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Vasaitis, L., Nordmark, G., Theander, E., Backlin, C., Smedby, K. E., Askling, J., . . . Baecklund, E. (2019). Comparison of patients with and without pre-existing lymphoma at diagnosis of primary Sjögren's syndrome. Scandinavian Journal of Rheumatology, 48(3), 207-212
Open this publication in new window or tab >>Comparison of patients with and without pre-existing lymphoma at diagnosis of primary Sjögren's syndrome
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2019 (English)In: Scandinavian Journal of Rheumatology, ISSN 0300-9742, E-ISSN 1502-7732, Vol. 48, no 3, p. 207-212Article in journal (Refereed) Published
Abstract [en]

OBJECTIVE: In the 2016 American College of Rheumatology/European League Against Rheumatism classification criteria for primary Sjögren's syndrome (pSS), pre-existing lymphoma is not an exclusion criterion for pSS diagnosis, as in earlier criteria. We aimed to explore whether there are differences between pSS patients with and without pre-existing lymphoma at pSS diagnosis.

METHOD: Patients with ICD-7-10 codes for Sjögren's syndrome (SS) and a diagnosis of malignant lymphoma before or after SS diagnosis were identified by linking the Swedish Patient Register 1964-2007 with the Cancer Register 1990-2007 (n = 224). Clinical data were collected from medical records. Lymphoma diagnoses were evaluated by tissue review. Characteristics of pSS patients with and without pre-existing lymphoma were compared.

RESULTS: We identified 107 patients with pSS as the reason for an SS diagnosis code and a verified lymphoma. Of these, 18 (17%) had a pre-existing lymphoma at pSS diagnosis, defined as lymphoma diagnosed before or within 6 months of pSS diagnosis. Male gender (39% vs 10%, p = 0.006), enlarged lymph nodes during the pSS disease (61% vs 27%, p = 0.01), mucosa-associated lymphoid tissue (MALT) lymphoma (50% vs 22%, p = 0.02), and salivary gland lymphoma (61% vs 26%, p = 0.006) were more common in patients with a pre-existing lymphoma at pSS diagnosis. Other pSS characteristics were similar.

CONCLUSION: In a substantial proportion of patients, particularly in men, pSS remains undiagnosed until after lymphoma diagnosis. The study highlights the importance of pSS investigation in patients with lymphoma, especially MALT lymphoma, in the salivary glands.

National Category
Rheumatology and Autoimmunity
Research subject
Pathology
Identifiers
urn:nbn:se:uu:diva-366237 (URN)10.1080/03009742.2018.1523456 (DOI)000467940900005 ()30422723 (PubMedID)
Funder
Swedish Cancer SocietySwedish Rheumatism AssociationSwedish Society of MedicineThe King Gustaf V's Jubilee Foundation
Available from: 2018-11-18 Created: 2018-11-18 Last updated: 2019-06-18Bibliographically approved
Mofors, J., Arkema, E. V., Björk, A., Westermark, L., Kvarnström, M., Forsblad-d'Elia, H., . . . Wahren-Herlenius, M. (2019). Infections increase the risk of developing Sjogren's syndrome. Journal of Internal Medicine, 285(6), 670-680
Open this publication in new window or tab >>Infections increase the risk of developing Sjogren's syndrome
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2019 (English)In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 285, no 6, p. 670-680Article in journal (Refereed) Published
Abstract [en]

Objective Environmental factors have been suggested in the pathogenesis of rheumatic diseases. We here investigated whether infections increase the risk of developing primary Sjogren's syndrome (pSS). Methods Patients with pSS in Sweden (n = 945) and matched controls from the general population (n = 9048) were included, and data extracted from the National Patient Register to identify infections occurring before pSS diagnosis during a mean observational time of 16.0 years. Data were analysed using conditional logistic regression models. Sensitivity analyses were performed by varying exposure definition and adjusting for previous health care consumption. Results A history of infection associated with an increased risk of pSS (OR 1.9, 95% CI 1.6-2.3). Infections were more prominently associated with the development of SSA/SSB autoantibody-positive pSS (OR 2.7, 95% CI 2.0-3.5). When stratifying the analysis by organ system infected, respiratory infections increased the risk of developing pSS, both in patients with (OR 2.9, 95% CI 1.8-4.7) and without autoantibodies (OR 2.1, 95% CI 1.1-3.8), whilst skin and urogenital infections only significantly associated with the development of autoantibody-positive pSS (OR 3.2, 95% CI 1.8-5.5 and OR 2.7, 95% CI 1.7-4.2). Furthermore, a dose-response relationship was observed for infections and a risk to develop pSS with Ro/SSA and La/SSB antibodies. Gastrointestinal infections were not significantly associated with a risk of pSS. Conclusions Infections increase the risk of developing pSS, most prominently SSA/SSB autoantibody-positive disease, suggesting that microbial triggers of immunity may partake in the pathogenetic process of pSS.

