Hydroxychloroquine treatment during pregnancy in lupus patients is associated with lower risk of preeclampsia.

BACKGROUND: Hydroxychloroquine (HCQ) is regarded as a mainstay in the treatment of systemic lupus erythematosus (SLE) because of its efficacy in preventing flares, achieving remission, and reducing overall mortality. However, the impact of HCQ on pregnancy outcomes remains controversial. OBJECTIVE: We aimed to investigate the effect of HCQ on pregnancy outcomes in patients with SLE. METHODS: We performed a retrospective cohort study of 151 pregnancies in 122 patients with SLE (80 pregnancies in the HCQ treatment group and 71 pregnancies in the HCQ nontreatment group). We reviewed baseline characteristics including maternal comorbidities such as antiphospholipid syndrome, lupus nephritis, and autoimmune hepatitis. Pregnancy outcomes (preeclampsia, preterm delivery, and fetal growth restriction) and neonatal outcomes (gestational age at delivery and birth weight) were compared between HCQ treatment and nontreatment groups. RESULTS: Preeclampsia was significantly less complicated (7.5% vs 19.7%, p = 0.032) and neonatal birth weight was significantly greater (2757.0 ± 583.5 g vs 2542.3 ± 908.3 g, p = 0.001) in the HCQ treatment group than in the HCQ nontreatment group. Multiple logistic analysis adjusting for body mass index (BMI), lupus nephritis, serum uric acid, and estimated glomerular filtration rate revealed HCQ treatment was associated with exceedingly lower risk of preeclampsia in SLE pregnancy (odds ratio (OR) 0.106 (confidence interval (CI) 0.017-0.671)). Other independent risk factors for preeclampsia were a high prepregnancy BMI (OR 1.575 (CI 1.114-2.227)) and low eGFR level (OR 0.931 (CI 0.886-0.979)) before pregnancy. CONCLUSION: Our data showed pregnancy outcomes in SLE patients can be improved in the HCQ treatment group with about 90% reduction of preeclampsia.

Bone-density testing interval and transition to osteoporosis in patients with rheumatoid arthritis.

The study aims to evaluate the rate of transition to osteoporosis in 360 RA patients and estimate the rescreening intervals of bone mineral density (BMD) testing. Osteoporosis was newly developed in 24.8 % during mean follow-up of 7.4 years. The estimated time of a BMD testing interval was dependent on the baseline T-score in RA patients. INTRODUCTION: Although BMD testing is routinely performed in RA patients, the interval between BMD tests has not been determined. METHODS: We retrospectively recruited 360 consecutive female patients with RA, who underwent repeated BMD testing, with a mean age of 53.7 ± 10.2 years and a mean follow-up duration of 7.4 ± 5.0 years. We stratified the study participants into five groups based on their baseline T-score range. The testing interval was defined as the estimated time for 10 % of patients in each subgroup to transition to osteoporosis. Competing-risk analyses were performed with sensitivity analysis by menopausal status and risk factors for transition to osteoporosis. RESULTS: At baseline, 15 % of screened patients had osteoporosis, and during follow-up, that proportion increased to 24.8 %. The estimated BMD testing interval for 10 % of patients to develop osteoporosis was 9.6 years for those with normal BMD, 7.6 years for those with mild osteopenia, 4.7 years for those with moderate osteopenia, and 2.1 years for those with severe osteopenia. No significant risk factor for transition to osteoporosis was identified in this cohort. CONCLUSIONS: Our data indicate that osteoporosis will develop in less than 10 % of female RA patients during rescreening intervals of approximately 9 years for those with normal bone density at baseline, 7 years for those with mild osteopenia, 4 years for those with moderate osteopenia, and 2 years for those with severe osteopenia at baseline. BMD interval in RA patients could be adjusted according to their baseline BMD T-scores.

Gender differences in clinical and angiographic findings of patients with Takayasu arteritis.

