1. |
- Berglin, Ewa, MD, PhD, 1955-, et al.
(författare)
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Anti-neutrophil cytoplasmatic antibodies predate symptom onset of anca-associated vasculitis : a case-control study
- 2020
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Ingår i: Annals of the Rheumatic Diseases. - : BMJ Publishing Group Ltd. - 0003-4967 .- 1468-2060. ; 79, s. 1065-1066
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Presence of anti-neutrophil cytoplasmatic autoantibodies (ANCA) is important for the diagnosis of ANCA-associated vasculitis (AAV) and reflects on-going immune processes. The timing of the antibody development and its contribution to disease is not well established.Objectives:To investigate the presence of proteinase 3 (PR3)- and myeloperoxidase (MPO)-ANCA in blood samples collected from healthy individuals who subsequently developed AAV.Methods:The Swedish National Patient Register of inpatient care and the Swedish Cause of Death Register were used to identify individuals assigned ICD codes for AAV (1) in the discharge summary or cause of death, respectively. The resulted cohort was then linked to the registers of 4 different biobanks to identify those with available predating blood samples. Diagnoses of AAV were confirmed and time point for onset of symptoms was identified by reviewing all available case records (1); 68 were classified as granulomatosis with polyangiitis (GPA), 14 as microscopic polyangiitis (MPA), and 4 as eosinophilic GPA (EGPA). The 86 cases (36 males, 50 females) had a mean (SD) age of 51.9 (16.9) years at sampling, with ≥1 sample (26% plasma, 74% serum samples). The sampling time point before onset of symptoms was mean (SD); 4.4 (3.1) years. Serum and plasma control samples (n=198; 82 males, 116 females; mean age (SD); 52.0 (16.5) years) were identified and matched for sex, age and date of sampling. The samples were first screened for ANCA using high sensitive ELISA (ORGANTEC diagnostika, Germany) and samples close to or above cut-off level were further analysed for capture PR3- and capture MPO-ANCA (ELISA; SVAR Life Science, Sweden). For each case one control sample was included for the ANCA specificity tests. Statistical calculations were performed using SPSS software.Results:In ANCA-screen 36.0% of the cases and 2.6 % of controls tested positive (p<0.001). 23/52 (44.2%) of the cases were PR3-ANCA positive (OR 56.3; 95% CI 7.26-436.62) and 8/52 (15.4%) were MPO-ANCA positive (OR 4.18; 95% CI 1.05-16.62). The mean (SD) predating time for PR3-ANCA positivity was 3.73 (3.49) years and for MPO-ANCA positivity 2.11 (1.46) years. Cases with positive predating PR3-ANCA were younger (46.0±19.4 vs 65.6±12.0 years; P<0.001) than cases with a negative predating PR3-ANCA. MPO-ANCA positive vs. MPO-ANCA negative pre-dating cases had more often severe disease (kidney/lung/peripheral nervous system) (OR 15.08; 95% CI 1.68—135.54) at disease onset. Furthermore, predating MPO-ANCA positive vs predating PR3-ANCA positive cases had significantly more often severe manifestations at disease onset (87.5% vs 28.6%; p<0.05). Cases positive vs. negative for MPO-ANCA in predating samples were less often classified as GPA (37.5% vs 86.4%; p<0.01) and more often as MPA (62.5% vs 13.6%; p<0.05).Conclusion:The production of both PR3 and MPO-ANCA starts already years before onset of symptoms of AAV. Presence of MPO-ANCA appeared closer to symptom onset and with more severe disease presentation. Differences in the disease phenotype and disease severity were evident between the two ANCA serotypes.References:[1]Watts et al. Ann Rheum Dis 2007;66:222-22Acknowledgments: :Vasculitis Foundation, USADisclosure of Interests:Ewa Berglin: None declared, Aladdin J Mohammad Speakers bureau: lecture fees from Roche and Elli Lilly Sweden, PI (GiACTA study), Johanna Dahlqvist: None declared, Catharina Eriksson: None declared, Johanna Sjöwall: None declared, Solbritt Rantapää Dahlqvist: None declared
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2. |
- Berglin, Ewa, MD, PhD, 1955-, et al.