Place, publisher, year, edition, pages
John Wiley & Sons, 2019
Keywords
autoantibodies, infection, La, SSB, Ro, SSA, Sjogren's syndrome
National Category
Rheumatology and Autoimmunity
Identifiers
urn:nbn:se:uu:diva-390586 (URN)10.1111/joim.12888 (DOI)000473089500007 ()30892751 (PubMedID)
Funder
Swedish Research CouncilSwedish Rheumatism AssociationKing Gustaf V Jubilee FundSwedish Heart Lung FoundationStockholm County Council
Available from: 2019-08-13 Created: 2019-08-13 Last updated: 2019-08-13Bibliographically approved
Retamozo, S., Acar-Denizli, N., Ng, W. F., Zeher, M., Rasmussen, A., Seror, R., . . . Ramos-Casals, M. (2018). A North-South Worldwide Gradient in Systemic Activity of Primary Sjögren Syndrome: Increased Severe Disease in Patients from Southern Countries. Paper presented at Congress of the European-League-Against-Rheumatism (EULAR), JUN 13-16, 2018, Amsterdam, NETHERLANDS. Annals of the Rheumatic Diseases, 77, 1190-1190
Open this publication in new window or tab >>A North-South Worldwide Gradient in Systemic Activity of Primary Sjögren Syndrome: Increased Severe Disease in Patients from Southern Countries
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2018 (English)In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 77, p. 1190-1190Article in journal, Meeting abstract (Other academic) Published
Place, publisher, year, edition, pages
BMJ Publishing Group Ltd, 2018
National Category
Rheumatology and Autoimmunity
Identifiers
urn:nbn:se:uu:diva-368667 (URN)10.1136/annrheumdis-2018-eular.6446 (DOI)000444351003372 ()
Conference
Congress of the European-League-Against-Rheumatism (EULAR), JUN 13-16, 2018, Amsterdam, NETHERLANDS
Available from: 2018-12-10 Created: 2018-12-10 Last updated: 2018-12-10Bibliographically approved
Björk, A., Mofors, J., Kvarnström, M., Forsblad-d'Elia, H., Bucher, S. M., Hillert, J., . . . Wahren-Herlenius, M. (2018). Cigarette smoking is a risk factor for developing primary Sjögren's syndrome with Ro/SSA and La/SSB autoantibodies. Clinical and Experimental Rheumatology, 36(3), S330-S330
Open this publication in new window or tab >>Cigarette smoking is a risk factor for developing primary Sjögren's syndrome with Ro/SSA and La/SSB autoantibodies
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2018 (English)In: Clinical and Experimental Rheumatology, ISSN 0392-856X, E-ISSN 1593-098X, Vol. 36, no 3, p. S330-S330Article in journal, Meeting abstract (Other academic) Published
Place, publisher, year, edition, pages
CLINICAL & EXPER RHEUMATOLOGY, 2018
National Category
Rheumatology and Autoimmunity
Identifiers
urn:nbn:se:uu:diva-369078 (URN)000446486100248 ()
Available from: 2018-12-11 Created: 2018-12-11 Last updated: 2018-12-11Bibliographically approved
Retamozo, S., Kostov, B., Zeher, M., Sivils, K., Mandl, T., Seror, R., . . . Ramos-Casals, M. (2018). Clinical and immunological disease patterns of primary Sjögren syndrome driven by gender and age at diagnosis. Clinical and Experimental Rheumatology, 36(3), S269-S270
Open this publication in new window or tab >>Clinical and immunological disease patterns of primary Sjögren syndrome driven by gender and age at diagnosis
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2018 (English)In: Clinical and Experimental Rheumatology, ISSN 0392-856X, E-ISSN 1593-098X, Vol. 36, no 3, p. S269-S270Article in journal, Meeting abstract (Other academic) Published
Place, publisher, year, edition, pages
CLINICAL & EXPER RHEUMATOLOGY, 2018
National Category
Rheumatology and Autoimmunity
Identifiers
urn:nbn:se:uu:diva-369084 (URN)000446486100099 ()
Available from: 2018-12-11 Created: 2018-12-11 Last updated: 2018-12-11Bibliographically approved
Aqrawi, L. A., Ivanchenko, M., Björk, A., Ramírez Sepúlveda, J. I., Imgenberg-Kreuz, J., Kvarnström, M., . . . Wahren-Herlenius, M. (2018). Diminished CXCR5 expression in peripheral blood of patients with Sjögren's syndrome may relate to both genotype and salivary gland homing. Clinical and Experimental Immunology, 192(3), 259-270
Open this publication in new window or tab >>Diminished CXCR5 expression in peripheral blood of patients with Sjögren's syndrome may relate to both genotype and salivary gland homing
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2018 (English)In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 192, no 3, p. 259-270Article in journal (Refereed) Published
Abstract [en]

