Publications by authors named "Søren Jacobsen"

190 Publications

Distinct patterns of comorbidity prior to diagnosis of incident systemic lupus erythematosus in the Danish population.

J Autoimmun 2021 Sep 5;123:102692. Epub 2021 Aug 5.

Copenhagen Lupus and Vasculitis Clinic, Center for Rheumatology and Spine Diseases, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark; Blegdamsvej 9, 2100, København, Denmark; Department of Clinical Medicine, University of Copenhagen, Denmark; Nørregade 10, 1165, København, Denmark. Electronic address:

The objective of this study was to assess the cumulative prevalence of pre-existing comorbidities among patients diagnosed with systemic lupus erythematosus (SLE) in Denmark. The study included patients aged ≥18 years at the index date set to the date of first registration of SLE in the Danish National Patient Registry (DNPR) between 1996 and 2018. Up to 19 age- and sex-matched general population comparators per case were selected. Comorbidity diagnoses were retrieved from the DNPR based on International Classification of Diseases codes. We estimated cumulative prevalence of various comorbidities among cases and comparators, prevalence differences (PDs), and prevalence ratios (PRs), with PDs and PRs adjusted for age and sex, at the index date and 1, 2, 5, and 10 years before the index date. We identified 3,010 SLE cases and 57,046 comparators (mean age at index date: 47.3 years). Most comorbidities occurred more often in SLE patients versus comparators at the index date and up to 10 years before. Overrepresented comorbidities in SLE patients 10 years before SLE diagnosis included neuropsychiatric, cardiovascular, and venous thromboembolic diseases; PDs (95% CI) were 2.3% (1.4-3.3%), 1.3% (0.6-1.9%), and 1.1% (0.6-1.5%), respectively; corresponding PRs (95% CI) were 1.5 (1.3-1.8), 1.7 (1.4-2.1), and 4.3 (3.1-6.1). We found a higher prevalence of multiple comorbidities-not only at the time of SLE diagnosis but likewise during the 10-year pre-diagnosis period-among individuals with SLE. These findings underscore the importance of early clinical vigilance toward comorbidities starting in the diagnostic phase of SLE.
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http://dx.doi.org/10.1016/j.jaut.2021.102692DOI Listing
September 2021

Cluster of highly expressed interferon-stimulated genes associate more with African ancestry than disease activity in patients with systemic lupus erythematosus. A systematic review of cross-sectional studies.

Transl Res 2021 Jul 31. Epub 2021 Jul 31.

Copenhagen Lupus and Vasculitis Clinic, Rigshospitalet, Copenhagen University Hospital, Denmark. Electronic address:

Type I interferons (IFN) are central players in the pathogenesis of systemic lupus erythematosus (SLE) and the up-regulation of interferon-stimulated genes (ISGs) in SLE patients is subjected to increasing scrutiny as for its use in diagnosis, stratification and monitoring of SLE patients. Determinants of this immunological phenomenon are yet to be fully charted. The purpose of this systematic review was to characterize expressions of ISGs in blood of SLE patients and to analyze if they associated with core demographic and clinical features of SLE. Twenty cross-sectional, case-control studies comprising 1033 SLE patients and 602 study controls could be included. ISG fold-change expression values (SLE vs controls), demographic and clinical data were extracted from the published material and analyzed by hierarchical cluster analysis and generalized linear modelling. ISG expression varied substantially within each study with IFI27, IFI44, IFI44L, IFIT4 and RSAD2, being the top-five upregulated ISGs. Analysis of inter-study variation showed that IFI27, IFI44, IFI44L, IFIT1, PRKR and RSAD2 expression clustered with the fraction of SLE cases having African ancestry or lupus nephritis. Generalized linear models adjusted for prevalence of lupus nephritis and usage of hydroxychloroquine confirmed the observed association between African ancestry and IFI27, IFI44L, IFIT1, PRKR and RSAD2, whereas disease activity was associated with expression of IFI27 and RNASE2. In conclusion, this systematic review revealed that expression of ISGs often used for deriving an IFN signature in SLE patients were influenced by African ancestry rather than disease activity. This underscores the necessity of taking ancestry into account when employing the IFN signature for clinical research in SLE.
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http://dx.doi.org/10.1016/j.trsl.2021.07.006DOI Listing
July 2021

Characteristics of cardiovascular autonomic dysfunction and association with quality of life in patients with systemic lupus erythematosus.

Lupus Sci Med 2021 07;8(1)

Copenhagen Lupus and Vasculitis Clinic, Center for Rheumatology and Spine Diseases, Rigshospitalet, Copenhagen, Denmark.

Objectives: Cardiovascular autonomic neuropathy (CAN) may affect the clinical course of SLE leading to reduced quality of life. CAN is assessed by heart rate variability (HRV) measures and cardiovascular autonomic reflex tests (CARTs). In patients with SLE, we aimed to determine the characteristics of CAN and if CAN associates with health-related quality of life (HRQoL).

Methods: Patients with SLE and healthy controls (HCs) were CAN tested with 5 min HRV and three CARTs to determine parameters reflecting parasympathetic and mixed sympathetic-parasympathetic function. Subjects were classified as having no, early or definitive CAN by having none, one or more than one abnormal CART, respectively. HRQoL as determined by the Short Form 12 (SF-12) was assessed in SLE.

Results: Of 111 patients with SLE, 92 answered the SF-12 and 54 were matched with 54 HCs for characterisation of CAN. Definitive CAN was present in 24.1% (95% CI 15% to 37%) patients with SLE and 1.9% (95% CI 0.3% to 9.8%) HCs (OR 16.8, 95% CI 2.1 to 133.8, p=0.008). The corresponding prevalences of any CAN were 53.7% (95% CI 41% to 66%) and 22.6% (95% CI 13% to 35%). SLE patients with definitive CAN showed signs of mixed sympathetic-parasympathetic dysfunction, whereas patients without CAN primarily presented with impaired parasympathetic activity. Signs of parasympathetic as well as sympathetic-parasympathetic dysfunction were associated with low physical SF-12 component score (all: β>0.211, p<0.05). The mental SF-12 component score was not associated with any CAN indices.

Conclusions: CAN was a frequent finding in SLE and associated to self-report on impaired physical HRQoL. Even patients without CAN showed signs of impaired parasympathetic function compared with controls.
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http://dx.doi.org/10.1136/lupus-2021-000507DOI Listing
July 2021

Variants in BANK1 are associated with lupus nephritis of European ancestry.

