Gender-Specific Association of Serum Uric Acid and Pulmonary Function: Data from the Korea National Health and Nutrition Examination Survey.

Background and Objectives: Hyperuricemia is associated with several comorbidities. The association between uric acid (UA) and pulmonary function is still a controversial issue. This study evaluated the gender-specific association of serum UA and pulmonary function. Materials and Methods: A total of 3177 (weighted n = 19,770,902) participants aged 40 years or older were selected from the 2016 Korean National Health and Nutrition Examination Survey and included. Results: Female participants with hyperuricemia were older than participants with normouricemia. Body mass index (BMI), mean arterial pressure (MAP), hemoglobin A1c (HbA1c), and estimated glomerular filtration rate (eGFR) were significantly associated with UA levels in both males and females. Hyperuricemia and increase in UA quartile were significantly associated with decreased forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) in females after adjustment for age, income, region, education, marital status, alcohol consumption, smoking, BMI, MAP, HbA1c, and eGFR. There was no significant association between UA levels and lung function in males. After additional adjustment for respiratory disease including pulmonary tuberculosis, asthma, and lung cancer, the association between hyperuricemia and decreased FEV1 and FVC in females was revealed. Conclusions: Hyperuricemia was associated with decreased FVE1 and FVC in the female general population.

Selective estrogen receptor modulator lasofoxifene suppresses spondyloarthritis manifestation and affects characteristics of gut microbiota in zymosan-induced SKG mice.

Ankylosing spondylitis is a male-predominant disease and previous study revealed that estrogens have an anti-inflammatory effect on the spondyloarthritis (SpA) manifestations in zymosan-induced SKG mice. This study aimed to evaluate the effect of selective estrogen receptor modulator (SERM) lasofoxifene (Laso) on disease activity of SpA. Mice were randomized into zymosan-treated, zymosan + 17ß-estradiol (E2)-treated, and zymosan + Laso-treated groups. Arthritis was assessed by 18F-fluorodeoxyglucose (18F-FDG) small-animal positron emission tomography/computed tomography and bone mineral density (BMD) was measured. Fecal samples were collected and 16S ribosomal RNA gene sequencing was used to determine gut microbiota differences. Both zymosan + E2-treated mice and zymosan + Laso-treated mice showed lower arthritis clinical scores and lower 18F-FDG uptake than zymosan-treated mice. BMD was significantly higher in zymosan + E2-treated mice and zymosan + Laso-treated mice than zymosan-treated mice, respectively. Fecal calprotectin levels were significantly elevated at 8 weeks after zymosan injection in zymosan-treated mice, but it was not significantly changed in zymosan + E2-treated mice and zymosan + Laso-treated mice. Gut microbiota diversity of zymosan-treated mice was significantly different from zymosan + E2-treated mice and zymosan + Laso-treated mice, respectively. There was no significant difference in gut microbiota diversity between zymosan + E2-treated mice and zymosan + Laso -treated mice. Laso inhibited joint inflammation and enhanced BMD in SKG mice, a model of SpA. Laso also affected the composition and biodiversity of gut microbiota. This study provides new knowledge regarding that selected SpA patients could benefit from SERM treatment.

The Practice Guideline for Vaccinating Korean Patients with Autoimmune Inflammatory Rheumatic Disease.

To develop a clinical practice guideline for vaccination in patients with autoimmune inflammatory rheumatic disease (AIIRD), the Korean College of Rheumatology and the Korean Society of Infectious Diseases developed a clinical practice guideline according to the clinical practice guideline development manual. Since vaccination is unlikely to cause AIIRD or worsen disease activities, required vaccinations are recommended. Once patients are diagnosed with AIIRD, treatment strategies should be established and, at the same time, monitor their vaccination history. It is recommended to administer vaccines when the disease enters the stabilized stage. Administering live attenuated vaccines in patients with AIIRD who are taking immunosuppressants should be avoided. Vaccination should be considered in patients with AIIRD, prior to initiating immunosuppressants. It is recommended to administer influenza, Streptococcus pneumoniae, hepatitis A, hepatitis B, herpes zoster, measles-mumps-rubella virus, human papillomavirus, and tetanus-diphtheria-pertussis vaccines in patients with AIIRD; such patients who planned to travel are generally recommended to be vaccinated at the recommended vaccine level of healthy adults. Those who live in a household with patients with AIIRD and their caregivers should also be vaccinated at levels that are generally recommended for healthy adults.

