umu.sePublications
Change search
Link to record
Permanent link

Direct link
BETA
Rantapää-Dahlqvist, SolbrittORCID iD iconorcid.org/0000-0001-8259-3863
Alternative names
Publications (10 of 347) Show all publications
Reid, S., Alexsson, A., Frodlund, M., Morris, D., Sandling, J. K., Bolin, K., . . . Leonard, D. (2020). High genetic risk score is associated with early disease onset, damage accrual and decreased survival in systemic lupus erythematosus. Annals of the Rheumatic Diseases, 79(3), 363-369
Open this publication in new window or tab >>High genetic risk score is associated with early disease onset, damage accrual and decreased survival in systemic lupus erythematosus
Show others...
2020 (English)In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 79, no 3, p. 363-369Article in journal (Refereed) Published
Abstract [en]

Objectives To investigate associations between a high genetic disease risk and disease severity in patients with systemic lupus erythematosus (SLE).

Methods Patients with SLE (n=1001, discovery cohort and n=5524, replication cohort) and healthy controls (n=2802 and n=9859) were genotyped using a 200K Immunochip single nucleotide polymorphism array. A genetic risk score (GRS) was assigned to each individual based on 57 SLE risk loci.

Results SLE was more prevalent in the high, compared with the low, GRS-quartile (OR 12.32 (9.53 to 15.71), p=7.9x10(-86) and OR 7.48 (6.73 to 8.32), p=2.2x10(-304) for the discovery and the replication cohorts, respectively). In the discovery cohort, patients in the high GRS-quartile had a 6-year earlier mean disease onset (HR 1.47 (1.22 to 1.75), p=4.3x10(-5)), displayed higher prevalence of damage accrual (OR 1.47 (1.06 to 2.04), p=2.0x10(-2)), renal disorder (OR 2.22 (1.50 to 3.27), p=5.9x10(-5)), anti-dsDNA (OR 1.83 (1.19 to 2.81), p=6.1x10(-3)), end-stage renal disease (ESRD) (OR 5.58 (1.50 to 20.79), p=1.0x10(-2)), proliferative nephritis (OR 2.42 (1.30 to 4.49), p=5.1x10(-3)), anti-cardiolipin-IgG (OR 1.89 (1.13 to 3.18), p=1.6x10(-2)), anti-beta 2-glycoprotein-I-IgG (OR 2.29 (1.29 to 4.06), p=4.8x10(-3)) and positive lupus anticoagulant test (OR 2.12 (1.16 to 3.89), p=1.5x10(-2)) compared with patients in the low GRS-quartile. Survival analysis showed earlier onset of the first organ damage (HR 1.51 (1.04 to 2.25), p=3.7x10(-2)), first cardiovascular event (HR 1.65 (1.03 to 2.64), p=2.6x10(-2)), nephritis (HR 2.53 (1.72 to 3.71), p=9.6x10(-7)), ESRD (HR 6.78 (1.78 to 26.86), p=6.5x10(-3)) and decreased overall survival (HR 1.83 (1.02 to 3.30), p=4.3x10(-2)) in high to low quartile comparison.

Conclusions A high GRS is associated with increased risk of organ damage, renal dysfunction and all-cause mortality. Our results indicate that genetic profiling may be useful for predicting outcomes in patients with SLE.

Place, publisher, year, edition, pages
BMJ PUBLISHING GROUP, 2020
National Category
Rheumatology and Autoimmunity
Identifiers
urn:nbn:se:umu:diva-169376 (URN)10.1136/annrheumdis-2019-216227 (DOI)000519264600019 ()31826855 (PubMedID)
Available from: 2020-04-06 Created: 2020-04-06 Last updated: 2020-04-06Bibliographically approved
Svärd, A., Ljungberg, K. R., Brink, M., Martinsson, K., Sjöwall, C., Rantapää-Dahlqvist, S. & Kastbom, A. (2020). Secretory antibodies to citrullinated peptides in plasma and saliva from rheumatoid arthritis patients and their unaffected first-degree relatives. Clinical and Experimental Immunology, 199(2), 143-149
Open this publication in new window or tab >>Secretory antibodies to citrullinated peptides in plasma and saliva from rheumatoid arthritis patients and their unaffected first-degree relatives
Show others...
2020 (English)In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 199, no 2, p. 143-149Article in journal (Refereed) Published
Abstract [en]

