Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0003873 (rheumatoid arthritis)
53,068 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Rheumatoid arthritis is an inflammatory disease for which positive associations have been described with some HLA-DRB1 alleles. The associated alleles share a similar amino acid sequence in the third hypervariable region, the shared epitope, but differ at position 71 and 86. It has been suggested that HLA susceptibility to rheumatoid arthritis could be due not only to the shared epitope but could also be influenced by specific amino acids at positions 71 and 86. In this study, we investigated the role of these amino acids in rheumatoid arthritis on 203 unrelated patients. An involvement of amino acid 71 was detected but no conclusion was possible regarding amino acid 86. A study of the sensitivity of the conclusions to marker allele frequencies was performed. We showed that the results obtained for amino acid 71 are not very sensitive to allele frequencies but those obtained at position 86 are highly sensitive. This emphasizes the importance of studying the robustness of results to variations in allele frequencies before conclusions are drawn.
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PMID:Modeling the HLA component in rheumatoid arthritis: sensitivity to DRB1 allele frequencies. 1110 50

We investigated correlations between soluble HLA-DR (sHLA-DR) molecules and several clinical, biological and genetic parameters associated with rheumatoid arthritis (RA) disease activity. Serum sHLA-DR concentrations were determined in 146 samples from 89 RA patients by an ELISA format, using an antibody combination of mouse and rat monoclonal anti-human HLA-DR antibodies. The mean sHLA-DR serum level in RA patients was significantly increased with 277+/-19 ng/ml compared to 142+/-13 ng/ml of 80 healthy controls (P<0.001). In ascending order of significance, correlations were found between serum sHLA-DR and EULAR swelling and pain scores, Waaler-Rose, RA factor, ESR and CRP (P=0.025 to P<0.001). High sHLA-DR levels were defined above 374 ng/ml that was the 95% confidence interval of the controls. Thirty-seven blood samples (25%) in 31 RA patients were above this level. The EULAR pain and swelling scores, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) and RA factor were higher (P=0.044 to P<0.001) at the moment of high sHLA-DR concentrations, compared to the lower concentrations. Higher disease activity was further found in groups of RA patients respectively heterozygous or homozygous for the disease-associated epitope (Q)R/KRAA within the HLA-DRB1 chain, compared to the group without this epitope (P<0.017 for part of the results). Likewise, sHLA-DR was respectively 169+/-17 (no disease associated epitope), 324+/-34 (heterozygous) and 442+/-69 ng/ml (homozygous for the disease-associated epitope on HLA-DRB1 alleles) (P<0.017). In conclusion, this study shows significant correlations between serum sHLA-DR levels and RA disease activity parameters, as well as increased sHLA-DR in patients with disease-associated epitope on HLA-DRB1 alleles.
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PMID:Soluble HLA-DR antigen levels in serum correlate with rheumatoid arthritis disease activity and the presence of disease-associated epitopes. 1114 91

To investigate the association of HLA-DRB1 alleles with polymyalgia rheumatica (PMR) and rheumatoid arthritis (RA), 55 patients with PMR without giant cell arteritis, 203 patients with RA and 230 controls, all from the European population of Marseille, were HLA-DRB1 genotyped by PCR-SSO. HLA-DRB1*01 was significantly increased in both the PMR and RA groups compared to controls (35% versus 17%, P(c) < 0.05, and 41% versus 17%, P(c) < 0.001, respectively). HLA-DRB1*04 was significantly increased in the RA group compared to controls (48% versus 23%, P(c) < 0.001) but not in the PMR group. HLA-DRB1*04 subtype frequencies were significantly different between PMR patients and RA patients. Shared epitope-positive HLA-DRB1*04 alleles (DRB1*0401, 0404, 0405, 0408) were significantly overrepresented in RA patients compared to PMR patients and shared epitope-negative HLA-DRB1*04 alleles were overrepresented in PMR patients compared to RA patients. In conclusion, in the Mediterranean population studied, HLA-DRB1*01 is associated with RA and PMR whereas HLA-DRB1*04 is associated with RA only.
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PMID:DRB1 alleles in polymyalgia rheumatica and rheumatoid arthritis in southern France. 1125 89

