Effectiveness of paraffin bath therapy for the symptoms and function of hand diseases: A systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Paraffin bath therapy is noninvasive and is widely used in various hand diseases. Paraffin bath therapy is easy to use, has fewer side effects, and can be applied to various diseases with different etiologies. However, there are few large-scale studies of paraffin bath therapy, and there is insufficient evidence of its efficacy. PURPOSE: The purpose of the study was to investigate the effectiveness of paraffin bath therapy for pain relief and functional improvement in various hand diseases through a meta-analysis. STUDY DESIGN: Systematic review and meta-analysis of randomized controlled trials. METHODS: We searched for studies using PubMed and Embase. Eligible studies were selected based on the following criteria: (1) patients with any diseases of the hand; (2) comparison between paraffin bath therapy and no paraffin bath therapy; and (3) sufficient data on changes in the visual analog scale (VAS) score, grip strength, pulp-to-pulp pinch strength, or Austrian Canadian (AUSCAN) Osteoarthritis Hand index before and after paraffin bath therapy. Forest plots were drawn to visualize the overall effect. Jadad scale score, I2 statistics, and subgroup analyses were used to assess the risk of bias. RESULTS: A total of five studies included 153 patients who were treated and 142 who were not treated with paraffin bath therapy. The VAS were measured in all 295 patients included in the study, while the AUSCAN index was measured in the 105 patients with osteoarthritis. Paraffin bath therapy significantly reduced the VAS scores (mean difference [MD], -1.27; 95% confidence interval [CI] -1.93 to -0.60). In osteoarthritis, paraffin bath therapy significantly improved grip and pinch strength (MD -2.53; 95% CI 0.71-4.34; MD 0.77; 95% CI 0.71-0.83) and reduced the VAS and AUSCAN scores (MD -2.61; 95% CI -3.07 to -2.14; MD -5.02; 95% CI -8.95 to -1.09). DISCUSSION: Paraffin bath therapy significantly reduced the VAS and AUSCAN scores, and improved grip and pinch strength in patients with various hand diseases. CONCLUSIONS: Paraffin bath therapy is effective for alleviating pain and improving function in hand diseases, thereby improving quality of life. However, owing to the small number of patients included in the study and its heterogeneity, a further large-scale, well-structured study is needed.

The associations between interleukin 10 polymorphisms and susceptibility to autoimmune uveitis - a meta-analysis.

Autoimmune uveitis is an ocular inflammatory disease that is associated with genetic factors. Interleukin 10 (IL-10) is an immune-regulatory cytokine of autoimmune diseases. IL-10 is considered a candidate gene for uveitis. We evaluate the association of IL-10 with susceptibility to autoimmune uveitis. The results from seven studies were pooled in the meta-analysis, covering a total of 2893 cases of uveitis and 4873 controls. Published literature from MEDLINE and Embase was retrieved. Meta-analyses were conducted on the associations between autoimmune uveitis and the -1082 A/G and -819 C/T polymorphisms of the IL-10 gene. The meta-analysis revealed no association between uveitis and the IL-10 -1082 A allele (OR = 0.91, 95% CI = 0.64-1.30, p = 0.62). The recessive, dominant, and homozygous models of the IL-10 -1082 A/G allele also suggested no association between autoimmune uveitis and each genotype. The meta-analysis revealed significant association between uveitis and the -892 C allele (OR = 0.81, 95% CI = 0.67-0.98, p = 0.03). In addition, significant association was found in homozygous models (OR = 0.58, 95% CI = 0.36-0.92, p = 0.02). However, the dominant and recessive models of the IL-10 -819 C/T polymorphisms showed no association between uveitis and each genotype. This meta-analysis showed that the -1082 A/G polymorphisms of IL-10 were not associated with autoimmune uveitis, but the -819 C/T polymorphisms were significantly associated with uveitis.

Endovascular Versus Open Surgical Intervention in Patients with Takayasu's Arteritis: A Meta-analysis.