C reactive protein level as a marker for dyslipidaemia, diabetes and metabolic syndrome: results from the Korea National Health and Nutrition Examination Survey.

OBJECTIVE: Plasma C reactive protein (CRP) is a marker of inflammation, and increased plasma CRP is reported in many diseases, including cardiovascular disease, diabetes, metabolic syndrome, arthritis and malignancies. The aim of the study was to evaluate the association between plasma CRP levels and cardiovascular disease, metabolic syndrome, malignancies and other comorbidities. DESIGN: A retrospective, cross-sectional survey study. SETTING: Large population survey in Korea. METHODS: A total of 5887 (weighted n=40 251 868) participants aged 19 years or older from the 2016 Korea National Health and Nutrition Examination Survey were included for analysis. Weighted prevalence and OR of comorbidities were analysed according to the continuous variable of log plasma high-sensitivity CRP levels. RESULTS: The mean age was 46.7±0.37 years and the median plasma CRP was 0.58 mg/L (IQR 0.36-1.09). The mean plasma CRP levels were higher in participants with cardiovascular diseases and cardiovascular risk factors, osteoarthritis, rheumatoid arthritis, pulmonary tuberculosis, and several cancers, including gastric, colon, breast and cervix, than in the general population. In the multivariable analysis, plasma CRP concentration was associated with increased prevalence of hypertriglyceridaemia (OR 1.157, 95% CI 1.040 to 1.287, p=0.007), diabetes (OR 1.204, 95% CI 1.058 to 1.371, p=0.005) and metabolic syndrome (OR 1.228, 95% CI 1.112 to 1.357, p<0.001) after adjustment for socioeconomic and lifestyle characteristics. There was no significant association between plasma CRP level and cancers. CONCLUSION: Plasma CRP was associated with an increased risk of dyslipidaemia, diabetes and metabolic syndrome in the general population.

Clinical characteristics and risk factors for gout flare during the postsurgical period.

OBJECTIVES: To evaluate the clinical features and risk factors for gout flare during postsurgical period in patients who were previously diagnosed with gout. METHODS: Seventy patients who had histories of gout and had been consulted in the rheumatologic clinic before surgery under general anesthesia were included. Clinical characteristics of patients who developed a postsurgical gout flare were compared with those of patients who did not develop gout flare. RESULTS: Among 70 patients, 31 (44.3%) developed gout flare during the postsurgical period. Mean intervals from surgery to gout flare was 3.7 days. Flares tended to involve monoarticular joints (61.3%) and affect lower extremity joints (83.9%). Knee joints (26%) and foot joints except the first metatarsophalangeal (MTP) joint (26%) were more frequently involved than the first MTP joint (13%). Presurgical uric acid level ≥ 9 mg/dL (OR 3.77, 95% CI 1.28-11.10, p = 0.016) and amount of uric acid changes between before and after surgery (OR 1.62, 95% CI 1.21-2.18, p = 0.001) were risk factors for postsurgical gout flare. Taking allopurinol reduced the risk of postsurgical gout flare (OR 0.15, 95% CI 0.05-0.45, p = 0.001). Operation time, amount of blood loss during surgery, and surgery site were not significantly associated with postsurgical gout flare. CONCLUSIONS: Adequate uric acid control before surgery could prevent the postsurgical gout flare.

