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1.
Ann Rheum Dis ; 2021 Feb 23.
Artigo em Inglês | MEDLINE | ID: mdl-33622688

RESUMO

OBJECTIVES: To estimate absolute and relative risks for all-cause mortality and for severe COVID-19 in inflammatory joint diseases (IJDs) and with antirheumatic therapies. METHODS: Through Swedish nationwide multiregister linkages, we selected all adult patients with rheumatoid arthritis (RA, n=53 455 in March 2020), other IJDs (here: spondyloarthropathies, psoriatic arthritis and juvenile idiopathic arthritis, n=57 112), their antirheumatic drug use, and individually matched population referents. We compared annual all-cause mortality March-September 2015 through 2020 within and across cohorts, and assessed absolute and relative risks for hospitalisation, admission to intensive care and death due to COVID-19 March-September 2020, using Cox regression. RESULTS: During March-September 2020, the absolute all-cause mortality in RA and in other IJDs was higher than 2015-2019, but relative risks versus the general population (around 2 and 1.5) remained similar during 2020 compared with 2015-2019. Among patients with IJD, the risks of hospitalisation (0.5% vs 0.3% in their population referents), admission to intensive care (0.04% vs 0.03%) and death (0.10% vs 0.07%) due to COVID-19 were low. Antirheumatic drugs were not associated with increased risk of serious COVID-19 outcomes, although for certain drugs, precision was limited. CONCLUSIONS: Risks of severe COVID-19-related outcomes were increased among patients with IJDs, but risk increases were also seen for non-COVID-19 morbidity. Overall absolute and excess risks are low and the level of risk increases are largely proportionate to those in the general population, and explained by comorbidities. With possible exceptions, antirheumatic drugs do not have a major impact on these risks.

2.
Clin Exp Rheumatol ; 2020 Dec 18.
Artigo em Inglês | MEDLINE | ID: mdl-33337998

RESUMO

OBJECTIVES: Venous (VTE) and arterial (AT) thrombosis in systemic lupus erythematosus (SLE) are poorly explained and difficult to predict. Leptin and tumour necrosis factor-like weak inducer of apoptosis (TWEAK) have been linked to subclinical atherosclerosis and galectin-3-binding protein (G3BP) to type I interferon activation and a pro-thrombotic environment. Thus, we explore serum G3BP, interferon gamma-induced protein 10 (IP-10), soluble CD163 (sCD163), TWEAK and leptin as predictors of VTE and AT, damage accrual, and all-cause mortality during follow-up in a Swedish SLE cohort. METHODS: Baseline data were available from 162 SLE patients. VTE (deep vein thrombosis and/or pulmonary embolism), AT (myocardial infarction and/or stroke), damage accrual, and survival data were the main study outcomes and available at follow-up (median of five years). Baseline serum G3BP, IP-10, sCD163, TWEAK and leptin were measured and analysed by univariable and multivariable methods for association to the study outcomes. RESULTS: During the follow-up, 10 (6%) VTE and 13 (8%) AT events occurred. The SLICC/ACR Damage Index increased in 78 (48%) patients, and 19 (12%) patients died. In the univariable regression analysis G3BP levels were significantly associated with an increased risk of VTE (hazard ratio (HR) 1.11, 95% confidence interval (CI): 1.01-1.22, p=0.03). This persisted in the adjusted multivariable analyses (HR 1.18, 95% CI: 1.05-1.33, p=0.007). The other biomarkers were not associated with AT/VTE, damage accrual, or all-cause mortality. CONCLUSIONS: Our study identifies serum G3BP as a novel predictor of VTE in SLE. Further studies are needed to understand the role of G3BP in VTE and translate this into clinical practice.