Genes Immun 2021 Jul 14;22(3):194-202. Epub 2021 Jun 14.

Department of Medical Sciences and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.

The genetic background of lupus nephritis (LN) has not been completely elucidated. We performed a case-only study of 2886 SLE patients, including 947 (33%) with LN. Renal biopsies were available from 396 patients. The discovery cohort (Sweden, n = 1091) and replication cohort 1 (US, n = 962) were genotyped on the Immunochip and replication cohort 2 (Denmark/Norway, n = 833) on a custom array. Patients with LN, proliferative nephritis, or LN with end-stage renal disease were compared with SLE without nephritis. Six loci were associated with LN (p < 1 × 10, NFKBIA, CACNA1S, ITGA1, BANK1, OR2Y, and ACER3) in the discovery cohort. Variants in BANK1 showed the strongest association with LN in replication cohort 1 (p = 9.5 × 10) and proliferative nephritis in a meta-analysis of discovery and replication cohort 1. There was a weak association between BANK1 and LN in replication cohort 2 (p = 0.052), and in the meta-analysis of all three cohorts the association was strengthened (p = 2.2 × 10). DNA methylation data in 180 LN patients demonstrated methylation quantitative trait loci (meQTL) effects between a CpG site and BANK1 variants. To conclude, we describe genetic variations in BANK1 associated with LN and evidence for genetic regulation of DNA methylation within the BANK1 locus. This indicates a role for BANK1 in LN pathogenesis.
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http://dx.doi.org/10.1038/s41435-021-00142-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8277572PMC
July 2021

Neuropsychiatric Events in Systemic Lupus Erythematosus.

Arthritis Rheumatol 2021 May 27. Epub 2021 May 27.

Copenhagen Lupus and Vasculitis Clinic, 4242, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.

Objectives: To determine predictors for change in neuropsychiatric (NP) event status in a large, prospective, international, inception cohort of SLE patients METHODS: Upon enrollment and annually thereafter, NP events attributed to SLE and non-SLE causes and physician determined resolution were documented. Factors potentially associated with onset and resolution of NP events were determined by time-to-event analysis using a multistate modelling structure.

Results: NP events occurred in 955/1,827 (52.3%) patients and 592/1910 (31.0%) unique events were attributed to SLE. For SLE NP events multivariate analysis revealed positive associations with male sex, concurrent non-SLE NP events excluding headache, active SLE and corticosteroids. There was a negative association with Asian race/ethnicity, post-secondary education, and immunosuppressive or anti-malarial drugs. For non-SLE NP events, excluding headache, there was a positive association with concurrent SLE NP events and negative associations with African and Asian race/ethnicity. NP events attributed to SLE had a higher resolution rate than non-SLE NP events, with the exception of headache that had comparable resolution rates. For SLE NP events, multivariate analysis revealed resolution was more common with Asian race/ethnicity and for central/focal NP events. For non-SLE NP events resolution was more common with African race/ethnicity and less common with older age at SLE diagnosis.

Conclusions: In a large and long-term study of the occurrence and resolution of NP events in SLE we identified subgroups with better and worse prognosis. The course of NP events differs greatly depending on their nature and attribution.
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http://dx.doi.org/10.1002/art.41876DOI Listing
May 2021

Anti-beta 2 glycoprotein I IgA in the SLICC classification criteria dataset.

Lupus 2021 Jul 6;30(8):1283-1288. Epub 2021 May 6.

Amsterdam University Medical Centres, University of Amsterdam, Amsterdam, Netherlands.

Objective: Anti-beta 2 glycoprotein I IgA is a common isotype of anti-beta 2 glycoprotein I in SLE. Anti-beta 2 glycoprotein I was not included in the American College of Rheumatology (ACR) SLE classification criteria, but was included in the Systemic Lupus International Collaborating Clinics (SLICC) criteria. We aimed to evaluate the prevalence of anti-beta 2-glycoprotein I IgA in SLE versus other rheumatic diseases. In addition, we examined the association between anti-beta 2 glycoprotein I IgA and disease manifestations in SLE.

Methods: The dataset consisted of 1384 patients, 657 with a consensus physician diagnosis of SLE and 727 controls with other rheumatic diseases. Anti-beta 2 glycoprotein I isotypes were measured by ELISA. Patients with a consensus diagnosis of SLE were compared to controls with respect to presence of anti-beta 2 glycoprotein I. Among patients with SLE, we assessed the association between anti-beta 2 glycoprotein I IgA and clinical manifestations.

Results: The prevalence of anti-beta 2 glycoprotein I IgA was 14% in SLE patients and 7% in rheumatic disease controls (odds ratio, OR 2.3, 95% CI: 1.6, 3.3). It was more common in SLE patients who were younger patients and of African descent (p = 0.019). Eleven percent of SLE patients had anti-beta 2 glycoprotein I IgA alone (no anti-beta 2 glycoprotein I IgG or IgM). There was a significant association between anti-beta 2 glycoprotein I IgA and anti-dsDNA (p = 0.001) and the other antiphospholipid antibodies (p = 0.0004). There was no significant correlation of anti-beta 2 glycoprotein I IgA with any of the other ACR or SLICC clinical criteria for SLE. Those with anti-beta 2 glycoprotein I IgA tended to have a history of thrombosis (12% vs 6%, p = 0.071), but the difference was not statistically significant.

Conclusion: We found the anti-beta 2 glycoprotein I IgA isotype to be more common in patients with SLE and in particular, with African descent. It could occur alone without other isotypes.
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http://dx.doi.org/10.1177/09612033211014248DOI Listing
July 2021

Smoking associates with distinct clinical phenotypes in patients with systemic lupus erythematosus: a nationwide Danish cross-sectional study.

Lupus Sci Med 2021 04;8(1)

Lupus and Vasculitis Clinic, Copenhagen University Hospital Center for Rheumatology and Spine Diseases, Copenhagen, Hovedstaden, Denmark.

Objectives: SLE displays large clinical heterogeneity that beyond genetic factors may be determined by environmental exposures. In this Danish nationwide study, we aimed to determine if clinical subsets of SLE were associated with smoking history.

Methods: At each of six participating centres, incident or prevalent inpatients and outpatients with SLE were consecutively included. Manifestations forming the basis of SLE classification were registered in an electronic chart system. Patients also provided questionnaire-based data on environmental exposures, including smoking history. Hierarchical cluster analysis was conducted to determine and characterise subsets of patients with similar traits of disease manifestations. Levels of smoking exposure by pack-years were correlated to the identified SLE subsets, as well as discrete SLE manifestations.