OBJECTIVES: Because Takayasu arteritis (TA) predominantly affects females, few data regarding gender differences have been reported. The aim of the present study is to describe clinical features and angiographic findings of patients with TA according to gender. METHODS: According to the 1990 American College of Rheumatology criteria, 294 patients were diagnosed with TA between September 1994 and April 2014 at a single tertiary hospital. We reviewed clinical, laboratory, and radiologic data at the time of diagnosis. RESULTS: Among the 294 patients studied, 257 (87.4%) were female (male:female ratio=1:6.9). Female patients had a higher tendency to exhibit blood pressure differences between arms (p=0.595) and a weak pulse at the brachial artery (p=0.063). In male patients, we observed higher serum creatinine levels (p=0.038) and hypertension more frequently (p=0.061) than in females. Females exhibited more common lesions in the thoracic aorta and its branches, while males had more frequent lesions in the abdominal aorta and its branches. An analysis of angiographic classification according to the International TA Conference in Tokyo 1994 classification revealed that male patients had a higher incidence of type IV and females showed a higher incidence of types I, IIa, and IIb. CONCLUSIONS: Female patients with TA have more frequent involvement of the thoracic aorta and its branches, whereas involvement of the abdominal aorta and its branches is more common in males. Considering these gender-specific differences, adjustment of diagnostic criteria for TA according to gender may be necessary.

Cumulative survival rate and complication rates of single-tooth implant; focused on the coronal fracture of fixture in the internal connection implant.

This retrospective study evaluated the 5-year cumulative survival rate and complication rates of a 4·0-mm internal connection implant (MicroThread™ Osseospeed™, Astra Tech) installed for single-tooth restoration. The patients who were treated at Asan Medical Center between 2006 and 2007 were included in this study. A life table analysis was used to calculate the 5-year cumulative survival rate. Comparisons of cumulative survival rates among implant position (anterior, premolar and molar), jawbone (maxilla, mandible), gender and prosthesis type (screw-retained, cement-retained) were performed using the log-rank test. Post-loading complications were analysed using Fisher's exact test. Twelve of 136 implants (anterior; 22, premolar; 25, molar; 89) were lost during the loading period, and 11 were removed due to coronal fracture of fixture. The 5-year cumulative survival rate of the whole arch was 91·9%, and that of the molar region was 87·6%. Statistically significant differences were observed in cumulative survival rates among implant position (P = 0·037), whereas no statistically significant differences were observed among gender, jawbone, prosthesis type. Forty-seven of 114 (41·2%) implants in the posterior region showed post-loading complications, including coronal fracture of fixture and abutment screw loosening.

Expression of human TIM-3 and its correlation with disease activity in rheumatoid arthritis.

OBJECTIVE: T-cell immunoglobulin- and mucin-domain-containing molecule 3 (TIM-3) is a novel transmembrane protein that is involved in the regulation of T-helper 1 (Th1)-cell-mediated immunity. This study was undertaken to investigate the expressions of TIM-3 and its ligand galectin 9 (Gal-9) with respect to disease activity in rheumatoid arthritis (RA). METHODS: Blood was collected from 39 RA patients and 31 healthy controls. Blood leucocyte TIM-3 and Gal-9 mRNA levels and RA disease activity were determined. Synovial tissue (ST) from five RA patients and five osteoarthritis (OA) patients were examined for TIM-3 mRNA expression and were also analysed for TIM-3 by immunohistology. RESULTS: TIM-3 mRNA expression was significantly higher in the ST of RA patients than in the ST of OA patients. TIM-3 was expressed in the synovial sublining area in ST of RA patients but not in OA ST. TIM-3 mRNA expression from peripheral blood mononuclear cells (PBMCs) of RA patients was negatively correlated with the 28-joint Disease Activity Score (DAS28). Gal-9 mRNA level in PBMCs of RA patients was higher than in healthy controls, and was significantly higher in patients with low disease activity compared to those with moderate to high disease activity. Gal-9 mRNA expression in PBMCs of RA patients was positively correlated with forkhead box P3 (FoxP3) mRNA expression. CONCLUSION: TIM-3 and its interaction with Gal-9 are closely associated with RA disease activity and may play an important role in the pathogenesis of RA. In addition to the negative regulatory effect of Gal-9 mediated through the TIM-3-Gal-9 pathway, Gal-9 may exert its suppressive effect on RA disease activity by modulation of regulatory T (Treg) cells.