The aim of this study was to evaluate secretory antibodies to citrullinated proteins (ACPA) in plasma and immunoglobulin (Ig)A ACPA in saliva from patients with rheumatoid arthritis (RA) and their unaffected first-degree relatives (FDRs). Patients with RA (n = 194) and first-degree relatives unaffected by RA (n = 191) were recruited for analysis of secretory antibodies to second-generation cyclic citrullinated peptides (anti-CCP) in plasma. From a subpopulation (25 RA patients, 21 first-degree relatives and 11 controls), saliva samples were obtained for IgA anti-CCP analysis. The presence of secretory ACPA was compared between subject categories, and related to genetic and environmental risk factors. Secretory ACPA occurred in 37 (19%) plasma samples from patients with RA, but only in two (1%) of FDRs. IgA ACPA in saliva was found in three of 25 (12%) patients with RA, but not in any of the 21 FDRs (< 5%). No significant associations were seen between the presence of secretory ACPA and SE or smoking, either among RA patients or among FDRs. Despite occurring in 19% of RA plasma, secretory ACPA was rare in both saliva and plasma among FDRs, even among those positive for conventional ACPA of non-mucosal origin. Longitudinal studies are warranted to determine whether circulating secretory ACPA occurs before or in parallel with the development of clinical arthritis.

Place, publisher, year, edition, pages
WILEY, 2020
Keywords
ACPA, mucosa, relatives, rheumatoid arthritis, secretory immunoglobulin
National Category
Rheumatology and Autoimmunity
Identifiers
urn:nbn:se:umu:diva-167960 (URN)10.1111/cei.13381 (DOI)000506542200004 ()31605388 (PubMedID)
Available from: 2020-02-25 Created: 2020-02-25 Last updated: 2020-02-25Bibliographically approved
Skielta, M., Soderstrom, L., Rantapää-Dahlqvist, S., Jonsson, S. W. & Mooe, T. (2020). Trends in mortality, co-morbidity and treatment after acute myocardial infarction in patients with rheumatoid arthritis 1998-2013. European heart journal. Acute cardiovascular care., Article ID 2048872619896069.
Open this publication in new window or tab >>Trends in mortality, co-morbidity and treatment after acute myocardial infarction in patients with rheumatoid arthritis 1998-2013
Show others...
2020 (English)In: European heart journal. Acute cardiovascular care., ISSN 2048-8726, article id 2048872619896069Article in journal (Refereed) Epub ahead of print
Abstract [en]

Aims: Rheumatoid arthritis may influence the outcome after an acute myocardial infarction. We aimed to compare trends in one-year mortality, co-morbidities and treatments after a first acute myocardial infarction in patients with rheumatoid arthritis versus non-rheumatoid arthritis patients during 1998-2013. Furthermore, we wanted to identify characteristics associated with mortality. Methods and results: Data for 245,377 patients with a first acute myocardial infarction were drawn from the Swedish Register of Information and Knowledge about Swedish Heart Intensive Care Admissions for 1998-2013. In total, 4268 patients were diagnosed with rheumatoid arthritis. Kaplan-Meier analysis was used to study mortality trends over time and multivariable Cox regression analysis was used to identify variables associated with mortality. The one-year mortality in rheumatoid arthritis patients was initially lower compared to non-rheumatoid arthritis patients (14.7% versus 19.7%) but thereafter increased above that in non-rheumatoid arthritis patients (17.1% versus 13.5%). In rheumatoid arthritis patients the mean age at admission and the prevalence of atrial fibrillation increased over time. Congestive heart failure decreased more in non-rheumatoid arthritis than in rheumatoid arthritis patients. Congestive heart failure, atrial fibrillation, kidney failure, rheumatoid arthritis, prior diabetes mellitus and hypertension were associated with significantly higher one-year mortality during the study period 1998-2013. Conclusions: The decrease in one-year mortality after acute myocardial infarction in non-rheumatoid arthritis patients was not applicable to rheumatoid arthritis patients. This could partly be explained by an increased age at acute myocardial infarction onset and unfavourable trends with increased atrial fibrillation and congestive heart failure in rheumatoid arthritis. Rheumatoid arthritis per se was associated with a significantly worse prognosis.