OBJECTIVE/BACKGROUND: Although medical treatment has advanced, surgical treatment is needed to control symptoms of Takayasu's arteritis (TA), such as angina, stroke, hypertension, or claudication. Endovascular or open surgical intervention is performed; however, there are few comparative studies on these methods. This meta-analysis and systematic review aimed to examine the outcome of surgical treatment of TA. METHODS: A meta-analysis comparing outcomes of endovascular and open surgical intervention was performed using MEDLINE and Embase. This meta-analysis included only observational studies, and the evidence level was low to moderate. Data were pooled and analysed using a fixed or random effects model with the I2 statistic. RESULTS: The included studies involved a total of 770 patients and 1363 lesions, with 389 patients treated endovascularly and 420 treated by surgical revascularization. Restenosis was more common with endovascular than open surgical intervention (odds ratio [OR] 5.18, 95% confidence interval [CI] 2.78-9.62; p < .001). In subgroup analysis according to the involved lesions, endovascular intervention patients showed more restenosis than open surgical intervention patients in the coronary artery, supra-aortic branches, and renal artery. In both the active and inactive stages, restenosis was more common in those treated endovascularly than in those treated by open surgery. However, stroke occurred less often with endovascular intervention than with open surgical intervention (OR 0.33, 95% CI 0.12-0.90; p = .003). Mortality and complications other than stroke and mortality did not differ between endovascular and open surgical intervention. CONCLUSION: This meta-analysis has shown a lower risk of restenosis with open surgical intervention than with endovascular intervention. Stroke was generally more common with open surgical intervention than with endovascular intervention. However, there were differences according to the location of the lesion, and the risk of stroke in open surgery is higher when the supra-aortic branches are involved rather than the renal arteries.

Association of depression with socioeconomic status, anticardiolipin antibodies, and organ damage in patients with systemic lupus erythematosus: results from the KORNET registry.

OBJECTIVES: Depression is more common in patients with systemic lupus erythematosus (SLE) compared to the general population. However, few studies have investigated risk factors of depression in SLE patients, and the results are inconsistent. This study evaluated the prevalence of, and risk factors for, depression in ethnically homogeneous Korean SLE patients. METHODS: In this study, 505 consecutive SLE patients were enrolled from the Korean Lupus Network registry. Demographic variables, clinical manifestations, laboratory findings, physician global assessment, and SLEDAI-2000 and SLICC damage index were recorded at enrolment. Patients were identified as having depressive symptoms using the Korean version of the Beck Depression Inventory (BDI) with a cut-off ≥16, and categorised into four groups. Multivariable logistic regression analyses were performed to identify independent risk factors for depression defined as a BDI score ≥16. RESULTS: Of the 505 patients, 97 (19.2%) were diagnosed with depression. Patients with a higher BDI score were older, more likely to be a current smoker, and had a SLICC score >1. Conversely, they had lower income and educational levels. Regarding the serologic findings, patients with a higher BDI score had lower anti-double-stranded DNA positivity and higher anticardiolipin (aCL) positivity. On multivariate analysis, the following factors were associated with depression: current smoking status (OR 2.533, p=0.049), aCL-positivity (OR 2.009, p=0.035), and a SLICC damage index score >1 (OR 2.781, p=0.039). On the other hand, high-level education (OR 0.253, p=0.024) and a high income (OR 0.228, p=0.008) were negatively associated with depression. CONCLUSIONS: Our results show that depression is prevalent in patients with SLE and multiple factors are associated with depression in SLE. These data could help guide target programmes for those at high risk of depression in SLE.

Effects of risk factors for and components of metabolic syndrome on the quality of life of patients with systemic lupus erythematosus: a structural equation modeling approach.

PURPOSE: This study assessed the relationships among the risk factors for and components of metabolic syndrome (MetS) and health-related quality of life (HRQOL) in a hypothesized causal model using structural equation modeling (SEM) in patients with systemic lupus erythematosus (SLE). METHODS: Of the 505 SLE patients enrolled in the Korean Lupus Network (KORNET registry), 244 had sufficient data to assess the components of MetS at enrollment. Education level, monthly income, corticosteroid dose, Systemic Lupus Erythematosus Disease Activity Index, Physicians' Global Assessment, Beck Depression Inventory, MetS components, and the Short Form-36 at the time of cohort entry were determined. SEM was used to test the causal relationship based on the Analysis of Moment Structure. RESULTS: The average age of the 244 patients was 40.7 ± 11.8 years. The SEM results supported the good fit of the model (χ 2 = 71.629, p = 0.078, RMSEA 0.034, CFI 0.972). The final model showed a direct negative effect of higher socioeconomic status and a positive indirect effect of higher disease activity on MetS, the latter through corticosteroid dose. MetS did not directly impact HRQOL but had an indirect negative impact on it, through depression. CONCLUSIONS: In our causal model, MetS risk factors were related to MetS components. The latter had a negative indirect impact on HRQOL, through depression. Clinicians should consider socioeconomic status and medication and seek to modify disease activity, MetS, and depression to improve the HRQOL of SLE patients.

