Kuo-Lung Lai

Association between a history of periodontitis and the risk of rheumatoid arthritis: a nationwide, population-based, case–control study

Objective To investigate the association between the risk of rheumatoid arthritis (RA) and a history of periodontitis. Methods This nationwide, population-based, case–control study used administrative data to identify 13 779 newly diagnosed patients with RA (age ≥16 years) as the study group and 137 790 non-patients with RA matched for age, sex, and initial diagnosis date (index date) as controls. Using conditional logistic regression analysis after adjustment for potential confounders, including geographical region and a history of diabetes and Sjögrens syndrome, ORs with 95% CI were calculated to quantify the association between RA and periodontitis. To evaluate the effects of periodontitis severity and the lag time since the last periodontitis visit on RA development, ORs were calculated for subgroups of patients with periodontitis according to the number of visits, cumulative cost, periodontal surgery and time interval between the last periodontitis-related visit and the index date. Results An association was found between a history of periodontitis and newly diagnosed RA (OR=1.16; 95% CI 1.13 to 1.21). The strength of this association remained statistically significant after adjustment for potential confounders (OR=1.16; 95% CI 1.12 to 1.20), and after variation of periodontitis definitions. The association was dose- and time-dependent and was strongest when the interval between the last periodontitis-related visit and the index date was <3 months (OR=1.64; 95% CI 1.49 to 1.79). Conclusions This study demonstrates an association between periodontitis and incident RA. This association is weak and limited to lack of individual smoking status.

Involvement of TLR7 MyD88-dependent signaling pathway in the pathogenesis of adult-onset Still's disease

IntroductionThe objective of this study was to investigate the potential role of the Toll-like receptor 7 (TLR7) signaling pathway in the pathogenesis of adult-onset Stills disease (AOSD).MethodsFrequencies of TLR7-expressing precursor of myeloid dendritic cells (pre-mDCs) and mDCs in 28 AOSD patients, 28 patients with systemic lupus erythematosus (SLE) and 12 healthy controls (HC) were determined by flow cytometry analysis. Transcript and protein levels of TLR7 signaling molecules in peripheral blood mononuclear cells (PBMCs) were evaluated by quantitative PCR and western blotting respectively. Serum cytokines levels were measured by ELISA.ResultsSignificantly higher median frequencies of TLR7-expressing pre-mDCs and mDCs were observed in AOSD patients (65.5% and 14.9%, respectively) and in SLE patients (60.3% and 14.4%, respectively) than in HC (42.8% and 8.8%, respectively; both P <0.001). Transcript and protein levels of TLR7-signaling molecules, including MyD88, TRAF6, IRAK4 and IFN-α, were upregulated in AOSD patients and SLE patients compared with those in HC. Disease activity scores were positively correlated with the frequencies of TLR7-expressing mDCs and expression levels of TLR7 signaling molecules in both AOSD and SLE patients. TLR7 ligand (imiquimod) stimulation of PBMCs resulted in significantly enhanced levels of interleukin (IL)-1β, IL-6, IL-18 and IFN-α in AOSD and SLE patients. Frequencies of TLR7-expressing mDCs and expression levels of TLR7 signaling molecules significantly decreased after effective therapy.ConclusionsElevated levels of TLR7 signaling molecules and their positive correlation with disease activity in AOSD patients suggest involvement of the TLR7 signaling pathway in the pathogenesis of this disease. The overexpression of TLR7 MyD88-dependent signaling molecules may be a common pathogenic mechanism for both AOSD and SLE.

Germinal center kinase-like kinase (GLK/MAP4K3) expression is increased in adult-onset Still's disease and may act as an activity marker