Results: The cohort consisted of 485 patients (88% women and 92% Caucasian) with SLE of which 51% were ever smokers. Common disease manifestations comprised non-erosive arthritis (81%), malar rash (57%), lymphopenia (55%), photosensitivity (50%) and persistent proteinuria (41%). We identified three distinct phenotypic clusters characterised by their preponderance of (A) neurological, serosal and mucosal involvement; (B) renal, haematological and immunological disorders; and (C) acute and chronic skin manifestations. Cluster B was the youngest and had the lowest level of smoking exposure. Age-adjusted regression analyses showed that compared with never smokers a smoking history of >20 pack-years was associated with neurological disorder (OR=3.16), discoid rash (OR=2.22), photosensitivity (OR=2.19) and inversely with haematological disorder (OR=0.40), renal disorder (OR=0.40) and non-erosive arthritis (OR=0.45), p<0.05 for all.

Conclusions: Our findings support that SLE presents in varying clinical phenotypes and suggest that they may have differentiated associations with smoking history.
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http://dx.doi.org/10.1136/lupus-2021-000474DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8023756PMC
April 2021

Interaction between the rs11889341(T) risk allele and smoking confers increased risk of myocardial infarction and nephritis in patients with systemic lupus erythematosus.

Ann Rheum Dis 2021 09 25;80(9):1183-1189. Epub 2021 Mar 25.

Department of Medical Sciences, Rheumatology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.

Objective: To investigate how genetics influence the risk of smoking-related systemic lupus erythematosus (SLE) manifestations.

Methods: Patients with SLE (n=776, n=836) were genotyped using the 200K Immunochip single nucleotide polymorphisms (SNP) Array (Illumina) and a custom array. Sixty SNPs with SLE association (p<5.0×10) were analysed. Signal transducer and activator of transcription 4 (STAT4) activation was assessed in stimulated peripheral blood mononuclear cells from healthy controls (n=45).

Results: In the discovery cohort, smoking was associated with myocardial infarction (MI) (OR 1.96 (95% CI 1.09 to 3.55)), with a greater effect in patients carrying any rs11889341 risk allele (OR 2.72 (95% CI 1.24 to 6.00)) or two risk alleles (OR 8.27 (95% CI 1.48 to 46.27)).Smokers carrying the risk allele also displayed an increased risk of nephritis (OR 1.47 (95% CI 1.06 to 2.03)). In the replication cohort, the high risk of MI in smokers carrying the risk allele and the association between the risk allele and nephritis in smokers were confirmed (OR 6.19 (95% CI 1.29 to 29.79) and 1.84 (95% CI 1.05 to 3.29), respectively).The interaction between smoking and the risk allele resulted in further increase in the risk of MI (OR 2.14 (95% CI 1.01 to 4.62)) and nephritis (OR 1.53 (95% CI 1.08 to 2.17)), with 54% (MI) and 34% (nephritis) of the risk attributable to the interaction. Levels of interleukin-12-induced phosphorylation of STAT4 in CD8+ T cells were higher in smokers than in non-smokers (mean geometric fluorescence intensity 1063 vs 565, p=0.0063).Lastly, the rs564799 risk allele displayed association with MI in both cohorts (OR 1.53 (95% CI 1.01 to 2.31) and 2.15 (95% CI 1.08 to 4.26), respectively).

Conclusions: Smoking in the presence of the risk gene variant appears to increase the risk of MI and nephritis in SLE. Our results also highlight the role of the IL12-STAT4 pathway in SLE-cardiovascular morbidity.
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http://dx.doi.org/10.1136/annrheumdis-2020-219727DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8372395PMC
September 2021

Doppler ultrasound predicts successful discontinuation of biological DMARDs in rheumatoid arthritis patients in clinical remission.

Rheumatology (Oxford) 2021 Mar 20. Epub 2021 Mar 20.

Center for Rheumatology and Spine Diseases, Center of Head and Orthopedics, Glostrup, Rigshospitalet, Capital Region, Denmark.

Objective: To assess the ability of ultrasound to predict successful tapering and successful discontinuation of biological disease-modifying anti-rheumatic drugs (bDMARDs) at 2-year follow-up in rheumatoid arthritis (RA) patients in sustained remission.

Methods: Patients in sustained remission (DAS28-CRP≤2.6) and no radiographic progression the previous year tapered bDMARD according to a standardized regime. One-hundred-and-nineteen of these patients were included in this ultrasound sub-study. At baseline, clinical assessment, MRI, x-ray and ultrasound of 24 joints were performed. Ultrasound-detected synovitis was defined and scored 0-3 using the Outcome in Rheumatology (OMERACT) scoring system at joint level for both greyscale and Doppler activity. Sum scores for each ultrasound modality were calculated for 24 joints at patient level. Final state of treatment was assessed after 2 years. The predictive value of ultrasound measures for successful tapering and discontinuation at 2-year follow-up was assessed via logistic regression analyses.

Results: Negative IgM-RF (OR = 0.29; 95% Confidence Interval (CI)=0.10-0.85; p = 0.024) and lower Doppler sum score of 24 joints (OR(95%CI)=0.44;(0.15-0.87); p = 0.014) were independent predictors for successful discontinuation of bDMARD at 2-year follow-up. The predictive value of Doppler sum score was independent of MRI findings. Previous numbers of bDMARDs were predictive of successful tapering (OR(95% CI)=0.58(0.35-0.91); p = 0.018), whereas ultrasound was not. Clinical parameters were not predictive for successful tapering/discontinuation.

Conclusions: Doppler sum score was an independent predictor for successful discontinuation of bDMARDs at 2-year follow-up - the odds for achieving successful discontinuation decreased by 56% per one-unit increase in Doppler sum score. Ultrasound could not predict successful tapering.
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http://dx.doi.org/10.1093/rheumatology/keab276DOI Listing
March 2021

Association of soluble urokinase plasminogen activator receptor levels with fibrotic and vascular manifestations in systemic sclerosis.

PLoS One 2021 22;16(2):e0247256. Epub 2021 Feb 22.

Copenhagen Lupus and Vasculitis Clinic, Centre for Rheumatology and Spine Disease, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.