Clinical characteristics and risk factors for gout flare during the postsurgical period

Abstract Objectives: To evaluate the clinical features and risk factors for gout flare during postsurgical period in patients who were previously diagnosed with gout. Methods: Seventy patients who had histories of gout and had been consulted in the rheumatologic clinic before surgery under general anesthesia were included. Clinical characteristics of patients who developed a postsurgical gout flare were compared with those of patients who did not develop gout flare. Results: Among 70 patients, 31 (44.3%) developed gout flare during the postsurgical period. Mean intervals from surgery to gout flare was 3.7 days. Flares tended to involve monoarticular joints (61.3%) and affect lower extremity joints (83.9%). Knee joints (26%) and foot joints except the first metatarsophalangeal (MTP) joint (26%) were more frequently involved than the first MTP joint (13%). Presurgical uric acid level ≥ 9 mg/dL (OR 3.77, 95% CI 1.28-11.10, p = 0.016) and amount of uric acid changes between before and after surgery (OR 1.62, 95% CI 1.21-2.18, p = 0.001) were risk factors for postsurgical gout flare. Taking allopurinol reduced the risk of postsurgical gout flare (OR 0.15, 95% CI 0.05-0.45, p = 0.001). Operation time, amount of blood loss during surgery, and surgery site were not significantly associated with postsurgical gout flare. Conclusions: Adequate uric acid control before surgery could prevent the postsurgical gout flare.

Differences in quality of life determinants according to the presence of fibromyalgia in middle-aged female patients with systemic lupus erythematosus: a multicenter, cross-sectional, single-ethnicity cohort.

OBJECTIVE: The purpose of this study was to identify whether determinants of health-related quality of life (HRQoL) in middle-aged female patients with systemic lupus erythematosus (SLE) differed according to the presence or absence of fibromyalgia. METHODS: One hundred and fifty-two patients with SLE and 139 healthy controls (HCs) completed the Medical Outcomes Study 36-Item Short Form (SF-36) and EuroQol EQ-5D questionnaires about HRQoL. Disease activity and cumulative disease damage were assessed with standard indices. Sleep quality was assessed using the Korean version of the Pittsburgh Sleep Quality Index (K-PSQI). RESULT: The mean EQ-5D and physical and mental components of SF-36 were lower in SLE patients with fibromyalgia (n = 41) than in those without fibromyalgia (n = 111) and HCs. The scores in all eight domains of the SF-36 were lower in SLE patients with fibromyalgia than in patients without fibromyalgia and HCs. Poor sleep (defined as a K-PSQI > 5) was reported by 85% of SLE patients with fibromyalgia, by 51% of patients without fibromyalgia, and by 33% of HCs. Multivariate logistic regression analysis showed that lower educational level, cumulative organ damage severity and poor sleep quality were independent determinants of HRQoL in SLE patients with fibromyalgia, whereas disease activity, sleep quality and depressive mood were independent determinants of HRQoL in those without fibromyalgia. CONCLUSION: Poor sleep quality is the common independent risk factor for poor HRQoL in both middle-aged SLE patients with fibromyalgia and without fibromyalgia. Sleep quality improvement may improve HRQoL in female SLE patients, even in those without fibromyalgia.

Effect of tumor necrosis factor α inhibitors on spinal radiographic progression in patients with ankylosing spondylitis.

AIM: To evaluate the effect of tumor necrosis factor α inhibitors (TNFi) on spinal radiographic progression in patients with ankylosing spondylitis (AS). METHODS: Subjects were selected from patients at a single tertiary hospital between 1995 and 2014. Patients who used TNFi with baseline and paired follow-up radiographic data with a minimum interval of 2 years were included. Time to start TNFi was defined as the time from symptom onset to the start of TNFi use. TNFi index was defined as the ratio of the period of TNFi use to the entire period of disease. Radiographic damage was assessed by the modified Stoke Ankylosing Spondylitis Spine Score (mSASSS). Univariable and multivariable linear regression analyses were used to identify factors associated with radiographic progression. RESULTS: A total of 151 patients were included in the analysis. Seventeen (11.3%) patients were female and mean ΔmSASSS/year was 1.01 units/year. Mean X-ray follow-up duration was 102.9 ± 54.9 months. Mean time from symptom onset to start of TNFi use was 104.8 ± 83.6 months (median 84 months) and mean TNFi index was 42.9 ± 23.8% (median 40.9%). In multivariable analysis, initial mSASSS, initial C-reactive protein, body mass index, current smoker, and delayed start of TNFi use were associated with radiographic progression. Presence of peripheral arthritis and the TNFi index were negatively associated with radiographic progression. CONCLUSIONS: A delay in starting TNFi use and low TNFi index were associated with radiographic progression. Early and long-term use of TNFi appear to reduce spinal radiographic progression in patients with AS.

