Increased risk of periodontitis in patients with rheumatoid arthritis: A nationwide register study in Norway.

AIM: To investigate the risk of periodontitis in rheumatoid arthritis (RA) patients in a nationwide register-based study. MATERIALS AND METHODS: Patients and controls were defined using ICD-10 codes registered in the Norwegian Patient Registry (NPR), from 2011 to 2017. The 324,232 included subjects had at least one registered diagnostic code for RA (33,040 patients) or diagnostic codes for non-osteoporotic fractures or hip or knee replacement due to osteoarthritis (controls). The outcome was periodontitis, defined by codes for periodontal treatment from the Norwegian Control and Payment of Health Reimbursements Database (KUHR). Hazard ratios (HRs) were calculated for periodontitis in RA patients compared to controls. Generalized additive model in Cox regressions was estimated to visualize periodontitis occurrences as a function of number of RA visits. RESULTS: The risk of periodontitis increased with increasing number of RA visits. RA patients having 10 or more visits during the 7-year period had a 50% increased risk of periodontitis compared to controls (HR = 1.48, 95% confidence interval [CI]: 1.39-1.59); also, in patients with assumed new RA, an even higher risk estimate was seen (HR = 1.82, 95% CI: 1.53-2.17). CONCLUSIONS: In this register-based study in which periodontal treatment was used as a surrogate marker for periodontitis, we found an increased risk of periodontitis in RA patients, particularly those with active disease and new RA.

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).

Cytokine profile in gingival crevicular fluid and plasma of patients with aggressive periodontitis.

OBJECTIVE: This study aimed to determine the content of cytokines in gingival crevicular fluid (GCF) as well as in plasma of Sudanese patients with aggressive periodontitis (AgP) and healthy controls (HC). MATERIALS AND METHODS: Nineteen AgP patients and 19 HC were included. The mean probing pocket depth and clinical attachment level of the GCF sampled sites in patients were both ≥5 mm. The GCF and plasma levels of 27 cytokines were determined using 27-multiplex fluorescent bead-based immunoassays. Ratios were calculated among cytokines of the T-helper cell subsets Th1 and Th2. Descriptive statistics, the Mann-Whitney U-test and Spearman's rho rank correlation coefficient analysis were used. RESULTS: Interferon-γ was the only cytokine found in significantly lower levels in GCF of patients compared with HC. Levels of interleukin (IL)-10, IL-13, IL-1Ra, monocyte chemoattractant protein-1 (MCP-1), regulated on activation normal T-cell expressed and secreted (RANTES), granulocyte-colony-stimulating factor (G-CSF), and granulocyte-macrophage-CSF (GM-CSF) were significantly lower in plasma of AgP compared with HC. The ratios of Th1:Th2 in GCF and Treg:Th17 in plasma were significantly lower in AgP. CONCLUSIONS: The lower levels of cytokines detected systemically in plasma of AgP patients may have an impact on the immune response. The lower ratio of Th1:Th2 cytokines in GCF samples of AgP patients suggests a role for Th2 at the local site of disease.

Mutations in the gene encoding fibroblast growth factor 10 are associated with aplasia of lacrimal and salivary glands.

Autosomal dominant aplasia of lacrimal and salivary glands (ALSG; OMIM 180920 and OMIM 103420) is a rare condition characterized by irritable eyes and dryness of the mouth. We mapped ALSG to 5p13.2-5q13.1, which coincides with the gene fibroblast growth factor 10 (FGF10). In two extended pedigrees, we identified heterozygous mutations in FGF10 in all individuals with ALSG. Fgf10(+/-) mice have a phenotype similar to ALSG, providing a model for this disorder. We suggest that haploinsufficiency for FGF10 during a crucial stage of development results in ALSG.

Resolvin D1 protects periodontal ligament.

Resolution agonists are endogenous mediators that drive inflammation to homeostasis. We earlier demonstrated in vivo activity of resolvins and lipoxins on regenerative periodontal wound healing. The goal of this study was to determine the impact of resolvin D1 (RvD1) on the function of human periodontal ligament (PDL) fibroblasts, which are critical for wound healing during regeneration of the soft and hard tissues around teeth. Primary cells were cultured from biopsies obtained from three individuals free of periodontal diseases. Peripheral blood mononuclear cells were isolated by density gradient centrifugation from whole blood of healthy volunteers. PGE2, leukotriene B4 (LTB4), and lipoxin A4 (LXA4) in culture supernatants were measured by ELISA. The direct impact of RvD1 on PDL fibroblast proliferation was measured and wound closure was analyzed in vitro using a fibroblast culture "scratch assay." PDL fibroblast function in response to RvD1 was further characterized by basic FGF production by ELISA. IL-1ß and TNF-α enhanced the production of PGE2. Treatment of PDL cells and monocytes with 0.1-10 ng/ml RvD1 (0.27-27 M) reduced cytokine induced production of PGE2 and upregulated LXA4 production by both PDL cells and monocytes. RvD1 significantly enhanced PDL fibroblast proliferation and wound closure as well as basic FGF release. The results demonstrate that anti-inflammatory and proresolution actions of RvD1 with upregulation of arachidonic acid-derived endogenous resolution pathways (LXA4) and suggest resolution pathway synergy establishing a novel mechanism for the proresolution activity of the ω-3 docosahexaenoic acid-derived resolution agonist RvD1.