Objective: We assessed the association of suPAR (soluble urokinase plasminogen activator receptor) plasma levels with fibrotic and vascular manifestations in patients with systemic sclerosis (SSc).

Methods: suPAR plasma levels were measured in 121 consecutive patients with SSc and correlated to pulmonary and vascular features of SSc, including interstitial lung disease as characterized by percentage of predicted CO diffusing capacity (DLco) and forced vital capacity (FVC), pulmonary fibrosis by computed tomography, and pulmonary arterial hypertension, telangiectasias, and digital ulcers.

Results: Overall, 121 SSc patients (84% females; mean age, 57 ± 12 [range: 22-79] years) were enrolled; 35% had diffuse cutaneous SSc. suPAR plasma levels ranged from 1.3-10.2 [median: 2.9 (p25-p75: 2.3-3.9)] ng/mL. Log(suPAR) levels correlated with DLco (r = -0.41, p <0.0001) and FVC (r = -0.26, p = 0.004), also when adjusted for age, sex, and pulmonary hypertension. A suPAR cut-off level of >2.5 ng/mL showed a sensitivity of 91% for identifying patients with either DLco <50% or FVC < 60% of the predicted values. Similarly, 19 (90%) had a suPAR >2.5 ng/mL among those diagnosed with pulmonary fibrosis vs. 59 (60%) among those who did not (p = 0.008). suPAR values were not associated with vascular manifestations.

Conclusion: suPAR levels strongly correlated with pulmonary involvement in SSc. Future studies should test if suPAR estimation can be used for surveillance of severe pulmonary involvement in SSc.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0247256PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7899346PMC
August 2021

European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) SLE classification criteria item performance.

Ann Rheum Dis 2021 Feb 10. Epub 2021 Feb 10.

Department of Medicine, Division of Rheumatology, University of California at San Francisco and the VA Medical Center, San Francisco, California, USA.

Background/objectives: The European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) 2019 classification criteria for systemic lupus erythematosus system showed high specificity, while attaining also high sensitivity. We hereby analysed the performance of the individual criteria items and their contribution to the overall performance of the criteria.

Methods: We combined the EULAR/ACR derivation and validation cohorts for a total of 1197 systemic lupus erythematosus (SLE) and n=1074 non-SLE patients with a variety of conditions mimicking SLE, such as other autoimmune diseases, and calculated the sensitivity and specificity for antinuclear antibodies (ANA) and the 23 specific criteria items. We also tested performance omitting the EULAR/ACR criteria attribution rule, which defines that items are only counted if not more likely explained by a cause other than SLE.

Results: Positive ANA, the new entry criterion, was 99.5% sensitive, but only 19.4% specific, against a non-SLE population that included other inflammatory rheumatic, infectious, malignant and metabolic diseases. The specific criteria items were highly variable in sensitivity (from 0.42% for delirium and 1.84% for psychosis to 75.6% for antibodies to double-stranded DNA), but their specificity was uniformly high, with low C3 or C4 (83.0%) and leucopenia <4.000/mm³ (83.8%) at the lowest end. Unexplained fever was 95.3% specific in this cohort. Applying the attribution rule improved specificity, particularly for joint involvement.

Conclusions: Changing the position of the highly sensitive, non-specific ANA to an entry criterion and the attribution rule resulted in a specificity of >80% for all items, explaining the higher overall specificity of the criteria set.
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http://dx.doi.org/10.1136/annrheumdis-2020-219373DOI Listing
February 2021

Galectin-3-binding protein is a novel predictor of venous thromboembolism in systemic lupus erythematosus.

Clin Exp Rheumatol 2020 Dec 18. Epub 2020 Dec 18.

Copenhagen Lupus and Vasculitis Clinic, Center for Rheumatology and Spine Diseases, Rigshospitalet, Copenhagen University Hospital, Denmark.

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.
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December 2020

The global antiphospholipid syndrome score in women with systemic lupus erythematosus and adverse pregnancy outcomes.

Clin Exp Rheumatol 2021 Sep-Oct;39(5):1071-1076. Epub 2020 Nov 12.

Center of Research of Immunopathology and Rare Diseases - Coordinating Center of Piemonte and Valle d'Aosta Network for Rare Diseases, Department of Clinical and Biological Sciences, and SCDU Nephrology and Dialysis, S. Giovanni Bosco Hospital, Turin, Italy.

Objectives: To validate the global antiphospholipid syndrome score (GAPSS) in a cohort of women with systemic lupus erythematosus (SLE) and antiphospholipid antibodies (aPL).

Methods: This retrospective study included 143 women ever pregnant with SLE who presented in our outpatient clinic were included. Data on cardiovascular risk factors and aPL status were retrospectively collected and their individual GAPSS score was calculated.

Results: Significantly higher GAPSS values were found in women with any placental medicated complication (such as foetal death, placental abruption, prematurity, pre-eclampsia or intrauterine growth restriction (IUGR)) (GAPSS 8.2±3.0 vs. 3.5±3.0, p<0.001). Significantly higher GAPSS values were also found in those with recurrent miscarriages (RM) <10 weeks, foetal death, placental abruption, prematurity, pre-eclampsia or IUGR) (GAPSS 8.3±4.5 vs. 3.2±2.6, p<0.001). Patients with 3 or more consecutive early miscarriages (<10 weeks), foetal death, miscarriage <10 weeks' gestation, premature birth (<34 weeks), pre-eclampsia (<34 weeks), stillbirth, and placental infarction had significantly higher GAPSS values compared to those without previous pregnancy complications. The odds ratio of having any pregnancy morbidity when having a GAPSS value ≥8 was 20 compared to those with a GAPSS of ≤1 (p<0.001).

Conclusions: Women with a history of aPL-related pregnancy complications had higher GAPSS values in this retrospective cohort compared to women without pregnancy complications. This study is the first step to assess the clinical utility of the GAPSS score in pregnancy. A prospective validation is needed.
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September 2021

Prediction of hospitalizations in systemic lupus erythematosus using the Systemic Lupus International Collaborating Clinics Frailty Index (SLICC-FI).

Arthritis Care Res (Hoboken) 2020 Nov 5. Epub 2020 Nov 5.

Emory University School of Medicine, Division of Rheumatology, Atlanta, Georgia, USA.

Objective: The Systemic Lupus International Collaborating Clinics (SLICC) frailty index (FI) predicts mortality and damage accrual in SLE, but its association with hospitalizations has not been described. We estimated the association of baseline SLICC-FI values with future hospitalizations in the SLICC inception cohort.