Treat-to-Target Strategy for Asian Patients with Early Rheumatoid Arthritis: Result of a Multicenter Trial in Korea.

BACKGROUND: To evaluate the therapeutic benefits of the treat-to-target (T2T) strategy for Asian patients with early rheumatoid arthritis (RA) in Korea. METHODS: In a 1-year, multicenter, open-label strategy trial, 346 patients with early RA were recruited from 20 institutions across Korea and stratified into 2 groups, depending on whether they were recruited by rheumatologists who have adopted the T2T strategy (T2T group) or by rheumatologists who provided usual care (non-T2T group). Data regarding demographics, rheumatoid factor titer, anti-cyclic citrullinated peptide antibody titer, disease activity score of 28 joints (DAS28), and Korean Health Assessment Questionnaire (KHAQ) score were obtained at baseline and after 1 year of treatment. In the T2T group, the prescription for disease-modifying antirheumatic drugs was tailored to the predefined treatment target in each patient, namely remission (DAS28 < 2.6) or low disease activity (LDA) (2.6 ≤ DAS28 < 3.2). RESULTS: Data were available for 163 T2T patients and 162 non-T2T patients. At the end of the study period, clinical outcomes were better in the T2T group than in the non-T2T group (LDA or remission, 59.5% vs. 35.8%; P < 0.001; remission, 43.6% vs. 19.8%; P < 0.001). Compared with non-T2T, T2T was also associated with higher rate of good European League Against Rheumatism response (63.0% vs. 39.8%; P < 0.001), improved KHAQ scores (-0.38 vs. -0.13; P = 0.008), and higher frequency of follow-up visits (5.0 vs. 2.0 visits/year; P < 0.001). CONCLUSION: In Asian patients with early RA, T2T improves disease activity and physical function. Setting a pre-defined treatment target in terms of DAS28 is recommended.

The association between genetic polymorphisms of the interleukin-23 receptor gene and susceptibility to uveitis: a meta-analysis.

BACKGROUND: Uveitis is an eye inflammatory disease, which is sometimes associated with underlying systemic disease. Interleukin-23 plays an important role in autoimmune disease. The aim of this meta-analysis was to evaluate the association between the interleukin-23 receptor (IL-23R) and susceptibility to uveitis. METHODS: Published literature from PUBMED and EMBASE were retrieved. Seven studies were included in this meta-analysis, covering a total of 1309 cases of uveitis and 2400 controls. Meta-analyses were conducted on the associations between uveitisand rs7517847, rs17375018, and rs11209032 polymorphisms in the IL-23R gene. RESULTS: There were no significant associations between IL-23R polymorphisms and uveitis with regard to the following alleles: for G allele vs. T allele of rs7517847, OR 1.01, 95% CI 0.92-1.12, P = 0.83; for A allele vs. G allele of rs17375018, OR 0.68, 95% CI 0.47-0.99, P = 0.05; rs11209032 OR 1.12, 95% CI 0.84-1.51, P = 0.43. In contrast, there were significant associations between the AA + AG gene versus GG gene of rs17375018 and the AA gene versus AG + GG gene of rs11209032 polymorphism with uveitis (OR 0.59, 95% CI 0.35-0.99, P = 0.04; OR 1.32, 95% CI 1.10-1.59, P = 0.003). CONCLUSIONS: This meta-analysis suggests that each allele of IL-23R, including rs7519847, rs17375018 and rs11209032 was negatively associated with uveitis. However, homozygote models, including the rs17375018 GG genotype and rs11209032 AA genotype, were significantly associated with uveitis.

Relative efficacy and tolerability of etoricoxib, celecoxib, and naproxen in the treatment of osteoarthritis : A Bayesian network meta-analysis of randomized controlled trials based on patient withdrawal.

