Periodontitis in patients with systemic lupus erythematosus: A nation-wide study of 1990 patients

Background The aim of this study was to examine the association between systemic lupus erythematosus (SLE) and periodontitis in Norway during a 10-year period from 2008 through 2017. Methods In this population-based study, 1,990 patients were included in the SLE-cohort based on diagnostic codes registered in the Norwegian Patient Registry. The control group (n = 170,332) comprised patients registered with diagnostic codes for non-osteoporotic fractures or hip or knee replacement because of osteoarthritis. The outcome was periodontitis, defined by procedure codes registered in the Control and Payment of Health Refunds database. Logistic regression analyses were performed to estimate odds ratio for periodontitis in patients versus controls adjusted for potential covariates. Results Periodontitis was significantly more common in SLE patients compared to controls (OR 1.78, 95% CI 1.47-2.14) and the difference was highest in SLE-patients 20 to 30 years of age (OR 3.24, 95% CI 1.23 – 8.52). The periodontitis rate in SLE patients was in the same range as for patients with diabetes mellitus type 2. Conclusions Patients with SLE had an almost doubled risk of periodontitis compared with the control population, and the difference was most accentuated in the young patients. These findings warrant an increased focus on dental health in SLE-patients.publishedVersio

A five-year prospective study of fatigue in primary Sjögren's syndrome

Introduction: Fatigue is prevalent in primary Sjögren’s syndrome (pSS), and contributes to the considerably reduced health related quality of life in this disease. The symptom is included in proposed disease activity and outcome measures for pSS. Several studies indicate that there is an inflammatory component of fatigue in pSS and other chronic inflammatory rheumatic diseases. The purpose of this study was to investigate fatigue change in pSS in a longitudinal study, and explore whether any clinical or laboratory variables at baseline, including serum cytokines, were associated with a change in fatigue scores over time. Methods: A clinical and laboratory investigation of 141 patients fulfilling the American-European consensus criteria of pSS was undertaken in the period May 2004 to April 2005. Median time since diagnosis was 5.5 years. Examinations included the fatigue questionnaires: fatigue severity scale (FSS), fatigue visual analogue scale (VAS), functional assessment of chronic illness therapy - fatigue (FACIT-F) and medical outcome study short form-36 (SF- 36) vitality, which were repeated in a follow-up investigation in January and February 2010. Results: A total of 122 patients (87%) responded at both time-points. Thirty-five percent of patients experienced a clinically significant FSS increase. On the group level, fatigue measures did not change except that there was a slight deterioration in SF-36 vitality score. High serum anti-Sjögren’s syndrome A antigen (anti-SSA) showed weak associations with high baseline fatigue, and patients with increasing fatigue had lower baseline unstimulated whole salivary volume. Weak associations between increasing fatigue and serum immunoglobulin G (IgG), and the pro-inflammatory cytokine interleukin-17 (IL-17), were observed. Baseline sicca symptoms correlated with higher fatigue both at baseline and with increasing fatigue over time. Linear regression analysis did not identify any predictive ability of clinical or laboratory measures on fatigue change over time. Conclusions: Fatigue remained mainly unchanged over time. Using multivariate models did not reveal any clinical or laboratory predictors of fatigue change over time

Periodontitis in patients with primary Sjögren's syndrome: A nation-wide register study

The aim of this study was to compare the occurrence of periodontitis in patients with primary Sjögren's syndrome (pSS) and a non-Sjögren's patient group during a 7-year period from 2011 through 2017. In this population-based study, the patients were identified based on the International Classification of Diseases-10 (ICD-10) codes registered in the Norwegian Patient Registry (NPR), which contains information on diagnosis and time of admission for all hospitalized patients in Norway. The pSS group comprised patients with ≥4 registrations with ICD-10 code M35.0 (Sjögren's syndrome) as the main diagnosis. The dependent variable was periodontitis, defined by procedure codes registered in the Norwegian Control and Payment of Health Reimbursement (KUHR). Logistic regression analyses estimated the odds ratio for periodontitis in pSS patients relative to non-pSS patients, adjusted for relevant covariates. Lastly, regression analyses were performed separately for each of the 6 age categories. In total, 760 (7.5%) patients in the pSS group and 22,178 (7.1%) in the non-pSS group had periodontitis. When adjusting for covariates, the presence of pSS had no association with periodontitis (OR = 1.06, 95% CI: 0.98–1.14).publishedVersio