cells in circulation was also related to homing of B and T cells to the autoimmune target organ. Therapeutic drugs targeting the CXCR5/CXCL13 axis may be useful in SS. This article is protected by copyright. All rights reserved.

Place, publisher, year, edition, pages
John Wiley & Sons, 2018
Keywords
B cells, CXCR5, Sjögren's syndrome, T cells, eQTL
National Category
Rheumatology and Autoimmunity
Identifiers
urn:nbn:se:uu:diva-343237 (URN)10.1111/cei.13118 (DOI)000434078000002 ()29453859 (PubMedID)
Funder
Swedish Research CouncilSwedish Rheumatism AssociationKing Gustaf V Jubilee FundEU, FP7, Seventh Framework Programme, 608695Stockholm County Council
Available from: 2018-02-26 Created: 2018-02-26 Last updated: 2018-09-28Bibliographically approved
Imgenberg-Kreuz, J., Almlöf, J. C., Leonard, D., Alexsson, A., Nordmark, G., Eloranta, M.-L., . . . Sandling, J. K. (2018). DNA methylation mapping identifies gene regulatory effects in patients with systemic lupus erythematosus. Annals of the Rheumatic Diseases, 77(5), 736-743
Open this publication in new window or tab >>DNA methylation mapping identifies gene regulatory effects in patients with systemic lupus erythematosus
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2018 (English)In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 77, no 5, p. 736-743Article in journal (Refereed) Published
Abstract [en]

Objectives: Systemic lupus erythematosus (SLE) is a chronic autoimmune condition with heterogeneous presentation and complex aetiology where DNA methylation changes are emerging as a contributing factor. In order to discover novel epigenetic associations and investigate their relationship to genetic risk for SLE, we analysed DNA methylation profiles in a large collection of patients with SLE and healthy individuals.

Methods: DNA extracted from blood from 548 patients with SLE and 587 healthy controls were analysed on the Illumina HumanMethylation 450 k BeadChip, which targets 485 000 CpG sites across the genome. Single nucleotide polymorphism (SNP) genotype data for 196 524 SNPs on the Illumina ImmunoChip from the same individuals were utilised for methylation quantitative trait loci (cis-meQTLs) analyses.

Results: We identified and replicated differentially methylated CpGs (DMCs) in SLE at 7245 CpG sites in the genome. The largest methylation differences were observed at type I interferon-regulated genes which exhibited decreased methylation in SLE. We mapped cis-meQTLs and identified genetic regulation of methylation levels at 466 of the DMCs in SLE. The meQTLs for DMCs in SLE were enriched for genetic association to SLE, and included seven SLE genome-wide association study (GWAS) loci: PTPRC (CD45), MHC-class III, UHRF1BP1, IRF5, IRF7, IKZF3 and UBE2L3. In addition, we observed association between genotype and variance of methylation at 20 DMCs in SLE, including at the HLA-DQB2 locus.

Conclusions: Our results suggest that several of the genetic risk variants for SLE may exert their influence on the phenotype through alteration of DNA methylation levels at regulatory regions of target genes.

Keywords
gene polymorphism, systemic lupus erythematosus
National Category
Rheumatology and Autoimmunity
Identifiers
urn:nbn:se:uu:diva-342164 (URN)10.1136/annrheumdis-2017-212379 (DOI)000430492600020 ()29437559 (PubMedID)
Funder
Knut and Alice Wallenberg Foundation, KAW 2011.0073Swedish Research Council, 521-2014-2263; 521-2013-2830; 521-2014-3954; 2016-01982; 350-2012-256AstraZenecaSwedish Society for Medical Research (SSMF)Swedish Rheumatism AssociationThe King Gustaf V's Jubilee FoundationSwedish Heart Lung FoundationStockholm County CouncilScience for Life Laboratory - a national resource center for high-throughput molecular bioscience
Available from: 2018-02-19 Created: 2018-02-19 Last updated: 2018-06-19Bibliographically approved
Imgenberg-Kreuz, J., Sandling, J. K. & Nordmark, G. (2018). Epigenetic alterations in primary Sjogren's syndrome: an overview. Clinical Immunology, 196, 12-20
Open this publication in new window or tab >>Epigenetic alterations in primary Sjogren's syndrome: an overview
2018 (English)In: Clinical Immunology, ISSN 1521-6616, E-ISSN 1521-7035, Vol. 196, p. 12-20Article in journal (Refereed) Published
Abstract [en]

