| 1. |
- Langefeld, Carl D., et al.
(författare)
-
Transancestral mapping and genetic load in systemic lupus erythematosus
- 2017
-
Ingår i: Nature Communications. - : NATURE PUBLISHING GROUP. - 2041-1723. ; 8
-
Tidskriftsartikel (refereegranskat)abstract
- Systemic lupus erythematosus (SLE) is an autoimmune disease with marked gender and ethnic disparities. We report a large transancestral association study of SLE using Immunochip genotype data from 27,574 individuals of European (EA), African (AA) and Hispanic Amerindian (HA) ancestry. We identify 58 distinct non-HLA regions in EA, 9 in AA and 16 in HA (similar to 50% of these regions have multiple independent associations); these include 24 novel SLE regions (P < 5 x 10(-8)), refined association signals in established regions, extended associations to additional ancestries, and a disentangled complex HLA multigenic effect. The risk allele count (genetic load) exhibits an accelerating pattern of SLE risk, leading us to posit a cumulative hit hypothesis for autoimmune disease. Comparing results across the three ancestries identifies both ancestry-dependent and ancestry-independent contributions to SLE risk. Our results are consistent with the unique and complex histories of the populations sampled, and collectively help clarify the genetic architecture and ethnic disparities in SLE.
|
|
| 2. |
|
|
| 3. |
- Kienhöfer, D, et al.
(författare)
-
No evidence of pathogenic involvement of cathelicidins in patient cohorts and mouse models of lupus and arthritis
- 2014
-
Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 9:12, s. 1-19
-
Tidskriftsartikel (refereegranskat)abstract
- Apart from their role in the immune defence against pathogens evidence of a role of antimicrobial peptides (AMPs) in autoimmune diseases has accumulated in the past years. The aim of this project was to examine the functional impact of the human cathelicidin LL-37 and the mouse cathelicidin-related AMP (CRAMP) on the pathogenesis of lupus and arthritis. Serum LL-37 and anti-LL-37 levels were measured by ELISA in healthy donors and patients with Systemic Lupus Erythematosus (SLE) and Rheumatoid arthritis (RA). Pristane-induced lupus was induced in female wild type (WT) and cathelicidin-deficient (CRAMP-/-) mice. Serum levels of anti-Sm/RNP, anti-dsDNA, and anti-histone were determined via ELISA, cytokines in sera and peritoneal lavages were measured via Multiplex. Expression of Interferon I stimulated genes (ISG) was determined by real-time PCR. Collagen-induced arthritis (CIA) was induced in male WT and CRAMP-/- mice and arthritis severity was visually scored and analysed histomorphometrically by OsteoMeasure software. Serum levels of anti-LL-37 were higher in SLE-patients compared to healthy donors or patients with RA. However, no correlation to markers of disease activity or organ involvement was observed. No significant differences of autoantibody or cytokine/chemokine levels, or of expression of ISGs were observed between WT and CRAMP-/- mice after pristane-injection. Furthermore, lung and kidney pathology did not differ in the absence of CRAMP. Incidence and severity of CIA and histological parameters (inflammation, cartilage degradation, and bone erosion) were not different in WT and CRAMP-/- mice. Although cathelicidins are upregulated in mouse models of lupus and arthritis, cathelicidin-deficiency did not persistently affect the diseases. Also in patients with SLE, autoantibodies against cathelicidins did not correlate with disease manifestation. Reactivity against cathelicidins in lupus and arthritis could thus be an epiphenomenon caused by extensive overexpression in blood and affected tissues. In addition, other cationic AMPs could functionally compensate for the deficiency of cathelicidins.
|
|
| 4. |
- Stuemer, J., et al.
(författare)
-
Altered glycan accessibility on native immunoglobulin G complexes in early rheumatoid arthritis and its changes during therapy
- 2017
-
Ingår i: Clinical and Experimental Immunology. - : WILEY. - 0009-9104 .- 1365-2249. ; 189:3, s. 372-382
-
Tidskriftsartikel (refereegranskat)abstract
- The goal of this study was to investigate the glycosylation profile of native immunoglobulin (Ig)G present in serum immune complexes in patients with rheumatoid arthritis (RA). To accomplish this, lectin binding assays, detecting the accessibility of glycans present on IgG-containing immune complexes by biotinylated lectins, were employed. Lectins capturing fucosyl residues (AAL), fucosylated tri-mannose N-glycan core sites (LCA), terminal sialic acid residues (SNA) and O-glycosidically linked galactose/N-acetylgalactosamine (GalNac-L) were used. Patients with recent-onset RA at baseline and after 3-year follow-up were investigated. We found that native IgG was complexed significantly more often with IgM, C1q, C3c and C-reactive protein (CRP) in RA patients, suggesting alterations of the native structure of IgG. The total accessibility of fucose residues on captured immune complexes to the respective lectin was significantly higher in patients with RA. Moreover, fucose accessibility on IgG-containing immune complexes correlated positively with the levels of antibodies to cyclic citrullinated peptides (anti-CCP). We also observed a significantly higher accessibility to sialic acid residues and galactose/GalNAc glyco-epitopes in native complexed IgG of patients with RA at baseline. While sialic acid accessibility increased during treatment, the accessibility of galactose/GalNAc decreased. Hence, successful treatment of RA was associated with an increase in the SNA/GalNAc-L ratio. Interestingly, the SNA/GalNAc-L ratio in particular rises after glucocorticoid treatment. In summary, this study shows the exposure of glycans in native complexed IgG of patients with early RA, revealing particular glycosylation patterns and its changes following pharmaceutical treatment.