(författare)
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Protein profiling in individuals before onset of anca-associated vasculitis
- 2020
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Ingår i: Annals of the Rheumatic Diseases. - : BMJ Publishing Group Ltd. - 0003-4967 .- 1468-2060. ; 79, s. 372-372
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Etiology and pathogenesis of ANCA-associated vasculitis (AAV) is multifactorial and understanding of the processes leading from a healthy immune system to autoimmunity and on to debut of symptoms in AAV is rudimentary.Objectives:To identify inflammatory proteins related to the early processes preceding AAV development, and potential novel biomarkers, using large-scale protein analysesMethods:The Swedish National Patient Register of in-patient carevand the Swedish Cause of Death Register with discharge diagnosis from ICD-9 and-10 for AAV were co-analysed with the registers of 4 different blood biobanks to identify AAV individuals with available samples predating onset of symptom. Of the pre-AAV cases 86 (36 male, 50 female; mean age (SD); 51.9 (16.9) years) were identified with at least one plasma or serum sample (28 plasma, and 100 serum) pre-dating symptom onset (mean (SD); -4.3 (3.1) years), and 14 had 2-3 samples. Serum and plasma control samples matched for sex, age and sampling date were identified (n=198; 82 male, 116 female; mean age (SD); 51.9±15.9 years). The samples were analysed for levels of 92 proteins using proximity extension assay (OLINK inflammation panel, SciLifeLab, Uppsala, Sweden). Data were analysed using routine statistical methods, random forest and Partial Least square-discriminant analysis (PLS-DA).Results:As previously described for the assay significant difference between plasma and serum samples were observed both in pre-AAV individuals and controls. In pre-AAV plasma samples significantly increased concentrations of interleukin (IL)-2, chemokine ligand (CCL)-4, fibroblast growth factor (FGF)21, IL-4 and CCL20 were found closer to symptom onset, (<5 years) than later (> 5 years) and compared with controls. In serum tumor necrosis factor receptor superfamily member (TNFRSF)9, CXCL9, osteoprotegerin and vascular endothelial growth factor-A were significantly increased <5 years before onset vs. later (>5 years) and compared with controls. PLS-DA score scattered plot separated the pre-AAV individuals from healthy controls (R2=0.26), with significantly increased levels of CCL23, CXCL5, and matrix metalloproteinases-1 (MMP-1),transforming growth factor-ß, orosomucoid, en-rage (S100A12) and IL-7 and decreased FGF-19 level in serum. Binary logistic regression analyses comparing tertiles for these proteins confirmed significantly increased odds ratios for disease development of CCL23, CXCL5 and MMP-1. The findings were confirmed in random forest analysis where these factors were among the 20 most discriminatory factors between pre-symptomatic AAV and controls.Conclusion:In serum samples collected years before symptom onset of AAV, proteins involved in immune system activation were increased, suggesting that the inflammatory process is initiated long before clinical manifestations of the disease appear. These findings propose the elevated proteins as novel biomarkers for disease progression.References:[1]Watts et al. Ann Rheum Dis 2007;66:222-22Acknowledgments:Vasculitis Foundation, USADisclosure of Interests:Ewa Berglin: None declared, Anders Esberg: None declared, Johanna Dahlqvist: None declared, Johanna Sjöwall: None declared, Anders Lundquist: None declared, Kristina Lejon: None declared, Ingegerd Johansson: None declared, Aladdin J Mohammad Speakers bureau: lecture fees from Roche and Elli Lilly Sweden, PI (GiACTA study), Solbritt Rantapää Dahlqvist: None declared
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3. |
- Björsenius, I, et al.