4.
Front Immunol ; 11: 578848, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33329548

RESUMO

Rheumatoid arthritis (RA) is a complex autoimmune disease targeting synovial joints. Traditionally, RA is divided into seropositive (SP) and seronegative (SN) disease forms, the latter consisting of an array of unrelated diseases with joint involvement. Recently, we described a severe form of SN-RA that associates with characteristic joint destruction. Here, we sought biological characteristics to differentiate this rare but aggressive anti-citrullinated peptide antibody-negative destructive RA (CND-RA) from early seropositive (SP-RA) and seronegative rheumatoid arthritis (SN-RA). We also aimed to study cytotoxic CD8+ lymphocytes in autoimmune arthritis. CND-RA, SP-RA and SN-RA were compared to healthy controls to reveal differences in T-cell receptor beta (TCRß) repertoire, cytokine levels and autoantibody repertoires. Whole-exome sequencing (WES) followed by single-cell RNA-sequencing (sc-RNA-seq) was performed to study somatic mutations in a clonally expanded CD8+ lymphocyte population in an index patient. A unique TCRß signature was detected in CND-RA patients. In addition, CND-RA patients expressed higher levels of the bone destruction-associated TNFSF14 cytokine. Blood IgG repertoire from CND-RA patients recognized fewer endogenous proteins than SP-RA patients' repertoires. Using WES, we detected a stable mutation profile in the clonally expanded CD8+ T-cell population characterized by cytotoxic gene expression signature discovered by sc-RNA-sequencing. Our results identify CND-RA as an independent RA subset and reveal a CND-RA specific TCR signature in the CD8+ lymphocytes. Improved classification of seronegative RA patients underlines the heterogeneity of RA and also, facilitates development of improved therapeutic options for the treatment resistant patients.

5.
Artigo em Inglês | MEDLINE | ID: mdl-33341888

RESUMO

OBJECTIVE: In light of reports of de novo LN during belimumab (BLM) treatment, we sought to determine its frequency and contributing or protective factors in a real-life setting. METHODS: Patients with SLE who received BLM between 2011 and 2017 at five European academic practices were enrolled (n = 95) and followed longitudinally for a median time of 13.1 months [interquartile range (IQR): 6.0-34.7]; 52.6% were anti-dsDNA positive, 60.0% had low complement levels, and 69.5% had no renal involvement prior to/at BLM initiation [mean disease duration at baseline: 11.4 (9.3) years]. Age- and sex-matched patients with non-renal SLE who had similar serological profiles, but were not exposed to BLM, served as controls (median follow-up: 132.0 months; IQR: 98.3-151.2). RESULTS: We observed 6/66 cases (9.1%) of biopsy-proven de novo LN (4/6 proliferative) among the non-renal BLM-treated SLE cases after a follow-up of 7.4 months (IQR: 2.7-22.2). Among controls, 2/66 cases (3.0%) of de novo LN (both proliferative) were observed after 21 and 50 months. BLM treatment was associated with an increased frequency and/or shorter time to de novo LN [hazard ratio (HR): 10.7; 95% CI: 1.7, 67.9; P = 0.012], while concomitant use of antimalarial agents along with BLM showed an opposing association (HR: 0.2; 95% CI: 0.03, 0.97; P = 0.046). CONCLUSION: Addition of BLM to standard-of-care did not prevent LN in patients with active non-renal SLE, but a favourable effect of concomitant use of antimalarials was implicated. Studies of whether effects of B-cell activating factor inhibition on lymphocyte subsets contribute to LN susceptibility are warranted.