|
|
| 5. |
- Van Hoovels, L., et al.
(författare)
-
IgA rheumatoid factor in rheumatoid arthritis
- 2022
-
Ingår i: Clinical Chemistry and Laboratory Medicine. - : Walter de Gruyter GmbH. - 1434-6621 .- 1437-4331. ; 60:10, s. 1617-1626
-
Tidskriftsartikel (refereegranskat)abstract
- Objectives Rheumatoid factor (RF) is a well-established marker for the diagnosis and classification of rheumatoid arthritis (RA). Most studies evaluated IgM RF or isotype-nonspecific total RF assays. We evaluated the added value of IgA RF in this context. Methods An international sample cohort consisting of samples from 398 RA patients and 1073 controls was tested for IgA RF with 3 commercial assays. For all RA patients and 100 controls essential clinical and serological data for ACR/EULAR classification were available. Results The sensitivity of IgA RF for diagnosing RA was lower than the sensitivity of IgM RF. Differences in numerical values between IgA RF assays were observed. With all assays, the highest IgA RF values were found in patients with primary Sjogren's syndrome. Double positivity for IgM RF and IgA RF had a higher specificity for RA than either IgM RF or IgA RF. The sensitivity of double positivity was lower than the sensitivity of either IgA RF or IgM RF. Single positivity for IgA RF was at least as prevalent in controls than in RA patients. Adding IgA RF to IgM RF and anti-citrullinated protein antibodies (ACPA) did not affect RA classification. However, combined positivity for IgA RF, IgM RF and IgG ACPA had a higher specificity and lower sensitivity for RA classification than positivity for either of the antibodies. Conclusions IgA RF showed a lower sensitivity than IgM RF. Combining IgA RF with IgM RF and ACPA did not improve sensitivity of RA classification. Combined positivity (IgA-RF/IgM-RF/ACPA) increased specificity.
|
|
| 6. |
- Van Hoovels, L., et al.
(författare)
-
Multicentre study to improve clinical interpretation of rheumatoid factor and anti-citrullinated protein/peptide antibodies test results
- 2022
-
Ingår i: RMD Open. - : BMJ. - 2056-5933. ; 8:1
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Rheumatoid factor (RF) and anti-citrullinated protein/peptide antibodies (ACPA) are important biomarkers for diagnosis of rheumatoid arthritis (RA). However, there is poor harmonisation of RF and ACPA assays. The aim of this study was to refine RF and ACPA interpretation across commercial assays. MATERIALS AND METHODS: Six total RF isotype-non-specific assays, 3 RF IgM isotype-specific assays and 9 ACPA immunoglobulin G assays of 13 different companies were evaluated using 398 diagnostic samples from patients with RA and 1073 disease controls. RESULTS: Using cut-offs proposed by the manufacturer, there was a large variability in diagnostic sensitivity and specificity between assays. Thresholds of antibody levels were determined based on predefined specificities and used to define test result intervals. Test result interval-specific likelihood ratios (LRs) were concordant across the different RF and ACPA assays. For all assays, the LR for RA increased with increasing antibody level. Higher LRs were found for ACPA than for RF. ACPA levels associated with LRs >80 were found in a substantial fraction (>22%) of patients with RA. CONCLUSION: Defining thresholds for antibody levels and assigning test result interval-specific LRs allows alignment of clinical interpretation for all RF and ACPA assays. © Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.
|
|
| 7. |
- Van Hoovels, L., et al.