Role of hypoxia-inducible factor-1alpha in hypoxia-induced expressions of IL-8, MMP-1 and MMP-3 in rheumatoid fibroblast-like synoviocytes.

OBJECTIVES: Hypoxia-inducible factor-1alpha (HIF-1alpha) is a master regulator in the cellular response to hypoxic conditions, and rheumatoid synovial tissue is known to exist under hypoxic conditions. Therefore, this study was conducted to determine the contribution of HIF-1alpha to hypoxia-induced MMP and cytokine production in fibroblast-like synoviocytes (FLS). METHODS: RA FLS were transfected with either a plasmid that expresses HIF-1alpha or an empty vector as a control, and then cultured under normoxia (21% O(2)). Also, FLS were transfected with either HIF-1alpha small interfering RNA (siRNA) or control siRNA, and cultured under hypoxic conditions (1% O(2)). Following transfection, the amounts of MMP and cytokine mRNAs and HIF-1alpha protein were examined using real-time RT-PCR and western blotting, respectively. RESULTS: The expression of HIF-1alpha, MMP-1, MMP-3, IL-6 and IL-8 was markedly enhanced in FLS that were cultured under hypoxia. We confirmed that transient transfection of HIF-1alpha overexpressing vector or siRNA had occurred using western blotting, and in vitro studies conducted using FLS transfected with HIF-1alpha overexpression vector showed that they had significantly increased MMP-1, MMP-3 and IL-8 expression levels. Further, hypoxia-induced MMP-3 expression was significantly attenuated by knock-down of HIF-1alpha, whereas hypoxia-induced IL-8 or MMP-1 expression was not significantly repressed by HIF-1alpha siRNA. CONCLUSIONS: Hypoxia-induced MMP-3 expression is exclusively regulated by HIF-1alpha, and hypoxia-induced MMP-1 or IL-8 expression appears to have salvage pathways other than the HIF-1alpha pathway. Together, these data provide new insight regarding the mechanism by which hypoxia participates in joint inflammation and destruction in RA.

Behcet's disease associated with bone marrow failure in Korean patients: clinical characteristics and the association of intestinal ulceration and trisomy 8.

OBJECTIVES: The aim of this study was to determine the clinical characteristics of Behcet's disease (BD) associated with bone marrow failure (BMF), classified as conditions such as myelodysplastic syndrome (MDS) or aplastic anaemia (AA), in Korea. METHODS: A retrospective analysis was made of 13 patients with BD associated with BMF (MDS 8 cases, AA 5 cases) and 66 patients with BD not associated with BMF. These patients all fulfilled the diagnostic criteria of the international BD study group. RESULTS: BD patients with BMF showed significantly lower leucocyte count, haemoglobin level and platelet count when compared with patients without BMF (P < 0.001). BD patients with BMF had significantly higher serum CRP level at the time of BD diagnosis compared with patients without BMF (P = 0.03). Intestinal lesions were more frequent in BD patients with BMF than those without BMF (61.5% vs 13.6%, P = 0.001). Cytogenetic abnormality was observed in 90.9% of BD patients with BMF. Of the cytogenetic abnormalities, trisomy 8 was most common, occurring in 70% of the patients. In four patients with refractory BD associated with BMF, successful treatment of BMF by haematopoietic stem cell transplantation resulted in clinical remission of BD. CONCLUSIONS: Our study indicates that intestinal ulceration is a characteristic finding in BD associated with BMF. It also suggests that cytogenetic aberration, especially trisomy 8, may play an important role in the pathogenesis of BD associated with BMF.

Genetic variations in the leptin and leptin receptor genes are associated with type 2 diabetes mellitus and metabolic traits in the Korean female population.