AIMS: This study aimed to assess the relative efficacy and tolerability of etoricoxib, celecoxib, and naproxen at recommended dosages in patients with osteoarthritis (OA). METHODS: Randomized controlled trials (RCTs) examining the efficacy and tolerability of etoricoxib 30-60 mg, celecoxib 200-400 mg, and naproxen 1000 mg, based on the number of patient withdrawals among those with OA, were included in this network meta-analysis. We performed a Bayesian random-effects network meta-analysis to combine direct and indirect evidence from the RCTs. RESULTS: Eight RCTs, including 5,942 patients, met the inclusion criteria. The proportion of patient withdrawals due to lack of efficacy was significantly lower in the etoricoxib 30-60 mg (OR 0.21, 95 % CrI 0.12-0.38), celecoxib 200-400 mg (OR 0.29, 95 % CrI 0.18-0.47), and naproxen 1000 mg (OR 0.31, 95 % CrI 0.18-0.51) groups than in the placebo group. The number of patient withdrawals due to lack of efficacy tended to be lower in the etoricoxib 30-60 mg group than in the naproxen 1000 mg and celecoxib 200-400 mg groups, although they did not reach statistical significance (OR 0.68, 95 % CrI 0.36-1.33 and OR 0.70, 95 % CrI 0.38-1.37, respectively). Ranking probabilities based on the surface under the cumulative ranking curve (SUCRA) indicated that etoricoxib 30-60 mg had the highest probability of being the best treatment based on the number of withdrawals due to lack of efficacy (SUCRA = 0.9168) followed by celecoxib 200-400 mg (SUCRA = 0.5659), naproxen 1000 mg (SUCRA = 0.5171), and placebo (SUCRA = 0.000189). With respect to tolerability, the number of withdrawals due to adverse events was not significantly different among etoricoxib, celecoxib, naproxen, and placebo, although it tended to be lower with etoricoxib and placebo. CONCLUSIONS: Etoricoxib 30-60 mg, celecoxib 200-400 mg, and naproxen 1000 mg were more efficacious than placebo. However, there was no significant difference in efficacy and tolerability between the medications.

Association between FCGR3B copy number variations and susceptibility to autoimmune diseases: a meta-analysis.

OBJECTIVE: This study determined whether FCGR3B copy number variations (CNVs) were associated with susceptibility to autoimmune diseases. METHODS: A meta-analysis was conducted to determine the association between FCGR3B CNVs and susceptibility to autoimmune diseases by comparing low FCGR3B CN (<2 to ≥2) and high FCGR3B CN (>2 to ≤2). RESULTS: In all, 28 comparative studies from 15 reports involving 12,160 patients and 11,103 controls were included in this meta-analysis. The meta-analysis showed a significant association between low FCGR3B CN and autoimmune diseases (OR=1.496, 95% CI=1.301-1.716, p=1.0×10(-9)). Subgroup analysis according to ethnicity indicated an association between low FCGR3B CN and autoimmune diseases in Caucasians (OR=1.482, 95% CI=1.219-1.801, p=7.7×10(-6)) and Asians (OR=1.498, 95% CI=1.306-1.717, p=1.0×10(-9)). Meta-analysis according to the type of autoimmune disease indicated a significant association of low FCGR3B CN with systemic lupus erythematosus (SLE; OR=1.797, 95% CI=1.562-2.068, p<1.0×10(-9)), primary Sjogren's syndrome (pSS; OR=2.263, 95% CI=1.316-3.892, p=0.003), and Wegener's granulomatosis (WG; OR=1.973, 95% CI=1.178-3.302, p=0.010), but not with rheumatoid arthritis (RA; OR=1.333, 95% CI=0.947-1.877, p=0.099). However, the meta-analysis showed no association between high FCGR3B CN and SLE, RA, pSS, and WG. CONCLUSIONS: Thus, the results of this meta-analysis indicated that low FCGR3B CN increased susceptibility to autoimmune diseases, especially SLE, pSS, and WG.

Association between TNF-α promoter -308 A/G polymorphism and Alzheimer's disease: a meta-analysis.

The aim of this study was to determine whether the tumor necrosis factor-α (TNF-α) promoter -308 A/G polymorphism is associated with susceptibility to Alzheimer's disease (AD) in multi-ethnic populations. MEDLINE and EMBASE databases and manual literature search were used to identify published articles in which TNF-α polymorphism was determined in AD patients and control subjects. Meta-analysis was conducted on the association between the TNF-α -308 A/G polymorphism and AD using allele contrast and the recessive, dominant, and additive models. A total of 16 studies involving 3,826 AD patients and 4,327 control subjects were examined. The meta-analysis showed no association between the TNF-α -308 A allele and AD when all the subjects were considered [odds ratio (OR) = 1.275, 95 % CI 0.966-1.685, p = 0.087]. After stratification by ethnicity, the meta-analysis indicated that the A allele is significantly associated with AD in East Asian (OR = 1.743, 95 % CI 1.256-2.418, p = 0.001), but not in the European (OR = 0.963, 95 % CI 0.822-1.128, p = 0.637) or Middle Eastern populations (OR = 3.921, 95 % CI 0.411-37.42, p = 0.235). Meta-analysis under dominant, recessive, and additive models also showed a similar pattern of results as with the A allele. This meta-analysis shows that the TNF-α -308 A/G polymorphism may represent a significant risk factor for AD in East Asians but not in the European or Middle Eastern populations.