Place, publisher, year, edition, pages
SAGE PUBLICATIONS LTD, 2020
Keywords
Mortality, rheumatoid arthritis, myocardial infarction, congestive heart failure, atrial fibrillation
National Category
Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:umu:diva-168126 (URN)10.1177/2048872619896069 (DOI)000509936500001 ()31990203 (PubMedID)
Available from: 2020-02-21 Created: 2020-02-21 Last updated: 2020-02-21
Lindquist, S., Alenius, G.-M., Berntson, L., Rantapää-Dahlqvist, S., Lundberg, L., Wang, Y. & Hernell, O. (2019). A novel target for treatment of inflammatory joint diseases. Paper presented at Annual European Congress of Rheumatology (EULAR), Madrid, Spain, June 12-15, 2019. Annals of the Rheumatic Diseases, 78, 1525-1526
Open this publication in new window or tab >>A novel target for treatment of inflammatory joint diseases
Show others...
2019 (English)In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 78, p. 1525-1526Article in journal, Meeting abstract (Other academic) Published
Abstract [en]

Background: The bile salt-stimulated lipase (BSSL) is a hitherto unrecognized player in inflammation. Animals devoid of BSSL (knockout mice) are protected from developing collagen induced arthritis (CIA) and collagen antibody induced arthritis (CAIA), and antibodies directed towards BSSL has been proven to prevent or mitigate arthritis in mouse and rat arthritis models1. In humans, BSSL is present in blood2 and accumulate at sites of inflammation. Patients with acute pancreatitis have significantly increased plasma BSSL levels compared to healthy controls. Whether BSSL in blood originates from pancreas, inflammatory cells, or both remains to be elucidated.

Objectives: To determine BSSL concentration in blood samples from patients with inflammatory joint disorders and to evaluate possible relationships between circulating BSSL levels and disease-activity variables.

Methods: BSSL concentrations in plasma or serum were determined in patients with rheumatoid arthritis (RA), psoriasis arthritis (PsA), and juvenile idiopathic arthritis (JIA) by a sandwich enzyme-linked immunosorbent assay (ELISA). Correlations between BSSL concentrations and disease activity score, erythrocyte sedimentation rate (ESR), blood levels of C-reactive protein (CRP), S100A8/9, leukocyte- and neutrophil counts, proinflammatory cytokines and chemokines were analyzed using Spearman rank-order correlation.

Results: Significant correlations between BSSL concentration in plasma and disease activity score (DAS28, rS=0.31, p=0.007), ESR (rS=0.58, p<0.000), CRP (rS=0.42, p=0.012), leukocytes (rS=0.66, p<0.000), and neutrophils (rS=0.71, p<0.000) were found in RA. The BSSL plasma concentration decreased with duration of treatment with the TNFα inhibitor infliximab, in parallel with decreasing DAS28 score.

BSSL concentration was significantly higher in sera from PsA patients with both oligo- and polyarthritis compared with healthy controls. Moreover, BSSL concentration in serum correlated significantly with S100A8/A9 and CRP concentrations (rS=0.54, p<0.001 and rS=0.49, p<0.001, respectively). No correlation between levels of BSSL and cytokines or chemokines were found in RA or PsA plasma or serum, respectively.