Type 2 diabetes mellitus (T2DM) is a metabolic disorder that is characterized by insulin resistance and hyperglycemia. Leptin inhibits the glucose-stimulated insulin secretion, and leptin receptors are present on beta cells as well as on fat cells, thus enabling leptin to modulate both insulin secretion and action. Therefore, leptin (LEP) and leptin receptor (LEPR) genes could play a role in the regulation of glucose and insulin after an oral glucose load. For the association study of LEP and LEPR with T2DM and metabolic traits, 752 women from Seoul National University Hospital (SNUH data) and 532 women from the Korean Health and Genome Study (KHGS data) were selected. Using the SNUH data, we identified that LEP-632G>A and +4998A>C polymorphisms were marginally associated with T2DM, LEP+4950G>A was significantly associated with several metabolic traits, and LEPR+5193G>A, +7187A>C, +27265G>A, +35861T>C, and +52289A>G showed strongly significant association with body mass index (BMI). We observed reproducibility of these results using the KHGS data; LEP+4950G>A and +4998A>C were significantly associated with systolic blood pressure and low-density lipoprotein cholesterol level, respectively. In conclusion, we observed that several polymorphisms in LEPR that had previous reports of association with BMI were significantly replicated in our samples and newly found that some variations of LEP were associated with T2DM and metabolic traits.

Hypoxia appears at pre-arthritic stage and shows co-localization with early synovial inflammation in collagen induced arthritis.

OBJECTIVE: The presence of hypoxia in rheumatoid synovium has been well known, but exact correlation between hypoxia and synovitis is unclear. The aim of our study was to investigate the time and spatial relationship and the correlation of severity between hypoxia and synovitis in pre-arthritic or early stage of inflammatory joint disease. METHODS: DBA/1J mice were injected intradermally with type II collagen and adjuvant solution to induce arthritis; mice injected with only adjuvant were used as a control group. CIA and control mice were sacrificed weekly after the injection to evaluate serial pathological changes. H&E stain and hydroxyprobe-1 stain were performed to look at the status of inflammation and hypoxia. RESULTS: In serial observations of tissue pathology, we could note the inflammation of synovium developing a week after the injection of type II collagen. Hypoxic change, measured by the hydroxyprobe-1 stain, was also identified in synovium as early as 1 week after the collagen injection, prior to clinically evident arthritis. In addition, we could observe that inflammation and hypoxia co-localize in the synovium and there was a positive correlation between the severity of hypoxia and the degree of synovitis. CONCLUSION: Our results demonstrate that hypoxia takes place in synovium at the pre-arthritic stage of disease and have a close spatial relationship and a positive severity correlation with synovitis.

Prevalence and risk factors for erectile dysfunction in primary care: results of a Korean study.

In order to assess the prevalence and associated factors for erectile dysfunction (ED) in primary care, a cross-sectional study was undertaken by questionnaire distributed to consecutive adult male attendees at 32 family practices. ED was assessed by the Korean five-item version of the International Index of Erectile Function (IIEF-5). In total, 3501 completed questionnaires were available for analysis. The prevalence of ED was severe (IIEF-5 score: 5-9) in 1.6% of cases, moderate (10-13) in 10.2%, mild (14-17) in 24.7%, and normal (18-25) in 63.4%. The prevalence of ED increased with age, lower educational status, heavy job-related physical activity, and lower income. ED prevalence was significantly higher in patients with chronic diseases such as diabetes, depression, and anxiety. These results suggest that the age-adjusted prevalence of ED among Korean men can be estimated as 32.2% (95% CI 30.6-33.7). Low socioeconomic status and several diseases such as diabetes, anxiety, and depression, as well as age, were associated with ED.

Influence of hypoxia on the expression of matrix metalloproteinase-1, -3 and tissue inhibitor of metalloproteinase-1 in rheumatoid synovial fibroblasts.

OBJECTIVE: The rheumatoid synovium is a hypoxic environment, and hypoxia has been implicated as a factor in the pathogenesis of rheumatoid arthritis (RA). The purpose of this study was to investigate the effect of hypoxia on the expression of matrix metalloproteinase (MMP)-1, -3 and tissue inhibitor of metalloproteinase (TIMP)-1 in rheumatoid synovial fibroblasts. METHODS: Synovial fibroblasts obtained from RA patients were cultured for 48 h under normoxic or hypoxic conditions. Assays included western blot analysis and enzyme-linked immunosorbent assay (ELISA) for MMP-1, -3 and TIMP-1, and northern blot analysis to measure TIMP-1 mRNA levels. RESULTS: Compared with normoxic culture, hypoxia increased MMP-1 and MMP-3 expression in rheumatoid synovial fibroblasts. Hypoxia decreased TIMP-1 expression in rheumatoid synovial fibroblasts, as measured by both protein and mRNA levels. CONCLUSION: These results suggest that microenvironmental conditions, such as hypoxia, may directly contribute to joint destruction in RA by increasing the ratio of MMP-1, -3 to TIMP-1 production in synovial fibroblasts.

