Rheumatoid Arthritis: Rho YH

Avalos I, Rho YH, Chung CP, Stein CM. · Department of Medicine, Division of Rheumatology, Beth Israel Deaconess Medical Center, Boston, MA, USA. · Clin Exp Rheumatol. · Pubmed #19026140 No free full text.

This publication has no abstract.

Lee YH, Rho YH, Choi SJ, Ji JD, Song GG, Nath SK, Harley JB. · Division of Rheumatology, Department of Internal Medicine, Korea University Medical Center, Seoul, Korea. · Rheumatology (Oxford). · Pubmed #16760194 links to  free full text

Abstract: OBJECTIVE: To assess whether combined evidence shows the association between the protein tyrosine phosphatase non-receptor 22 (PTPN22) C1858T polymorphism and autoimmune diseases, and to summarize the effect size of the polymorphism associated with susceptibility of autoimmune diseases. METHODS: We surveyed studies on the PTPN22 C1858T polymorphism and autoimmune diseases using comprehensive Medline search and review of the references. Meta-analysis was performed for genotypes T/T (recessive effect), T/T + C/T (dominant effect) and T-allele in random effects models. RESULTS: Twenty-nine studies with 43 comparisons including 13 rheumatoid arthritis (RA), six systemic lupus erythematosus (SLE), six type-1 DM (T1D), three Grave's disease (GD), four inflammatory bowel diseases (IBD), three juvenile idiopathic arthritis (JIA), two psoriasis, two multiple sclerosis, two Addison's disease and two Celiac disease were available for the meta-analysis. The overall odds ratios (ORS) for T-allele, T/T and T/T + C/T genotypes were significantly increased in RA, SLE, GD and T1D (OR for T-allele = 1.58, 1.49, 1.85, 1.61, respectively, P < 0.00001). This meta-analysis showed the association between the T-allele and the T/T genotype and JIA (OR = 1.34, P = 0.03; OR = 1.97, P = 0.02) but did not reveal the association between the PTPN22 C1858T polymorphism and IBD, psoriasis, multiple sclerosis, Addison's disease and Celiac disease. CONCLUSION: This meta-analysis demonstrates that the PTPN22 1858T allele confers susceptibility to RA, SLE, GD, T1D and JIA, supporting evidence of association of the PTPN22 gene with subgroup of autoimmune diseases.

Rho YH, Solus J, Sokka T, Oeser A, Chung CP, Gebretsadik T, Shintani A, Pincus T, Stein CM. · Vanderbilt University, Nashville, Tennessee. · Arthritis Rheum. · Pubmed #19565493 No free full text.

Abstract: OBJECTIVE: Obesity protects against radiographic joint damage in rheumatoid arthritis (RA) through poorly defined mechanisms. Adipocytokines are produced in adipose tissue and modulate inflammatory responses and radiographic joint damage in animal models. The purpose of this study was to examine the hypothesis that adipocytokines modulate inflammation and radiographic joint damage in patients with RA. METHODS: We compared serum concentrations of leptin, resistin, adiponectin, and visfatin in 167 RA patients and 91 control subjects. The independent association between adipocytokines and body mass index (BMI), measures of inflammation (C-reactive protein [CRP], interleukin-6 [IL-6], and tumor necrosis factor alpha [TNFalpha]), and radiographic joint damage (Larsen score; n = 93 patients) was examined in RA patients by multivariable regression analysis first controlling for age, race, and sex, and then for obesity (BMI) and inflammation (TNFalpha, IL-6, and CRP). RESULTS: Concentrations of all adipocytokines were significantly higher in RA patients than in controls; for visfatin and adiponectin, this association remained significant after adjusting for BMI, inflammation, or both. Visfatin concentrations were associated with higher Larsen scores, and this association remained significant after adjustment for age, race, sex, disease duration, BMI, and inflammation (odds ratio [OR] 2.38 [95% confidence interval (95% CI) 1.32-4.29], P = 0.004). Leptin concentrations showed a positive association with the BMI (rho = 0.58, P < 0.01) and showed a negative association with the Larsen score after adjustment for inflammation (OR 0.32 [95% CI 0.17-0.61], P < 0.001), but not after adjustment for BMI (OR 0.86 [95% CI 0.42-1.73], P = 0.67). CONCLUSION: Concentrations of adipocytokines are increased in patients with RA and may modulate radiographic joint damage. Visfatin is associated with increased, and leptin with reduced, levels of radiographic joint damage.