In JIA, levels of BSSL in serum correlated significantly with JIA disease activity score (JADAS27) (rS=0.26, p=0.007), ESR (rS=0.47, p<0.000), and leukocytes (rS=0.32, p<0.000).

Conclusion: BSSL concentration in serum and plasma correlated with disease activity in patients with inflammatory joint disorders, i.e. RA, PsA and JIA. These data in humans support the relevance of our previous studies in rodents and therefore also our hypothesis 1 that BSSL is a novel target for treatment of inflammatory diseases.

Place, publisher, year, edition, pages
BMJ Publishing Group Ltd, 2019
National Category
Rheumatology and Autoimmunity
Identifiers
urn:nbn:se:umu:diva-161720 (URN)10.1136/annrheumdis-2019-eular.2165 (DOI)000472207104460 ()
Conference
Annual European Congress of Rheumatology (EULAR), Madrid, Spain, June 12-15, 2019
Available from: 2019-07-26 Created: 2019-07-26 Last updated: 2019-07-26Bibliographically approved
Farias, F. H. G., Dahlqvist, J., Kozyrev, S. V., Leonard, D., Wilbe, M., Abramov, S. N., . . . Lindblad-Toh, K. (2019). A rare regulatory variant in the MEF2D gene affects gene regulation and splicing and is associated with a SLE sub-phenotype in Swedish cohorts. European Journal of Human Genetics, 27(3), 432-441
Open this publication in new window or tab >>A rare regulatory variant in the MEF2D gene affects gene regulation and splicing and is associated with a SLE sub-phenotype in Swedish cohorts
Show others...
2019 (English)In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 27, no 3, p. 432-441Article in journal (Refereed) Published
Abstract [en]

Systemic lupus erythematosus (SLE) is an autoimmune disorder with heterogeneous clinical presentation and complex etiology involving the interplay between genetic, epigenetic, environmental and hormonal factors. Many common SNPs identified by genome wide-association studies (GWAS) explain only a small part of the disease heritability suggesting the contribution from rare genetic variants, undetectable in GWAS, and complex epistatic interactions. Using targeted resequencing of coding and conserved regulatory regions within and around 215 candidate genes selected on the basis of their known role in autoimmunity and genes associated with canine immune-mediated diseases, we identified a rare regulatory variant rs200395694:G > T located in intron 4 of the MEF2D gene encoding the myocyte-specific enhancer factor 2D transcription factor and associated with SLE in Swedish cohorts (504 SLE patients and 839 healthy controls, p = 0 .014 , CI = 1.1-10). Fisher's exact test revealed an association between the genetic variant and a triad of disease manifestations including Raynaud, anti-Ul-ribonucleoprotein (anti-RNP), and anti-Smith (anti-Sm) antibodies (p = 0.00037) among the patients. The DNA-binding activity of the allele was further studied by EMSA, reporter assays, and minigenes. The region has properties of an active cell-specific enhancer, differentially affected by the alleles of rs200395694:G > T. In addition, the risk allele exerts an inhibitory effect on the splicing of the alternative tissue-specific isoform, and thus may modify the target gene set regulated by this isoform. These findings emphasize the potential of dissecting traits of complex diseases and correlating them with rare risk alleles with strong biological effects.

Place, publisher, year, edition, pages
Nature Publishing Group, 2019
National Category
Medical Genetics
Identifiers
urn:nbn:se:umu:diva-156863 (URN)10.1038/s41431-018-0297-x (DOI)000458626500013 ()30459414 (PubMedID)
Available from: 2019-03-12 Created: 2019-03-12 Last updated: 2019-03-12Bibliographically approved
Boman, A., Brink, M., Lundquist, A., Hansson, M., Mathsson-Alm, L., Rönnelid, J., . . . Rantapää-Dahlqvist, S. (2019). Antibodies against citrullinated peptides are associated with clinical and radiological outcomes in patients with early rheumatoid arthritis: a prospective longitudinal inception cohort study. RMD Open, 5(2), Article ID e000946.
Open this publication in new window or tab >>Antibodies against citrullinated peptides are associated with clinical and radiological outcomes in patients with early rheumatoid arthritis: a prospective longitudinal inception cohort study
Show others...
2019 (English)In: RMD Open, E-ISSN 2056-5933, Vol. 5, no 2, article id e000946Article in journal (Refereed) Published
Abstract [en]