Comparison of the efficacy and safety of naproxen CR and nabumetone in the treatment of patients with osteoarthritis of the knee.

OBJECTIVE: To comparre the safety and efficacy of naproxen CR (1,000 mg once daily) with that of nabumetone (1,000 mg once daily) in the treatment of patients with symptomatic knee osteoarthritis(OA). METHODS: A total of 159 Korean patients (80 in the naproxen CR group and 79 in the nabumetone group) were enrolled in this 4-week, single-blind, controlled, randomized, parallel study and an intention-to-treat model was used for data analysis. Six efficacy parameters were measured: Lequesne index, visual analogue pain scale at rest and atactivity, patient's and physician's global assessment, and time to walk 50 feet. RESULTS: Significant improvement in all efficacy parameters except time to walk 50 feet occurred at Week 2 and Week 4 in both groups. Themean improvement from baseline at Week 2 and Week 4 for the efficacy variables was not different between naproxen CR and nabumetone group. Twenty-four patients (30%) in the naproxen CR group and 18 patients (22.8%) in the nabumetone group withdrew from the study. Among them, only 1patient in the naproxen CR group terminated the study prematurely due to an adverse event of dyspepsia. No statistically significant difference in the frequency of adverse events, including gastrointestinal symptoms, was observed between these 2 groups during the treatment period. Significant laboratory abnormalities also did not occur during the study period in both groups. CONCLUSIONS: Naproxen CR is an effective and tolerable drug in the treatment of knee OA. Efficacy and safety profiles are comparable to those of nabumetone.

Glucocorticoid-induced tumour necrosis factor receptor-related protein-mediated macrophage stimulation may induce cellular adhesion and cytokine expression in rheumatoid arthritis.

Glucocorticoid-induced tumour necrosis factor receptor (TNFR)-related protein (GITR) is one of the T cell co-stimulatory molecules and is associated with the pathogenesis of a number of autoimmune diseases. We investigated the expression patterns of GITR in human arthritic synovium and the role of GITR in the pathogenesis of rheumatoid arthritis (RA). Immunohistochemical analyses revealed the expression of GITR and its cognate ligand, GITRL, in macrophages in RA, but not in osteoarthritis (OA), synovium. To investigate the role of GITR in macrophage functions, primary macrophages from RA patients and a human macrophage cell line, THP-1, were analysed. Stimulation of the macrophages with anti-GITR monoclonal antibody induced up-regulation of intercellular adhesion molecule (ICAM)-1 and subsequent aggregation/adhesion, which was enhanced by the presence of extracellular matrix proteins and blocked by anti-ICAM-1 monoclonal antibody. The validity of these in vitro observations was confirmed by immunohistochemical analyses of RA synovium, which showed strong expression of ICAM-1 in GITR-positive macrophages. Additionally, GITR stimulation induced expression of proinflammatory cytokines/chemokines and matrix metalloproteinase-9 in synovial macrophages. These data indicate that GITR, expressed on macrophages in human RA synovium, may enhance inflammatory activation of macrophages by promoting cytokine gene expression and adhesion between cells and to extracellular matrix in RA synovium.

Inhibitory effect of cyclo-oxygenase-2 inhibitor on the production of matrix metalloproteinases in rheumatoid fibroblast-like synoviocytes.

Cyclo-oxygenase (COX)-2 has been associated with inflammation in rheumatoid arthritis (RA), but its role in joint destruction remains unclear. In this study, we investigated the effect on cultured rheumatoid fibroblast-like synoviocytes (FLS) of the selective COX-2 inhibitor celecoxib on the expression of matrix metalloproteinases (MMPs), which play an important role in tissue degradation and angiogenesis in rheumatoid synovium. Treatment with nontoxic doses of celecoxib resulted in dose-dependent inhibition of MMP-1, -2, and -3 secretion from FLS when measured by enzyme-linked immunosorbent assay. Celecoxib suppressed proinflammatory cytokines (tumor necrosis factor-alpha and interleukin-1beta) induced augmentation of the gelatinolytic activity on zymography. These results suggest that COX-2 inhibitors might influence matrix degradation or angiogenesis in RA by downregulating the expression of various MMPs in rheumatoid FLS.