Lee YH, Woo JH, Rho YH, Choi SJ, Ji JD, Song GG. · Division of Rheumatology, Department of Internal Medicine, Korea University Medical Center, 126-1 Ka, Anam-Dong, Seongbuk-Ku, Seoul 136-705, South Korea. · Rheumatol Int. · Pubmed #17943257 No free full text.

Abstract: This present study was designed to examine (1) whether a combination therapy of TNF (tumor necrosis factor) blockers and methotrexate (MTX) is better than MTX monotherapy, and (2) if the TNF inhibitors such as etanercept, infliximab and adalimumab are all same for treating patients with active rheumatoid arthritis (RA). We performed meta-analysis of a combination therapy of TNF-blockers and MTX compared to MTX monotherapy and we performed adjusted indirect comparison of the TNF-blocking agents for their efficacy and toxicity. Three studies met the inclusion criteria for the analysis. Meta-analysis showed that the combination of MTX with anti-TNF inhibitors was more effective than MTX monotherapy and this indicated that combination therapy of anti-TNF inhibitors and MTX was comparable with MTX monotherapy in terms of withdrawal due to the side effects (RR: 1.05, 95% CI: 0.52-2.09, P = 0.86). The adjusted indirect comparison did not show any differences between infliximab and adalimumab. However, there was a significant difference for clinical efficacy and side effects between etanercept, adalimumab and infliximab. The RRs for achieving ACR20, ACR50 and ACR70 responses and withdrawal due to the side effect in the etanercept group were lower when compared with the adalimumab group. The RR for achieving an ACR20 response in the etanercept group was lower when compared with the infliximab group. The adjusted indirect comparison analysis suggests that the TNF-blocking agents all are not the same with respect to effectiveness and toxicity for the treatment of active RA.

Lee YH, Rho YH, Choi SJ, Ji JD, Song GG. · Division of Rheumatology, Department of Internal Medicine, Korea University Medical Center, 126-1 Ka, Anam-Dong, Seongbuk-Ku, Seoul, 136-705, Korea. · Rheumatol Int. · Pubmed #17265154 No free full text.

Abstract: We conducted a comprehensive meta-analysis with all available data on the association of allele and genotype of peptidylarginine deiminases 4 (PADI4) polymorphisms with RA overall and in each ethnic population to explore whether the PADI4 polymorphisms confer susceptibility to RA. Nine comparisons, three Asians and six Europeans, from eight studies were included in this meta-analysis. Overall meta-analysis shows a significant association of PADI4_94, 104 and 90 with RA (OR = 1.20, 1.17, 1.35, P = 0.001, <0.0001, 0.006, respectively). There was a significant association with all of the PADI4 polymorphisms with RA in people of Asian descent. However, there was no significant association of PADI4 polymorphisms with RA in people of European descent, except for PADI_94. The presence of 2/2 genotype of the PADI4 significantly increased the risk for RA in European populations (OR = 2.10, 95% CI, 1.66-2.66, P < 0.0001) without between-study heterogeneity (I (2) = 44.3, P = 0.15). In conclusion, this meta-analysis demonstrates that the PADI4 polymorphisms may represent a significant risk factor for RA in Asians and Europeans and may play a larger role in susceptibility to RA in Asian than in European populations. Further studies are needed to see if the PADI4 gene confers a risk of RA in other ethnic groups.

Lee YH, Rho YH, Choi SJ, Ji JD, Song GG. · Division of Rheumatology, Department of Internal Medicine, Korea University Medical Center, 126-1 Ka, Anam-Dong, Seongbuk-Ku, Seoul 136-705, South Korea. · Rheumatol Int. · Pubmed #16909270 No free full text.