Introduction: Anticitrullinated peptide antibody (ACPA) responses for 22 citrullinated peptides in patients with early rheumatoid arthritis (RA) were analysed and related to radiological and clinical outcome during the first 2 years in a prospective inception cohort.

Methods: The ACPA reactivities were assessed in 1022 patients with early RA (symptoms <12 months) using the custom-made microarray chip (Thermo Fisher Scientific, Uppsala, Sweden) in a prospective longitudinal study of observational assessments of Disease Activity Score (DAS28 and its components) and radiology during the first 24 months, accounting for the treatment.

Results: Frequency of ACPA reactivities varied between 13.3% and 63.1%. Of the anticyclic citrullinated peptide-2 (anti-CCP2) antibody-negative patients, ACPA reactivities were positive in 32.6%. Smoking, human leucocyte antigen-shared epitope (HLA-SE), anti-CCP2/rheumatoid factor, protein tyrosine phosphatase non-receptor type 22 (1858C/T) and DAS28 were significantly associated with number of ACPA reactivities. The ACPA reactivities modified differently the development of DAS28 over 24 months (identified using trajectories). Anti-Filaggrin307-324, anti-hnRNP (Peptide)-Z1 and anti-F4-CIT-R antibodies anticipated lower DAS28 values (p<0.01–0.05), while positivity for anti-Fibrinogen(Fib)β62-78(74), and anti-Fibα563-583 predicted higher DAS28 (p<0.01 both). Interaction between anti-Fibß36-52, anti-Pept-5 and anti-Bla-26 antibodies, respectively, and DAS28 during 24 months decreased significantly the DAS28 values (p<0.01–0.05). Corticosteroids and biologicals were related to DAS28-area under the curve and Larsen score 24 months. Anti-vimentin2-17 antibodies remained significantly associated with Larsen score at baseline and 24 months, respectively, and radiological progression, besides biologicals at 24 months adjusted for sex and age.

Conclusions: Several ACPA reactivities modified significantly the DAS28 development during the first 24 months and were significantly associated with Larsen score at baseline, 24 months and radiological progression.

Place, publisher, year, edition, pages
BMJ Publishing Group Ltd, 2019
National Category
Rheumatology and Autoimmunity
Identifiers
urn:nbn:se:umu:diva-165746 (URN)10.1136/rmdopen-2019-000946 (DOI)000496133800042 ()31565241 (PubMedID)
Funder
Swedish Research Council, K2013-52X-2030707-3Swedish Research Council, Dnr:2018-02551King Gustaf V Jubilee Fund
Available from: 2019-12-10 Created: 2019-12-10 Last updated: 2020-03-10Bibliographically approved
Södergren, A., Karp, K., Bengtsson, C., Möller, B., Rantapää-Dahlqvist, S. & Wållberg-Jonsson, S. (2019). Biomarkers associated with cardiovascular disease in patients with early rheumatoid arthritis. PLoS ONE, 14(8), Article ID e0220531.
Open this publication in new window or tab >>Biomarkers associated with cardiovascular disease in patients with early rheumatoid arthritis
Show others...
2019 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 14, no 8, article id e0220531Article in journal (Refereed) Published
Abstract [en]

Objectives: Patients with rheumatoid arthritis (RA) have an increased mortality and morbidity due to cardiovascular disease (CVD). In this prospective 5-year follow up of patients with RA, we analysed several biomarkers, known to be associated with atherosclerosis and/or inflammation in the general population. The aim of this study was to find out whether the RA-disease per se affect these biomarkers and if those could be associated with the progression of atherosclerosis, as measured by intima media thickness (IMT) among patients with early RA.