(författare)
-
Standardisation of ACPA tests: evaluation of a new candidate reference preparation
- 2022
-
Ingår i: Annals of the Rheumatic Diseases. - : BMJ. - 0003-4967 .- 1468-2060. ; 81:10, s. 1379-1384
-
Tidskriftsartikel (refereegranskat)abstract
- Introduction Commercial assays measuring antibodies to citrullinated protein/peptide (ACPA) show poor quantitative agreement. The diagnostic industry has never adopted the International Union of Immunological Societies-Centers for Disease Control and Prevention (IUIS-CDC) ACPA reference standard. Recently, the National Institute for Biological Standards and Control (NIBSC) prepared a new candidate ACPA standard (18/204). We evaluated both reference materials using different commercially available ACPA assays. Materials and methods This is an international study in which the NIBSC candidate ACPA standard and the IUIS-CDC ACPA reference material were analysed together with 398 diagnostic samples from individuals with rheumatoid arthritis (RA) and in 1073 individuals who did not have RA using nine commercial ACPA assays. Results For both reference materials and samples from individuals with RA and individuals who did not have RA, there were large differences in quantitative ACPA results between assays. For most assays, values for the IUIS-CDC standard were lower than values for NIBSC 18/204 and the IUIS-CDC/NIBSC ratio was comparable for several, but not all assays. When NIBSC 18/204 was used as a calibrator, an improvement in alignment of ACPA results across several of the evaluated assays was obtained. Moreover, NIBSC 18/204 could align clinical interpretation for some but not all assays. Conclusion Adoption of an international standard for ACPA determination is highly desirable. The candidate NIBSC 18/204 standard improved the standardisation and alignment of most ACPA assays and might therefore be recommended to be used as reference in commercial assays.
|
|
| 8. |
- Aoun, M., et al.
(författare)
-
Antigen-presenting autoreactive B cells activate regulatory T cells and suppress autoimmune arthritis in mice
- 2023
-
Ingår i: Journal of Experimental Medicine. - Stockholm : Karolinska Institutet, Dept of Medical Biochemistry and Biophysics. - 0022-1007 .- 1540-9538. ; 220:11
-
Tidskriftsartikel (refereegranskat)abstract
- B cells undergo several rounds of selection to eliminate potentially pathogenic autoreactive clones, but in contrast to T cells, evidence of positive selection of autoreactive B cells remains moot. Using unique tetramers, we traced natural autoreactive B cells (C1-B) specific for a defined triple-helical epitope on collagen type-II (COL2), constituting a sizeable fraction of the physiological B cell repertoire in mice, rats, and humans. Adoptive transfer of C1-B suppressed arthritis independently of IL10, separating them from IL10-secreting regulatory B cells. Single-cell sequencing revealed an antigen processing and presentation signature, including induced expression of CD72 and CCR7 as surface markers. C1-B presented COL2 to T cells and induced the expansion of regulatory T cells in a contact-dependent manner. CD72 blockade impeded this effect suggesting a new downstream suppressor mechanism that regulates antigen-specific T cell tolerization. Thus, our results indicate that autoreactive antigen-specific naive B cells tolerize infiltrating T cells against self-antigens to impede the development of tissue-specific autoimmune inflammation.
|
|
| 9. |
|
|
| 10. |
- Appelgren, Daniel, et al.
(författare)
-
Active NET formation in Libman–Sacks endocarditis without antiphospholipid antibodies : A dramatic onset of systemic lupus erythematosus
- 2018
-
Ingår i: Autoimmunity. - : Informa UK Limited. - 0891-6934 .- 1607-842X. ; 51:6, s. 310-318
-
Tidskriftsartikel (refereegranskat)abstract
- Although neutrophil extracellular traps (NETs) have been highlighted in several systemic inflammatory diseases, their clinical correlates and potential pathological role remain obscure. Herein, we describe a dramatic onset of systemic lupus erythematosus (SLE) with clear-cut pathogenic implications for neutrophils and NET formation in a young woman with cardiac (Libman–Sacks endocarditis) and central nervous system (psychosis and seizures) involvement. Despite extensive search, circulating antiphospholipid autoantibodies, a hallmark of Libman–Sacks endocarditis, could not be detected. Instead, we observed active NET formation in the tissue of the mitral valve, as well as in the circulation. Levels of NET remnants were significantly higher in serially obtained sera from the patient compared with sex-matched blood donors (p =.0011), and showed a non-significant but substantial correlation with blood neutrophil counts (r = 0.65, p =.16). The specific neutrophil elastase activity measured in serum seemed to be modulated by the provided immunosuppressive treatment. In addition, we found anti-Ro60/SSA antibodies in the cerebrospinal fluid of the patient but not NET remnants or increased elastase activity. This case illustrates that different disease mechanisms mediated via autoantibodies can occur simultaneously in SLE. NET formation with release of cytotoxic NET remnants is a candidate player in the pathogenesis of this non-canonical form of Libman–Sacks endocarditis occurring in the absence of traditional antiphospholipid autoantibodies. The case description includes longitudinal results with clinical follow-up data and a discussion of the potential roles of NETs in SLE.
|
|
| 11. |
|
|
| 12. |
- Bentow, C., et al.