Primary Sjogren's syndrome (pSS) is a chronic autoimmune rheumatic disease characterized by inflammation of exocrine glands, mainly salivary and lacrimal glands. In addition, pSS may affect multiple other organs resulting in systemic manifestations. Although the precise etiology of pSS remains elusive, pSS is considered to be a multi factorial disease, where underlying genetic predisposition, environmental factors and epigenetic mechanisms contribute to disease development. Epigenetic mechanisms, such as DNA methylation, histone modifications and non-coding RNAs, may constitute a dynamic link between genome, environment and phenotypic manifestation by their modulating effects on gene expression. A growing body of studies reporting altered epigenetic landscapes in pSS suggests that epigenetic mechanisms play a role in the pathogenesis of pSS, and the reversible nature of epigenetic modifications suggests therapeutic strategies targeting epigenetic dysregulation in pSS. This article reviews our current understanding of epigenetic mechanisms in pSS and discusses implications for novel diagnostic and therapeutic approaches.

Keywords
Primary Sjogren's syndrome (pSS), Epigenetics, DNA methylation, Histone modification, Non-coding RNA (ncRNA), Interferon (IFN)
National Category
Rheumatology and Autoimmunity Immunology in the medical area
Identifiers
urn:nbn:se:uu:diva-373212 (URN)10.1016/j.clim.2018.04.004 (DOI)000454373800003 ()29649576 (PubMedID)
Funder
Swedish Research Council, 2016-01982AstraZeneca
Available from: 2019-01-11 Created: 2019-01-11 Last updated: 2019-01-11Bibliographically approved
Khanam, S., Joachims, M. L., Means, N., Adrianto, I., Rasmussen, A., Bowman, S. J., . . . Lessard, C. J. (2018). Functional characterization of the Sjögren's syndrome-associated locus DDX6-CXCR5. Clinical and Experimental Rheumatology, 36(3), S286-S287
Open this publication in new window or tab >>Functional characterization of the Sjögren's syndrome-associated locus DDX6-CXCR5
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2018 (English)In: Clinical and Experimental Rheumatology, ISSN 0392-856X, E-ISSN 1593-098X, Vol. 36, no 3, p. S286-S287Article in journal, Meeting abstract (Other academic) Published
Place, publisher, year, edition, pages
CLINICAL & EXPER RHEUMATOLOGY, 2018
National Category
Rheumatology and Autoimmunity
Identifiers
urn:nbn:se:uu:diva-369079 (URN)000446486100141 ()
Available from: 2018-12-11 Created: 2018-12-11 Last updated: 2018-12-11Bibliographically approved
Khanam, S., Joachims, M. L., Means, N., Omdal, R., Wahren-Herlenius, M., Alevizos, I., . . . Lessard, C. (2018). Functional characterization of the sjögren’s syndrome-associated locus DDX6-CXCR5. Paper presented at Congress of the European-League-Against-Rheumatism (EULAR), JUN 13-16, 2018, Amsterdam, NETHERLANDS. Annals of the Rheumatic Diseases, 77, 1267-1267
Open this publication in new window or tab >>Functional characterization of the sjögren’s syndrome-associated locus DDX6-CXCR5
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2018 (English)In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 77, p. 1267-1267Article in journal, Meeting abstract (Other academic) Published
Place, publisher, year, edition, pages
BMJ Publishing Group Ltd, 2018
National Category
Rheumatology and Autoimmunity
Identifiers
urn:nbn:se:uu:diva-368668 (URN)10.1136/annrheumdis-2018-eular.3814 (DOI)000444351003555 ()
Conference
Congress of the European-League-Against-Rheumatism (EULAR), JUN 13-16, 2018, Amsterdam, NETHERLANDS
Available from: 2018-12-10 Created: 2018-12-10 Last updated: 2018-12-10Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0002-3829-7431

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