Gwan Gyu Song

Increased expression of pro-inflammatory cytokines and metalloproteinase-1 by TGF-β1 in synovial fibroblasts from rheumatoid arthritis and normal individuals

Transforming growth factor (TGF)‐β1 is expressed abundantly in the rheumatoid synovium. In this study, the inflammatory effect of TGF‐β1 in rheumatoid arthritis (RA) was investigated using cultured fibroblast‐like synoviocytes (FLS) from RA and osteoarthritis (OA) patients, as well as non‐arthritic individuals. mRNA expressions of IL‐1β, tumour necrosis factor (TNF)‐α, IL‐8, macrophage inflammatory protein (MIP)‐1α and metalloproteinase (MMP)‐1 were increased in RA and OA FLS by TGF‐β1 treatment, but not in non‐arthritic FLS. Enhanced protein expression of IL‐1β, IL‐8 and MMP‐1 was also observed in RA FLS. Moreover, TGF‐β1 showed a synergistic effect in increasing protein expression of IL‐1β and matrix metalloproteinase (MMP)‐1 with TNFα and IL‐1β, respectively. Biological activity of IL‐1 determined by mouse thymocyte proliferation assay was also enhanced by 50% in response to TGF‐β1 in the culture supernatant of RA FLS. DNA binding activities of nuclear factor (NF)‐κB and activator protein (AP)‐1 were shown to increase by TGF‐β1 as well. These results suggest that TGF‐β1 contributes for the progression of inflammation and joint destruction in RA, and this effect is specific for the arthritic synovial fibroblasts.

The Prevalence of Metabolic Syndrome in Patients with Gout: A Multicenter Study

It has been suggested that hyperuricemia and possibly gout are associated with the metabolic syndrome, but there have been no direct studies. This study was undertaken to obtain the prevalence of the metabolic syndrome in patients with gout and to compare it with those from the general population studies. This was a 4-institutional case-historical control study composed of 168 patients with gout. We assessed the prevalence of metabolic syndrome according to the ATP III criteria and compared the prevalence with that of the historical controls. To elucidate the factors in gout that were associated with metabolic syndrome, a multivariate analysis was done. The age-adjusted prevalence of metabolic syndrome in gout patients was 43.6%, which was significantly higher than that of the Korean control population (5.2%) from the previous studies. Patients with gout had more components of metabolic syndrome than did the controls. Body mass index (BMI, OR=1.357 (95%CI 1.111-1.657)) and high density lipoprotein (HDL, OR=0.774 (95%CI 0.705-0.850)) were the variables most significantly associated with the occurrence of metabolic syndrome in gout, but alcohol consumption did not show such associations. Gout is associated with the metabolic syndrome, and furthermore, obesity and dyslipidemia were the factors most associated with the syndrome in these patients.

Prostaglandin E2 augments IL-10 signaling and function.

In inflamed joints of rheumatoid arthritis, PGE2 is highly expressed, and IL-10 and IL-6 are also abundant. PGE2 is a well-known activator of the cAMP signaling pathway, and there is functional cross-talk between cAMP signaling and the Jak-STAT signaling pathway. In this study, we evaluated the modulating effect of PGE2 on STAT signaling and its biological function induced by IL-10 and IL-6, and elucidated its mechanism in THP-1 cells. STAT phosphorylation was determined by Western blot, and gene expression was analyzed using real-time PCR. Pretreatment with PGE2 significantly augmented IL-10-induced STAT3 and STAT1 phosphorylation, as well as suppressors of cytokine signaling 3 (SOCS3) and IL-1R antagonist gene expression. In contrast, PGE2 suppressed IL-6-induced phosphorylation of STAT3 and STAT1. These PGE2-induced modulating effects were largely reversed by actinomycin D. Pretreatment with dibutyryl cAMP augmented IL-10-induced, but did not change IL-6-induced STAT3 phosphorylation. Misoprostol, an EP2/3/4 agonist, and butaprost, an EP2 agonist, augmented IL-10-induced STAT3 phosphorylation and SOCS3 gene expression, but sulprostone, an EP1/3 agonist, had no effect. H89, a protein kinase A inhibitor, and LY294002, a PI3K inhibitor, diminished PGE2-mediated augmentation of IL-10-induced STAT3 phosphorylation. In this study, we found that PGE2 selectively regulates cytokine signaling via increased intracellular cAMP levels and de novo gene expression, and these modulating effects may be mediated through EP2 or EP4 receptors. PGE2 may modulate immune responses by alteration of cytokine signaling in THP-1 cells.

