Does decision tree analysis predict oral ulcer activity-related factors in patients with Behçet's syndrome?

OBJECTIVES: The study aimed to identify the interactions among treatment protocols and oral ulcer activity related factors in patients with Behçet's syndrome (BS) using the Classification and Regression Tree (CART) algorithm. METHODS: In this cross-sectional study, 979 patients with BS were included from16 centres in Turkey, Jordan, Brazil and the United Kingdom. In the CART algorithm, activities of oral ulcer (active vs. inactive), genital ulcer (active vs. inactive), cutaneous involvement (active vs. inactive), musculoskeletal involvement (active vs. inactive), gender (male vs. female), disease severity (mucocutaneous and musculoskeletal involvement vs. major organ involvement), smoking habits (current smoker vs. non-smoker), tooth brushing habits (irregular vs. regular), were input variables. The treatment protocols regarding immunosuppressive (IS) or non-IS medications were the target variable used to split from parent nodes to purer child nodes in the study. RESULTS: In mucocutaneous and musculoskeletal involvement (n=538), the ratio of IS use was higher in patients with irregular toothbrushing (ITB) habits (27.1%) than in patients with regular toothbrushing (RTB) habits (14.2%) in oral ulcer activity. In major organ involvement (n=441), male patients with ITB habits were more likely treated with IS medications compared to those with RTB habits (91.6% vs. 77.6%, respectively). CONCLUSIONS: Male BS patients on IS who have major organ involvement and oral ulcer activity with mucocutaneous and musculoskeletal involvement have irregular toothbrushing habits. Improved oral hygiene practices should be considered to be an integral part for implementing patient empowerment strategies for BS.

A genome-wide association study identifies nucleotide variants at SIGLEC5 and DEFA1A3 as risk loci for periodontitis.

Periodontitis is one of the most common inflammatory diseases, with a prevalence of 11% worldwide for the severe forms and an estimated heritability of 50%. The disease is characterized by destruction of the alveolar bone due to an aberrant host inflammatory response to a dysbiotic oral microbiome. Previous genome-wide association studies (GWAS) have reported several suggestive susceptibility loci. Here, we conducted a GWAS using a German and Dutch case-control sample of aggressive periodontitis (AgP, 896 cases, 7,104 controls), a rare but highly severe and early-onset form of periodontitis, validated the associations in a German sample of severe forms of the more moderate phenotype chronic periodontitis (CP) (993 cases, 1,419 controls). Positive findings were replicated in a Turkish sample of AgP (223 cases, 564 controls). A locus at SIGLEC5 (sialic acid binding Ig-like lectin 5) and a chromosomal region downstream of the DEFA1A3 locus (defensin alpha 1-3) showed association with both disease phenotypes and were associated with periodontitis at a genome-wide significance level in the pooled samples, with P = 1.09E-08 (rs4284742,-G; OR = 1.34, 95% CI = 1.21-1.48) and P = 5.48E-10 (rs2738058,-T; OR = 1.28, 95% CI = 1.18-1.38), respectively. SIGLEC5 is expressed in various myeloid immune cells and classified as an inhibitory receptor with the potential to mediate tyrosine phosphatases SHP-1/-2 dependent signaling. Alpha defensins are antimicrobial peptides with expression in neutrophils and mucosal surfaces and a role in phagocyte-mediated host defense. This study identifies the first shared genetic risk loci of AgP and CP with genome-wide significance and highlights the role of innate and adaptive immunity in the etiology of periodontitis.

Oral health is a mediator for disease severity in patients with Behçet's disease: A multiple mediation analysis study.

OBJECTIVES: The aim of the study was to examine whether oral health as an infection focus could mediate disease course in patients with Behçet's disease (BD). METHODS: In the study, oral health of 194 BD patients was examined at baseline and follow-up periods. The reasons for last dental visits were recorded as tooth extraction or regular control visits/planned treatments at the end of follow-up period. The Behçet's disease severity score was calculated with higher scores indicating a more severe course. Mediation analysis was carried out to assess the effects of oral health on disease severity score at follow-up period in the study. RESULTS: Dental and periodontal indices were found to be higher at follow-up visit compared to those of baseline (P < 0.05). Disease severity score was found to be higher in males (5.3 ± 2.4) compared to females (4.4 ±2.5) in the whole group (P = 0.005). Moreover, patients having tooth extraction at their last dental visit and patients with dental caries had a more severe disease course (5.4 ± 2.4; 5.5 ± 2.5) compared to others (4.2 ± 2.3; 4.4 ± 2.4; P < 0.0001). In multiple mediation analysis, disease severity score was a dependent variable and was directly mediated by male gender (B = -0.8822, P = 0.0145) and indirectly mediated through the presence of dental caries (B = 0.9509 P = 0.0110) and need of tooth extraction (B = 0.8758, P = 0.0128). CONCLUSION: Both presence of dental caries and need of tooth extraction were observed to be effective mediators for a more severe disease course in BD. Therefore, better oral health should be aimed to eliminate microbial factors, which are a part of pathogenic processes.