(författare)
-
International multi-center evaluation of a novel chemiluminescence assay for the detection of anti-dsDNA antibodies
- 2016
-
Ingår i: Lupus. - : SAGE PUBLICATIONS LTD. - 0961-2033 .- 1477-0962. ; 25:8, s. 864-872
-
Tidskriftsartikel (refereegranskat)abstract
- Objective: Anti-double stranded desoxyribonucleic acid (anti-dsDNA) antibodies are considered fairly specific for systemic lupus erythematosus (SLE) and their quantification is useful for the clinical management of SLE patients. We assessed the diagnostic performance of the QUANTA Flash dsDNA chemiluminescent immunoassay (CIA) in comparison to an ELISA, using patients from five participating countries. The main focus was to evaluate the correlation between anti-dsDNA antibody results from the CIA and global SLE disease activity, as measured by the SLE Disease Activity Index 2000 (SLEDAI-2K). Patients and methods: A total of 1431 samples (SLE, n=843; disease controls, n=588) from five countries (Canada, USA, Portugal, Sweden and Spain) were tested with QUANTA Flash dsDNA (Inova Diagnostics, San Diego, CA, USA). Data obtained with the QUANTA Lite dsDNA SC ELISA (Inova Diagnostics) were available for samples from three sites (Canada, USA and Sweden, n=566). The SLEDAI-2K scores were available for 805 SLE patients and a cut-off ofamp;gt;4 was used to define active disease. Results: QUANTA Flash dsDNA had a sensitivity of 54.3% for the diagnosis of SLE, combined with 89.8% specificity. Anti-dsDNA antibody levels were significantly higher (pamp;lt;0.0001) in active SLE (SLEDAI-2Kamp;gt;4; n=232; median value 83.0IU/mL) versus the inactive patients (n=573; median value 22.3IU/mL), and the SLEDAI-2K scoring correlated with their dsDNA antibody levels (Spearmans rho=0.44, pamp;lt;0.0001). Similar but less pronounced findings were also found for the ELISA, in relation to disease activity. Conclusions: The QUANTA Flash dsDNA assay showed good clinical performance in a large international multi-center study. Additionally, the strong correlation between anti-dsDNA antibody results and SLEDAI-2K scores supported the potential utility of QUANTA Flash dsDNA for monitoring disease activity.
|
|
| 13. |
- Berglin, Ewa, MD, PhD, 1955-, et al.
(författare)
-
Anti-neutrophil cytoplasmatic antibodies predate symptom onset of anca-associated vasculitis : a case-control study
- 2020
-
Ingår i: Annals of the Rheumatic Diseases. - : BMJ Publishing Group Ltd. - 0003-4967 .- 1468-2060. ; 79, s. 1065-1066
-
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
|
|
| 14. |
- Enocsson, Helena, et al.
(författare)
-
Soluble urokinase plasminogen activator receptor (suPAR) levels predict damage accrual in patients with recent-onset systemic lupus erythematosus
- 2020
-
Ingår i: Journal of Autoimmunity. - : Elsevier BV. - 0896-8411 .- 1095-9157. ; 106
-
Tidskriftsartikel (refereegranskat)abstract
- 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.
|
|
| 15. |
- Gomez, A., et al.
(författare)
-
OBESITY AND TOBACCO SMOKING ARE INDEPENDENTLY ASSOCIATED WITH POOR PATIENT-REPORTED OUTCOMES IN PATIENTS WITH SYSTEMIC LUPUS ERYTHEMATOSUS FROM A SWEDISH TERTIARY REFERRAL CENTRE
- 2022
-
Ingår i: Annals of the Rheumatic Diseases. - : HighWire Press. - 0003-4967 .- 1468-2060. ; 81:Suppl. 1, s. 1402-1402
-
Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Patients with systemic lupus erythematosus (SLE) experience impaired health-related quality of life (HRQoL), pain, fatigue and functional disability. The effect of pharmacotherapy on these aspects has been inconclusive in literature. In light of this, investigation of the impact of lifestyle facets is needed to support complementary non-pharmacological interventions such as weight control strategies and tobacco smoking cessation.ObjectivesTo evaluate associations of obesity and tobacco smoking with SLE patients’ HRQoL, pain, fatigue and functional disability.MethodsPatients from the Linköping University Hospital with an SLE diagnosis according to the 1982 American College of Rheumatology (ACR) and/or the 2012 Systemic Lupus International Collaborating Clinics (SLICC) criteria (n=325) were included in the present cross-sectional analysis of data captured at visits between January 2008 and September 2021. Among consecutive visits, the first visit with complete demographic, clinical and patient-reported data was selected for the present analysis.Body mass index (BMI) categories were based on the World Health Organization classification: underweight (BMI <18.5 kg/m2), normal weight (18.5≤ BMI <25 kg/m2), pre-obesity (25≤ BMI <30 kg/m2) and obesity (BMI ≥30 kg/m2). Smoking status was self-reported and categorised into never, prior and current smoking.HRQoL was self-reported using the 3-level EuroQoL 5-Dimension (EQ-5D-3L) index scores. Visual analogue scales (VAS; 0–100) were used to