Blockade of lymphotoxin-beta receptor signaling reduces aspects of Sjogren's syndrome in salivary glands of non-obese diabetic mice

Introduction The lymphotoxin-beta receptor (LTβR) pathway is important in the development and maintenance of lymphoid structures. Blocking this pathway has proven beneficial in murine models of autoimmune diseases such as diabetes and rheumatoid arthritis. The aim of this study was to determine the effects of LTβR pathway blockade on Sjögren syndrome (SS)-like salivary gland disease in non-obese diabetic (NOD) mice. Methods The course of SS-like disease was followed in NOD mice that were given lymphotoxin-beta receptor-immunoglobulin fusion protein (LTβR-Ig) starting at 9 weeks of age. Treatment was given as a single weekly dose for 3, 7, or 10 weeks. Age-matched NOD mice treated with mouse monoclonal IgG1, or not treated at all, were used as controls. The severity of inflammation, cellular composition, and lymphoid neogenesis in the submandibular glands were determined by immunohistochemistry. Mandibular lymph nodes were also studied. Saliva flow rates were measured, and saliva was analyzed by a multiplex cytokine assay. The salivary glands were analyzed for CXCL13, CCL19, and CCL21 gene expression by quantitative polymerase chain reaction. Results Treatment with LTβR-Ig prevented the increase in size and number of focal infiltrates normally observed in this SS-like disease. Compared with the controls, the submandibular glands of LTβR-Ig-treated mice had fewer and smaller T- and B-cell zones and fewer high endothelial venules per given salivary gland area. Follicular dendritic cell networks were lost in LTβR-Ig-treated mice. CCL19 expression was also dramatically inhibited in the salivary gland infiltrates. Draining lymph nodes showed more gradual changes after LTβR-Ig treatment. Saliva flow was partially restored in mice treated with 10 LTβR-Ig weekly injections, and the saliva cytokine profile of these mice resembled that of mice in the pre-disease state. Conclusions Our findings show that blocking the LTβR pathway results in ablation of the lymphoid organization in the NOD salivary glands and thus an improvement in salivary gland function.publishedVersio

Blockade of lymphotoxin-beta receptor signaling reduces aspects of Sjögren's syndrome in salivary glands of non-obese diabetic mice

Introduction The lymphotoxin-beta receptor (LTβR) pathway is important in the development and maintenance of lymphoid structures. Blocking this pathway has proven beneficial in murine models of autoimmune diseases such as diabetes and rheumatoid arthritis. The aim of this study was to determine the effects of LTβR pathway blockade on Sjögren syndrome (SS)-like salivary gland disease in non-obese diabetic (NOD) mice. Methods The course of SS-like disease was followed in NOD mice that were given lymphotoxin-beta receptor-immunoglobulin fusion protein (LTβR-Ig) starting at 9 weeks of age. Treatment was given as a single weekly dose for 3, 7, or 10 weeks. Age-matched NOD mice treated with mouse monoclonal IgG1, or not treated at all, were used as controls. The severity of inflammation, cellular composition, and lymphoid neogenesis in the submandibular glands were determined by immunohistochemistry. Mandibular lymph nodes were also studied. Saliva flow rates were measured, and saliva was analyzed by a multiplex cytokine assay. The salivary glands were analyzed for CXCL13, CCL19, and CCL21 gene expression by quantitative polymerase chain reaction. Results Treatment with LTβR-Ig prevented the increase in size and number of focal infiltrates normally observed in this SS-like disease. Compared with the controls, the submandibular glands of LTβR-Ig-treated mice had fewer and smaller T- and B-cell zones and fewer high endothelial venules per given salivary gland area. Follicular dendritic cell networks were lost in LTβR-Ig-treated mice. CCL19 expression was also dramatically inhibited in the salivary gland infiltrates. Draining lymph nodes showed more gradual changes after LTβR-Ig treatment. Saliva flow was partially restored in mice treated with 10 LTβR-Ig weekly injections, and the saliva cytokine profile of these mice resembled that of mice in the pre-disease state. Conclusions Our findings show that blocking the LTβR pathway results in ablation of the lymphoid organization in the NOD salivary glands and thus an improvement in salivary gland function

The influence of the NOD Nss1/Idd5 loci on sialadenitis and gene expression in salivary glands of congenic mice