Methods: Baseline SLICC-FI scores were calculated. The number and duration of inpatient hospitalizations during follow-up were recorded. Negative binomial regression was used to estimate the association between baseline SLICC-FI values and the rate of hospitalizations per patient-year of follow-up. Linear regression was used to estimate the association of baseline SLICC-FI scores with the proportion of follow-up time spent in hospital. Multivariable models were adjusted for relevant baseline characteristics.

Results: The 1549 SLE patients eligible for this analysis were mostly female (88.7%) with mean (SD) age 35.7 (13.3) years and median (IQR) disease duration 1.2 (0.9-1.5) years at baseline. Mean (SD) baseline SLICC-FI was 0.17 (0.08). During mean (SD) follow-up of 7.2 (3.7) years, 614 patients (39.6%) experienced 1570 hospitalizations. Higher baseline SLICC-FI values (per 0.05 increment) were associated with more frequent hospitalizations during follow-up (Incidence Rate Ratio 1.21; 95%CI 1.13-1.30), adjusting for baseline age, sex, corticosteroid use, immunosuppressive use, ethnicity/location, SLE disease activity index 2000 (SLEDAI-2K), SLICC/ACR damage index (SDI), and disease duration. Among patients with ≥1 hospitalization, higher baseline SLICC-FI values predicted a greater proportion of follow-up time spent hospitalized (Relative Rate 1.09; 95%CI 1.02-1.16).

Conclusion: The SLICC-FI predicts future hospitalizations among incident SLE patients, further supporting the SLICC-FI as a valid health measure in SLE.
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http://dx.doi.org/10.1002/acr.24504DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8096857PMC
November 2020

Molecular pathways in patients with systemic lupus erythematosus revealed by gene-centred DNA sequencing.

Ann Rheum Dis 2021 01 9;80(1):109-117. Epub 2020 Oct 9.

Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection, Linköping University, Linköping, Sweden.

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.
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http://dx.doi.org/10.1136/annrheumdis-2020-218636DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7788061PMC
January 2021

Performance of the 2019 EULAR/ACR classification criteria for systemic lupus erythematosus in early disease, across sexes and ethnicities.

Ann Rheum Dis 2020 10 14;79(10):1333-1339. Epub 2020 Aug 14.

Rheumatology, Azienda Ospedaliero Universitaria Pisana, Pisa, Toscana, Italy.

Objectives: The European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) 2019 Classification Criteria for systemic lupus erythematosus (SLE) have been validated with high sensitivity and specificity. We evaluated the performance of the new criteria with regard to disease duration, sex and race/ethnicity, and compared its performance against the Systemic Lupus International Collaborating Clinics (SLICC) 2012 and ACR 1982/1997 criteria.

Methods: Twenty-one SLE centres from 16 countries submitted SLE cases and mimicking controls to form the validation cohort. The sensitivity and specificity of the EULAR/ACR 2019, SLICC 2012 and ACR 1982/1997 criteria were evaluated.

Results: The cohort consisted of female (n=1098), male (n=172), Asian (n=118), black (n=68), Hispanic (n=124) and white (n=941) patients; with an SLE duration of 1 to <3 years (n=196) and ≥5 years (n=879). Among patients with 1 to <3 years disease duration, the EULAR/ACR criteria had better sensitivity than the ACR criteria (97% vs 81%). The EULAR/ACR criteria performed well in men (sensitivity 93%, specificity 96%) and women (sensitivity 97%, specificity 94%). Among women, the EULAR/ACR criteria had better sensitivity than the ACR criteria (97% vs 83%) and better specificity than the SLICC criteria (94% vs 82%). Among white patients, the EULAR/ACR criteria had better sensitivity than the ACR criteria (95% vs 83%) and better specificity than the SLICC criteria (94% vs 83%). The EULAR/ACR criteria performed well among black patients (sensitivity of 98%, specificity 100%), and had better sensitivity than the ACR criteria among Hispanic patients (100% vs 86%) and Asian patients (97% vs 77%).

Conclusions: The EULAR/ACR 2019 criteria perform well among patients with early disease, men, women, white, black, Hispanic and Asian patients. These criteria have superior sensitivity than the ACR criteria and/or superior specificity than the SLICC criteria across many subgroups.
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http://dx.doi.org/10.1136/annrheumdis-2020-217162DOI Listing
October 2020

Cancer risk in a large inception SLE cohort: Effects of demographics, smoking, and medications.

Arthritis Care Res (Hoboken) 2020 Aug 19. Epub 2020 Aug 19.

Department of Rheumatology, Center for Rheumatology Research Fossvogur, Landspitali University Hospital, Reykjavik, Iceland.

Objective: To assess cancer risk factors in incident SLE.

Methods: Clinical variables and cancer outcomes were assessed annually among incident SLE patients. Multivariate hazard regression models (over-all risk, and most common cancers) included demographics and time-dependent medications (corticosteroids, antimalarial drugs, immunosuppressants), smoking, and adjusted mean SLE Disease Activity Index-2K.

Results: Among 1668 patients (average 9 years follow-up), 65 cancers occurred: 15 breast, 10 non-melanoma skin, seven lung, six hematological, six prostate, five melanoma, three cervical, three renal, two each gastric, head and neck, and thyroid, and one each rectal, sarcoma, thymoma, and uterine cancers. Half of cancers (including all lung cancers) occurred in past/current smokers, versus one-third of patients without cancer. Multivariate analyses indicated over-all cancer risk was related primarily to male sex and older age at SLE diagnosis. In addition, smoking was associated with lung cancer. For breast cancer risk, age was positively and anti-malarial drugs were negatively associated. Anti-malarial drugs and higher disease activity were also negatively associated with non-melanoma skin cancer (NMSC) risk, whereas age and cyclophosphamide were positively associated. Disease activity was associated positively with hematologic and negatively with NMSC risk.

Conclusions: Smoking is a key modifiable risk factor, especially for lung cancer, in SLE. Immunosuppressive medications were not clearly associated with higher risk except for cyclophosphamide and NMSC. Antimalarials were negatively associated with breast cancer and NMSC risk. SLE activity was associated positively with hematologic cancer and negatively with NMSC. Since the absolute number of cancers was small, additional follow-up will help consolidate these findings.
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http://dx.doi.org/10.1002/acr.24425DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7892637PMC
August 2020

[Acral ischaemia with multiple microthromboses and imminent gangrene in a 73-year-old woman with COVID-19].