self-report fatigue, pain and well-being within the preceding 7 days. Functional disability was evaluated using the Swedish version of the Health Assessment Questionnaires Disability Index (HAQ-DI). Disease activity was evaluated using the clinical (c)SLEDAI-2K (serology excluded).Comparisons of continuous data between different BMI and smoking categories were performed using the Mann-Whitney U test and Kruskal-Wallis test. Multivariable linear regression analysis was employed to assess independence and priority of contributors to HRQoL and functional impairment.ResultsCompared with normal weight, obese individuals reported lower EQ-5D-3L index score [0.73 (0.36–0.80) versus 0.78 (0.68–0.85); P=0.014], as well as higher VAS fatigue [50.0 (27.0–72.5) versus 32.0 (6.5–59.5); P=0.008], VAS pain [40.0 (11.0–67.0) versus 20.5 (5.3–46.5); P=0.011] and HAQ scores [0.63 (0.13–1.13) versus 0.13 (0.0–0.63); P<0.001]. Similarly, ongoing smokers reported higher VAS fatigue [56.0 (28.0–78.0) versus 32.0 (8.0–58.0); P=0.001], VAS pain [45.0 (18.0–62.0) versus 18.0 (5.0–39.8); P=0.001] and HAQ scores [0.63 (0.13–1.13) versus 0.13 (0.0–0.63); P=0.001] compared with individuals who were never exposed to regular tobacco smoking. There were no differences across groups regarding cSLEDAI-2K scores.In multivariable linear regression models, obesity and current tobacco smoking were independently associated with lower EQ-5D-3L index scores (β=-0.12; P=0.021 and β=-0.11; P=0.029, respectively), and higher VAS fatigue (β=12.8; P=0.007 and β=17.5; P<0.001), VAS pain (β=12.1; P=0.004 and β=15.5; P<0.001), VAS well-being (β=9.6; P=0.028 and β=9.8; P=0.035) and HAQ scores (β=0.30; P=0.001 and β=0.27; P=0.007), but not with cSLEDAI-2K (β=-0.73; P=0.189 and β=0.34; P=0.572).ConclusionIn a Swedish SLE population, obesity and ongoing tobacco smoking were independently associated with worse outcomes - compared with normal weight and individuals who never smoked, respectively - regarding HRQoL, fatigue, pain and functional disability but were not associated with clinical disease activity.Disclosure of InterestsNone declared
|
|
| 16. |
- Gron, KL, et al.
(författare)
-
Risk of serious infections in patients with rheumatoid arthritis treated in routine care with abatacept, rituximab and tocilizumab in Denmark and Sweden
- 2019
-
Ingår i: Annals of the rheumatic diseases. - : BMJ. - 1468-2060 .- 0003-4967. ; 78:3, s. 320-327
-
Tidskriftsartikel (refereegranskat)abstract
- To estimate (1) crude and age-and gender-adjusted incidence rates (IRs) of serious infections (SI) and (2) relative risks (RR) of SI in patients with rheumatoid arthritis (RA) initiating treatment with abatacept, rituximab or tocilizumab in routine care.MethodsThis is an observational cohort study conducted in parallel in Denmark and Sweden including patients with RA in Denmark (DANBIO) and Sweden (Anti-Rheumatic Treatment in Sweden Register/Swedish Rheumatology Quality Register) who started abatacept/rituximab/tocilizumab in 2010–2015. Patients could contribute to more than one treatment course. Incident SI (hospitalisations listing infection) and potential confounders were identified through linkage to national registries. Age- and gender-adjusted IRs of SI per 100 person years and additionally adjusted RRs of SI during 0–12 and 0–24 months since start of treatment were assessed (Poisson regression). Country-specific RRs were pooled using inverse variance weighting.ResultsWe identified 8987 treatment courses (abatacept: 2725; rituximab: 3363; tocilizumab: 2899). At treatment start, rituximab-treated patients were older, had longer disease duration and more previous malignancies; tocilizumab-treated patients had higher C reactive protein. During 0–12 and 0–24 months of follow-up, 456 and 639 SI events were identified, respectively. The following were the age- and gender-adjusted 12-month IRs for abatacept/rituximab/tocilizumab: 7.1/8.1/6.1 for Denmark and 6.0/6.4/4.7 for Sweden. The 24-month IRs were 6.1/7.5/5.2 for Denmark and 5.6/5.8/4.3 for Sweden. Adjusted 12-month RRs for tocilizumab versus rituximab were 0.82 (0.50 to 1.36) for Denmark and 0.76 (0.57 to 1.02) for Sweden, pooled 0.78 (0.61 to 1.01); for abatacept versus rituximab 0.94 (0.55 to 1.60) for Denmark and 0.86 (0.66 to 1.13) for Sweden, pooled 0.88 (0.69 to 1.12); and for abatacept versus tocilizumab 1.15 (0.69 to 1.90) for Denmark and 1.14 (0.83 to 1.55) for Sweden, pooled 1.13 (0.91 to 1.42). The adjusted RRs for 0–24 months were similar.ConclusionFor patients starting abatacept, rituximab or tocilizumab, differences in baseline characteristics were seen. Numerical differences in IR of SI between drugs were observed. RRs seemed to vary with drug (tocilizumab < abatacept < rituximab) but should be interpreted with caution due to few events and risk of residual confounding.