Paraoxonase 1 Q192R and L55M polymorphisms and susceptibility to amyotrophic lateral sclerosis: a meta-analysis.

This study aimed to investigate whether paraoxonase 1 (PON1) Q192R and L55M polymorphisms are associated with susceptibility to amyotrophic lateral sclerosis (ALS). We conducted a meta-analysis of the associations between the PON1 Q192R and L55M polymorphisms and ALS. A total of 2,831 patients and 3,123 controls from eight studies of the PON1 Q192R polymorphism and seven studies of the PON1 L55M T polymorphism were considered for this study. Meta-analysis showed no association between ALS and the PON1 192R allele (OR = 1.052, 95 % CI = 0.923-1.207, p = 0.447), and the PON1 55M allele (OR = 1.015, 95 % CI = 0.884-1.164, p = 0.837) in all study subjects. Similarly, no association was found between ALS and the PON1 Q192R and L55M polymorphisms using recessive, dominant or homozygote contrast models. Stratification by ethnicity indicated no association between ALS and the PON1 192R allele (OR = 1.058, 95 % CI = 0.910-1.231, p = 0.464) and the PON1 55M allele (OR = 1.027, 95 % CI = 0.889-1.185, p = 0.721) in the European population. This meta-analysis showed lack of associations between PON1 Q192R and L55M polymorphisms and susceptibility to ALS in the European population.

Meta-analysis of associations between MTHFR and GST polymorphisms and susceptibility to multiple sclerosis.

We examined whether methylenetetrahydrofolate reductase (MTHFR) and glutathione S-transferase (GST) polymorphisms are associated with susceptibility to multiple sclerosis (MS). We performed a meta-analysis on the association between MS and the following genotypes: MTHFR C677T, A1298C, and GSTP1 A313G polymorphisms, and GSTM1 and GSTT1 null alleles. Fifteen comparisons involving 2,486 patients and 2,861 controls were considered. Meta-analysis of all study subjects considered together showed no association between MS and the MTHFR 677 T allele (OR = 1.014, 95 % CI 0.803-1.280, p = 0.909). Stratification by ethnicity showed no similar association in Caucasian and Arab populations. Likewise, no link was found between MS and the MTHFR 1298 C allele in the total data (OR = 2.477, 95 % CI 0.507-12.10, p = 0.263), nor when it was stratified by ethnicity. No association with MS was observed in relation to the GSTM1 null genotype in Caucasian populations (OR = 1.229, 95 % CI 0.693-2.181, p = 0.481), nor with the GSTP1 A313G polymorphism (OR for G allele = 1.133, 95 % CI 0.903-1.421, p = 0.281). However, there was an association between MS and the GSTT1 null genotype in data obtained from Caucasian populations (OR = 1.945, 95 % CI 1.452-2.605, p = 8.6 × 10(-7)). GSTT1 null genotype is associated with MS in Caucasian populations; however, no association was found between MS and polymorphisms of MTHFR, GSTM1, and GSTP1.

Baseline Characteristics of the Korean Registry of Pulmonary Arterial Hypertension.