BackgroundGerminal center kinase-like kinase (GLK, also termed MAP4K3), a member of the MAP4K family, may regulate gene transcription, apoptosis and immune inflammation in response to extracellular signals. The enhanced expression of GLK has been shown to correspond with disease severity in patients with systemic lupus erythematosus. We investigated the role of GLK in the pathogenesis of adult-onset Stills disease, which shares some similar clinical characteristics with systemic lupus erythematosus.MethodsThe frequencies of circulating GLK-expressing T-cells in 24 patients with active adult-onset Stills disease and 12 healthy controls were determined by flow cytometry analysis. The expression levels of GLK proteins and transcripts were evaluated in peripheral blood mononuclear cells by immunoblotting and quantitative PCR. Serum levels of T helper (Th)17-related cytokines, including IL-1β, IL-6, IL-17 and TNF-α, were measured by ELISA.ResultsSignificantly higher median frequencies of circulating GLK-expressing T-cells were observed in patients with adult-onset Stills disease (31.85%) than in healthy volunteers (8.93%, P <0.001). The relative expression levels of GLK proteins and transcripts were also significantly higher in patients with adult-onset Stills disease (median, 1.74 and 2.35, respectively) compared with those in healthy controls (0.66 and 0.92, respectively, both P <0.001). The disease activity scores were positively correlated with the frequencies of circulating GLK-expressing T-cells (r = 0.599, P <0.005) and the levels of GLK proteins (r = 0.435, P <0.05) or GLK transcripts (r = 0.452, P <0.05) in patients with adult-onset Stills disease. Among the examined Th17-related cytokines, elevated levels of serum IL-6 and IL-17 were positively correlated with the frequencies of circulating GLK-expressing T-cells and the levels of GLK proteins as well as transcripts in patients with adult-onset Stills disease. GLK expression levels decreased significantly after effective therapy in these patients.ConclusionsElevated expression levels of GLK and their positive correlation with disease activity in patients with adult-onset Stills disease indicate that GLK may be involved in the pathogenesis and act as a novel activity biomarker of this disease.

Rheumatoid Arthritis Risk Associated with Periodontitis Exposure: A Nationwide, Population-Based Cohort Study

Background The risk of periodontitis (PD) is increased in the patient group of rheumatoid arthritis (RA). RA and PD also shared some pathological mechanism. The aim of this study is to investigate the risk of RA associated with PD exposure. Methods and Findings This study identified 3 mutually exclusive cohorts using the 1999–2010 Taiwanese National Health Insurance Research Database (NHIRD) to investigate the association between PD and the risk of incident RA. All patients with PD in 2000 were identified from the database of all enrollees as the PD cohort. From the representative database of 1,000,000 enrollees randomly selected in 2010 (LHID2010), individuals without any periodontal disease (PO) during 1999–2010 were selected as the non-PO cohort. Individuals who were not included in the non-PO cohort and received dental scaling (DS) no more than two times per year during 1999–2010 were selected as the DS cohort from LHID2010. Using cox proportional regression analysis, hazard ratios (HRs) with 95% confidence intervals (Cis) were calculated to quantify the association between PD exposure and RA development. In the three-group comparison using the non-PO cohort as reference, we found that the risk of RA was higher in the PD and DS cohorts (HRs, 1.89 and 1.43; 95% CIs, 1.56–2.29 and 1.09–1.87, respectively). For comparisons between two cohorts, the PD cohort had a higher risk of RA than the non-PO and DS cohorts (HRs, 1.91 and 1.35; 95% CIs, 1.57–2.30 and 1.09–1.67, respectively). Conclusion PD was associated with an increased risk of RA development.

Periodontitis and etanercept discontinuation risk in anti-tumor necrosis factor-naive rheumatoid arthritis patients: a nationwide population-based cohort study.

ObjectiveThe objective of this study was to investigate the association between periodontitis (PD) and etanercept (ETN) discontinuation in anti–tumor necrosis factor (anti-TNF)–naive patients with rheumatoid arthritis (RA). MethodsThis retrospective nationwide population-based cohort study identified 3359 anti-TNF–naive patients with RA (age at diagnosis ≥16 years) in whom ETN treatment was initiated using administrative data. We identified PD exposure within 5 years before ETN initiation and during ETN treatment. Cox proportional hazard models were used to assess ETN discontinuation risk associated with PD within 5 years before ETN initiation, shown as hazard ratios with 95% confidence intervals (CIs). Stratified analyses were performed on the basis of PD during ETN treatment to avoid violating the Cox regression assumptions. ResultsPatients with PD history during the 5 years before ENT initiation had a higher risk of ETN discontinuation compared with those without such history; the hazard ratios of ETN discontinuation were 1.27 (95% CI, 1.01–1.60) and 1.17 (95% CI, 1.06–1.30) among patients with and without PD during ETN treatment, respectively. Other risk factors included age older than 65 years and daily prednisolone dose greater than 10 mg/d within 1 year before ETN initiation. Concomitant methotrexate, leflunomide, salazopyrin, or hydroxychloroquine administration had a protective effect on ETN discontinuation in patients without PD during ETN treatment, but the protective effect by leflunomide, salazopyrin, and hydroxychloroquine was attenuated in patients with PD during ETN treatment (P for interaction <0.05). ConclusionsA PD history within 5 years before ETN administration was associated with increased ETN discontinuation risk in anti-TNF–naive patients with RA.

