Introduction: Interleukin (IL)-21 is a cytokine that controls the functional activity of effector T helper cells and the differentiation of Th17 cells, and promotes B-cell differentiation. To test whether IL-21 participates in the pathogenesis of primary Sjögren's syndrome (SS), serum IL-21 level was measured and IL-21 expression in the labial salivary glands (LSG) was examined. Methods: Serum IL-21 levels in 40 primary SS, 40 rheumatoid arthritis (RA), and 38 systemic lupus erythematosus (SLE) patients and 20 healthy controls were measured. Serum IL-21 levels of SS patients were assessed for correlations with laboratory data, including anti-nuclear antibody, anti-Ro/La antibodies, globulin, immunoglobulin (Ig) class, and IgG subclass. LSGs from 16 primary SS and 4 controls with sicca symptoms were evaluated for IL-21 and IL-21 receptor (IL-21R) expression by immunohistochemistry. Confocal microscopy was performed to further characterize the IL-21 positive cells. Results: Primary SS patients had significantly higher serum IL-21 levels than controls, and these increments correlated positively with levels of IgG, IgG1. Serum IgG1 levels correlated with anti-Ro antibody titers. Immunohistochemical analyses showed that lymphocytic foci and the periductal area of the LSGs from SS patients expressed high levels of IL-21 and lower levels of IL-21R, whereas the control LSGs showed minimal expression of both antigens. The more the lymphocyte infiltrated, IL-21expression in LSGs showed a tendency to increase. Confocal microscopic analyses revealed that IL-21 expressing infiltrating lymphocytes in the LSGs of SS patients also expressed CXCR5. Conclusions: Primary SS is associated with high serum IL-21 levels that correlate positively with serum IgG, especially IgG1, levels. The expression of IL-21 is increased as more lymphocytes infiltrated in LSGs. These observations suggest that IL-21 may play an important role in primary SS pathogenesis.

Rheumatoid arthritis (RA) is a chronic autoimmune disease that causes mild to severe joint inflammation. During RA pathogenesis, fibroblast-like synoviocytes (FLS) acquire a tumor-like phenotype and mediate cartilage destruction both directly and indirectly by producing proinflammatory cytokines and matrix metalloproteinases (MMPs). Kruppel-like factor (KLF) 4, a member of the KLF family, plays significant roles in cell survival, proliferation, and differentiation. A recent study reported increased expression of KLF4 in synovial tissue from RA patients. However, its precise role in RA in different models, including mouse autoimmune disease models, remains unclear. In this study, we examined the role of KLF4 during development of autoimmune arthritis in mouse models. To do this, we used KLF4 knockout mice rendered by ribonucleic acid (RNA)-guided endonuclease (RGEN) and performed collagen antibody-induced arthritis (CAIA). We found that deletion of KLF4 reduces inflammation induced by CAIA. In addition, we assessed collagen-induced arthritis (CIA) in control mice and KLF4-overexpressing mice generated by a minicircle vector treatment. Severity of CIA in mice overexpressing KLF4 was greater than that in mice injected with control vector. Finally, we verified the inflammatory roles of KLF4 in CIA by treating Kenpaullone which is used as KLF4 inhibitor. Next, we focused on human/mouse FLS to discover the cellular process involved in RA pathogenesis including proliferation, apoptosis, and inflammation including MMPs. In FLS, KLF4 upregulated expression of mRNA encoding proinflammatory cytokines interleukin (IL)-1β and IL-6. KLF4 also regulated expression of matrix metallopeptidase 13 in the synovium. We found that blockade of KLF4 in FLS increased apoptosis and suppressed proliferation followed by downregulation of antiapoptotic factor BCL2. Our results indicate that KLF4 plays a crucial role in pathogenesis of inflammatory arthritis in vivo, by regulating apoptosis, MMP expression, and cytokine expression by FLS. Thus, KLF4 might be a novel transcription factor for generating RA by modulating cellular process of FLS.