Despite recent advances in understanding of the pathobiology and targeted treatments of pulmonary arterial hypertension (PAH), epidemiologic data from large populations have been limited to western countries. The aim of the Korean Registry of Pulmonary Arterial Hypertension (KORPAH) was to examine the epidemiology and prognosis of Korean patients with PAH. KORPAH was designed as a nationwide, multicenter, prospective data collection using an internet webserver from September 2008 to December 2011. A total of 625 patients were enrolled. The patients' mean age was 47.6 ± 15.7 yr, and 503 (80.5%) were women. The diagnostic methods included right heart catheterization (n = 249, 39.8%) and Doppler echocardiography (n = 376, 60.2%). The etiologies, in order of frequency, were connective tissue disease (CTD), congenital heart disease, and idiopathic PAH (IPAH) (49.8%, 25.4%, and 23.2%, respectively). Patients with WHO functional class III or IV at diagnosis were 43.4%. In total, 380 (60.8%) patients received a single PAH-specific treatment at the time of enrollment, but only 72 (18.9%) patients received combination therapy. Incident cases during the registry represented 297 patients; therefore, the incidence rate of PAH was 1.9 patients/yr/million people. The 1st-, 2nd-, and 3rd-yr estimated survival rates were 90.8%, 87.8%, and 84.4%, respectively. Although Korean PAH patients exhibited similar age, gender, and survival rate compared with western registries, they showed relatively more CTD-PAH in the etiology and also systemic lupus erythematosus among CTD-PAH. The data suggest that earlier diagnosis and more specialized therapies should be needed to improve the survival of PAH patients.

Seasonality of gout in Korea: a multicenter study.

The object of this study was to evaluate the seasonality of gout in Korea. We retrospectively examined data from 330 patients seen at nine rheumatology clinics, treated with urate lowering therapy (ULT) more than one year after stopping prophylactic medication. Demographic data, clinical and laboratory features, and seasonality of gout onset and flares were collected. Season was classified in three-month intervals. The mean age was 52.2 yr and mean disease duration was 26.8 months. The male to female count was 318:12. The onset of acute gouty attacks was obtained in 256 patients. Gout developed most commonly in summer season (36.7%) (P<0.001) and in June (15.6%, P=0.002). During ULT, there were 147 (male 97.3%) gout flares. Although there was no statistically significant difference, gout flares were more common in summer (30.6%). Aggravating factors were identified in 57 flares: alcohol (72.0%) was most common. In the patients who attained target serum uric acid (<6 mg/dL) at the end of prophylaxis, gout flares were high in fall (35.8%) and September (17.0%). In Korea, the summer is most common season of gout onset and there is a tendency for gout flares to increase during ULT in summer/fall season.

Association between IL-6 -174 G/C, IL-6 -634 G/C, and IFN-γ +874 A/T polymorphisms and susceptibility to recurrent pregnancy loss: a meta-analysis.

OBJECTIVE: The aim of this study was to determine whether interleukin-6 (IL-6) -174 G/C, IL-6 -634 G/C, and interferon-γ (IFN-γ) +874 A/T polymorphisms are associated with susceptibility to recurrent pregnancy loss (RPL). METHODS: We conducted a literature search using PubMed and EMBASE databases and performed a meta-analysis using fixed- or random-effects models. RESULTS: A total of 15 articles met the study inclusion criteria. When all study subjects were considered together, meta-analysis showed no association between RPL and the IL-6 -174 GG + GC genotype (odds ratio [OR] = 0.794, 95 % confidence interval [CI] = 0.542-1.163, p = 0.236). However, stratification of the data by ethnicity indicated an association between this genotype and RPL in non-Caucasians (OR = 0.528, 95 % CI = 0.302-0.925, p = 0.028), but not in Caucasian populations. Moreover, meta-analysis revealed an association between RPL and the IL-6 -634 GG + GC genotype in all study subjects (OR = 0.556, 95 % CI = 0.383-0.806, p = 0.002), while stratification by ethnicity revealed a negative association between this genotype and RPL in Asian (OR = 0.545, 95 % CI = 0.371-0.800, p = 0.002) but not Middle Eastern populations. Furthermore, a relationship between the IFN-γ +874 A allele and RPL was identified in non-Caucasians (OR = 1.403, 95 % CI = 1.133-1.734, p = 0.002), but not in Caucasians. CONCLUSIONS: This meta-analysis demonstrates that IL-6 -174 G/C, IL-6 -634 G/C, and IFN-γ +874 A/T polymorphisms are associated with susceptibility to RPL, particularly in non-Caucasians.

Prediction of antiarthritic drug efficacies by monitoring active matrix metalloproteinase-3 (MMP-3) levels in collagen-induced arthritic mice using the MMP-3 probe.