6.
Front Med (Lausanne) ; 7: 581336, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33163501

RESUMO

Introduction: Despite improved therapies and management, patients with systemic lupus erythematosus (SLE) still have increased risks of cerebrovascular and cardiovascular disease. High-frequency ultrasound (US) provides an opportunity to distinguish atherosclerosis from inflammation in the vessels. We hypothesized that an extended US protocol may add information regarding vascular affection in SLE. Methods: Sixty patients (52 women, 8 men; mean age 43.2 ± 11.3 years) with SLE characterized by either lupus nephritis (LN; n = 20), antiphospholipid syndrome (APS; n = 20), or skin and joint involvement (n = 20) as well as matched healthy controls (n = 60) were included. Intima-media thickness (IMT), assessment of vessel walls, and plaque occurrence were recorded using high-frequency US (GE Logic E9) in common carotid, internal carotid, brachiocephalic, subclavian, axillary, common femoral, and proximal superficial femoral arteries as well as in the aortic arch. Results: For the entire SLE group, IMT was increased in the internal carotid artery (0.52 ± 0.17 vs. 0.45 ± 0.09 mm, p = 0.004), the common femoral artery (0.57 ± 0.23 vs. 0.49 ± 0.11 mm, p < 0.01), the subclavian artery (0.58 ± 0.19 vs. 0.53 ± 0.13 mm, p = 0.02), and the aortic arch (1.21 ± 0.63 vs. 0.98 ± 0.25 mm, p = 0.002) compared to controls. These differences were primarily observed in the APS and LN groups compared to controls. Vessels with increased IMT ≥0.9 mm had a smooth, medium echogenic appearance in areas free of atherosclerotic plaques. Atherosclerotic plaques were detected in 15/60 patients (25%) as compared to 2/60 of the controls (3%). Plaques were predominantly (67%) located in the carotid bifurcation. Multivariate analysis revealed influence of age on IMT in all vessel areas. Furthermore, in the common femoral artery, sagittal abdominal diameter, diastolic blood pressure, and cholesterol all showed association with increased IMT. In the internal carotid artery, male sex and presence of Raynaud phenomenon influenced IMT. Conclusion: Among SLE patients without presence of plaques, an extended US protocol revealed increased wall thickness with predominantly medium echogenic appearance highlighting possibly inflammation or early atherosclerosis. The appearance of vessel walls has not previously been studied in detail. An increased number of plaques were found in SLE compared to age- and sex-matched healthy controls. We found similar risk factors for increased IMT and occurrence of plaques, possibly indicating atherosclerotic mechanisms rather than inflammation.

8.
Ann Rheum Dis ; 2020 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-33037003

RESUMO

OBJECTIVES: Systemic lupus erythematosus (SLE) is an autoimmune disease with extensive heterogeneity in disease presentation between patients, which is likely due to an underlying molecular diversity. Here, we aimed at elucidating the genetic aetiology of SLE from the immunity pathway level to the single variant level, and stratify patients with SLE into distinguishable molecular subgroups, which could inform treatment choices in SLE. METHODS: We undertook a pathway-centred approach, using sequencing of immunological pathway genes. Altogether 1832 candidate genes were analysed in 958 Swedish patients with SLE and 1026 healthy individuals. Aggregate and single variant association testing was performed, and we generated pathway polygenic risk scores (PRS). RESULTS: We identified two main independent pathways involved in SLE susceptibility: T lymphocyte differentiation and innate immunity, characterised by HLA and interferon, respectively. Pathway PRS defined pathways in individual patients, who on average were positive for seven pathways. We found that SLE organ damage was more pronounced in patients positive for the T or B cell receptor signalling pathways. Further, pathway PRS-based clustering allowed stratification of patients into four groups with different risk score profiles. Studying sets of genes with priors for involvement in SLE, we observed an aggregate common variant contribution to SLE at genes previously reported for monogenic SLE as well as at interferonopathy genes. CONCLUSIONS: Our results show that pathway risk scores have the potential to stratify patients with SLE beyond clinical manifestations into molecular subsets, which may have implications for clinical follow-up and therapy selection.

10.
ACS Chem Biol ; 15(9): 2605-2615, 2020 09 18.
Artigo em Inglês | MEDLINE | ID: mdl-32909734

RESUMO

Type II collagen (CII) is the most abundant protein in joint cartilage. Antibodies to CII appear around the clinical onset of the autoimmune disease rheumatoid arthritis (RA) in a subset of patients. They target specific epitopes on CII and can be pathogenic or protective. Assays for early detection of such autoantibodies may provide new opportunities for selecting effective treatment strategies of RA. We report the efficient and reproducible assembly of an array of covalently branched native and citrullinated triple helical peptides (THPs) from CII that contain defined autoantibody epitopes. Both monoclonal antibodies and sera from experimental mouse models show a unique reactivity toward the THPs, compared to cyclic peptides containing the epitopes, revealing the importance that the epitopes are displayed in a triple-helical conformation. Importantly, antibodies against three of the THPs that contain major CII epitopes were found to be increased in sera from patients with RA, compared to control persons. These results indicate that such synthetic THPs should be included in multiplex analysis of autoantibodies that are uniquely occurring in individuals with early RA, to provide valuable information on disease prognosis and on what type of therapy should be chosen for individual patients.

