingår i: International Journal of Molecular Sciences. - : MDPI AG. - 1661-6596 .- 1422-0067. ; 21:10
  • Tidskriftsartikel (refereegranskat)abstract
    • We investigated whether belimumab treatment impacts on levels of autoantibodies and cytokines of interest in systemic lupus erythematosus (SLE). Longitudinally collected serum samples from 78 belimumab-treated Swedish SLE patients were analysed. Serum cytokine levels were determined using Luminex xMAP technology, and nuclear antigen autoantibody specificities using addressable laser bead immunoassay. In patients with detectable levels at baseline, interferon (IFN)-α2 levels were lower at month 6 (median; interquartile range (IQR): 8.9; 1.5–54.9 pg/mL) versus baseline (28.4; 20.9–100.3 pg/mL; p = 0.043). Interleukin (IL)-6 (baseline: 7.1; 2.9–16.1 pg/mL) decreased from month 6 (0.5; 0.5–6.3 pg/mL; p = 0.018) and throughout a 24 month follow-up. IL-10 (baseline: 12.6; 2.8–29.7 pg/mL) showed more rapid decreases from month 3 (1.8; 0.6–9.1 pg/mL; p = 0.003). Levels of anti-dsDNA (p < 0.001), anti-Smith antigen (Sm) (p = 0.002), anti-U1 small nuclear ribonucleoprotein (U1RNP) (p < 0.001), anti-Sm-U1RNP complex (p = 0.028), and anti-ribosomal P (p = 0.012) antibodies decreased from month 3 and remained decreased. Anti-Sm positivity at baseline was associated with higher probability and/or shorter time to achieve sustained SLE responder index-4 response (hazard ratio (HR): 2.52; 95% CI: 1.20–5.29; p = 0.015), independently of other factors. Decline of IL-6 levels through month 3 was greater in responders. In summary, belimumab treatment lowered IFN-α2, IL-6, and IL-10 levels, as well as levels of multiple autoantibodies, however after different time spans. Notably, anti-Sm positivity and early decline in IL-6 levels were associated with favorable treatment outcome.
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7.
  • Parodis, Ioannis, et al. (författare)
  • Smoking and pre-existing organ damage reduce the efficacy of belimumab in systemic lupus erythematosus.
  • 2017
  • Ingår i: Autoimmunity Reviews. - : Elsevier BV. - 1568-9972 .- 1873-0183. ; 16:4, s. 343-351
  • Tidskriftsartikel (refereegranskat)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 53months. Surveillance outcomes included the SLE Disease Activity Index 2000 (SLEDAI-2K), 100mm 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 ≥1.2ng/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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8.
  • Parodis, Ioannis, et al. (författare)
  • Smoking reduces the efficacy of belimumab in mucocutaneous lupus.
  • 2018
  • Ingår i: Expert Opinion on Biological Therapy. - : Informa Healthcare. - 1471-2598 .- 1744-7682. ; 18:8, s. 911-920
  • Tidskriftsartikel (refereegranskat)abstract
    • OBJECTIVES: Recently, we demonstrated a negative impact of smoking on belimumab efficacy in patients with systemic lupus erythematosus (SLE). Here, we particularly investigated clinical effects of belimumab and a potential impact of smoking in mucocutaneous and articular SLE.METHODS: We surveyed 62 SLE patients treated between 2011 and 2017. Evaluation included the mucocutaneous descriptors of SLEDAI-2K (rash, alopecia, mucosal ulcers; mcSLEDAI-2K), CLASI, the arthritis SLEDAI-2K descriptor (arSLEDAI-2K) and the 28-joint count.RESULTS: mcSLEDAI-2K and CLASI activity decreased from baseline to month 6 and 12 (P<0.001 for all). No worsening in CLASI damage was observed. Current or previous smokers displayed a higher probability of unchanged/worsened mcSLEDAI-2K compared to never smokers (OR: 6.4; 95% CI: 1.5-27.4; P=0.012), also after adjustment for antimalarial agents. arSLEDAI-2K scores had decreased at month 6 (P<0.001) and 12 (P<0.001). Likewise, tender and swollen 28-joint counts had improved at month 6 (P=0.010 and P<0.001, respectively) and 12 (P=0.001 for both). We observed no impact of smoking on belimumab efficacy in articular SLE.CONCLUSION: We observed a negative impact of smoking on the efficacy of belimumab in mucocutaneous SLE. In contrast, no impact of smoking on belimumab efficacy was seen in patients with articular manifestations.