Active matrix metalloproteinase-3 (MMP-3) is a prognostic marker of rheumatoid arthritis (RA). We recently developed an MMP-3 probe that can specifically detect the active form of MMP-3. The aim of this study was to investigate whether detection and monitoring of active MMP-3 could be useful to predict therapeutic drug responses in a collagen-induced arthritis (CIA) model. During the period of treatment with drugs such as methotrexate (MTX) or infliximab (IFX), MMP-3 mRNA and protein levels were correlated with fluorescence signals in arthritic joint tissues and in the serum of CIA mice. Also, bone volume density and erosion in the knee joints and the paws of CIA mice were measured with microcomputed tomography (micro-CT), X-ray, and histology to confirm drug responses. In joint tissues and serum of CIA mice, strong fluorescence signals induced by the action of active MMP-3 were significantly decreased when drugs were applied. The decrease in RA scores in drug-treated CIA mice led to fluorescence reductions, mainly as a result of down-regulation of MMP-3 mRNA or protein. The micro-CT, X-ray, and histology results clearly showed marked decreases in bone and cartilage destruction, which were consistent with the reduction of fluorescence by down-regulation of active MMP-3 in drug-treated CIA mice. We suggest that the MMP-3 diagnostic kit could be used to detect and monitor the active form of MMP-3 in CIA mice serum during a treatment course and thereby used to predict the drug response or resistance to RA therapies at an earlier stage. We hope that monitoring of active MMP-3 levels in arthritis patients using the MMP-3 diagnostic kit will be a promising tool for drug discovery, drug development, and monitoring of drug responses in RA therapy.

Efficacy and safety of PG201 (Layla(®)) and celecoxib in the treatment of symptomatic knee osteoarthritis: a double-blinded, randomized, multi-center, active drug comparative, parallel-group, non-inferiority, phase III study.

The objectives of the study are to demonstrate the non-inferiority of PG201 (Layla(®)) 600 mg in comparison with celecoxib 200 mg for the treatment of symptomatic knee osteoarthritis (OA). In total, 309 patients were randomly assigned to receive either the test drug, PG201 600 mg (n = 154) or celecoxib 200 mg (n = 155). The primary efficacy variable was improvement in mean 100-mm pain VAS score from baseline to the final visit (week 8), and this value was compared between the 2 treatment groups. Secondary outcome variables included changes from baseline in the Western Ontario and McMaster Universities Arthritis Index (WOMAC) pain VAS score and subscale score, patient's global assessment of disease status quality of life (short form-36) and responder index at weeks 4 and 8. For safety assessment, adverse events were recorded at each clinical visit. At weeks 8, the 100-mm pain VAS scores were significantly decreased in patients receiving both PG201 600 mg (p < 0.0001) and celecoxib 200 mg (p < 0.0001) as compared to the baseline scores; however, no statistically significant differences in these values were noted between the groups (p = 0.312). These results met pre-specified criteria for non-inferiority for both the intent-to-treat and per-protocol populations. PG201 600 mg and celecoxib 200 mg were both well tolerated and no statistically significant differences in the tolerability profile between the groups. PG201 600 mg was as effective and safe as celecoxib 200 mg in the treatment of symptomatic knee OA and might be a useful new medication for the treatment of symptomatic knee OA.

Detection of active matrix metalloproteinase-3 in serum and fibroblast-like synoviocytes of collagen-induced arthritis mice.

The activity of rheumatoid arthritis (RA) correlates with the expression of proteases. Among several proteases, matrix metalloproteinase-3 (MMP-3) is one of the biological markers used to diagnose RA. The active form of MMP-3 is a key enzyme involved in RA-associated destruction of cartilage and bone. Thus, detection of active MMP-3 in serum or in vivo is very important for early diagnosis of RA. In this study, a soluble MMP-3 probe was prepared to monitor RA progression by detecting expression of active MMP-3 in collagen-induced arthritis (CIA) mice in vivo in both serum and fibroblast-like synoviocytes (FLSs). The MMP-3 probe exhibited strong sensitivity to MMP-3 and moderate sensitivity to MMP-7 at nanomolecular concentrations, but was not sensitive to other MMPs such as MMP-2, MMP-9, and MMP-13. In an optical imaging study, the MMP-3 probe produced early and strong NIR fluorescence signals prior to observation of erythema and swelling in CIA mice. The MMP-3 probe was able to rapidly and selectively detect and monitor active MMP-3 in diluted serum from CIA mice. Furthermore, histological data demonstrated that activated FLSs in arthritic knee joints expressed active MMP-3. Together, our results demonstrated that the MMP-3 probe may be useful for detecting active MMP-3 for diagnosis of RA. More importantly, the MMP-3 probe was able to detect active MMP-3 in diluted serum with high sensitivity. Therefore, the MMP-3 probe developed in this study may be a very promising probe, useful as a biomarker for early detection and diagnosis of RA.