Ugeskr Laeger 2020 06;182(26)

This is a report of an atypical presentation of COVID-19. The patient had sparse pulmonary symptoms despite characteristic COVID-19 lesions on CT-thorax and developed severe acral ischaemic change, after a few days of hospitalisation. The condition could not be explained by classical sepsis with hypotension and hypoperfusion, disseminated intravascular coagulation, vasculitis, endocarditis or severe peripheral arteriosclerosis. A skin biopsy showed microthrombosis, interpreted as an activation of the coagulation system associated with COVID-19. Apparently, there are multiple COVID-19 phenotypes.
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June 2020

Accrual of Atherosclerotic Vascular Events in a Multicenter Inception Systemic Lupus Erythematosus Cohort.

Arthritis Rheumatol 2020 10 25;72(10):1734-1740. Epub 2020 Aug 25.

Hairmyres Hospital, East Kilbride, Scotland, UK.

Objective: In previous studies, atherosclerotic vascular events (AVEs) were shown to occur in ~10% of patients with systemic lupus erythematosus (SLE). We undertook this study to investigate the annual occurrence and potential risk factors for AVEs in a multinational, multiethnic inception cohort of patients with SLE.

Methods: A large 33-center cohort of SLE patients was followed up yearly between 1999 and 2017. AVEs were attributed to atherosclerosis based on SLE being inactive at the time of the AVE as well as typical atherosclerotic changes observed on imaging or pathology reports and/or evidence of atherosclerosis elsewhere. Analyses included descriptive statistics, rate of AVEs per 1,000 patient-years, and univariable and multivariable relative risk regression models.

Results: Of the 1,848 patients enrolled in the cohort, 1,710 had ≥1 follow-up visit after enrollment, for a total of 13,666 patient-years. Of these 1,710 patients, 3.6% had ≥1 AVEs attributed to atherosclerosis, for an event rate of 4.6 per 1,000 patient-years. In multivariable analyses, lower AVE rates were associated with antimalarial treatment (hazard ratio [HR] 0.54 [95% confidence interval (95% CI) 0.32-0.91]), while higher AVE rates were associated with any prior vascular event (HR 4.00 [95% CI 1.55-10.30]) and a body mass index of >40 kg/m (HR 2.74 [95% CI 1.04-7.18]). A prior AVE increased the risk of subsequent AVEs (HR 5.42 [95% CI 3.17-9.27], P < 0.001).

Conclusion: The prevalence of AVEs and the rate of AVE accrual demonstrated in the present study is much lower than that seen in previously published data. This may be related to better control of both the disease activity and classic risk factors.
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http://dx.doi.org/10.1002/art.41392DOI Listing
October 2020

Comparison of the 2019 European Alliance of Associations for Rheumatology/American College of Rheumatology Systemic Lupus Erythematosus Classification Criteria With Two Sets of Earlier Systemic Lupus Erythematosus Classification Criteria.

Arthritis Care Res (Hoboken) 2021 09 14;73(9):1231-1235. Epub 2021 Jul 14.

Kantonsspital, Schaffhausen, Switzerland.

Objective: The Systemic Lupus International Collaborating Clinics (SLICC) 2012 systemic lupus erythematosus (SLE) classification criteria and the revised American College of Rheumatology (ACR) 1997 criteria are list based, counting each SLE manifestation equally. We derived a classification rule based on giving variable weights to the SLICC criteria and compared its performance to the revised ACR 1997, the unweighted SLICC 2012, and the newly reported European Alliance of Associations for Rheumatology (EULAR)/ACR 2019 criteria sets.

Methods: The physician-rated patient scenarios used to develop the SLICC 2012 classification criteria were reemployed to devise a new weighted classification rule using multiple linear regression. The performance of the rule was evaluated on an independent set of expert-diagnosed patient scenarios and compared to the performance of the previously reported classification rules.

Results: The weighted SLICC criteria and the EULAR/ACR 2019 criteria had less sensitivity but better specificity compared to the list-based revised ACR 1997 and SLICC 2012 classification criteria. There were no statistically significant differences between any pair of rules with respect to overall agreement with the physician diagnosis.

Conclusion: The 2 new weighted classification rules did not perform better than the existing list-based rules in terms of overall agreement on a data set originally generated to assess the SLICC criteria. Given the added complexity of summing weights, researchers may prefer the unweighted SLICC criteria. However, the performance of a classification rule will always depend on the populations from which the cases and non-cases are derived and whether the goal is to prioritize sensitivity or specificity.
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http://dx.doi.org/10.1002/acr.24263DOI Listing
September 2021

Early life body size, growth and risks of systemic lupus erythematosus - A large Danish observational cohort study.

Semin Arthritis Rheum 2020 12 4;50(6):1507-1512. Epub 2020 Feb 4.

Center for Clinical Research and Prevention, Bispebjerg and Frederiksberg Hospital, The Capital Region, Copenhagen, Denmark; Novo Nordisk Foundation Center for Basic Metabolic Research, Human Genomics and Metagenomics in Metabolism, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark. Electronic address:

Objectives: Adult obesity may increase the risks of systemic lupus erythematosus (SLE), and there are genetic links between adult height and SLE. Thus, it is plausible that size earlier in life may be important in the aetiology of SLE as well. We investigated whether birthweight, childhood body mass index (BMI; [kg/m]), height and growth are associated with risks of adult SLE.

Methods: The study included 346,627 children from the Copenhagen School Health Records Register, born 1930-1996 with measured weights and heights from 7-13 years. Birthweight information was available from 1936. Linkages were made to the Danish National Patient Register for information on registrations of SLE. During follow-up, 435 individuals (366 women) were registered with SLE. Cox proportional hazards regressions were performed to estimate hazard ratios (HR) and 95% confidence intervals (CI).

Results: No differences by sex were detected in any of the associations. Birthweight was not associated with SLE risks. Childhood BMI and height were positively and linearly associated with SLE risks. For BMI at age 7, the HR was 1.11 (95% CI: 1.01-1.23) per z-score. For height at age 7, the HR was 1.13 (95% CI: 1.02-1.24) per z-score. The estimates were similar in magnitude across all childhood ages for BMI and height. There were limited indications that change in BMI or growth in height during childhood influence the risks of SLE in adulthood.