Pulmonary alveolar hemorrhage in patients with rheumatic diseases in Korea.

Pulmonary alveolar hemorrhage (PAH) is a rare and often fatal presenting feature of rheumatic diseases, with high mortality rate ranging from 40% to 90%. This study was undertaken to review the clinical manifestations, disease course, prognosis, and treatment of PAH in rheumatic diseases in Korea. A retrospective analysis was performed from October 1995 to March 1999 at the Samsung Medical Center. Ten cases were diagnosed as having pulmonary hemorrhage with rheumatic diseases that comprised the following: 6 systemic lupus erythematosus (SLE), 3 microscopic polyangiitis (MPA), and 1 mixed connective tissue disease (MCTD). In 80% of the patients in the present series, PAH was the first clinical manifestation of rheumatic diseases. The most consistent systemic manifestation occurring in conjunction with PAH was renal involvement (80%). The overall patient mortality rate was 50% (5/10) in the current series. Our study suggests that PAH often occurs as the first clinical manifestation of rheumatic diseases and needs urgent medical treatment including plasmapheresis in addition to cyclophosphamide and methylprednisolone.

Association of the oestrogen receptor alpha gene polymorphisms with disease onset in systemic lupus erythematosus.

OBJECTIVE: To evaluate the genetic influence of PvuII and XbaI polymorphisms of oestrogen receptor alpha (ORalpha) in patients with systemic lupus erythematosus (SLE) in Korea. METHODS: Genomic DNA from 268 female controls and 137 female SLE patients (41 childhood onset and 96 adult onset) were analysed using PvuII and XbaI restriction fragment length polymorphism. Comparison of the frequencies of alleles and genotypes was made in control and patient groups and in childhood onset and adult onset SLE subgroups. RESULTS: Although the Pp genotype occurred more often in SLE patients than in controls (p(c) = 0.017), ORalpha genotype distributions of adult onset SLE did not differ significantly from controls. The PP, Pp, and xx genotypes occurred less often in childhood onset SLE (p(c) = 0.0045, 0.0498, and 0.0255, respectively) than in controls. Additionally, the PP genotype was less common in childhood onset than in adult onset SLE (p(c) = 0.016). SLE patients with the PP genotypes were older at disease onset than those with the other genotypes (p = 0.001). Patients with the Xx genotype had an earlier onset of SLE than those with the xx genotype (p = 0.025). The frequency of the combined ppXx genotype was greater in childhood onset SLE than in controls (p(c) = 0.0009) or adult onset SLE (p(c) = 0.027). The same trend was supported by subgroup analyses according to age at menarche and logistic multivariate analyses. CONCLUSIONS: ORalpha polymorphisms are significantly associated with the age at disease onset in Koreans with SLE.

Autoantibodies to glucose-6-phosphate isomerase are elevated in the synovial fluid of rheumatoid arthritis patients.

OBJECTIVE: This study investigated whether anti-glucose-6-phosphate isomerase (GPI) antibody in the synovial fluid is specifically related to human rheumatoid arthritis (RA). METHODS: Synovial fluid was collected from patients with RA, osteoarthritis (OA), gout, Behcet's disease, or ankylosing spondylitis. GPI-binding activity was measured in the synovial fluid using a surface plasmon resonance (SPR) biosensor. RESULTS: The mean level of anti-GPI signal in the synovial fluid of RA patients was significantly elevated compared with that of OA patients (2.84 +/- 1.41 AU versus 1.19 +/- 0.42 AU, respectively; p < 0.0001). Anti-GPI signals in the synovial fluids of patients with non-rheumatoid arthritis, such as gout, Behcet's disease, or ankylosing spondylitis were significantly lower than in the synovial fluid of RA patients (p < 0.005), and were similar to those of OA patients. CONCLUSION: Our study indicates that anti-GPI antibody in the synovial fluid is specifically related to RA, and suggests that GPI and its autoantibody might be important in the pathogenesis of human RA.