α11ß1 integrin-mediated MMP-13-dependent collagen lattice contraction by fibroblasts: evidence for integrin-coordinated collagen proteolysis.

We have previously determined that integrin α11ß1 is required on mouse periodontal ligament (PDL) fibroblasts to generate the force needed for incisor eruption. As part of the phenotype of α11(-/-) mice, the incisor PDL (iPDL) is thickened, due to disturbed matrix remodeling. To determine the molecular mechanism behind the disturbed matrix dynamics in the PDL we crossed α11(-/-) mice with the Immortomouse and isolated immortalized iPDL cells. Microarray analysis of iPDL cells cultured inside a 3D collagen gel demonstrated downregulated expression of a number of genes in α11-deficient iPDL cells, including matrix metalloproteinase-13 (MMP-13) and cathepsin K. α11(-/-) iPDL cells in vitro displayed disturbed interactions with collagen I during contraction of attached and floating collagen lattices and furthermore displayed reduced MMP-13 protein expression levels. The MMP-13 specific inhibitor WAY 170523 and the Cathepsin K Inhibitor II both blocked part of the α11 integrin-mediated collagen remodeling. In summary, our data demonstrate that in iPDL fibroblasts the mechanical strain generated by α11ß1 integrin regulates molecules involved in collagen matrix dynamics. The positive regulation of α11ß1-dependent matrix remodeling, involving MMP-13 and cathepsin K, might also occur in other types of fibroblasts and be an important regulatory mechanism for coordinated extracellular and intracellular collagen turnover in tissue homeostasis.

Role of integrins in the periodontal ligament: organizers and facilitators.

The periodontal ligament is the tissue that connects teeth to bone. The periodontal ligament is a fascinating tissue from a cell biologist's point of view, and because of its special properties and stem-cell content it has also come into the limelight in emerging fields of regenerative medicine. An increased range of genetically modified mouse models offer new tools for studying molecular mechanisms of tooth development. However, owing to species-specific organization of the tooth apparatus, the use of genetic animal models to study the role of the periodontal ligament in normal human tooth physiology and tooth pathology is challenging.

A regulatory polymorphism in PDCD1 is associated with susceptibility to systemic lupus erythematosus in humans.

Systemic lupus erythematosus (SLE, OMIM 152700) is a complex autoimmune disease that affects 0.05% of the Western population, predominantly women. A number of susceptibility loci for SLE have been suggested in different populations, but the nature of the susceptibility genes and mutations is yet to be identified. We previously reported a susceptibility locus (SLEB2) for Nordic multi-case families. Within this locus, the programmed cell death 1 gene (PDCD1, also called PD-1) was considered the strongest candidate for association with the disease. Here, we analyzed 2,510 individuals, including members of five independent sets of families as well as unrelated individuals affected with SLE, for single-nucleotide polymorphisms (SNPs) that we identified in PDCD1. We show that one intronic SNP in PDCD1 is associated with development of SLE in Europeans (found in 12% of affected individuals versus 5% of controls; P = 0.00001, r.r. (relative risk) = 2.6) and Mexicans (found in 7% of affected individuals versus 2% of controls; P = 0.0009, r.r. = 3.5). The associated allele of this SNP alters a binding site for the runt-related transcription factor 1 (RUNX1, also called AML1) located in an intronic enhancer, suggesting a mechanism through which it can contribute to the development of SLE in humans.

Association between genetic variants in the tumour necrosis factor/lymphotoxin α/lymphotoxin ß locus and primary Sjogren's syndrome in Scandinavian samples.

OBJECTIVES: Lymphotoxin ß (LTB) has been found to be upregulated in salivary glands of patients with primary Sjögren's syndrome (pSS). An animal model of pSS also showed ablation of the lymphoid organisation and a marked improvement in salivary gland function on blocking the LTB receptor pathway. This study aimed to investigate whether single-nucleotide polymorphisms (SNP) in the lymphotoxin α (LTA)/LTB/tumour necrosis factor (TNF) gene clusters are associated with pSS. METHODS: 527 pSS patients and 532 controls participated in the study, all of Caucasian origin from Sweden and Norway. 14 SNP markers were genotyped and after quality control filtering, 12 SNP were analysed for their association with pSS using single marker and haplotype tests, and corrected by permutation testing. RESULTS: Nine markers showed significant association with pSS at the p=0.05 level. Markers rs1800629 and rs909253 showed the strongest genotype association (p=1.64E-11 and p=4.42E-08, respectively, after correcting for sex and country of origin). When the analysis was conditioned for the effect of rs1800629, only the association with rs909253 remained nominally significant (p=0.027). In haplotype analyses the strongest effect was observed for the haplotype rs909253G_rs1800629A (p=9.14E-17). The associations were mainly due to anti-Ro/SSA and anti-La/SSB antibody-positive pSS. CONCLUSIONS: A strong association was found between several SNP in the LTA/LTB/TNFα locus and pSS, some of which led to amino acid changes. These data suggest a role for this locus in the development of pSS. Further studies are needed to examine if the genetic effect described here is independent of the known genetic association between HLA and pSS.

Periodontitis in patients with systemic lupus erythematosus: A nationwide study of 1,990 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.