Conclusions: Childhood body size is associated with risks of adult SLE, which supports the hypothesis that early life factors are important in SLE aetiology.
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http://dx.doi.org/10.1016/j.semarthrit.2020.01.011DOI Listing
December 2020

Association between MRI findings and patient-reported outcomes in patients with rheumatoid arthritis in clinical remission and at relapse.

Int J Rheum Dis 2020 Apr 28;23(4):488-498. Epub 2020 Jan 28.

Copenhagen Center for Arthritis Research (COPECARE), Center for Rheumatology and Spine Diseases, Centre of Head and Orthopaedics, Rigshospitalet, Glostrup, Denmark.

Objective: To investigate whether magnetic resonance imaging (MRI) pathologies in the wrist/hand of rheumatoid arthritis (RA) patients are associated with patient-reported outcomes (PROs) at clinical remission and relapse.

Methods: Wrist/hand MRIs and wrists/hands/feet radiographs were obtained in 114 established RA patients in clinical remission, before tapering their biologic disease-modifying antirheumatic drugs. MRIs were assessed according to the Outcome Measures in Rheumatology (OMERACT) RA MRI score (RAMRIS) for inflammation (synovitis/tenosynovitis/bone marrow edema) and damage (bone erosion/joint space narrowing) at baseline (ie remission) and in case of a relapse (n = 70). Radiographs were assessed according to the Sharp/van der Heijde (SvH) method at baseline. These scores were assessed for associations with health assessment questionnaires (HAQ), visual analog scales (VAS global/pain), EuroQol-5 dimensions and Short-Form 36 physical and mental component summary (SF-36 PCS/MCS) using Spearman correlations, univariate/multivariable linear regression analyses and generalized estimating equations. Furthermore, MRI pathologies were assessed for association with specific hand-related HAQ items using Jonckheere trend tests.

Results: Magnetic resonance imaging-assessed damage was associated with impaired HAQ and SF-36 PCS at remission and relapse (P < .01), independent of clinical and radiographic measures, and was also associated with most of the hand-related HAQ items (P < .03). In multivariate models including MRI, SvH scores were not associated with PROs. MRI-assessed inflammation was not associated with PROs at remission or relapse.

Conclusion: Magnetic resonance imaging-assessed wrist/hand damage, but not inflammation, in patients with established RA is associated with patient-reported physical impairment at remission and relapse. The amount of damage in the wrist/hand is associated with reduced hand function.
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http://dx.doi.org/10.1111/1756-185X.13790DOI Listing
April 2020

Neuropsychiatric events in systemic lupus erythematosus: a longitudinal analysis of outcomes in an international inception cohort using a multistate model approach.

Ann Rheum Dis 2020 03 8;79(3):356-362. Epub 2020 Jan 8.

Copenhagen Lupus and Vasculitis Clinic, 4242, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.

Objectives: Using a reversible multistate model, we prospectively examined neuropsychiatric (NP) events for attribution, outcome and association with health-related quality of life (HRQoL), in an international, inception cohort of systemic lupus erythematosus (SLE) patients.

Methods: Annual assessments for 19 NP events attributed to SLE and non-SLE causes, physician determination of outcome and patient HRQoL (short-form (SF)-36 scores) were measured. Time-to-event analysis and multistate modelling examined the onset, recurrence and transition between NP states.

Results: NP events occurred in 955/1827 (52.3%) patients and 592/1910 (31.0%) unique events were attributed to SLE. In the first 2 years of follow-up the relative risk (95% CI) for SLE NP events was 6.16 (4.96, 7.66) and non-SLE events was 4.66 (4.01, 5.43) compared with thereafter. Patients without SLE NP events at initial assessment had a 74% probability of being event free at 10 years. For non-SLE NP events the estimate was 48%. The majority of NP events resolved over 10 years but mortality was higher in patients with NP events attributed to SLE (16%) versus patients with no NPSLE events (6%) while the rate was comparable in patients with non-SLE NP events (7%) compared with patients with no non-SLE events (6%). Patients with NP events had lower SF-36 summary scores compared with those without NP events and resolved NP states (p<0.001).

Conclusions: NP events occur most frequently around the diagnosis of SLE. Although the majority of events resolve they are associated with reduced HRQoL and excess mortality. Multistate modelling is well suited for the assessment of NP events in SLE.
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http://dx.doi.org/10.1136/annrheumdis-2019-216150DOI Listing
March 2020

Epidemiology of hepatitis E virus infection in a cohort of 4023 immunocompromised patients.

Int J Infect Dis 2020 Feb 20;91:188-195. Epub 2019 Nov 20.

Department of Clinical Immunology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark; Department of Clinical Medicine, Faculty of Health Sciences, University of Copenhagen, Denmark.

Objectives: The prevalence of active, chronic, and former hepatitis E virus (HEV) infections was investigated in a cohort of immunocompromised patients. The association with transfusion transmitted HEV was evaluated, and the HEV seroprevalence was compared with that in healthy blood donors.

Study Design And Methods: Serum samples from 4023 immunocompromised patients at Rigshospitalet, Denmark were retrospectively tested for HEV RNA and anti-HEV IgG. HEV RNA-positive patients were followed up by HEV testing, clinical symptoms, and transfusion history. Factors associated with anti-HEV were explored by multivariable logistic regression analysis. Samples from 1226 blood donors were retrospectively tested for anti-HEV IgG.

Results: HEV RNA was detected in six patients (0.15%) with no indications of chronic HEV infection. HEV RNA prevalence rates among recipients of allogeneic haematopoietic stem cell transplantation (allo-HSCT) and solid organ transplantation (SOT) were 0.58% and 0.21%, respectively. Transfusion transmitted infections were refuted, and transfusion history was not associated with anti-HEV positivity. The difference in HEV seroprevalence between patients (22.0%) and blood donors (10.9%) decreased when adjusting for age and sex (odds ratio 1.20, 95% confidence interval 0.97-1.48).

Conclusions: HEV viremia among allo-HSCT and SOT recipients suggests that clinicians should be aware of this diagnosis. The lack of association of blood transfusion with anti-HEV positivity supports food-borne transmission as the main transmission route of HEV common to both patients and blood donors.
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http://dx.doi.org/10.1016/j.ijid.2019.11.014DOI Listing
February 2020

Stimulation of Mononuclear Cells Through Toll-Like Receptor 9 Induces Release of Microvesicles Expressing Double-Stranded DNA and Galectin 3-Binding Protein in an Interferon-α-Dependent Manner.