|
|
| 17. |
|
|
| 18. |
- Loeff, Floris C., et al.
(författare)
-
Belimumab concentration measurements using a homologous anti-idiotype immunoassay
- 2024
-
Ingår i: JIM - Journal of Immunological Methods. - : Elsevier. - 0022-1759 .- 1872-7905.
-
Tidskriftsartikel (refereegranskat)abstract
- Monitoring belimumab concentrations in patients can be a valuable tool for assessing treatment response and for personalizing drug doses. Various assay formats may be used to measure concentrations of therapeutic monoclonal antibodies. A particularly useful format involves the use of anti-idiotype monoclonal antibodies, selected to be highly specific to the antibody of interest. Here, we describe the development of a specific, high-affinity anti-idiotype antibody to belimumab, and the application of this antibody in a homologous sandwich ELISA to measure belimumab concentrations.
|
|
| 19. |
- Lundtoft, Christian, et al.
(författare)
-
Strong Association of Combined Genetic Deficiencies in the Classical Complement Pathway With Risk of Systemic Lupus Erythematosus and Primary Sjogren's Syndrome
- 2022
-
Ingår i: Arthritis & Rheumatology. - : Wiley. - 2326-5191 .- 2326-5205. ; 74:11, s. 1842-1850
-
Tidskriftsartikel (refereegranskat)abstract
- Objective Complete genetic deficiency of the complement component C2 is a strong risk factor for monogenic systemic lupus erythematosus (SLE), but whether heterozygous C2 deficiency adds to the risk of SLE or primary Sjogren's syndrome (SS) has not been studied systematically. This study was undertaken to investigate potential associations of heterozygous C2 deficiency and C4 copy number variation with clinical manifestations in patients with SLE and patients with primary SS. Methods The presence of the common 28-bp C2 deletion rs9332736 and C4 copy number variation was examined in Scandinavian patients who had received a diagnosis of SLE (n = 958) or primary SS (n = 911) and in 2,262 healthy controls through the use of DNA sequencing. The concentration of complement proteins in plasma and classical complement function were analyzed in a subgroup of SLE patients. Results Heterozygous C2 deficiency-when present in combination with a low C4A copy number-substantially increased the risk of SLE (odds ratio [OR] 10.2 [95% confidence interval (95% CI) 3.5-37.0]) and the risk of primary SS (OR 13.0 [95% CI 4.5-48.4]) when compared to individuals with 2 C4A copies and normal C2. For patients heterozygous for rs9332736 with 1 C4A copy, the median age at diagnosis was 7 years earlier in patients with SLE and 12 years earlier in patients with primary SS when compared to patients with normal C2. Reduced C2 levels in plasma (P = 2 x 10(-9)) and impaired function of the classical complement pathway (P = 0.03) were detected in SLE patients with heterozygous C2 deficiency. Finally, in a primary SS patient homozygous for C2 deficiency, we observed low levels of anti-Scl-70, which suggests a risk of developing systemic sclerosis or potential overlap between primary SS and other systemic autoimmune diseases. Conclusion We demonstrate that a genetic pattern involving partial deficiencies of C2 and C4A in the classical complement pathway is a strong risk factor for SLE and for primary SS. Our results emphasize the central role of the complement system in the pathogenesis of both SLE and primary SS.
|
|
| 20. |
- Olsson, Lina M., et al.