The Incidence and Prevalence of Common Variable Immunodeficiency Disease in Taiwan, A Population-Based Study

Common variable immunodeficiency (CVID) is one of the primary immunodeficiency diseases that occur in both children and adults. We present here a nationwide, population-based epidemiological study of CVID across all ages in Taiwan during 2002–2011. Using the International Classification of Diseases, Ninth Revision code 279.06, cases of CVID were identified from Taiwans National Health Insurance Research Database from January 2002 to December 2011. Age- and sex-specific incidence and prevalence rates were calculated. A total of 47 new cases of CVID during 2002–2011 were identified. Total prevalence rose from 0.13 per 100,000 in 2002 to 0.28 per 100,000 in 2011. The annual incidence rate during 2002–2011 was 0.019 per 100,000. Cases were equally distributed between males and females and males mostly occurred in younger patients. This nationwide population-based study showed that the incidence and prevalence of CVID in Taiwan were lower than that in Western countries.

Elevated Expression of the NLRP3 Inflammasome and Its Correlation with Disease Activity in Adult-onset Still Disease

Objective. The dysregulation of the NLRP3 (NLR containing a pyrin domain) inflammasome is involved in autoinflammatory diseases. Adult-onset Still disease (AOSD) is regarded as an autoinflammatory disease. However, the pathogenic involvement of NLRP3 inflammasome in AOSD remains unclear and NLRP3 activators in AOSD are currently unknown. Methods. The mRNA expression of NLRP3 inflammasome signaling in peripheral blood mononuclear cells (PBMC) from 34 patients with AOSD and 14 healthy subjects was determined using quantitative-PCR (qPCR). The changes in mRNA and protein levels of NLRP3 inflammasome signaling in PBMC treated with the potential activator [imiquimod (IMQ)] or inhibitor of NLRP3 were evaluated using qPCR and immunoblotting, respectively. The supernatant levels of interleukin (IL)-1β and IL-18 were determined by ELISA. Results. Significantly higher mRNA levels of NLRP3 inflammasome signaling were observed in patients with AOSD compared with healthy controls. NLRP3 expressions were positively correlated with disease activity in patients with AOSD. IMQ (an effective Toll-like receptor 7 ligand; 10 µg/ml and 25 µg/ml) stimulation of PBMC from patients with AOSD induced dose-dependent increases of mRNA expression of NLRP3 (mean ± standard error of the mean, 2.06 ± 0.46 and 6.05 ± 1.84, respectively), caspase-1 (1.81 ± 0.23 and 4.25 ± 0.48), IL-1β (5.68 ± 1.51 and 12.13 ± 3.71), and IL-18 (2.32 ± 0.37 and 4.81 ± 0.51) compared with controls (all p < 0.005). IMQ stimulation of PBMC from patients similarly induced greater increases in protein expressions of NLRP3 inflammasome compared with controls. The protein expressions of NLRP3, IL-1β, and IL-18 on PBMC significantly decreased after treatment with NLRP3 inhibitor in patients with AOSD. Conclusion. Increased expression of NLRP3 inflammasome and its positive correlation with disease activity in AOSD suggest its involvement in disease pathogenesis. IMQ upregulated expressions of NLRP3 inflammasome signaling, and IMQ might be an activator of NLRP3 inflammasome in AOSD.