Toll-like receptor polymorphisms and vasculitis susceptibility: meta-analysis and systematic review.

The aim of this study was to determine whether toll-like receptor (TLR) polymorphisms confers susceptibility to vasculitis. A literature search was conducted using the PubMed and Embase. A meta-analysis on the associations between the TLR4 Asp299Gly polymorphisms and vasculitis was carried out using allele contrast, dominant, and codominant models and a systematic review of other TLR polymorphisms. Fourteen studies involving 2,064 patients and 2,481 controls were included in this systematic review, which comprised nine on Behcet's disease (BD), three on giant cell arteritis (GCA), and one on Henoch-Schenlein purpura (HSP). Meta-analysis of six studies showed a significant association between the Gly/Gly+Gly/Asp genotype of the TLR4 Asp299Gly polymorphism and vasculitis and GCA (Odds ratio [OR] = 1.368, 95 % confidence interval [CI] = 1.300-1.815, p = 0.030; OR = 1.523, 95 % CI = 1.099-2.112, p = 0.012). Under a random effects model, the adjusted ORs calculated using the trim and fill technique revealed an association between the Gly/Gly+Gly/Asp genotype of the TLR4 Asp299Gly polymorphism and vasculitis (OR = 1.544, 95 % CI = 1.091-2.185, p < 0.05). Stratification by vasculitis type using the codominant model showed the trend for the association with GCA (OR = 1.569, 95 % CI = 0.970-2.538, p = 0.066). There were three studies on the TLR2 Arg753Gln polymorphism and two on the TLR4 Thr399Ile polymorphism; no association with vasculitis was evident. Among the TLR2, TLR7, and TLR9 polymorphisms included in this review, one Asian study revealed a significant association between the TLR7 rs5743733 and rs3853839 with BD (p = 0.002, 0.036) and one Asian study showed an association of TLR9 rs352140 with BD (p = 0.009). This meta-analysis demonstrates that the TLR4 Asp299Gly polymorphism may confer susceptibility to GCA. The review of published data suggests that other TLR polymorphisms such as TLR7 and TLR9 may play a role in vasculitis.

Association between tumor necrosis factor-α promoter -308 A/G, -238 A/G, interleukin-6 -174 G/C and -572 G/C polymorphisms and periodontal disease: a meta-analysis.

The aim of this study was to determine whether tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) promoter polymorphisms confer susceptibility to periodontitis in ethnically different populations. A literature search was performed using PubMed and Embase and a meta-analysis of the identified studies was conducted to explore the associations between TNF-α -308 A/G, -238 A/G, IL-6 promoter -174 G/C and -572 G/C polymorphisms and periodontitis. Seventeen comparison studies for the TNF-α -308 A/G polymorphism and three studies for the TNF-α -238 A/G polymorphism were included in the meta-analysis. And 16 separate studies for the IL-6 -174 G/C polymorphism and 10 studies for the IL-6 -572 G/C polymorphism were considered in our meta-analysis. Analysis after stratification by ethnicity indicated that the TNF-α -308 A allele was associated with periodontitis in Brazilian, Asian, and Turkish populations (OR=0.637, 95% CI=0.447-0.907, p=0.013; OR=0.403, 95% CI=0.204-0.707, p=0.009; OR=1.818, 95; % CI=1.036-3.189, p=0.037). The meta-analysis showed no association between the TNF-α -238 A/G polymorphism and periodontitis. The meta-analysis indicated an association of the IL-6 -174 G/C polymorphisms with periodontitis in Brazilian populations (OR for GG+GC=2.394, 95% CI=1.081-5.302, p=0.031). Stratification by ethnicity and disease type indicated an association between the IL-6 -572 G allele and chronic periodontitis (OR=1.585, 95 % CI=1.030-2.439, p=0.036), and periodontitis in Europeans (OR=2.118, 95% CI=1.254-3.577, p=0.005). This meta-analysis demonstrates that the TNF-α -308 A/G polymorphism confers susceptibility to periodontitis in Brazilian, Asian and Turkish populations. The IL-6 -174 G/C polymorphism may confer susceptibility to periodontitis in Brazilians, and the IL-6 -572 G/C polymorphism may be associated with susceptibility to periodontitis in Europeans, and chronic periodontitis.