Methods: Patients from northern Sweden diagnosed with early RA, are consecutively recruited into an ongoing prospective study on CVD comorbidity. A subgroup of patients, aged ≤60 years (n = 71) was included for ultrasound measurements of IMT at inclusion (T0) and after 5 years (T5) together with age-sex-matched controls (n = 40). The patients were clinically assessed. Blood was analysed for lipids, ESR and CRP and several biomarkers known to be associated with atherosclerosis in the general population.

Results: At T0, the patients with RA had significantly lower levels of MIF and significantly higher levels of interleukin (IL)-18 and MIC-1 compared with controls. At T5, the patients with RA had significantly higher levels of pentraxin3, MIC-1, TNF-R2, ICAM-1, VCAM-1 and endostatin compared with controls. At T0 the levels of MPO correlated with DAS28, sCD40L with CRP and IL-18 with systolic blood pressure and Reynolds risk score. Using PLSR on a CVD-panel analysed with multiplex immunoassay, the patients with RA could be correctly classified into those who had a worsening in their IMT over the five years or not. Here, MMP3 was identified as influential.

Conclusions: This study indicates that the RA disease itself could affect several of the biomarkers in this study, and possibly also the processes involved in the development of atherosclerosis.

Place, publisher, year, edition, pages
Public Library of Science, 2019
National Category
Rheumatology and Autoimmunity
Identifiers
urn:nbn:se:umu:diva-164650 (URN)10.1371/journal.pone.0220531 (DOI)000484993600022 ()31381601 (PubMedID)2-s2.0-85070281863 (Scopus ID)
Available from: 2019-10-25 Created: 2019-10-25 Last updated: 2019-10-25Bibliographically approved
Terao, C., Brynedal, B., Chen, Z., Jiang, X., Westerlind, H., Hansson, M., . . . Raychaudhuri, S. (2019). Distinct HLA Associations with Rheumatoid Arthritis Subsets Defined by Serological Subphenotype. American Journal of Human Genetics, 105(3), 616-624
Open this publication in new window or tab >>Distinct HLA Associations with Rheumatoid Arthritis Subsets Defined by Serological Subphenotype
Show others...
2019 (English)In: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 105, no 3, p. 616-624Article in journal (Refereed) Published
Abstract [en]

Rheumatoid arthritis (RA) is the most common immune-mediated arthritis. Anti-citrullinated peptide antibodies (ACPA) are highly specific to RA and assayed with the commercial CCP2 assay. Genetic drivers of RA within the MHC are different for CCP2-positive and -negative subsets of RA, particularly at HLA-DRB1. However, aspartic acid at amino acid position 9 in HLA-B (Bpos-9) increases risk to both RA subsets. Here we explore how individual serologies associated with RA drive associations within the MHC. To define MHC differences for specific ACPA serologies, we quantified a total of 19 separate ACPAs in RA-affected case subjects from four cohorts (n = 6,805). We found a cluster of tightly co-occurring antibodies (canonical serologies, containing CCP2), along with several independently expressed antibodies (non-canonical serologies). After imputing HLA variants into 6,805 case subjects and 13,467 control subjects, we tested associations between the HLA region and RA subgroups based on the presence of canonical and/or non-canonical serologies. We examined CCP2(+) and CCP2(−) RA-affected case subjects separately. In CCP2(−) RA, we observed that the association between CCP2(−) RA and Bpos-9 was derived from individuals who were positive for non-canonical serologies (omnibus_p = 9.2 × 10−17). Similarly, we observed in CCP2(+) RA that associations between subsets of CCP2(+) RA and Bpos-9 were negatively correlated with the number of positive canonical serologies (p = 0.0096). These findings suggest unique genetic characteristics underlying fine-specific ACPAs, suggesting that RA may be further subdivided beyond simply seropositive and seronegative.