(författare)
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Extent of atherosclerosis after 11-year prospective follow-up in patients with early rheumatoid arthritis was affected by disease severity at diagnosis
- 2020
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Ingår i: Scandinavian Journal of Rheumatology. - : Taylor & Francis. - 0300-9742 .- 1502-7732. ; 49:6, s. 443-451
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Cardiovascular disease (CVD) is increased among patients with rheumatoid arthritis (RA). The underlying cause is not clear. In this prospective study, patients with early RA were investigated for associations between subclinical atherosclerosis and CVD risk factors as well as inflammation.Method: At diagnosis, RA patients were recruited into a prospective study. A subgroup was included (n = 55) for ultrasound measurements of intima–media thickness (IMT) at inclusion (T0), and after 5 years (T5) and 11 years (T11). Thirty-one age and gender-matched controls were also included for comparison.Results: IMT increased significantly between T0 and T11 among patients and controls (p < 0.0001). No statistically significant differences in IMT between patients and controls were detected at T11, T5, or T0 (p > 0.05 for all). In simple regression models, IMT at T11 was significantly associated with age (p < 0.0001), as well as systolic blood pressure at T0 (p < 0.01) and T11 (p < 0.01) among RA patients. Furthermore, the composite Systematic COronary Risk Evaluation (SCORE) measurements (p < 0.0001) and Reynolds risk score (p < 0.01) and the radiographic Larsen score (p < 0.05) at T0 were all significantly associated with IMT at T11. Results from conditional logistic regression analysis showed an increased progression rate between T0 and T11 in the RA group compared with controls (p < 0.05).Conclusion: We found increased atherosclerotic development among patients with RA compared with controls 11 years after diagnosis. The atherosclerotic burden was associated with disease severity at baseline.
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4. |
- Gomez-Bañuelos, Eduardo, et al.
(författare)
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Exposure to Aggregatibacter Actinomycetemcomitans before Symptom Onset and the Risk of Evolving to Rheumatoid Arthritis
- 2020
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Ingår i: Journal of Clinical Medicine. - Basel : MDPI. - 2077-0383. ; 9:6
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Tidskriftsartikel (refereegranskat)abstract
- Periodontal disease has been implicated in the pathogenesis of rheumatoid arthritis (RA), an autoimmune disease characterized by immune-mediated synovial damage, and antibodies to citrullinated antigens. Here, we investigate the association between exposure to the periodontal pathogen Aggregatibacter actinomycetemcomitans (Aa) and the development of RA. IgM, IgG and IgA antibodies to Aa leukotoxin A (LtxA) were detected by ELISA in plasma from a cohort of Swedish adults at different stages of RA development, from before onset of symptoms to established disease. Patients with early and established RA had increased levels of anti-LtxA IgM compared with matched non-RA controls and periodontally healthy individuals. Logistic regression revealed that anti-LtxA IgM levels were associated with RA during early disease (OR 1.012, 95%CI 1.007, 1.017), which was maintained after adjustment for smoking, anti-CCP antibodies, rheumatoid factor, HLA-DRB1 shared epitope alleles and sex. We found no association between anti-LtxA IgG/IgA antibodies and RA at any stage of disease development. The data support a temporal association between anti-LtxA IgM antibodies and the development of RA, suggesting that a subset of RA patients may have been exposed to Aa around the time of transition from being asymptomatic to become a patient with RA.
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5. |
- Reid, Sarah, et al.
(författare)
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High genetic risk score is associated with early disease onset, damage accrual and decreased survival in systemic lupus erythematosus
- 2020
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Ingår i: Annals of the Rheumatic Diseases. - : BMJ Publishing Group Ltd. - 0003-4967 .- 1468-2060. ; 79:3, s. 363-369
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Tidskriftsartikel (refereegranskat)abstract
- 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-β2-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.
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6. |
- Roelsgaard, Ida K., et al.