(författare)
-
A single nucleotide polymorphism in the NCF1 gene leading to reduced oxidative burst is associated with systemic lupus erythematosus
- 2017
-
Ingår i: Annals of the Rheumatic Diseases. - : BMJ Publishing Group Ltd. - 0003-4967 .- 1468-2060. ; 76:9, s. 1607-1613
-
Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: Ncf1 polymorphisms leading to low production of reactive oxygen species (ROS) are strongly associated with autoimmune diseases in animal models. The human NCF1 gene is very complex with both functional and non-functional gene copies and genotyping requires assays specific for functional NCF1 genes. We aimed at investigating association and function of the missense single nucleotide polymorphism (SNP), rs201802880 (here denoted NCF1-339) in NCF1 with systemic lupus erythematosus (SLE).METHODS: We genotyped the NCF1-339 SNP in 973 Swedish patients with SLE and 1301 controls, using nested PCR and pyrosequencing. ROS production and gene expression of type 1 interferon-regulated genes were measured in isolated cells from subjects with different NCF1-339 genotypes.RESULTS: We found an increased frequency of the NCF1-339 T allele in patients with SLE, 11% compared with 4% in controls, OR 3.0, 95% CI 2.4 to 3.9, p=7.0×10(-20). The NCF1-339 T allele reduced extracellular ROS production in neutrophils (p=0.004) and led to an increase expression of type 1 interferon-regulated genes. In addition, the NCF1-339 T allele was associated with a younger age at diagnosis of SLE; mean age 30.3 compared with 35.9, p=2.0×1(-6).CONCLUSIONS: These results clearly demonstrate that a genetically controlled reduced production of ROS increases the risk of developing SLE and confirm the hypothesis that ROS regulate chronic autoimmune inflammatory diseases.
|
|
| 21. |
- Parodis, I., 1981-, et al.
(författare)
-
De novo renal flares in SLE patients treated for active extra renal disease within five phase Ill clinical trials of belimumab : Implications for revisiting belimumab dose
- 2023
-
Ingår i: Scandinavian Journal of Rheumatology. - : Taylor & Francis. - 0300-9742 .- 1502-7732. ; 52:Suppl. 131, s. 46-46
-
Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Background including aims: Each lupus nephritis (LN) flare causes substantial nephron loss. Identification of reliable signals of impending flare is imperative. In light of observed cases of de novo LN during belimumab treatment, we evaluated predictors of de novo renal flare occurrence in patients with systemic lupus erythematosus (SLE) and no prior history of renal disease undergoing standard therapy with or without add-on belimumab within the frame of five phase III clinical trials.Methods: Data from five phase III clinical trials of belimumab in SLE i.e., BLISS-52 (NCT00424476; N=865); BLISS-76 (NCT00410384; N=819); BLISS-NEA (NCT01345253; N=677); BLISS-SC (NCT01484496; N=836); EMBRACE (NCT0163224; N=448) were utilised. De novo renal flares were defined as a change from renal British Isles Lupus Assessment Group (BILAG) E to A or B within a 52-week follow-up. Predictors of renal flare occurrence were investigated using Cox regression analysis.Results: Of 1844 eligible patients, 136 (7.4%) developed a de novo renal flare during a 52-week long follow-up. In multivariable analysis adjusting for potential confounders, Asian origin (HR: 1.97; 95% CI: 1.33–2.94; p=0.001), high mean prednisone dose from baseline until renal flare occurrence or throughout follow-up (HR: 1.03; 95% CI: 1.02–1.04; p<0.001), and positive levels of anti-dsDNA (HR: 1.32; 95% CI: 1.08–1.63; p=0.008) were associated with de novo renal flares. Low-dose intravenous (IV) belimumab (1 mg/kg) yielded a nearly 3-fold lower hazard of de novo renal flare occurrence (HR: 0.38; 95% CI: 0.20–0.73; p=0.004) and subcutaneous (SC) belimumab (200 mg weekly) yielded a lower, but less decreased, hazard (HR: 0.69; 95% CI: 0.54–0.88; p=0.003). However, the labelled dose of IV belimumab (10 mg/kg) did not provide protection (HR: 0.74; 95% CI: 0.50–1.09; p=0.127).Conclusions: Our findings corroborate the substantial vulnerability of Asian SLE populations to renal affliction. Add-on low-dose IV belimumab 1 mg/kg appeared most protective against renal flares in nephritis-naïve SLE patients, while the approved IV dose (10 mg/kg) yielded no clear protection.
|
|
| 22. |
- Peretz, A. S. R., et al.
(författare)
-
Galectin-3-binding protein is a novel predictor of venous thromboembolism in systemic lupus erythematosus
- 2021
-
Ingår i: Clinical and Experimental Rheumatology. - Pisa, Italy : Clinical and Experimental Rheumatology. - 0392-856X .- 1593-098X. ; 39:6, s. 1360-1368
-
Tidskriftsartikel (refereegranskat)abstract
- Objective 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. Conclusion 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.
|
|
| 23. |
- Sjöwall, Christopher, et al.