11.
Front Med (Lausanne) ; 7: 316, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32754605

RESUMO

B cell hyperactivity and breach of tolerance constitute hallmarks of systemic lupus erythematosus (SLE). The heterogeneity of disease manifestations and relatively rare prevalence of SLE have posed difficulties in trial design and contributed to a slow pace for drug development. The anti-BAFF monoclonal antibody belimumab is still the sole targeted therapy licensed for SLE, lending credence to the widely accepted notion that B cells play central roles in lupus pathogenesis. However, more therapeutic agents directed toward B cells or B cell-related pathways are used off-label or have been trialed in SLE. The anti-CD20 monoclonal antibody rituximab has been used to treat refractory SLE during the last two decades, and the anti-type I IFN receptor anifrolumab is currently awaiting approval after one phase III clinical trial which met its primary endpoint and one phase III trial which met key secondary endpoints. While the latter does not directly affect the maturation and antibody production activity of B cells, it is expected to affect the contribution of B cells in proinflammatory cytokine excretion. The proteasome inhibitor bortezomib, primarily directed toward the plasma cells, has been used in few severe cases as an escape regimen. Collectively, current clinical experience and primary results of ongoing clinical trials prophesy that B cell therapies of selective targets will have an established place in the future personalized therapeutic management of lupus patients.

12.
J Clin Med ; 9(8)2020 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-32796552

RESUMO

While the management of pregnant patients with systemic lupus erythematosus (SLE) has improved over the last decades, the risk of maternal, foetal, and neonatal complications is still substantial. We evaluated the occurrence of adverse pregnancy outcomes (APO) occurring in 2002-2018 among patients with SLE from the catchment area of the Department of Rheumatology in Lund, Sweden. Longitudinal clinical and laboratory data were collected and analysed. Results were stratified according to the sequence of conception. We investigated a total of 59 pregnancies in 28 patients. Prior lupus nephritis was the clinical feature that, in a multivariable regression analysis, displayed the strongest association with APO overall (OR 6.0, p = 0.02). SLE combined with antiphospholipid syndrome (APS) was associated with the risk of miscarriage (OR 3.3, p = 0.04). The positivity of multiple antiphospholipid antibodies (aPL) was associated with APO overall (OR 3.3, p = 0.05). IgG anti-cardiolipin during pregnancy resulted in a higher risk of preterm delivery (OR 6.8, p = 0.03). Hypocomplementaemia was associated with several APO, but only in the first pregnancies. We conclude that, despite the close follow-up provided, a majority of pregnancies resulted in ≥1 APO, but a few of them were severe. Our study confirms the importance of previous lupus nephritis as a main risk factor for APO in patients with SLE.

13.
Eur J Hum Genet ; 2020 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-32724065

RESUMO

By performing whole-genome sequencing in a Swedish cohort of 71 parent-offspring trios, in which the child in each family is affected by systemic lupus erythematosus (SLE, OMIM 152700), we investigated the contribution of de novo variants to risk of SLE. We found de novo single nucleotide variants (SNVs) to be significantly enriched in gene promoters in SLE patients compared with healthy controls at a level corresponding to 26 de novo promoter SNVs more in each patient than expected. We identified 12 de novo SNVs in promoter regions of genes that have been previously implicated in SLE, or that have functions that could be of relevance to SLE. Furthermore, we detected three missense de novo SNVs, five de novo insertion-deletions, and three de novo structural variants with potential to affect the expression of genes that are relevant for SLE. Based on enrichment analysis, disease-affecting de novo SNVs are expected to occur in one-third of SLE patients. This study shows that de novo variants in promoters commonly contribute to the genetic risk of SLE. The fact that de novo SNVs in SLE were enriched to promoter regions highlights the importance of using whole-genome sequencing for identification of de novo variants.

14.
Int J Mol Sci ; 21(10)2020 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-32422945

RESUMO

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.