The nonobese diabetic (NOD) Nss1 and Idd5 loci have been associated with sialadenitis development in mice. In this study the NOD Nss1 and Idd5 loci were backcrossed onto the healthy control strain B10.Q by using the speed congenic breeding strategy, resulting in three congenic strains: B10.Q.Nss1, B10.Q.Nss1/Idd5 heterozygous and B10.Q.Nss1/Idd5 homozygous. We investigated the effects of the Nss1 and Idd5 loci on sialadenitis and gene expression in NOD congenic mice. One submandibular salivary gland from each mouse was used for histological analysis of sialadenitis, whereas the contralateral salivary gland was used for gene expression profiling with the Applied Biosystems Mouse Genome Survey chip v.1.0. The results were validated using quantitative reverse transcriptase PCR. The NOD Nss1 and Idd5 loci had clear influence on the onset and progression of sialadenitis in congenic mice. Double congenic mice exhibited the most severe phenotype. We successfully identified several genes that are located in the NOD congenic regions to be differentially expressed between the congenic strains and the control strain. Several of these were found to be co-regulated, such as Stat1, complement component C1q genes and Tlr12. Also, a vast contingency of interferon-regulated genes (such as Ltb, Irf7 and Irf8) and cytokine and chemokine genes (such as Ccr7 and Ccl19) were differentially expressed between the congenic strains and the control strain. Over-representation of inflammatory signalling pathways was observed among the differentially expressed genes. We have found that the introgression of the NOD loci Nss1 and Idd5 on a healthy background caused sialadenitis in NOD congenic mouse strains, and we propose that genes within these loci are important factors in the pathogenesis. Furthermore, gene expression profiling has revealed several differentially expressed genes within and outside the NOD loci that are similar to genes found to be differentially expressed in patients with Sjögren's syndrome, and as such are interesting candidates for investigation to enhance our understanding of disease mechanisms and to develop future therapies

Marine ω-3, vitamin D levels, disease outcome and periodontal status in rheumatoid arthritis outpatients

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Leukocyte transmigration into tissue-engineered constructs is influenced by endothelial cells through Toll-like receptor signaling

Introduction Inflammation plays a crucial role in tissue regeneration, wound healing, and the success of tissue-engineered constructs. The aim of this study was to investigate the influence of human umbilical vein endothelial cells (ECs) on leukocyte transmigration when co-cultured with primary human bone marrow-derived multipotent stromal cells (MSCs). Methods MSCs with and without ECs were cultured in poly (L-lactide-co-1, 5-dioxepan-2-one) (poly (LLA-co-DXO)) scaffolds for 1 week in vitro in a bioreactor system, after which they were implanted subcutaneously in non-obese diabetic/severe combined immunodeficient mice. After 1 and 3 weeks, scaffolds were retrieved, and the mRNA expression of interleukin 1-beta (IL-1β), IL-6, IL-10, hypoxia-inducible factor 1-alpha (HIF-1α), HIF-1β, and mammalian target of rapamycin was examined by real-time reverse transcription-polymerase chain reaction. Furthermore, immunofluorescent staining was performed for IL-1β, IL-6, neutrophils, and CD11b. In addition, Western blotting was done for IL-1β and IL-6. Leukocyte transmigration genes and genes in Toll-like receptor pathways, expressed by MSCs cultured in vitro with or without ECs, were further investigated with a microarray dataset. Results In vitro, genes involved in leukocyte transmigration and Toll-like receptor pathways were clearly influenced by the addition of ECs. Platelet/endothelial cell adhesion molecule-1 (PECAM-1) and cadherin-5 (CDH5), both genes involved in leukocyte transmigration, were expressed significantly higher in the MSC/EC group. In vivo, the MSC/EC group showed higher mRNA expression of hypoxia-inducible factors HIF-1α and HIF-1β. The mRNA expression of anti-inflammatory cytokine IL-10 showed no significant difference, whereas the mRNA and protein expression of pro-inflammatory cytokines IL-1β and IL-6 were lower in the MSC/EC group. The quantitative analysis of immunofluorescent staining revealed a significant difference in the number of neutrophils migrating into constructs, with the highest density found in the MSC/EC group. The number of macrophages positive for IL-6 and CD11b was significantly reduced in the MSC/EC group. Conclusions The recruitment of leukocytes into tissue-engineered constructs with MSCs is strongly influenced by the addition of ECs via activation of leukocyte transmigration and Toll-like receptor pathways.publishedVersio