Cryoglobulinaemia and rheumatic manifestations in patients with hepatitis C virus infection

OBJECTIVES To investigate the association of cryoglobulinaemia and rheumatic manifestations in Korean patients with hepatitis C virus (HCV) infection. METHODS Forty nine Korean patients with HCV infection were recruited. The prevalence, concentration, and type of cryoglobulin (by immunofixation), rheumatoid factor (RF), antinuclear antibody (ANA), and various rheumatological symptoms were investigated and HCV genotype was determined by polymerase chain reaction with genotype specific primer. RESULTS The prevalence of cryoglobulin was 59% in Korean HCV patients and the concentration of cryoglobulin was 9.8 (7.9) g/l (mean (SD)). The type of cryoglobulinaemia was identified in 23 (80%) of 29 HCV patients with cryoglobulinaemia and they were all type III. There were no differences in age, sex, history of operation and transfusion, proportion of liver cirrhosis between the patients with cryoglobulinaemia and those without cryoglobulinaemia. The frequencies of RF and ANA were 14% and 3.4% respectively in HCV patients with cryoglobulinaemia. There was no difference in HCV genotype between the patients with cryoglobulinaemia and those without cryoglobulinaemia. Clinical features of HCV patients were as follows: arthralgia/arthritis (35%), cutaneous manifestation (37%), Raynaud’s phenomenon (8%), paresthesia (44%), dry eyes (22%), dry mouth (10%), oral ulcer (33%), and abdominal pain (14%). However, these rheumatological symptoms did not differ between the two groups. CONCLUSION Although the rheumatological symptoms were not different between HCV patients with and without cryoglobulinaemia, HCV patients showed various rheumalogical manifestations. These result suggests that HCV infection could be included as one of the causes in patients with unexplained rheumatological symptoms.

Associations between the C677T and A1298C polymorphisms of MTHFR and the efficacy and toxicity of methotrexate in rheumatoid arthritis: a meta-analysis.

AbstractBackground and Objective: The C677T and A1298C polymorphisms of the methylenetetrahydrofolate reductase (MTHFR) gene have been reported to be associated with the toxicity and efficacy of methotrexate in rheumatoid arthritis (RA), although the results of previous studies have been inconsistent. The aim of this study was to explore whether the C677T and A1298C polymorphisms of MTHFR play a role in the toxicity and efficacy of methotrexate in RA. Methods: The authors identified and evaluated studies conducted on the association between the C677T and A1298C polymorphisms of MTHFR and on the toxicity and efficacy of methotrexate in RA. A meta-analysis was then conducted to compare the toxicity and efficacy of methotrexate with respect to the 677CC and 677CT/TT genotypes and the 1298AA and 1298AC/CC genotypes. Results: Eight studies, which included a total of 1514 patients with RA, were included in this meta-analysis. Meta-analysis did not show any association between the C677T and A1298C polymorphisms of MTHFR and the toxicity of methotrexate in RA in all patients or in Asian patients. The odds ratios (ORs) for adverse effects with 677CC versus 677CT/TT in all patients and in Asian patients were 0.633 (95% CI 0.325, 1.234; p = 0.180) and 0.621 (95% CI 0.233, 1.655; p = 0.341), respectively. The ORs for adverse effects with 1298AA versus 1298AC/CC in all patients and in Asian patients were 0.942 (95% CI 0.479, 1.851; p = 0.861) and 0.978 (95% CI 0.569, 1.681; p = 0.936), respectively. Heterogeneities were evident among the included studies. In addition, no association was found between the C677T and A1298C polymorphisms and the efficacy of methotrexate in RA in all patients. Conclusions: Our meta-analysis including 1514 patients with RA found no association between the C677T and A1298C polymorphisms of MTHFR and the toxicity and efficacy of methotrexate in RA. Because of the paucity of pharmacogenetic data, further studies are needed to determine the role of MTHFR polymorphisms in the toxicity and efficacy of methotrexate.

Associations Between Tumor Necrosis Factor-α (TNF-α) −308 and −238 G/A Polymorphisms and Shared Epitope Status and Responsiveness to TNF-α Blockers in Rheumatoid Arthritis: A Metaanalysis Update

Objective. To investigate whether tumor necrosis factor-α (TNF-α) promoter −308 A/G and −238 A/G polymorphisms and shared epitope (SE) status are associated with responsiveness to anti-TNF therapy in patients with rheumatoid arthritis (RA). Methods. A comparative metaanalysis was conducted on A allele carriers (genotypes A/A + A/G) of the TNF-α promoter −308 and −238 A/G polymorphisms and SE status in responders and nonresponders to anti-TNF therapy. Results. A total of 13 studies were included in the metaanalysis. Metaanalysis showed that the TNF-α −308 A/G polymorphism is not associated with responsiveness to TNF blockers in RA patients. Studies with a small number of subjects (< 100) showed that the odds ratio for the A allele carrier state was significantly lower among responders (OR 0.344, 95% CI 0.152–0.779, p = 0.01). Studies with a higher number of subjects (≥ 100) found no association between the TNF-α −308 A/G polymorphism and responsiveness to TNF blockers. The overall metaanalysis showed that the TNF-α −238 A/G polymorphism was not associated with the responsiveness of RA patients to TNF blockers, and stratification by TNF blocker revealed that the TNF-α −238 A/G polymorphism was associated with response of infliximab (OR 0.441, 95% CI 0.203–0.609, p = 0.039). SE status was found not to be associated with response to TNF blockers. Conclusion. Metaanalysis of available data revealed an association between treatment response to infliximab and the TNF-α −238 A/G polymorphism, but no associations between treatment response and the TNF-α −308 A/G polymorphism or SE status.