The risk of tuberculosis disease in rheumatoid arthritis patients on biologics and targeted therapy: A 15-year real world experience in Taiwan

The objective of this study is to determine the risk of tuberculosis (TB) disease in biologics users among rheumatoid arthritis (RA) patients in Taiwan from 2000 to 2015. This retrospective cohort study enrolled adult RA patients initiated on first biologics at Taichung Veterans General Hospital. TB risks were determined as hazard ratio (HR) with 95% confidence interval (CI) using cox regression. A total of 951 patients were recruited; etanercept (n = 443), adalimumab (n = 332), abatacept (n = 74), golimumab (n = 60), tocilizumab (n = 31) and tofacitinib (n = 11). Twenty-four TB cases were identified; 13 in etanercept and 11 in adalimumab group with the TB incidence rate of 889.3/ 100,000 and 1055.6/ 100,000 patient-years respectively. There was no significant difference in TB risk between adalimumab and etanercept users with an incidence rate ratio of 1.27 (p = 0.556 by Poisson model). Significant 2-year TB risk factors included elderly patient >65 year-old (HR: 2.72, 95% CI: 1.06–6.99, p = 0.037), history of TB (HR: 6.24, 95% CI: 1.77–22.00, p = 0.004) and daily glucocorticoid use ≥5mg (HR:5.01, 95% CI: 1.46–17.21, p = 0.010). Sulfasalazine treatment appeared to be protective (HR: 0.32, 95% CI: 0.11–0.97, p = 0.043). Risk management plan (RMP) for TB before initiation of biologics commenced in 2012. The 2-year TB risks after RMP was compared with that before 2012 (HR:0.67, 95% CI: 0.30–1.49, p = 0.323). Elderly RA patients with a history of previous TB infection and concomitant moderate dose glucocorticoid were at higher risk of TB disease. Concurrent sulfasalazine treatment appeared to be a protective factor against TB disease.

Minimally Invasive Ultrasound-guided Synovial Biopsy Using SuperCoreBiopsy Instrument

Background: To develop a new method for synovial biopsy with ultrasound (US) guidance and a semi-automatic SuperCore biopsy instrument. Materials and Methods: Twenty-two patients (8 men and 14 women, median age 57 years (range 22–79 years)) with active arthritis or tenosynovitis were enrolled from April 2012 through October 2012. Each patient had one joint or tendon biopsied. US examination was performed to determine the optimal synovial site for biopsy. After skin disinfection and local anaesthesia, a portal was established using a trephine needle as needed. An 18-gauge SuperCore biopsy needle was placed into the target synovial site via the portal or just percutaneously under US guidance with free hand technique. Repeated needle passes and cuts to obtain 3-10 pieces of synovial tissues in each joint. The success of biopsy was defined as identification of synovium on histological examination. Results: Synovium of 21 joints (10 knees, 6 wrists, 3 ankles, 1 elbow and 1 metacarpophalangeal joint) were biopsied. One patient had biopsy of flexor digitorum tendon sheath. All biopsies obtained adequate amounts of synovial tissues for histologic reading with a success rate of 100%. Synovial lining was identified in 18 (85.7%) of 21 joints. The patient with flexor digitorum tenosynovitis was proven to have mycobacterial infectionby histological examination. All patients tolerated the procedures well, and no complication was observed during 2-week follow up. Conclusions: US-guided synovial biopsy using SuperCore biopsy instrument is a promising method for synovial research. It has the advantages of simple, mini-invasiveness and high success rate. The complication is rare.

What does power Doppler signal indicate in rheumatoid synovitis? A point of view from synovial histopathology

&NA; To clarify the nature of power Doppler (PD) signals in rheumatoid synovium and to establish the connection between PD signals and active inflammation using synovial histopathology. Ten adult patients (median age 57.0 years, 9 women and one man) with rheumatoid arthritis (RA) were enrolled and received ultrasound (US) examinations. US‐guided synovial biopsies using core needle were performed in 7 knees, 2 wrists and one elbow. Each patient had one joint biopsied. In total, 11 synovial specimens were obtained for hematoxylin and eosin staining and histopathologic examinations. The US examinations revealed prominent synovial hypertrophy in all biopsied joints. Six synovial specimens were PD‐positive (from 3 knees, 2 wrists and 1 elbow) while 5 synovial specimens were PD‐negative (from 5 knees). In comparison with the PD‐negative synovial specimens, the PD‐positive synovial specimens had significantly more lymphocyte infiltration, vessel proliferation and lining hyperplasia on histologic examination. There was no significant difference in fibrin exudate and stromal fibrosis between the PD‐positive and the PD‐negative synovial specimens. PD signals in rheumatoid synovium indicate active inflammation and vascularization supported by synovial histopathology. Our study establishes the connection between synovial PD signals and active synovitis in RA.