Spondyloarthritis features in zymosan-induced SKG mice.

OBJECTIVES: Spondyloarthritis (SpA) encompasses a group of disorders including ankylosing spondylitis, psoriatic arthritis, reactive arthritis, and enteropathic arthritis. SpA pathogenesis is still not well understood. Animal models are important for studying disease mechanisms and identifying new therapeutic agents. Recently, a ß-glucan-induced SKG mouse was used as an animal model for SpA. The aim of this study was to evaluate the clinical and molecular characteristics of a zymosan-induced SKG mouse. METHODS: Zymosan was injected intraperitoneally into SKG mice. Clinical arthritis scores were measured, and fluorine-18 fluorodeoxyglucose (18F-FDG) small-animal positron emission tomography/computed tomography (PET/CT) was performed to quantify joint inflammation. Histologic features of the joints, intestines, skin, and eyes were evaluated. Inflammatory cytokine and Wnt inhibitor expression was measured in mouse serum. RESULTS: Zymosan exposure triggered SpA-like diseases in SKG mice, including peripheral arthritis, spondylitis, dactylitis, enteritis, and psoriatic skin lesions. 18F-FDG uptake was significantly higher in the zymosan-treated mice compared with controls. The expression of tumor necrosis factor α, interleukin (IL)-6, and Dickkopf-1 increased significantly, while IL-4 and sclerostin expression decreased significantly in zymosan-induced mice compared with control mice. CONCLUSIONS: Zymosan-induced SKG mice developed articular and extra-articular features as well as molecular changes that resembled those of human SpA. These findings suggest that the zymosan-induced SKG mouse is a good animal model to reflect the complex features of human SpA.

Comorbidities and health-related quality of life in Koreans with knee osteoarthritis: Data from the Korean National Health and Nutrition Examination Survey (KNHANES).

OBJECTIVES: This study aimed to evaluate the association of knee osteoarthritis (OA) with comorbidities and health-related quality of life (HRQOL). METHODS: A total of 8,907 (weighted n = 13,687,058) participants aged ≥50 years who had undergone knee radiography were selected from the 2010-2012 Korea National Health and Nutrition Examination Survey. OA was classified into four subgroups based on the presence or absence of pain and radiographic OA (ROA): non-OA (Pain-/ROA-), pain only (Pain+/ROA-), ROA only (Pain-/ROA+), and painful ROA (Pain+/ROA+). ROA was defined as Kellgren-Lawrence grade ≥ 2. HRQOL measurements including EuroQOL visual analogue scale (EQ-VAS) scores and the five dimensions and summary index of the EuroQOL-5 dimension (EQ-5D index) were also analyzed. Multivariable logistic regression and linear regression analyses were performed. RESULTS: After adjustment for socioeconomic and lifestyle characteristics, cardiovascular disease, malignancy, and other comorbidities were not significantly associated with OA. Pain only and painful ROA were each significantly associated with limitations in physical activity (odds ratio (OR) 2.66, 95% CI 2.07-3.44, p < 0.001 and OR 2.83, 95% CI 2.25-3.58, p < 0.001, respectively), lower EQ-VAS (ß-coefficient = -10.95, p < 0.001 and ß-coefficient = -9.75, p < 0.001, respectively), and EQ-5D index (ß-coefficient = -0.10, p < 0.001 and ß-coefficient = -0.13, p < 0.001) compared with the non-OA group, whereas ROA only was not associated with limitations in physical activity or lower HRQOL score. CONCLUSIONS: Comorbidities were not significantly associated with knee OA after adjustment. Knee OA was associated with physical activity and HRQOL. Painful knee OA, with or without ROA, was more strongly associated with decreased physical activity and lower quality of life than ROA without pain.