15.
Semin Arthritis Rheum ; 50(6): 1387-1393, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32229040

RESUMO

OBJECTIVE: Detailed analysis of hematological manifestations (HM) in systemic lupus erythematosus (SLE) are limited and their clinical impact on disease remain obscure. Here, we aimed to decipher factors associated with different hematological abnormalities in SLE patients and to assess their impact on disease related outcomes. METHODS: A dataset (GIPT) originating from SLE patients of six European tertiary centers was assessed. Six-monthly visits of each patient for at least 2 years were registered. The association between hematologic manifestations (HM; per ACR-1997criteria) and clinical/serologic variables, as well as the impact of HM on disease related outcomes (damage, infection and hemorrhage) were explored. Scores on the Systemic Lupus Erythematosus Disease Activity Index 2000(SLEDAI2K), the Systemic Lupus International Collaborating Clinics (SLICC)/American College of Rheumatology (ACR) Damage Index (SDI) and events for any infection and hemorrhage were recorded. Results were compared with a cross-sectional, well-characterized SLE dataset from Sweden. Descriptive statistics, the generalized estimating equations (GEE), general linear models (GLM), Cox regression models were applied. RESULTS: We monitored 1425 longitudinal visits in 286 SLE patients with HM (GIPT dataset: 88% female, 95% Caucasian, 68% dsDNA positive). Thrombocytopenia (regression coefficient [95% confidence interval] 1.86[1.1-3.13]) and neurologic involvement (ACR-8) (2.1[1.10-3.89]) were associated with lymphopenia (<1000/mm3); the latter was an independent predictor of organ damage accrual (1.68[1.2-2.62]). These associations were confirmed in an independent dataset of 1348 SLE patients (86% female, 93% Caucasian, 61% dsDNA positive) in Sweden.Severe lymphopenia (<500/mm3) and severe thrombocytopenia (<20 K/mm3) were associated with increased risk for infection (hazard ratio [95% confidence interval] 2.56[1.23-5.31]) and hemorrhage (4.38[2.10-11.1]), respectively, independent of the effect of other predictors. CONCLUSION: Lymphopenia in SLE is independently associated with neurologic involvement and organ damage accrual, and thus, may be considered as a marker of severe/progressive disease.

17.
Rheumatology (Oxford) ; 59(5): 979-987, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-31504979

RESUMO

OBJECTIVES: Considering growing evidence of mucosal involvement in RA induction, this study investigated circulating free secretory component (SC) in patients with either recent-onset RA or with ACPA and musculoskeletal pain. METHODS: Two prospective cohorts were studied: TIRA-2 comprising 452 recent-onset RA patients with 3 years of clinical and radiological follow-up, and TIRx patients (n = 104) with ACPA IgG and musculoskeletal pain followed for 290 weeks (median). Blood donors and three different chronic inflammatory diseases served as controls. Free SC was analysed by sandwich ELISA. RESULTS: Serum levels of free SC were significantly higher in TIRA-2 patients compared with TIRx and all control groups (P < 0.01). Among TIRx patients who subsequently developed arthritis, free SC levels were higher compared with all control groups (P < 0.05) except ankylosing spondylitis (P = 0.74). In TIRA-2, patients with ACPA had higher baseline levels of free SC compared with ACPA negative patients (P < 0.001). Free SC status at baseline did not predict radiographic joint damage or disease activity over time. In TIRx, elevated free SC at baseline trendwise associated with arthritis development during follow-up (P = 0.066) but this disappeared when adjusting for confounders (P = 0.72). Cigarette smoking was associated with higher levels of free SC in both cohorts. CONCLUSION: Serum free SC levels are increased in recent-onset RA compared with other inflammatory diseases, and associate with ACPA and smoking. Free SC is elevated before arthritis development among ACPA positive patients with musculoskeletal pain, but does not predict arthritis development. These findings support mucosal engagement in RA development.