Abstract: Tumor necrosis factor (TNF) antagonists are among the most effective therapies for rheumatoid arthritis (RA), yet not all patients show a response. Using meta-analysis, this present study was designed to investigate whether or not the TNF-alpha promoter -308 A/G polymorphism is associated with responsiveness to anti-TNF therapy in RA patients. We performed an exhaustive search for studies that examined the association of the TNF-alpha promoter -308 A/G polymorphism and responsiveness of anti-TNF therapy in RA using MEDLINE citations and manual review. Meta-analysis was performed for A allele carrier (genotypes A/A + A/G) between responders to anti-TNF therapy and a non-responder group in a random effects model. A total of 6 studies met the inclusion criteria. The number of patients in individual studies ranged from 33 to 123. There were 311 RA patients who were included in this meta-analysis. There was no heterogeneity between studies (I (2) = 0%, P = 0.42). The overall OR for the A allele carrier status was significantly decreased in the responder group (OR = 0.33, 95% confidence interval = 0.17-0.63, P = 0.0008). The frequency of the A allele carrier was 53/240 (22.1%) in responders and 32/71 (45.1%) in non-responders. Patients not responding to anti-TNF therapy showed an increased frequency of the A allele. The meta-analysis of the available data shows a significant association between the TNF-alpha promoter -308 A/G polymorphism and responsiveness to anti-TNF therapy, suggesting that the individuals with RA who carry the A allele have a poorer response to anti-TNF therapy than those with the G allele.

Cheon H, Rho YH, Choi SJ, Lee YH, Song GG, Sohn J, Won NH, Ji JD. · Department of Pathology, College of Medicine, Korea University, 126-1, Anam-Dong 5-Ga, Sungbuk-Gu, Seoul 136-705, Korea. · J Immunol. · Pubmed #16818766 links to  free full text

Abstract: In inflamed joints of rheumatoid arthritis, PGE(2) is highly expressed, and IL-10 and IL-6 are also abundant. PGE(2) 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 PGE(2) 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 PGE(2) 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, PGE(2) suppressed IL-6-induced phosphorylation of STAT3 and STAT1. These PGE(2)-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 PGE(2)-mediated augmentation of IL-10-induced STAT3 phosphorylation. In this study, we found that PGE(2) 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. PGE(2) may modulate immune responses by alteration of cytokine signaling in THP-1 cells.

Choi SJ, Rho YH, Ji JD, Song GG, Lee YH. · Division of Rheumatology, Department of Internal Medicine, Korea University Medical Center, 126-1 Ka, Anam-Dong, Seongbuk-Ku, Seoul 136-705, Korea. · Rheumatology (Oxford). · Pubmed #16278286 links to  free full text

Abstract: OBJECTIVE: Genome scans for rheumatoid arthritis (RA) have yielded inconsistent results. The absence of replication of linkage might be due to lack of power of individual studies. We performed a genome scan meta-analysis of published data to increase statistical power and to assess evidence for linkage of RA across genome scan studies. METHODS: Four RA whole-genome scans containing 767 families with 964 sibling pairs were included for the genome scan meta-analysis (GSMA). The GSMA method was applied to pool the results obtained from four genome scans. For each study, 120 genomic bins of approximately 30 centimorgans 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. RESULTS: A total of nine bins lay above the 95% confidence level (P=0.05) and four bins were above the 99% confidence level (P=0.01) in the RA GSMA, suggesting that these bins contain RA-linked loci: bins 6.2, 6.4, 8.1, 18.3, 12.3, 12.2, 1.5, 6.3 and 16.2. The strongest evidence for linkage occurred on chromosome 6p22.3-6p21.1 (bin 6.2), containing the HLA region (P(sumrnk)=0.0000008). CONCLUSION: This RA GSMA confirmed the evidence for HLA loci as the greatest susceptibility factor to RA and showed evidence for linkage at non-HLA loci, such as chromosomes 1p, 6, 8p, 12, 16 and 18q, across studies. These data may provide a basis to carry out targeted linkage and candidate gene studies, particularly in the regions.