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9.
  • Sohrabian, Azita, et al. (författare)
  • Increased levels of anti-dsDNA antibodies in immune complexes before treatment with belimumab associate with clinical response in patients with systemic lupus erythematosus
  • 2019
  • Ingår i: Arthritis Research & Therapy. - : BMC. - 1478-6354 .- 1478-6362. ; 21
  • Tidskriftsartikel (refereegranskat)abstract
    • Introduction: Immune complexes are of importance in systemic lupus erythematosus pathogenesis, and autoantibodies are believed to participate in immune complex formation. Quantification of autoantibody levels in circulating IC might be of prognostic value.Methods: A C1q-binding-eluting technique was applied to purify immune complexes from 55 belimumab-treated systemic lupus erythematosus patients during a 24-month follow-up. Autoantibodies in serum and in solubilized immune complexes were quantified using addressable laser bead immunoassay. We investigated whether levels of autoantibodies in immune complexes associate with disease activity and response to belimumab treatment.Results: High baseline anti-double-stranded DNA and anti-histone levels in immune complexes associated with attainment of zero scores in clinical systemic lupus erythematosus disease activity index 2000 during the 24-month follow-up (p = 0.003 and p = 0.048, respectively). Low complement levels associated with high serum anti-double-stranded DNA and anti-ribosomal P levels (p = 0.003 and p = 0.008, respectively) and high anti-double-stranded DNA (p = 0.002) but not anti-ribosomal P levels in immune complexes. Anti-SSA/SSB serum levels were lower in patients attaining lupus low disease activity state at month 6; these associations were stronger for corresponding immune complex levels. Serum levels of most autoantibodies had declined at month 3, whereas autoantibody levels in immune complexes, except for anti-double-stranded DNA, showed a more gradual decline over 1-2 years. Serum anti-double-stranded DNA levels decreased in all patients irrespective of systemic lupus erythematosus disease activity index 2000=0 attainment, whereas immune complex levels decreased only in achievers.Conclusion: Immune complex levels of autoantibodies against double-stranded DNA and the SSA/SSB complex show more specific associations with treatment outcome compared with serum levels in belimumab-treated systemic lupus erythematosus patients. Characterization of autoantibody content in circulating immune complexes could prove useful in treatment evaluation in systemic lupus erythematosus and other immune complex-associated diseases.
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10.
  • Stockfelt, Marit, et al. (författare)
  • Activated low-density granulocytes in peripheral and intervillous blood and neutrophil inflammation in placentas from SLE pregnancies
  • 2021
  • Ingår i: Lupus Science and Medicine. - : BMJ. - 2053-8790. ; 8:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Objective Women with SLE face an increased risk of adverse pregnancy outcomes compared with healthy women, but the underlying immunological mechanisms are unknown. Given the recognised association of neutrophil activation with SLE pathogenesis, we examined whether there is increased neutrophil activation and inflammation in blood and placenta in SLE relative to healthy pregnancy. Methods At delivery, peripheral blood, maternal-derived intervillous blood and placentas were collected from 12 SLE and 10 healthy control pregnancies. The proportion of low-density granulocytes (LDGs) and the activation status of LDG and normal-density granulocytes were examined with flow cytometry. The chemokines CXCL8 and CXCL1 were quantified with a cytometric bead-based assay and interferon alpha (IFNα) protein levels with a Simoa method. IFNα-stimulated maternal-derived decidual stromal cells were examined for CXCL8 gene expression with qPCR. A pathologist, blinded to the patient background, examined all placentas. Results Women with SLE had significantly higher proportions of LDG in peripheral blood compared with controls (p=0.02), and LDG in both peripheral and intervillous blood were more activated in SLE relative to healthy pregnancies (peripheral blood: p=0.002 and intervillous blood: p=0.05). There were higher levels of CXCL8 and CXCL1 in intervillous compared with peripheral blood in women with SLE (p=0.004 and p=<0.0001, respectively) but not in controls. In SLE pregnancy, IFNα was detectable in 6 out of 10 intervillous blood samples but only in one control. Stimulation with IFNα upregulated CXCL8 gene expression in decidual stromal cells from both SLE and healthy pregnancy. Histological chorioamnionitis was present in 6 out of 12 placentas from women with SLE and in 1 out of 10 controls. Conclusions In women with SLE, locally produced chemokines in the placenta are increased and may attract and activate neutrophils. This in turn could contribute to placental inflammation and dysfunction and increased risk of placenta-related pregnancy complications.
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