Estrogen attenuates the spondyloarthritis manifestations of the SKG arthritis model.

BACKGROUND: Ankylosing spondylitis (AS) is a male-predominant disease, and radiographic evidence of damage is also more severe in males. Estrogen modulates immune-related processes such as T cell differentiation and cytokine production. This study aimed to evaluate the effect of estrogen on the disease activity of spondyloarthritis (SpA). METHODS: The effects of estrogen on the development of arthritis were evaluated by performing ovariectomy and 17ß-estradiol (E2) pellet implantation in zymosan-treated SKG mice. Clinical arthritis scores were measured, and 18F-fluorodeoxyglucose (18F-FDG) small-animal positron emission tomography/computed tomography performed to quantify joint inflammation. The expression of inflammatory cytokines in joint tissue was measured. RESULTS: E2-treated mice showed remarkable suppression of arthritis clinically and little infiltration of inflammatory cells in the Achilles tendon and intervertebral disc. 18F-FDG uptake was significantly lower in E2-treated mice than in sham-operated (sham) and ovariectomized mice. Expression of TNF, interferon-γ, and IL-17A was significantly reduced in E2-treated mice, whereas expression of sclerostin and Dickkopf-1 was increased in E2-treated mice compared with sham and ovariectomized mice. CONCLUSIONS: Estrogen suppressed arthritis development in SKG mice, a model of SpA. Results of this study suggest that estrogen has an anti-inflammatory effect on the spondyloarthritis manifestations of the SKG arthritis model.

Relapsing Polychondritis with Central Nervous System Involvement: Experience of Three Different Cases in a Single Center.

Relapsing polychondritis (RP) is an autoimmune disorder characterized by inflammation in cartilaginous structures including the ears, noses, peripheral joints, and tracheobronchial tree. It rarely involves the central nervous system (CNS) but diagnosis of CNS complication of RP is challenging because it can present with varying clinical features. Herein we report 3 cases of relapsing polychondritis involving CNS with distinct manifestations and clinical courses. The first patient presented with rhombencephalitis resulting in brain edema and death. The second patient had acute cognitive dysfunction due to limbic encephalitis. He was treated with steroid pulse therapy and recovered without sequelae. The third patient suffered aseptic meningitis that presented as dementia, which was refractory to steroid and immune suppressive agents. We also reviewed literature on CNS complications of RP.

Liver cirrhosis due to autoimmune hepatitis combined with systemic sclerosis.

Systemic sclerosis (SSc) is a chronic systemic disease that affects the skin, lungs, heart, gastrointestinal tract, kidneys, and musculoskeletal system. Although up to 90% of patients with scleroderma have been estimated to have gastrointestinal involvement, liver disease has been reported only rarely. A 51-year-old woman was hospitalized due to esophageal variceal bleeding. Her serum was positive for anti-nuclear antibody and anti-centromere antibody. Sclerodactyly was noted on both hands, and she had recently developed Raynaud's syndrome. Punch biopsy of the hand showed hyperkeratosis, regular acanthosis, and increased basal pigmentation in the epidermis, and thick pale collagenous bundles in the dermis. Liver biopsy showed chronic active hepatitis with bridging fibrosis. Consequently, she was diagnosed with liver cirrhosis due to autoimmune hepatitis (AIH) combined with SSc. AIH had subsided after administration of prednisolone at 40 mg per day. She received 5-10 mg/day of prednisolone as an outpatient, and her condition has remained stable. Patients with either AIH or SSc should be monitored for further development of concurrent autoimmune diseases. The early diagnosis of AIH combined with SSc will be helpful in achieving optimal management.

The role of Raf kinase inhibitor protein in rheumatoid fibroblast-like synoviocytes invasiveness and cytokine and matrix metalloproteinase expression.