Could Sublingual Immunotherapy Affect Oral Health in Children with Asthma and/or Allergic Rhinitis Sensitized to House Dust Mite?

BACKGROUND: Sublingual immunotherapy (SLIT) has been successfully employed in IgE-mediated respiratory allergies. However, it is not known whether the modulation of immune responses in the sublingual area during SLIT has any deleterious effect on oral health. We sought to determine the oral health prospectively in children receiving SLIT for house dust mite allergy. MATERIAL AND METHODS: Eighteen children with allergic asthma and/or rhinitis and 31 age-matched healthy controls (HC) were included in an open-labeled trial. Oral health was evaluated by scoring the decayed, missing, and filled teeth for primary (dmft) and permanent (DMFT) dentition, and the plaque and gingival indices. Moreover, cariogenic food intake and teeth-brushing habits were also noted at baseline and at 19 months. RESULTS: The mean age of the SLIT participants was 9.5 ± 3.1 years and that of the HC was 9.2 ± 3.7 years. The mean duration of SLIT was 19.13 ± 3.81 months. At baseline, the total dmft and DMFT indices were similar in the SLIT and HC groups (p > 0.05), which demonstrated poor hygiene overall. In the within-group comparisons at the examination at 19 months, the SLIT group had a lower number of carious primary teeth and a higher number of filled primary teeth compared to the count at baseline (p = 0.027 and p = 0.058, respectively). CONCLUSION: Our study showed no detrimental effect of SLIT on oral health during a period of 19 months of follow-up. Parents should be motivated to use dental health services to prevent new caries formation since our cohort had overall poor oral hygiene at the baseline.

Sequencing of 16S rRNA reveals a distinct salivary microbiome signature in Behçet's disease.

Behçet's disease (BD) is characterized by recurrent oro-genital ulcers, mucocutaneous lesions, and serious organ involvement. We investigated the salivary microbiome in BD using high-throughput sequencing of the 16S rRNA V4 region. Stimulated saliva samples were collected from 31 BD patients and 15 healthy controls, and in 9 BD patients, a second saliva sample was collected following dental and periodontal treatment. Sequence analysis identified a total of 908 operational taxonomic units (OTUs) present across all samples. Patients had a microbial community structure that is significantly less diverse than healthy controls. The most overabundant species in BD was Haemophilus parainfluenzae, while the most depleted included Alloprevotella rava and species in the genus Leptotrichia. Periodontal treatment improved oral health indices in BD but had no short-term effect on bacterial community structure. Neither the BD-associated genetic risk locus within the HLA-B/MICA region nor being on immunosuppressive medications explained the differences between patients and controls.

Oral health and oral quality of life in inactive patients with familial Mediterranean fever without amyloidosis.

OBJECTIVES: The aim of this study was to investigate oral and general health-related quality of life (QoL) in patients with familial Mediterranean fever (FMF) disease. METHODS: In this cross-sectional study, 45 patients with FMF, 50 age- and sex-matched healthy controls (HC), and 50 patients with Behçet's disease (BD) as the disease control group were included. FMF disease activity was evaluated by using the FMF-severity score, as well as with erythrocyte sedimentation rate (ESR), and serum C-reactive protein and fibrinogen levels. Oral health-related QoL and general QoL were evaluated using oral health impact profile-14 (OHIP-14) and Medical Outcomes Short-Form Health Survey Questionnaire 36 (SF-36), respectively. RESULTS: Only the numbers of extracted teeth (4.13±4.72 vs. 1.55±3.6) and filled teeth (2.33±3.19 vs. 0.66±1.46) were significantly higher in FMF group compared to HC group (p=0.005 and p=0.013, respectively). OHIP-14 score was significantly higher in FMF and BD groups compared to HC group. In FMF patients, OHIP-14 score was positively correlated with the number of extracted teeth (r=0.38, p=0.010), while the number of carious teeth was positively correlated with ESR (r=0.43, p=0.003). When FMF patients were sub-classified according to disease severity, no significant difference was observed with respect to oral health status. CONCLUSIONS: In patients with FMF, some of the parameters of oral health status were found to be worse compared to HC group. Tooth loss appears to be to be a critical factor contributing to impaired oral QoL. In general, oral health status in FMF patients is better than in BD patients.