Front Immunol 2019 11;10:2391. Epub 2019 Oct 11.

Center for Rheumatology and Spine Diseases, Institute for Inflammation Research, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.

Microvesicles (MVs) expressing the type 1 interferon (IFN)-inducible protein galectin-3 binding protein (G3BP) may play a pathogenic role in systemic lupus erythematosus (SLE). Co-expression of double-stranded DNA (dsDNA) on such MVs may render them immunogenic and targets for anti-dsDNA antibodies. Little is known about the mechanisms underlying generation of this MV population. In this study, we investigated how Toll-like receptors (TLRs), IFN-α, and T cells are involved in this process in healthy subjects. Peripheral blood mononuclear cells (PBMCs) isolated from 12 healthy donors were stimulated for 24 h with a series of TLR-agonists or the T cell activating antibody OKT3 or were subjected to apoptosis by incubation with staurosporine. MVs in the supernatants were subsequently isolated by differential centrifugation and were quantified and characterized with respect to expression of G3BP and dsDNA by flow cytometry. Stimulation of PBMCs with the TLR9-agonist and strong IFN-α inducer ODN2395 significantly increased the release of MVs expressing G3BP. The production of MVs with this phenotype was markedly enhanced by co-stimulation of T cells. Furthermore, dependency on IFN-α in the generation of G3BP-expressing MVs was indicated by a marked reduction following addition of the IFN-α inhibitor IFN alpha-IFNAR-IN-1 hydrochloride. Release of G3BP-expressing MVs from healthy donor PBMCs is induced by stimulation of TLR9 in an IFN-α-dependent manner and is enhanced by co-stimulation of T cells.
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http://dx.doi.org/10.3389/fimmu.2019.02391DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6797593PMC
October 2020

Prediction of Damage Accrual in Systemic Lupus Erythematosus Using the Systemic Lupus International Collaborating Clinics Frailty Index.

Arthritis Rheumatol 2020 04 12;72(4):658-666. Epub 2020 Feb 12.

Emory University School of Medicine, Atlanta, Georgia.

Objective: The Systemic Lupus International Collaborating Clinics (SLICC) frailty index (FI) has been shown to predict mortality, but its association with other important outcomes is unknown. We examined the association of baseline SLICC FI values with damage accrual in the SLICC inception cohort.

Methods: The baseline visit was defined as the first visit at which both organ damage (SLICC/American College of Rheumatology Damage Index [SDI]) and health-related quality of life (Short Form 36) were assessed. Baseline SLICC FI scores were calculated. Damage accrual was measured by the increase in SDI between the baseline assessment and the last study visit. Multivariable negative binomial regression was used to estimate the association between baseline SLICC FI values and the rate of increase in the SDI during follow-up, adjusting for relevant demographic and clinical characteristics.

Results: The 1,549 systemic lupus erythematosus (SLE) patients eligible for this analysis were mostly female (88.7%) with a mean ± SD age of 35.7 ± 13.3 years and a median disease duration of 1.2 years (interquartile range 0.9-1.5 years) at baseline. The mean ± SD baseline SLICC FI was 0.17 ± 0.08. Over a mean ± SD follow-up of 7.2 ± 3.7 years, 653 patients (42.2%) had an increase in SDI. Higher baseline SLICC FI values (per 0.05 increase) were associated with higher rates of increase in the SDI during follow-up (incidence rate ratio [IRR] 1.19 [95% confidence interval 1.13-1.25]), after adjusting for age, sex, ethnicity/region, education, baseline SLE Disease Activity Index 2000, baseline SDI, and baseline use of glucocorticoids, antimalarials, and immunosuppressive agents.

Conclusion: Our findings indicate that the SLICC FI predicts damage accrual in incident SLE, which further supports the SLICC FI as a valid health measure in SLE.
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http://dx.doi.org/10.1002/art.41144DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7113092PMC
April 2020

Soluble urokinase plasminogen activator receptor (suPAR) levels predict damage accrual in patients with recent-onset systemic lupus erythematosus.

J Autoimmun 2020 01 17;106:102340. Epub 2019 Oct 17.

Department of Clinical Sciences Lund, Section of Rheumatology, Lund University, Lund, Sweden.

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.
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http://dx.doi.org/10.1016/j.jaut.2019.102340DOI Listing
January 2020

Economic Evaluation of Damage Accrual in an International Systemic Lupus Erythematosus Inception Cohort Using a Multistate Model Approach.

Arthritis Care Res (Hoboken) 2020 12;72(12):1800-1808

Hairmyres Hospital, East Kilbride, Scotland, UK.

Objective: There is a paucity of data regarding health care costs associated with damage accrual in systemic lupus erythematosus. The present study was undertaken to describe costs associated with damage states across the disease course using multistate modeling.

Methods: Patients from 33 centers in 11 countries were enrolled in the Systemic Lupus International Collaborating Clinics (SLICC) inception cohort within 15 months of diagnosis. Annual data on demographics, disease activity, damage (SLICC/American College of Rheumatology Damage Index [SDI]), hospitalizations, medications, dialysis, and selected procedures were collected. Ten-year cumulative costs (Canadian dollars) were estimated by multiplying annual costs associated with each SDI state by the expected state duration using a multistate model.

Results: A total of 1,687 patients participated; 88.7% were female, 49.0% were white, mean ± SD age at diagnosis was 34.6 ± 13.3 years, and mean time to follow-up was 8.9 years (range 0.6-18.5 years). Mean annual costs were higher for those with higher SDI scores as follows: $22,006 (Canadian) (95% confidence interval [95% CI] $16,662, $27,350) for SDI scores ≥5 versus $1,833 (95% CI $1,134, $2,532) for SDI scores of 0. Similarly, 10-year cumulative costs were higher for those with higher SDI scores at the beginning of the 10-year interval as follows: $189,073 (Canadian) (95% CI $142,318, $235,827) for SDI scores ≥5 versus $21,713 (95% CI $13,639, $29,788) for SDI scores of 0.

Conclusion: Patients with the highest SDI scores incur 10-year cumulative costs that are ~9-fold higher than those with the lowest SDI scores. By estimating the damage trajectory and incorporating annual costs, data on damage can be used to estimate future costs, which is critical knowledge for evaluating the cost-effectiveness of novel therapies.
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http://dx.doi.org/10.1002/acr.24092DOI Listing
December 2020
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