(författare)
-
Altered glycosylation of complexed native IgG molecules is associated with disease activity of systemic lupus erythematosus
- 2015
-
Ingår i: Lupus. - : Sage Publications. - 0961-2033 .- 1477-0962. ; 24:6, s. 569-581
-
Tidskriftsartikel (refereegranskat)abstract
- In addition to the redundancy of the receptors for the Fc portion of immunoglobulins, glycans result in potential ligands for a plethora of lectin receptors found in immune effector cells. Here we analysed the exposure of glycans containing fucosyl residues and the fucosylated tri-mannose N-type core by complexed native IgG in longitudinal serum samples of well-characterized patients with systemic lupus erythematosus. Consecutive serum samples of a cohort of 15 patients with systemic lupus erythematosus during periods of increased disease activity and remission were analysed. All patients fulfilled the 1982 American College of Rheumatology classification criteria. Sera of 15 sex- and age-matched normal healthy blood donors served as controls. The levels and type of glycosylation of complexed random IgG was measured with lectin enzyme-immunosorbent assays. After specifically gathering IgG complexes from sera, biotinylated lectins Aleuria aurantia lectin and Lens culinaris agglutinin were employed to detect IgG-associated fucosyl residues and the fucosylated tri-mannose N-glycan core, respectively. In sandwich-ELISAs, IgG-associated IgM, IgA, C1q, C3c and C-reactive protein (CRP) were detected as candidates for IgG immune complex constituents. We studied associations of the glycan of complexed IgG and disease activity according to the physician's global assessment of disease activity and the systemic lupus erythematosus disease activity index 2000 documented at the moment of blood taking. Our results showed significantly higher levels of Aleuria aurantia lectin and Lens culinaris agglutinin binding sites exposed on IgG complexes of patients with systemic lupus erythematosus than on those of normal healthy blood donors. Disease activity in systemic lupus erythematosus correlated with higher exposure of Aleuria aurantia lectin-reactive fucosyl residues by immobilized IgG complexes. Top levels of Aleuria aurantia lectin-reactivity were found in samples taken during the highest activity of systemic lupus erythematosus. Our results show that native circulating IgG complexes from active systemic lupus erythematosus patients expose fucosyl residues and their glycan core is accessible to soluble lectins. Two putative mechanisms may contribute to the increased exposure of these glycans: (1) the canonical N-glycosylation site of the IgG-CH2 domain; (2) an IgG binding non-IgG molecule, like complement or C-reactive protein. In both cases the complexed IgG may be alternatively targeted to lectin receptors of effector cells, e.g. dendritic cells.
|
|
| 24. |
- Sjöwall, J, et al.
(författare)
-
Innate immune responses in Lyme borreliosis : enhanced tumour necrosis factor-alpha and interleukin-12 in asymptomatic individuals in response to live spirochetes
- 2005
-
Ingår i: Clinical and Experimental Immunology. - Oxford : Blackwell Publishing. - 0009-9104 .- 1365-2249. ; 141:1, s. 89-98
-
Tidskriftsartikel (refereegranskat)abstract
- Innate immunity is important for early defence against borrelia spirochetes and should play a role in the clinical outcome of the infection. In order to study early cytokine responses, in vitro differentiated dendritic cells (DCs) and whole blood cells from 21 patients with different clinical outcomes of Lyme neuroborreliosis were stimulated with live borrelia spirochetes. The borrelia-induced secretion of interleukin (IL)-4, IL-10, IL-12p70, interferon (IFN)-gamma and tumour necrosis factor (TNF)-alpha in DCs and IL-1 beta, IL-6, IL-8, IL-10, IL-12p70, TNF-alpha, regulated upon activation normal T cell expressed and secreted (RANTES), monocyte chemoattractant protein (MCP)-1, macrophage inflammatory protein (MIP)-1 alpha, MIP-1 beta and eotaxin in whole blood cells was measured by enzyme-linked immunospot (ELISPOT) and multiplex arrays, respectively. We found increased numbers of TNF-alpha-secreting DCs (P = 0.018) in asymptomatic seropositive individuals compared to patients with subacute neuroborreliosis and seronegative controls. Asymptomatic individuals were also found to have elevated levels of IL-12p70 (P = 0.031) in whole blood cell supernatants compared to seronegative controls. These results are in line with previous experiments using cells of the adaptive immune response, indicating that strong T helper type 1 (Th1) proinflammatory responses might be associated with a successful resolution of Lyme disease.
|
|
| 25. |
- Viljanen, Johan V., et al.
(författare)
-
Synthesis of an Array of Triple-Helical Peptides from Type II Collagen for Multiplex Analysis of Autoantibodies in Rheumatoid Arthritis
- 2020
-
Ingår i: ACS Chemical Biology. - : American Chemical Society (ACS). - 1554-8929 .- 1554-8937. ; 15:9, s. 2605-2615
-
Tidskriftsartikel (refereegranskat)abstract
- 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. Copyright © 2020 American Chemical Society.
|
|