Assuntos
Anticorpos Anti-Proteína Citrulinada/imunologia , Artrite Reumatoide/sangue , Dor Musculoesquelética/fisiopatologia , Medição da Dor , Componente Secretório/sangue , Doença Aguda , Adulto , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/imunologia , Autoanticorpos/sangue , Biomarcadores/sangue , Estudos de Casos e Controles , Doença Crônica , Ensaio de Imunoadsorção Enzimática , Feminino , Hospitais Universitários , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Medição de Risco , Índice de Gravidade de Doença , Suécia
18.
J Autoimmun ; 106: 102340, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31629628

RESUMO

OBJECTIVE: The soluble urokinase plasminogen activator receptor (suPAR) has potential as a prognosis and severity biomarker in several inflammatory and infectious diseases. In a previous cross-sectional study, suPAR levels were shown to reflect damage accrual in cases of systemic lupus erythematosus (SLE). Herein, we evaluated suPAR as a predictor of future organ damage in recent-onset SLE. METHODS: Included were 344 patients from the Systemic Lupus International Collaborating Clinics (SLICC) Inception Cohort who met the 1997 American College of Rheumatology classification criteria with 5-years of follow-up data available. Baseline sera from patients and age- and sex-matched controls were assayed for suPAR. Organ damage was assessed annually using the SLICC/ACR damage index (SDI). RESULTS: The levels of suPAR were higher in patients who accrued damage, particularly those with SDI≥2 at 5 years (N = 32, 46.8% increase, p = 0.004), as compared to patients without damage. Logistic regression analysis revealed a significant impact of suPAR on SDI outcome (SDI≥2; OR = 1.14; 95% CI 1.03-1.26), also after adjustment for confounding factors. In an optimized logistic regression to predict damage, suPAR persisted as a predictor, together with baseline disease activity (SLEDAI-2K), age, and non-Caucasian ethnicity (model AUC = 0.77). Dissecting SDI into organ systems revealed higher suPAR levels in patients who developed musculoskeletal damage (SDI≥1; p = 0.007). CONCLUSION: Prognostic biomarkers identify patients who are at risk of acquiring early damage and therefore need careful observation and targeted treatment strategies. Overall, suPAR constitutes an interesting biomarker for patient stratification and for identifying SLE patients who are at risk of acquiring organ damage during the first 5 years of disease.

19.
Ann Rheum Dis ; 79(3): 363-369, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31826855

RESUMO

OBJECTIVES: To investigate associations between a high genetic disease risk and disease severity in patients with systemic lupus erythematosus (SLE). METHODS: Patients with SLE (n=1001, discovery cohort and n=5524, replication cohort) and healthy controls (n=2802 and n=9859) were genotyped using a 200K Immunochip single nucleotide polymorphism array. A genetic risk score (GRS) was assigned to each individual based on 57 SLE risk loci. RESULTS: SLE was more prevalent in the high, compared with the low, GRS-quartile (OR 12.32 (9.53 to 15.71), p=7.9×10-86 and OR 7.48 (6.73 to 8.32), p=2.2×10-304 for the discovery and the replication cohorts, respectively). In the discovery cohort, patients in the high GRS-quartile had a 6-year earlier mean disease onset (HR 1.47 (1.22 to 1.75), p=4.3×10-5), displayed higher prevalence of damage accrual (OR 1.47 (1.06 to 2.04), p=2.0×10-2), renal disorder (OR 2.22 (1.50 to 3.27), p=5.9×10-5), anti-dsDNA (OR 1.83 (1.19 to 2.81), p=6.1×10-3), end-stage renal disease (ESRD) (OR 5.58 (1.50 to 20.79), p=1.0×10-2), proliferative nephritis (OR 2.42 (1.30 to 4.49), p=5.1×10-3), anti-cardiolipin-IgG (OR 1.89 (1.13 to 3.18), p=1.6×10-2), anti-ß2-glycoprotein-I-IgG (OR 2.29 (1.29 to 4.06), p=4.8×10-3) and positive lupus anticoagulant test (OR 2.12 (1.16 to 3.89), p=1.5×10-2) compared with patients in the low GRS-quartile. Survival analysis showed earlier onset of the first organ damage (HR 1.51 (1.04 to 2.25), p=3.7×10-2), first cardiovascular event (HR 1.65 (1.03 to 2.64), p=2.6×10-2), nephritis (HR 2.53 (1.72 to 3.71), p=9.6×10-7), ESRD (HR 6.78 (1.78 to 26.86), p=6.5×10-3) and decreased overall survival (HR 1.83 (1.02 to 3.30), p=4.3×10-2) in high to low quartile comparison. CONCLUSIONS: A high GRS is associated with increased risk of organ damage, renal dysfunction and all-cause mortality. Our results indicate that genetic profiling may be useful for predicting outcomes in patients with SLE.