(författare)
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Smoking cessation is associated with lower disease activity and predicts cardiovascular risk reduction in rheumatoid arthritis patients
- 2020
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Ingår i: Rheumatology. - : Oxford University Press. - 1462-0324 .- 1462-0332. ; 59:8, s. 1997-2004
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: Smoking is a major risk factor for the development of both cardiovascular disease (CVD) and RA and may cause attenuated responses to anti-rheumatic treatments. Our aim was to compare disease activity, CVD risk factors and CVD event rates across smoking status in RA patients. Methods: Disease characteristics, CVD risk factors and relevant medications were recorded in RA patients without prior CVD from 10 countries (Norway, UK, Netherlands, USA, Sweden, Greece, South Africa, Spain, Canada and Mexico). Information on CVD events was collected. Adjusted analysis of variance, logistic regression and Cox models were applied to compare RA disease activity (DAS28), CVD risk factors and event rates across categories of smoking status. Results: Of the 3311 RA patients (1012 former, 887 current and 1412 never smokers), 235 experienced CVD events during a median follow-up of 3.5 years (interquartile range 2.5-6.1). At enrolment, current smokers were more likely to have moderate or high disease activity compared with former and never smokers (P < 0.001 for both). There was a gradient of worsening CVD risk factor profiles (lipoproteins and blood pressure) from never to former to current smokers. Furthermore, former and never smokers had significantly lower CVD event rates compared with current smokers [hazard ratio 0.70 (95% CI 0.51, 0.95), P = 0.02 and 0.48 (0.34, 0.69), P < 0.001, respectively]. The CVD event rates for former and never smokers were comparable. Conclusion: Smoking cessation in patients with RA was associated with lower disease activity and improved lipid profiles and was a predictor of reduced rates of CVD events.
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7. |
- Skielta, Mattias, et al.
(författare)
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Trends in mortality, co-morbidity and treatment after acute myocardial infarction in patients with rheumatoid arthritis 1998-2013
- 2020
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Ingår i: European Heart Journal. - : Sage Publications. - 2048-8726 .- 2048-8734. ; 9:8, s. 931-938
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Tidskriftsartikel (refereegranskat)abstract
- Aims: Rheumatoid arthritis may influence the outcome after an acute myocardial infarction. We aimed to compare trends in one-year mortality, co-morbidities and treatments after a first acute myocardial infarction in patients with rheumatoid arthritis versus non-rheumatoid arthritis patients during 1998-2013. Furthermore, we wanted to identify characteristics associated with mortality.Methods and results: Data for 245,377 patients with a first acute myocardial infarction were drawn from the Swedish Register of Information and Knowledge about Swedish Heart Intensive Care Admissions for 1998-2013. In total, 4268 patients were diagnosed with rheumatoid arthritis. Kaplan-Meier analysis was used to study mortality trends over time and multivariable Cox regression analysis was used to identify variables associated with mortality. The one-year mortality in rheumatoid arthritis patients was initially lower compared to non-rheumatoid arthritis patients (14.7% versus 19.7%) but thereafter increased above that in non-rheumatoid arthritis patients (17.1% versus 13.5%). In rheumatoid arthritis patients the mean age at admission and the prevalence of atrial fibrillation increased over time. Congestive heart failure decreased more in non-rheumatoid arthritis than in rheumatoid arthritis patients. Congestive heart failure, atrial fibrillation, kidney failure, rheumatoid arthritis, prior diabetes mellitus and hypertension were associated with significantly higher one-year mortality during the study period 1998-2013.Conclusions: The decrease in one-year mortality after acute myocardial infarction in non-rheumatoid arthritis patients was not applicable to rheumatoid arthritis patients. This could partly be explained by an increased age at acute myocardial infarction onset and unfavourable trends with increased atrial fibrillation and congestive heart failure in rheumatoid arthritis. Rheumatoid arthritis per se was associated with a significantly worse prognosis.