Fibroblast-like synoviocytes (FLS) play an important role in the pathogenesis of rheumatoid arthritis. Raf kinase inhibitor protein (RKIP) negatively regulates the Raf/MEK/ERK and NF-κB pathway. The role of RKIP in rheumatoid FLS is unknown. The purpose of the present study was to investigate the function of RKIP in rheumatoid FLS. Rheumatoid FLS were transfected with either RKIP-expressing plasmids or RKIP small interfering RNA (siRNA). RKIP protein was detected in rheumatoid synovial tissue (ST) and FLS. RKIP overexpression significantly decreased IL-6 mRNA expression in TNF-α-stimulated rheumatoid FLS. RKIP overexpression also showed a decreased trend in IL-8, MMP-1, and MMP-3 mRNA expression in TNF-α-stimulated rheumatoid FLS. RKIP silencing resulted in significantly increased MMP-1 and MMP-3 mRNA expression in TNF-α-stimulated rheumatoid FLS. RKIP silencing also increased IL-6 and IL-8 mRNA expression in TNF-α-stimulated rheumatoid FLS, but this increase did not reach statistical significance. TNF-α-induced ERK and NF-κB activation was suppressed in FLS with RKIP overexpression. RKIP silencing resulted in a significantly higher invasion index in TNF-α-stimulated rheumatoid FLS compared to controls. These results suggest that RKIP might be a potential therapeutic target for rheumatoid arthritis.

Measurement of interleukin-33 (IL-33) and IL-33 receptors (sST2 and ST2L) in patients with rheumatoid arthritis.

The interleukin-33 (IL-33)/ST2 pathway has emerged as an intercellular signaling system that participates in antigen-allergen response, autoimmunity and fibrosis. It has been suggested that IL-33/ST2 signaling has been involved in the pathogenesis of rheumatoid arthritis (RA), because IL-33 and its receptor have been specifically mapped to RA synovium. The aim of this study was to determine the levels of IL-33 and sST2 in sera and synovial fluids in patients with RA. The serum level of IL-33 was significantly higher in patients with RA (294.9 ± 464.0 pg/mL) than in healthy controls (96.0 ± 236.9 pg/mL, P = 0.002). The synovial fluid level of IL-33 was significantly higher in RA patients than in osteoarthritis patients. The level of serum sST2 was higher in RA patients than in healthy controls (P = 0.042). A significant relationship was found between the levels of IL-33 and IL-1ß (r = 0.311, P = 0.005), and IL-33 and IL-6 (r = 0.264, P = 0.017) in 81 RA patients. The levels of IL-33, sST2 and C-reactive protein decreased after conventional disease-modifying antirheumatic drugs treatment in 10 patients with treatment-naïve RA. Conclusively, IL-33 is involved in the pathogenesis of RA and may reflect the degree of inflammation in patients with RA.

Tumor necrosis factor-alpha induces vascular endothelial growth factor-C expression in rheumatoid synoviocytes.

OBJECTIVE: To determine the expression of vascular endothelial growth factor-C (VEGF-C) in the synovial fluid of patients with rheumatoid arthritis (RA) and to investigate the regulation of VEGF-C production by major proinflammatory cytokines in fibroblast-like synoviocytes (FLS). METHODS: The concentrations of VEGF-C, tumor necrosis factor-alpha (TNF-alpha), and interleukin 1beta (IL-1beta) were measured using an ELISA method in synovial fluids obtained from 20 patients with RA and 20 with osteoarthritis (OA). Primary cultured RA FLS were stimulated with TNF-alpha or IL-1beta, and the expression levels of VEGF-C mRNA and protein were assessed by quantitative real-time polymerase chain reaction and ELISA. RESULTS: Significantly higher levels of VEGF-C were found in RA synovial fluids compared to OA synovial fluids. VEGF-C levels showed a highly significant correlation with the levels of both TNF-alpha and IL-1beta in the synovial fluid of patients with RA. TNF-alpha stimulation significantly increased VEGF-C mRNA and protein expression in RA FLS in a dose-dependent manner. A tendency to increased expression of VEGF-C was also observed after IL-1beta stimulation in FLS. CONCLUSION: Overexpression of VEGF-C in FLS by stimulation with TNF-alpha may play an important role in the progression of synovial inflammation and hyperplasia in RA by contributing to local lymphangiogenesis and angiogenesis.