Introduction: The objective of this study was to investigate the effects of tumor necrosis factor (TNF)-α inhibitors on circulating T helper-type 17 (Th17) cells and Th17-related cytokines in patients with rheumatoid arthritis (RA). Methods: The frequencies of circulating Th17 cells and serum levels of Th17-related cytokines were determined using flow cytometry analysis and ELISA, respectively, in 48 RA patients both before (baseline) and six months after anti-TNF-α therapy. Therapeutic response was evaluated using European League Against Rheumatism (EULAR) response criteria. Results: Significantly higher baseline frequencies of circulating Th17 cells and serum levels of interleukin (IL)-6, IL-17, IL-21, IL-23 and TNF-α were observed in active RA patients than in 12 healthy controls (all P < 0.001). After anti-TNF-α therapy, 36 patients (75%) were EULAR responders (20 good responders and 16 moderate responders) and 12 (25.0%) were non-responders. The mean levels of circulating Th17 cells and IL-17 significantly decreased (1.13% vs. 0.79%; 43.1 pg/ml vs. 27.8 pg/ml; respectively, both P < 0.001) in parallel with clinical remission in responders. Levels of IL-6, IL-21, IL-23 and TNF-α were significantly decreased after anti-TNF-α therapy in responders. In contrast, the mean levels of circulating Th17 cells and IL-17 significantly increased after anti-TNF-α therapy (2.94% vs. 4.23%; 92.1 pg/ml vs. 148.6 pg/ml; respectively, both P < 0.05) in non-responders. Logistic regression analysis identified a high baseline level of IL-17 as a significant predictor of poor therapeutic response. Conclusions: The beneficial effect of anti-TNF-α therapy might involve a decrease in Th17-related cytokines in responders, whereas rising levels of circulating Th17-cells and IL-17 were observed in patients with an inadequate response to anti-TNF-α therapy.

We aimed to investigate the association of gut microbiota with disease activity, inflammatory parameters, and auto-antibodies profile in rheumatoid arthritis (RA). A total of 138 RA patients and 21 healthy controls (HC) were enrolled. Fecal samples were collected for bacterial DNA extraction and 16S ribosome (r)RNA sequencing, followed by analyses of gut microbiota composition. Serum levels of tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IL-17A were determined by using ELISA. Our results indicated that RA patients had lower diversity index, which reflects both evenness and richness of gut microbiota, compared to HC. The alpha-diversity was lower in anti-citrullinated peptide antibodies (ACPA)-positive patients than in HC. The phylum Verrucomicrobiae and genus Akkermansia were more abundant in patients compared to HC. There was increased relative abundance of Enterobacteriaceae as well as Klebsiella, and less abundance of Bifidobacterium in patients with high levels of TNF-α or IL-17A compared to those who had low levels of these cytokines. In addition, ACPA-positive patients had higher proportions of Blautia, Akkermansia, and Clostridiales than ACPA-negative patients. Gut dysbiosis in RA patients was presented as different microbial composition and its association with inflammatory parameters as well as ACPA seropositivity. These findings support the involvement of gut microbiota in RA pathogenesis.

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. 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). PD was associated with an increased risk of RA development.

To investigate the risk of atrial fibrillation or atrial flutter in patients with periodontitis (PD) in comparison with individuals without PD. We used the 1999–2010 Taiwanese National Health Insurance Research Database to identify cases of PD in the year 2000 matching (1:1) with persons without PD during 1999–2000 according to sex and individual age as the control group. Using Cox proportional regression analysis adjusting for potential confounders, including age, sex, and comorbidities at baseline, and average annual number of ambulatory visits and dental scaling frequency during the follow-up period, we estimated hazard ratios (HRs) with 95% confidence intervals (CIs) to examine the risk of atrial fibrillation or flutter in PD patients in comparison with the control group. Subgroup analyses according to age, gender, or comorbidities were conducted to study the robustness of the association and investigate possible interaction effects. We enrolled 393,745 patients with PD and 393,745 non-PD individuals. The incidence rates of atrial fibrillation or flutter were 200 per 10⁵ years among the PD group and 181 per 10⁵ years in the non-PD group (incidence rate ratio, 1.10; 95% CI, 1.06–1.14). After adjusting for potential confounders, we found an increased risk of atrial fibrillation or flutter in the PD group compared with the non-PD group (HR, 1.31; 95% CI, 1.25–1.36). The greater risk of atrial fibrillation or flutter in the PD group remained significant across all disease subgroups except hyperthyroidism and sleep apnea. The present study results indicate an increased risk of atrial fibrillation or flutter in patients with PD. Lack of individual information about alcohol consumption, obesity, and tobacco use was a major limitation.