Novel and known periodontal pathogens residing in gingival crevicular fluid are associated with rheumatoid arthritis.

BACKGROUND: Periodontitis is a suspected environmental risk factor for the development of rheumatoid arthritis (RA). However, correlation mechanisms between the two pathologies remain elusive. This study examined potential correlations between detached subgingival bacteria collected in gingival crevicular fluid (GCF) and RA parameters. METHODS: RA patients (n = 52, F:M = 40:12), patients with Behcet's disease (BD, n = 40, F:M = 29:11) as another systemic inflammatory disease were studied along with a systemically healthy control group (HC, n = 57, F:M = 40:17). All participants were non-smokers. Full mouth periodontal parameters were recorded. RA activity was assessed using the 28-joint Disease Activity Score (DAS-28). Rheumatoid factors (RFs)-IgM and -IgA were measured by ELISA. GCF samples were investigated by means of fluorescent in situ hybridization for 10 different bacterial taxa. RESULTS: The taxa TM7, Synergistetes cluster B, Leptotrichia, Megasphaera, Anaeroglobus geminatus, and Tannerella forsythia displayed significantly differential abundances between the groups. Whereas abundances of Megasphaera and A. geminatus were significantly increased in the RA group, only Porphyromonas gingivalis displayed significant correlations with plaque scores, bleeding on probing, and RF-IgA. RA patients displaying RF-IgA levels >75 IU/mL exhibited five-fold more abundant P. gingivalis levels than patients below the threshold. This association with RF-IgA levels appeared even more pronounced, by six-fold more P. gingivalis (P = 0.025), in patients with a DAS-28 score >3.2, indicative of moderate/very active RA. CONCLUSIONS: Unattached GCF bacteria may mediate the association between periodontitis and RA, and monitoring the bacterial composition of GCF might inform on RA activity. The role of newly identified bacterial taxa in RA warrants further investigations.

Elevated serum TREM-1 is associated with periodontitis and disease activity in rheumatoid arthritis.

The triggering receptor expressed on myeloid cells 1 (TREM-1) and peptidoglycan recognition protein 1 (PGLYRP1) are involved in the propagation of inflammatory responses. This study investigated whether serum levels of TREM-1 and PGLYRP1 correlate with periodontitis in rheumatoid arthritis (RA) patients. A total of 154 non-smoking participants with RA (n = 55, F/M: 41/14), Behçet´s disease (BD, n = 41, F/M: 30/11) and healthy controls (HC, n = 58, F/M: 40/18) were recruited. Serum and saliva were collected, the 28-joint disease activity score (DAS-28) was calculated and dental/periodontal measurements were recorded. Serum TREM-1 and PGLYRP1 levels were measured by ELISA and salivary bacterial DNA counts by quantitative polymerase chain reaction. TREM-1 and PGLYRP1 levels were higher in RA (166.3 ± 94.3; 155.5 ± 226.9 pg/ml) than BD (102.3 ± 42.8; 52.5 ± 26.3 pg/ml) and HCs (89.8 ± 55.7; 67.4 ± 37.3 pg/ml) (p < 0.05). In RA, periodontitis was associated with increased TREM-1 and PGLYRP1 levels (p < 0.05), yet in patients under methotrexate TREM-1 levels were lower. TREM-1 correlated with C-reactive protein (CRP) levels, DAS-28 and erythrocyte sedimentation rate, whereas PGLYRP1 positively correlated with CRP. RA patients displayed 3.5-fold higher salivary bacterial DNA counts than HCs. Increased serum TREM-1 levels correlated with PGLYRP1, CRP and DAS-28-ESR in RA patients with periodontitis.

Are Salivary Gland Ultrasonography Scores Associated with Salivary Flow Rates and Oral Health-related Quality of Life in Sjögren Syndrome?