Meta-analysis of genome-wide linkage studies for bone mineral density

AbstractGenome-wide linkage studies have shown several chromosome loci that may harbor genes that regulate bone mineral density (BMD), but results have been inconsistent. A meta-analysis was performed to assess evidence for linkage of BMD across whole genome scan studies. Eleven whole-genome scans of BMD or osteoporosis containing 3,097 families with 12,685 individuals were included in this genome scan meta-analysis (GSMA). For each study, 120 genomic bins of ∼30 cM were defined and ranked according to maximum evidence for linkage within each bin. Bin ranks were weighted and summed across all studies. The summed rank for each bin was assessed empirically for significance using permutation methods. A total of seven bins lie above the 95% confidence level (P=0.05) and one bin was above the 99% confidence level (P=0.01) in the GSMA of eleven linkage studies: bins 16.1 (16pter-16p12.3, Psumrnk <0.01), 3.3 (3p22.2-3p14.1), 1.1 (1pter-1p36.22), 18.2 (18p11.23-18q12.2), 6.3 (6p21.1-6q15), 20.1 (20pter-20p12.3), and 18.1 (18pter-18p11.23). GSMA was performed with seven studies with linkage scores of LOD >1-1.85 for sensitivity test, confirming the linkage on chromosome 16p and 3p and revealing evidence of new linkage in bins 10.2 (10p14-10q11.21) and 22.2 (22q12.3-22pter). In conclusion, the meta-analysis of whole-genome linkage studies of BMD has shown chromosome 16pter-16p12.3 to have the greatest evidence of linkage as well as revealing evidence of linkage in chromosomes 1p, 3p, 6, 10, 18, 20p, and 22q across studies. This data may provide a basis with which to carry out targeted linkage and candidate gene studies particularly in these regions.

Hepatitis B virus reactivation in HBsAg-positive patients with rheumatic diseases undergoing anti-tumor necrosis factor therapy or DMARDs.

The aim of this study was to assess the effects of anti‐tumor necrosis factor (TNF) agents or disease‐modifying antirheumatic drugs (DMARDs) on hepatitis B virus (HBV) reactivation in hepatitis B surface antigen (HBsAg)‐positive patients with rheumatic diseases.

Association of STAT4 polymorphism with rheumatoid arthritis and systemic lupus erythematosus: a meta-analysis

STAT4 is a transcription factor that has been implicated in the pathogenesis of rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Recently, several reports has documented that a STAT4 haplotype is associated with RA, SLE and Sjogren’s syndrome. To summarize and review these findings, we conducted a meta-analysis of all relevant reports published before September 2008. Studies on STAT4 rs7574865 single nucleotide polymorphism (SNP) of RA and SLE were identified using PubMed. Meta-analyses were performed for 15,609 patients with RA and 15,793 controls from 14 published studies and for 2,478 patients with SLE and 5,058 controls from 8 published studies. Meta-odds ratios (ORs) and 95% confidence intervals (CIs) based on random effects models were calculated for all available studies. The overall ORs for the minor T allele of STAT4 rs7574865 SNP were 1.27 (95% CI 1.20–1.34) in RA and 1.57 (95% CI 1.44–1.71) in SLE. Asian controls have significantly higher allele frequency (32%) for the minor T allele of STAT4 rs7574865 SNP than population of European origin (22%), however, there was no significant difference of ORs for RA and SLE by ethnicity. No apparent effect of anti-CCP positivity was found in stratified analysis. The risk of STAT4 genotype for SLE was significantly higher than for RA in populations of European origin and Asian. The results of our meta-analysis demonstrated that STAT4 rs7574865 SNP is significantly associated with RA and SLE. In addition to specific alleles of HLA-DRB1, the minor T allele of STAT4 rs7574865 SNP is a common RA risk factor in populations of European origin and Asian.

Scleroderma associated with ANCA-associated vasculitis

Scleroderma and ANCA-associated vasculitides (AAV), such as microscopic polyangiitis, are distinct disease entities, but are rarely known to coexist with each other. We have reported on two cases of scleroderma patients for the first time in Korea, and these patients were initially known to have only limited type scleroderma with pulmonary fibrosis, but eventually they were found to be ANCA-positive with the associated clinical features of vasculitis. Both were treated with high-dose steroids and cyclophosphamide and remitted without major sequelae. When scleroderma patients exhibit atypical features such as normotensive renal failure with signs of active inflammation, the possibility of AAV should always be considered.