Assuntos
Predisposição Genética para Doença/epidemiologia , Lúpus Eritematoso Sistêmico/genética , Nefrite Lúpica/genética , Medição de Risco/estatística & dados numéricos , Índice de Gravidade de Doença , Adulto , Anticorpos Anticardiolipina/sangue , Estudos de Casos e Controles , Feminino , Genótipo , Humanos , Falência Renal Crônica/genética , Falência Renal Crônica/mortalidade , Inibidor de Coagulação do Lúpus/sangue , Lúpus Eritematoso Sistêmico/sangue , Lúpus Eritematoso Sistêmico/mortalidade , Nefrite Lúpica/mortalidade , Masculino , Pessoa de Meia-Idade , Prevalência , Risco , Fatores de Risco , Taxa de Sobrevida , beta 2-Glicoproteína I/imunologia
20.
Ann Rheum Dis ; 79(2): 254-261, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31704719

RESUMO

​OBJECTIVES: A single nucleotide polymorphism in the NCF1 gene (NCF1-339, rs201802880), encoding NADPH oxidase type II subunit NCF1/p47phox, reducing production of reactive oxygen species (ROS) is strongly associated with the development of systemic lupus erythematosus (SLE). This study aimed at characterising NCF1-339 effects on neutrophil extracellular trap (NET) formation, type I interferon activity and antibody profile in patients with SLE. ​METHODS: Neutrophil NET-release pathways (n=31), serum interferon (n=141) and finally antibody profiles (n=305) were investigated in SLE subjects from Lund, genotyped for NCF1-339. Then, 1087 SLE subjects from the rheumatology departments of four Swedish SLE centres, genotyped for NCF1-339, were clinically characterised to validate these findings. ​RESULTS: Compared with patients with normal-ROS NCF1-339 genotypes, neutrophils from patients with SLE with low-ROS NCF1-339 genotypes displayed impaired NET formation (p<0.01) and increased dependence on mitochondrial ROS (p<0.05). Low-ROS patients also had increased frequency of high serum interferon activity (80% vs 21.4%, p<0.05) and positivity for anti-ß2 glycoprotein I (p<0.01) and anticardiolipin antibodies (p<0.05) but were not associated with other antibodies. We confirmed an over-representation of having any antiphospholipid antibody, OR 1.40 (95% CI 1.01 to 1.95), anti-ß2 glycoprotein I, OR 1.82 (95% CI 1.02 to 3.24) and the antiphospholipid syndrome (APS), OR 1.74 (95% CI 1.19 to 2.55) in all four cohorts (n=1087). ​CONCLUSIONS: The NCF1-339 SNP mediated decreased NADPH oxidase function, is associated with high interferon activity and impaired formation of NETs in SLE, allowing dependence on mitochondrial ROS. Unexpectedly, we revealed a striking connection between the ROS deficient NCF1-339 genotypes and the presence of phospholipid antibodies and APS.


Assuntos
Síndrome Antifosfolipídica/genética , Armadilhas Extracelulares/genética , Interferon Tipo I/sangue , Lúpus Eritematoso Sistêmico/genética , NADPH Oxidases/genética , Adulto , Anticorpos Anticardiolipina/sangue , Anticorpos Antifosfolipídeos/sangue , Síndrome Antifosfolipídica/imunologia , Feminino , Genótipo , Humanos , Lúpus Eritematoso Sistêmico/sangue , Lúpus Eritematoso Sistêmico/imunologia , Masculino , NADPH Oxidase 2/genética , Polimorfismo de Nucleotídeo Único , Espécies Reativas de Oxigênio , Suécia
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