Place, publisher, year, edition, pages
Cell Press, 2019
Keywords
rheumatoid arthritis; MHC; major histocompatability complex; genetics; HLA; citrullinated peptides
National Category
Rheumatology and Autoimmunity
Identifiers
urn:nbn:se:umu:diva-164625 (URN)10.1016/j.ajhg.2019.08.002 (DOI)000484435700014 ()31474319 (PubMedID)2-s2.0-85071458389 (Scopus ID)
Note

A correction has been published: https://doi.org/10.1016/j.ajhg.2019.09.018

Available from: 2019-11-12 Created: 2019-11-12 Last updated: 2019-11-12Bibliographically approved
Odqvist, L., Jevnikar, Z., Riise, R., Oberg, L., Rhedin, M., Leonard, D., . . . Vaarala, O. (2019). Genetic variations in A20 DUB domain provide a genetic link to citrullination and neutrophil extracellular traps in systemic lupus erythematosus. Annals of the Rheumatic Diseases, 78(10), 1363-1370
Open this publication in new window or tab >>Genetic variations in A20 DUB domain provide a genetic link to citrullination and neutrophil extracellular traps in systemic lupus erythematosus
Show others...
2019 (English)In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 78, no 10, p. 1363-1370Article in journal (Refereed) Published
Abstract [en]

Objectives: Genetic variations in TNFAIP3 (A20) de-ubiquitinase (DUB) domain increase the risk of systemic lupus erythematosus (SLE) and rheumatoid arthritis. A20 is a negative regulator of NF-κB but the role of its DUB domain and related genetic variants remain unclear. We aimed to study the functional effects of A20 DUB-domain alterations in immune cells and understand its link to SLE pathogenesis.

Methods: CRISPR/Cas9 was used to generate human U937 monocytes with A20 DUB-inactivating C103A knock-in (KI) mutation. Whole genome RNA-sequencing was used to identify differentially expressed genes between WT and C103A KI cells. Functional studies were performed in A20 C103A U937 cells and in immune cells from A20 C103A mice and genotyped healthy individuals with A20 DUB polymorphism rs2230926. Neutrophil extracellular trap (NET) formation was addressed ex vivo in neutrophils from A20 C103A mice and SLE-patients with rs2230926.

Results: Genetic disruption of A20 DUB domain in human and murine myeloid cells did not give rise to enhanced NF-κB signalling. Instead, cells with C103A mutation or rs2230926 polymorphism presented an upregulated expression of PADI4, an enzyme regulating protein citrullination and NET formation, two key mechanisms in autoimmune pathology. A20 C103A cells exhibited enhanced protein citrullination and extracellular trap formation, which could be suppressed by selective PAD4 inhibition. Moreover, SLE-patients with rs2230926 showed increased NETs and increased frequency of autoantibodies to citrullinated epitopes.

Conclusions: We propose that genetic alterations disrupting the A20 DUB domain mediate increased susceptibility to SLE through the upregulation of PADI4 with resultant protein citrullination and extracellular trap formation.

National Category
Rheumatology and Autoimmunity
Identifiers
urn:nbn:se:umu:diva-165690 (URN)10.1136/annrheumdis-2019-215434 (DOI)000487465000024 ()31300459 (PubMedID)
Available from: 2019-12-06 Created: 2019-12-06 Last updated: 2019-12-06Bibliographically approved
Zhang, Y., Johansson, L., Rudin, A., Carlsson, L., Rantapää-Dahlqvist, S. & Maglio, C. (2019). In overweight subjects, serum adiponectin predicts the development of rheumatoid arthritis independently of other adipokines. Paper presented at Annual European Congress of Rheumatology (EULAR), Madrid, Spain, June 12-15, 2019. Annals of the Rheumatic Diseases, 78, 298-298
Open this publication in new window or tab >>In overweight subjects, serum adiponectin predicts the development of rheumatoid arthritis independently of other adipokines
Show others...
2019 (English)In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 78, p. 298-298Article in journal, Meeting abstract (Other academic) Published
Abstract [en]