OBJECTIVE: Major salivary gland ultrasonography (SGUS) is a widely used imaging technique to evaluate salivary gland involvement in primary Sjögren syndrome (pSS). The aim of this study was to evaluate the relationship between SGUS, salivary flow rate (SFR) as an objective measure of the gland function, and oral health-related quality of life (OHRQOL) as a patient-reported outcome measure (PROM) in a pSS cohort. METHODS: Sixty-six patients with pSS were examined by SGUS according to Hocevar and Milic scoring systems. Patients with inhomogeneity/hypoechoic areas with scores ≥ 2 in parotid and submandibular glands were classified separately as "severe glandular involvement." Further, oral health, SFR, and Oral Health Impact Profile-14 (OHIP-14) for OHRQOL were assessed. RESULTS: Both total Hocevar and Milic scores were higher in 21 pSS patients with low unstimulated whole salivary flow rate (U-WSFR) than 45 pSS patients without low U-WSFR (P = 0.001 and P < 0.0001, respectively). Increased scores of homogeneity, hypoechoic areas and glandular border visibility were observed in patients with low U-WSFR (P < 0.05). Among these variables, homogeneity score was found to be an independent risk factor for low U-WSFR in pSS according to logistic regression analysis (OR 1.586, P = 0.001). Moreover, a higher OHIP-14 score was observed in severe parotid involvement compared to nonsevere cases (23.26 ± 21.19 vs 8.32 ± 13.82, P = 0.004). CONCLUSION: High Milic and Hocevar SGUS scores are associated with reduced SFR and poor OHRQOL as a PROM. The inhomogeneity component of the SGUS score is associated with low U-WSFR and is an indicator of severely affected gland function.

The close association between dental and periodontal treatments and oral ulcer course in behcet's disease: a prospective clinical study.

OBJECTIVE: The aim of the study was to evaluate the influence of dental and periodontal treatments to the course of oral ulcers in patients with Behcet's disease (BD). METHODS: Fifty-eight consecutive BD patients with oral ulcers were studied. Twenty-nine patients were in the intervention group (F/M: 15/14, mean age: 39.6 +/- 6.9 years) and 29 (F/M: 15/14, 39.4 +/- 10.6 years) were followed with a conventional treatment approach. In addition to oral hygiene education, dental and periodontal treatments were carried out in the intervention group, whereas the control group was only given oral hygiene education. Patients were evaluated in the pre-treatment observation period (1 month), treatment period (1 month) and 6 months after treatment. RESULTS: An increase in the number of new oral ulcers (4.1 +/- 3.5) was observed within 2 days during the treatment compared with 3-30 days during treatment month (2.3 +/- 1.2) (P = 0.002). However, 6 months after the treatment, the number of oral ulcers (1.9 +/- 1.5) was significantly lower compared with the pre-treatment observation (4.8 +/- 3.2) (P = 0.000) and treatment periods (6.4 +/- 2.3) in the intervention group (P = 0.05), whereas a similar oral ulcer presence was observed in the control group (2.8 +/- 2.4, 3.7 +/- 2.3 and 4.8 +/- 4.3, respectively) (P > 0.05). Dental and periodontal indices were also better in the intervention group during the 6-month follow-up. CONCLUSION: Our results suggest that, in BD patients, dental and periodontal therapies could be associated with a flare-up of oral ulcers in the short term, but may decrease their number in longer follow-up. They also lead to a better oral health.

Long-Term Efficacy of Pegylated Interferon Alpha-2b in Behçet's Uveitis: A Small Case Series.

PURPOSE: To assess the long-term efficacy and safety of pegylated interferon alpha-2b (peg-IFN-α-2b) for severe uveitis associated with Behçet's disease. METHODS: Peg-IFN-α-2b was administrated at an initial dosage of 0,5-1,5 µg/kg/week. If any complications were observed, the dosage was tapered. Ocular examinations, systemic findings, and treatment compliance of the patients were evaluated. RESULTS: Control of ocular inflammation was achieved in all patients (n = 4). The average increase in visual acuity after drug administration of 0,425 ± 0,125 logMAR was not statistically significant (Wilcoxon Test, p = 0,066) due to small number of cases. Any side-effects with laboratory abnormalities returned to baseline levels with reduction of the doses. Due to less frequent injections, increased satisfaction of the patients was noted. CONCLUSIONS: This series highlights the peg-IFN-α-2b administration in Behçet's uveitis. Peg-IFN-α-2b has a potential long-term therapeutic effect for the treatment of severe uveitis. Efficacy with a reduced number of injections improved the quality of Behçet patients' lives.

The assessment of contributing factors to oral ulcer presence in Behçet's disease: Dietary and non-dietary factors.