We aimed to investigate the association of serum UA level with muscle strength assessed by handgrip strength (HGS) in a large Korean adult population. Cross-sectional data were obtained from the seventh Korea National Health and Nutrition Examination Survey (KNHANES) 2016. The KNHANES 2016 study included 8150 subjects, of whom 4230 subjects were analyzed in this study. The association between serum UA level and HGS was investigated with adjustment for confounding factors. Serum UA was divided into sex-specific tertiles After adjustment for potential confounding factors, HGS was significantly greater in the high serum UA group (the third tertile) than in the low UA group (the first tertile) in the elderly (age ≥ 60 years) population (coefficient β [95% confidence interval (CI)] = 1.017 [0.115–1.920]). When the elderly population was subdivided according to the presence of metabolic syndrome (metS), the impact of UA remained significant only in individuals with metS. In the aged population, high serum UA level reduced the risk for low HGS (OR, 95% CI = 0.69, 0.48–0.98, p = 0.041) only in male subjects. A population-based cross-sectional survey in Korea revealed that high serum UA level is associated with increased HGS in the aged population. The antioxidant property of UA may enhance muscle strength, especially in the elderly population.

To compare the trabecular bone score (TBS) between patients with axial spondyloarthritis (axSpA) and matched normal controls and identify risk factors associated with a low TBS. TBS and BMD were assessed in the two groups (axSpA and control) using DXA. Osteoporosis risk factors and inflammatory markers were also assessed. Disease activity and radiographic progression in the sacroiliac joint and spine were evaluated in the axSpA group. Multivariate linear regression analysis was performed to identify risk factors associated with TBS. In the axSpA group, 248 subjects were enrolled; an equal number of age- and sex-matched subjects comprised the control group. The mean TBS was 1.43 (0.08) and 1.38 (0.12) in the control and axSpA groups, respectively (P < 0.001); BMD at the lumbar spine did not differ between the two groups. The TBS was negatively correlated with ESR and CRP levels in the axSpA group only (P < 0.001 and P = 0.007, respectively). Syndesmophytes in the axSpA group was associated with lower TBS (P < 0.001) but higher lumbar BMD (P = 0.021) vs controls. In the multivariate analyses, ESR, CRP and spinal radiographic progression were significantly associated with TBS. TBS assessments revealed poor bone quality in patients with axSpA compared with the matched controls. In axSpA, systemic inflammatory markers were negatively correlated with TBS and spinal radiographic progression and inflammatory markers were independently correlated with low TBS. TBS may, therefore, be a useful clinical tool to identify the risk of osteoporosis in patients with axSpA.

This study aimed to investigate whether the presence of low bone mineral density (BMD) in patients with axial spondyloarthritis (axSpA) predicts formation of new syndesmophytes over 2 years. One hundred and nineteen patients fulfilling the imaging arm of the Assessment of SpondyloArthritis International Society axSpA criteria were enrolled. All patients were under 50 years of age. The modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS) was assessed by two trained readers blinded to the patients’ data. BMD (lumbar spine, femoral neck or total hip) at baseline was assessed using dual-energy absorptiometry. Low BMD was defined as Z score ≤ − 2.0. Spinal radiographic progression was defined as worsening of the mSASSS by ≥ 2 points over 2 years. Logistic regression analyses were performed to identify predictors associated with development of new syndesmophytes and spinal radiographic progression. At baseline, 19 (16%) patients had low BMD. New syndesmophytes had developed in 22 (21%) patients at 2-year follow-up. New syndesmophyte formation after 2 years occurred more in patients with low BMD than in those with normal BMD (p = 0.047). In the multivariable analysis, current smoking, existing syndesmophytes and low BMD at baseline were associated with spinal radiographic progression (OR (95% CI) 3.0 (1.1, 7.7), 4.6 (1.8, 11.8) and 3.6 (1.2, 11.2), respectively). The presence of syndesmophytes at baseline and low BMD were predictors of new syndesmophytes over the following 2 years (OR (95% CI) 5.5 (2.0, 15.2) and 3.6 (1.1, 11.8), respectively). Low BMD and existing syndesmophytes at baseline were independently associated with the development of new syndesmophytes in young axSpA patients.