Background: Adipokines, such as adiponectin, leptin, resistin and visfatin, are cytokines produced by the adipose tissue and involved in metabolism and inflammation1 . Adiponectin is elevated in both serum and synovial fluid of subjects with rheumatoid arthritis (RA), suggesting a possible role of this adipokine in the pathogenesis of RA 2,3. Circulating levels of leptin, resistin, and visfatin are also higher in subjects with RA compared to controls 2,4.

Objectives: Aim of this study was to determine if adiponectin, leptin, resistin, and visfatin predict the development of RA.

Methods: Two nested-case control studies were performed including presymptomatic participants of two cohorts from Sweden: the Swedish Obese Subjects (SOS) study and a cohort of individuals identified within the Medical Biobank of northern Sweden. The SOS is a clinical trial including 4047 subjects with obesity6 . During a follow-up for up to 29 years, 92 subjects developed RA. Among those 92 subjects, 82 subjects with available serum at baseline were matched 1:5 with 410 subjects who did not develop RA during follow-up. Matching was based on baseline age, sex, body-mass index (BMI), bariatric surgery yes/no, year of inclusion, and smoking. A nested case-control study of 88 sex- and age-matched pairs was performed within the Medical Biobank of Northern Sweden using blood samples donated before the onset of the first RA symptoms. The pre-dating time before onset of symptoms of RA was 8.5±5.0 years7 . Baseline serum levels of adiponectin, leptin, resistin, and visfatin were measured using the Quantikine ELISA kit from R&D Systems (Wiesbaden, Germany). Visfatin could not be measured in the Biobank cohort, due to lack of serum. Both binary logistic as well as conditional logistic regression analyses were used to determine if adipokines were elevated years before the onset of RA.

Results: In a multivariable analysis including adiponectin, leptin, resistin, visfatin performed in the SOS cohort, serum adiponectin was associated with a higher risk for RA independently of other adipokines (Odds ratio, OR, 1.1, 95% confidence interval, CI, 1.0-1.1, p value=0.01). Leptin, resistin and visfatin levels were not associated with the risk of RA. In the Biobank cohort, no association between adipokines and risk for RA was detected. However, when stratifying the population according to BMI, in the subgroup having BMI>25 (n=109), adiponectin levels were associated with higher risk for RA (OR 1.2, 95% CI 1.0-1.36, p=0.03), independently of leptin and resistin levels. Virtually the same results were obtained in both the SOS and the Biobank cohorts when conditional logistic regression analysis was used.

Conclusion: Our results suggest that higher serum adiponectin levels predict the development of RA in subjects with overweight/obesity.

Place, publisher, year, edition, pages
BMJ Publishing Group Ltd, 2019
National Category
Rheumatology and Autoimmunity
Identifiers
urn:nbn:se:umu:diva-161730 (URN)10.1136/annrheumdis-2019-eular.5314 (DOI)000472207100635 ()
Conference
Annual European Congress of Rheumatology (EULAR), Madrid, Spain, June 12-15, 2019
Available from: 2019-07-26 Created: 2019-07-26 Last updated: 2019-07-26Bibliographically approved
Projects
Aetio-patogenetic factors of importance for development of rheumatoid arthritis, disease severity and co-morbidity, in particular cardio-vascular disease [2009-03388_VR]; Umeå UniversityAetio-patogenetic factors of importance for development of rheumatoid arthritis, disease severity and co-morbidity, in particular cardio-vascular disease [2012-04096_VR]; Umeå UniversityAetio-pathogenic factors of importance for development of rheumatoid arthritis and of disease progression. Analyses of prospective material from biobanks of northern Sweden. [2018-02551_VR]; Umeå University
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0001-8259-3863

Search in DiVA

Show all publications