The goal of the present study was to estimate the risk ratio of herpes zoster among systemic lupus erythematosus patients after disease onset compared with a cohort of patients without systemic lupus erythematosus over a three-year period. A nationwide population-based cohort study using the National Health Insurance Research Database identified 10,337 new cases of systemic lupus erythematosus as the study cohort. In addition, 62,022 patients without systemic lupus erythematosus, who were matched for age, gender, and date of systemic lupus erythematosus diagnosis, were used as the comparison cohort. These cohorts were followed-up for three years. A Cox proportional hazard regression was performed to estimate the risk ratio of herpes zoster, with adjustments for age, gender, level of insurance, urbanization level, geographic region, comorbid medical conditions, average daily dosage of corticosteroids, and the use of immune-modulation agents. Compared to patients without systemic lupus erythematosus, the crude risk ratio and adjusted risk ratio of herpes zoster among systemic lupus erythematosus patients were 7.37 (95% confidence interval 6.75-8.04) and 2.45 (95% confidence interval 1.77-3.40), respectively. Stratified by gender, the adjusted risk ratio of herpes zoster was 2.10 (95% confidence interval 1.45-2.99) in women and 7.51 (95% confidence interval 2.89-19.52) in men. Stratified by age, the adjusted risk ratio peaked in systemic lupus erythematosus patients who were aged 18 to 24 years (risk ratio 8.78, 95% confidence interval 3.08-24.97). Based on nationwide population-based data, there is an increased risk of herpes zoster in systemic lupus erythematosus patients compared with non-systemic lupus erythematosus patients, particularly among males and patients aged 18 to 24 years. Further research on the associated risk factors for herpes zoster in systemic lupus erythematosus patients is needed.

Increasing evidence indicates a pathogenic role of deregulated autophagy in rheumatoid arthritis (RA). We examined the relationship between autophagy and inflammatory parameters in patients with RA receiving biologic therapy. In 72 patients with RA and 20 healthy control subjects (HC), autophagosome levels were determined by the mean fluorescence intensity (MFI) of autophagosomotropic dye incorporated into circulating immune cells, and p62 expression levels in immune cells were measured by flow cytometry. We used immunoblotting to examine protein expression of LC3-II and p62 in peripheral blood mononuclear cells. Patients with RA had significantly higher levels of autophagosome reflected by MFI of Cyto-ID in circulating lymphocytes, monocytes, and granulocytes (median values, 3.6, 11.6, and 64.8, respectively) compared with HC (1.9, 6.0, and 35.8; respectively) (all p < 0.001). p62 MFI levels in lymphocytes and granulocytes from patients with RA (17.1 and 8.6, respectively) were significantly lower than those in the corresponding cells from HC (20.2, p < 0.05; and 13.1, p < 0.001, respectively). Significantly higher levels of LC3-II protein expression in contrast to lower p62 protein levels were observed in patients with RA than in HC. The autophagosome levels in immune cells were significantly correlated with inflammatory parameters in patients with RA, and they were significantly decreased with disease remission after treatment with tumor necrosis factor-α inhibitors or interleukin-6 receptor inhibitor. Elevated autophagy with significant correlation to inflammation suggests the involvement of autophagy in RA pathogenesis. The effectiveness of biologic therapy might be partly related to the downregulation of autophagy expression.