Kim HJ, Rho YH, Choi SJ, Lee YH, Cheon H, Um JW, Sohn J, Song GG, Ji JD. · Department of Microbiology and Immunology, College of Medicine, Korea University, Seoul 136-705, Republic of Korea. · Exp Mol Med. · Pubmed #16000871 links to  free full text

Abstract: 15-deoxy-delta(12,14)-PGJ(2)(15d-PGJ(2)) is a natural ligand that activates the peroxisome proliferators-activated receptor (PPAR) gamma, a member of nuclear receptor family implicated in regulation of lipid metabolism and adipocyte differentiation. Recent studies have shown that 15d-PGJ(2) is the potent anti-inflammatory agent functioning via PPARgamma-dependent and -independent mechanisms. Most postulated mechanisms for anti-inflammatory action of PPARgamma agonists are involved in inhibiting NF-kappaB signaling pathway. We examined the possibility that IL-6 signaling via the Jak-Stat pathway is modulated by 15d-PGJ(2) in lymphocytes and also examined whether the inhibition of IL-6 signaling is dependent of PPARgamma. 15d-PGJ(2) blocked IL-6 induced Stat1 and Stat3 activation in primary human lymphocytes, Jurkat cells and immortalized rheumatoid arthritis B cells. Inhibition of IL-6 signaling was induced rapidly within 15 min after treatment of 15d-PGJ(2). Other PPARgamma-agonists, such as troglitazone and ciglitazone, did not inhibit IL-6 signaling, indicating that 15d-PGJ(2) affect the IL-6-induced Jak-Stat signaling pathway via PPARgamma-independent mechanism. Although cycloheximide reversed 15d-PGJ(2)-mediated inhibition of Stat3 activation, actinomycin D had no effect on 15d-PGJ(2)-mediated inhibition of IL-6 signaling, indicating that inhibition of IL-6 signaling occur independent of de novo gene expression. These results show that 15d-PGJ(2) specifically inhibit Jak-Stat signaling pathway in lymphocytes, and suggest that 15d-PGJ(2) may regulate inflammatory reactions through the modulation of different signaling pathway other than NF-kappaB in lymphocytes.

Lee YH, Kim HJ, Rho YH, Choi SJ, Ji JD, Song GG. · Division of Rheumatology, Department of Internal Medicine, Anam Hospital, Korea University College of Medicine, 126-1 Ka, Anam-Dong, Seongbuk-Ku, Seoul 136-705, Korea. · Rheumatol Int. · Pubmed #14872281 No free full text.

Abstract: The aim of this study was to evaluate the association of polymorphism in IL-1 receptor antagonist (IL-1RA) gene intron 2 with susceptibility to rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) and their clinical features. Polymerase chain reaction of a genomic DNA was used to determine genotypes of the IL-1RA in 138 RA, 93 SLE, and 127 healthy control subjects. The frequency of IL-1RA allele 2 (IL-1RN*2) was lower in RA patients (2.5%) than in control subjects (7.1%) (odds ratio 0.34, 95% confidence interval 0.13-0.88, P=0.02). There was a significant difference in genotype and allele distribution between RA patients and controls. However, it did not differ between SLE patients and controls. In SLE and RA patients, there was no significant difference in clinical and laboratory findings concerning IL-1RA polymorphisms. In conclusion, our data suggest that IL-1RA gene polymorphism is not responsible for specific clinical characteristics in RA and SLE but that IL-1RN*2 is relevant in the susceptibility to RA, suggesting a protective role of IL-1RN*2 in the pathogenesis of RA.

Lee YH, Kim HJ, Rho YH, Choi SJ, Ji JD, Song GG. · Division of Rheumatology, Department of Internal Medicine, College of Medicine, Korea University, Seoul, Korea. · Scand J Rheumatol. · Pubmed #14626631 No free full text.

Abstract: The aim of this study is to investigate whether the functional polymorphisms in the promoter of matrix metalloproteinase-1 (MMP-1) and in the regulatory region of the monocyte chemoattractant protein-1 (MCP-1) gene are associated with susceptibility to rheumatoid arthritis (RA) and its clinical features. The MMP-1 1G/2G polymorphism and the MCP-1 promoter A/G polymorphism were determined by polymerase chain reaction-restriction fragment length polymorphism in 117 RA patients and 97 healthy controls. The genotype distribution of the MMP-1 promoter did not differ between RA patients and control subjects. However, in the 2G/2G genotype, ESR and Plat were higher than the 1G/1G genotype. The genotype distribution of the MCP-1 promoter did not differ between the RA and control groups. Clinically there was no significant difference among RA patients according to the MCP-1 promoter genotypes. Our data show that the functional promoter polymorphism in the MMP-1 promoter may not play an important role in the susceptibility of RA, but the polymorphism may be related to clinical phenotypes.