OBJECTIVE: The aim of this study was to assess the contributing factors for oral ulcer activity in Behçet's disease (BD). METHODS: Ninety-two patients with BD (F/M: 42/50, mean age: 38.7±10.02 years) participated in this cross-sectional study. Data regarding disease-related factors, smoking patterns, and self-reported dietary/non-dietary triggering factors for oral ulcer activity were collected by a questionnaire. Treatment protocol was categorized as mild and intensive groups associated with organ involvements. RESULTS: A mild treatment protocol was more common in females (52.4% vs 20%) than in males (p=0.002). During the last three months, the number of oral ulcers in female patients was higher in the mild treatment group (6.4±6.5) than in the intensive treatment group (3.3±4.9) (p=0.045). In patients with active oral ulcers (n=63), rate of being a non-smoker was also higher in females (86.7% vs 63.6%) than in males. Daily frequency of tooth brushing was 1.2±0.8 in patients with BD, and was higher in females (1.5±0.9 vs 0.9±0.6) (p=0.001). Stress and fatigue (78.3%) were reported as the most frequent triggering factors for oral ulcer presence in patients with BD. A total of 148 different dietary factors associated with oral ulcer presence were reported in the study. CONCLUSION: A mild treatment protocol and being a non-smoker were found to be the contributing factors associated with oral ulcer activity in patients with BD. Being motivated for oral hygiene and being non-smokers were positive health behaviors observed in females. Irrespective of gender, stress and fatigue were defined as the most common self-reported triggering factors for oral ulcer presence in BD. In addition, the roles of some dietary factors were also reported.

Salivary levels of HNP 1-3 are related to oral ulcer activity in Behçet's disease.

BACKGROUND: Saliva contains antimicrobial peptides derived from oral epithelium as well as neutrophils in the innate immune response. The aim of this study was to examine the association between salivary human neutrophil peptide (HNP) 1-3 levels originating from neutrophils and oral ulcers in patients with Behçet's disease (BD). METHODS: Ninety-five patients with BD (F/M: 39/56; mean age: 38.7 ± 11.9 years) and 53 healthy controls (HC; F/M: 23/30; mean age: 35.2 ± 10.1 years) were included in the study. The disease control group (F/M: 20/33; mean age: 33.7 ± 10.7 years) was comprised of patients with oral infection regarding endodontic infection (n = 32) and pericoronitis (n = 21). Salivary HNP 1-3 levels of groups were measured in unstimulated samples by ELISA (Hycult, the Netherlands). RESULTS: A statistically significant increase was found in salivary HNP 1-3 levels of patients with BD (2268.28 ± 1216.38 µg/ml) compared with HC (1836.49 ± 857.76 µg/ml), patients with endodontic infection (849.9 ± 376.1 µg/ml), and patients with pericoronitis (824.3 ± 284.02 µg/ml; P = 0.024, 0.000 and 0.000, respectively). The ratio of active oral ulcer (100%, n = 14) was higher in low HNP 1-3 levels (≤ 1000 µg/ml) than the others (66.7%, n = 54) in active patients with BD (P = 0.008). Moreover, salivary HNP 1-3 levels were significantly lower in patients with endodontic infection and patients with pericoronitis compared with those in the HC group and patients with BD (P = 0.000). CONCLUSION: A decrease in salivary HNP 1-3 levels might be a biological factor for predisposition to oral ulcers in patients with BD and oral infection in healthy patients.

Salivary levels of antimicrobial peptides Hnp 1-3, Ll-37 and S100 in Behcet's disease.

BACKGROUND: Oral ulcer is the cardinal clinical sign and increased neutrophilic activity is a part of the pathogenesis in Behcet's disease (BD). Saliva, as a part of the innate immune response, contains antimicrobial peptides (AMPs) that are derived from both oral epithelial cells and neutrophils. The aim of this study was to investigate the associations between salivary levels of AMPs HNP 1-3, LL-37 and S100 and disease course in patients with Behcet's disease (BD). METHODS: Fifty-three patients with BD and 44 healthy controls (HC) were included in the study. Disease severity score reflecting organ involvement was calculated. Salivary HNP 1-3, LL-37 and S100 levels were measured in unstimulated saliva samples by ELISA. RESULTS: Salivary HNP 1-3 and S100 levels in BD patients (2715.2 ± 1333.4 µg/ml and 430.6 ± 203.9 ng/ml) were significantly higher compared to HC (1780.6 ± 933.2 µg/ml and 365.3 ± 84.7 ng/ml) (p = 0.000 and p = 0.004, respectively). Although LL-37 levels were also higher in BD than HC (190.9 ± 189.1 vs 143.1 ± 128.9 ng/ml), no significant difference was observed (p = 0.53). Salivary HNP 1-3 and LL-37 levels were associated with the severity of BD (mild disease: 1975.1 ± 1174.2 µg/ml and 115.9 ± 109.4 ng/ml vs severe disease: 2955.7 ± 1305.6 µg/ml and 215.3 ± 203.8 ng/ml, p=0.020 and p=0.031, respectively). Salivary LL-37 levels also correlated with the number of monthly oral ulcers (r = 0.5 p = 0.000). CONCLUSION: An increase in salivary HNP 1-3 and S100 levels might be associated with enhanced local and systemic innate responses in BD.