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8. |
- Svärd, Anna, et al.
(författare)
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Secretory antibodies to citrullinated peptides in plasma and saliva from rheumatoid arthritis patients and their unaffected first-degree relatives
- 2020
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Ingår i: Clinical and Experimental Immunology. - : WILEY. - 0009-9104 .- 1365-2249. ; 199:2, s. 143-149
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Tidskriftsartikel (refereegranskat)abstract
- The aim of this study was to evaluate secretory antibodies to citrullinated proteins (ACPA) in plasma and immunoglobulin (Ig)A ACPA in saliva from patients with rheumatoid arthritis (RA) and their unaffected first-degree relatives (FDRs). Patients with RA (n = 194) and first-degree relatives unaffected by RA (n = 191) were recruited for analysis of secretory antibodies to second-generation cyclic citrullinated peptides (anti-CCP) in plasma. From a subpopulation (25 RA patients, 21 first-degree relatives and 11 controls), saliva samples were obtained for IgA anti-CCP analysis. The presence of secretory ACPA was compared between subject categories, and related to genetic and environmental risk factors. Secretory ACPA occurred in 37 (19%) plasma samples from patients with RA, but only in two (1%) of FDRs. IgA ACPA in saliva was found in three of 25 (12%) patients with RA, but not in any of the 21 FDRs (< 5%). No significant associations were seen between the presence of secretory ACPA and SE or smoking, either among RA patients or among FDRs. Despite occurring in 19% of RA plasma, secretory ACPA was rare in both saliva and plasma among FDRs, even among those positive for conventional ACPA of non-mucosal origin. Longitudinal studies are warranted to determine whether circulating secretory ACPA occurs before or in parallel with the development of clinical arthritis.
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9. |
- Wibetoe, Grunde, et al.
(författare)
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Prediction of cardiovascular events in rheumatoid arthritis using risk age calculations : evaluation of concordance across risk age models
- 2020
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Ingår i: Arthritis Research & Therapy. - : Springer Nature. - 1478-6354 .- 1478-6362. ; 22:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: In younger individuals, low absolute risk of cardiovascular disease (CVD) may conceal an increased risk age and relative risk of CVD. Calculation of risk age is proposed as an adjuvant to absolute CVD risk estimation in European guidelines. We aimed to compare the discriminative ability of available risk age models in prediction of CVD in rheumatoid arthritis (RA). Secondly, we also evaluated the performance of risk age models in subgroups based on RA disease characteristics.Methods: RA patients aged 30–70 years were included from an international consortium named A Trans-Atlantic Cardiovascular Consortium for Rheumatoid Arthritis (ATACC-RA). Prior CVD and diabetes mellitus were exclusion criteria. The discriminatory ability of specific risk age models was evaluated using c-statistics and their standard errors after calculating time until fatal or non-fatal CVD or last follow-up.Results: A total of 1974 patients were included in the main analyses, and 144 events were observed during follow-up, the median follow-up being 5.0 years. The risk age models gave highly correlated results, demonstrating R2 values ranging from 0.87 to 0.97. However, risk age estimations differed > 5 years in 15–32% of patients. C-statistics ranged 0.68–0.72 with standard errors of approximately 0.03. Despite certain RA characteristics being associated with low c-indices, standard errors were high. Restricting analysis to European RA patients yielded similar results.Conclusions: The cardiovascular risk age and vascular age models have comparable performance in predicting CVD in RA patients. The influence of RA disease characteristics on the predictive ability of these prediction models remains inconclusive.
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10. |
- Yavuz, Sule, et al.
(författare)
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Lymphopenia as a risk factor for neurologic involvement and organ damage accrual in patients with systemic lupus erythematosus : A multi-center observational study
- 2020
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Ingår i: Seminars in Arthritis & Rheumatism. - : Elsevier BV. - 0049-0172 .- 1532-866X. ; 50:6, s. 1387-1393
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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