Experimental studies in transgenic mice have suggested that HLA-DQ predisposes to rheumatoid arthritis (RA), but could also modulate disease severity by presenting peptides derived from self-DR molecules. In particular, a short amino acid sequence, (70)DERAA(74), in the third hypervariable region of HLA-DRB1 confers protection for the disease, while particular HLA-DQ [DQB1*0501/DQA1*01 (DQ5) and DQB1*03/DQA1*03 (DQ3)] molecules predispose to the disease. We have therefore analyzed the allelic distribution of HLA-DRB1, DQA1, and DQB1 and the presence of rheumatoid factor and nodules among 199 German RA patients and 196 healthy controls. Our results show that HLA-DQB1*03/DQA1*03 (or DRB1*04) predisposes to RA more than HLA-DQB1*0501/DQA1*01 (i.e., DRB1*01 and DRB1*10). Homozygosity for DQ3 confers the strongest genetic risk for RA (OR = 19.79 compared to OR = 10.05 for two doses of shared epitope (SE) positive HLA-DRB1 alleles). Furthermore, patients carrying both predisposing DQ and (70)DERAA(74)-positive HLA-DRB1 alleles are more often rheumatoid factor (RF) negative than patients carrying predisposing DQ alleles alone. Only one out of 14 patients (7%) with a protective combination (DQ3/(70)DERAA(74) and DQ5/(70)DERAA(74)) had rheumatoid nodules compared to 67 out of 144 patients (46.5%) with predisposing DQ alleles alone (OR = 0.12, 95% CI: 0.02-0.72, p = 0.004). These results demonstrate a protective role of (70)DERAA(74)-positive DRB1 alleles against disease severity among RA patients.
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PMID:Protection against severe disease is conferred by DERAA-bearing HLA-DRB1 alleles among HLA-DQ3 and HLA-DQ5 positive rheumatoid arthritis patients. 1133 77

Inflammatory polyarthritis can be a self-limiting disease, develop into rheumatoid arthritis (RA) or differentiate into another form of chronic arthritis. It remains a clinical and scientific challenge to understand the relationship between these phenotypes, determine their aetiologies and predict the course and outcome for individual patients. Even patients labelled as having RA show a wide spectrum of clinical phenotypes. Disease definition is a major problem in studying the aetiology of RA as currently used classification criteria were derived using patients with established disease. RA is thought to result from the combination of genetic susceptibility and exposure to an appropriate environmental trigger. The genetic component is probably oligogenic. The association with HLA has been known for over 25 years. RA is now thought to be associated with a conserved sequence of amino acids in a number of HLA-DRB1 alleles, called the RA shared epitope. However, the shared epitope appears to be associated with RA chronicity and severity more than with susceptibility. Other potential RA susceptibility genes include IL-1, aromatase, corticotropin-releasing hormone and a region on the X chromosome. Hormonal and reproductive factors also influence RA susceptibility and severity. RA is more common in women than men, especially before the menopause. Men may be protected by hormonal factors and require a stronger genetic component to develop disease. Although infectious triggers of RA have long been suspected, no definitive evidence has been obtained. Previous blood transfusion, smoking and obesity are also possible risk factors. Chronicity and remission are important aspects of the natural history of early RA. Although we can identify patients at risk of adverse prognosis with some accuracy, we remain unable to predict remission. Functional disability and radiological damage are the most studied outcomes in RA. Radiological damage often occurs early in the course of RA, but patients may show erosion for the first time several years after symptom onset. Many studies have demonstrated a relationship between HLA and features of severe RA in established patients. This appears to be related to gene dosage.
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PMID:What is the natural history of rheumatoid arthritis? 1135 13

Susceptibility to rheumatoid arthritis (RA) is associated with defined HLA-DRB1 alleles. However the molecular basis of this association is not known. Peculiarities in the expression of disease-linked DRB1 alleles could be involved since in healthy controls HLA-DRB1 gene expression varies according to the alleles in B cells. Peripheral blood B cells of healthy controls and RA patients were examined for their level of allelic DRB1 transcripts using a competitive PCR approach. Levels of DRB1 transcripts were greatly modified in RA and influenced by HLA-DRB1 genotype: patients with double dose of RA-associated alleles displayed up-regulated amounts of DRB1 gene transcripts whereas patients carrying either a single or no at risk allele had low levels of DRB1 transcripts, compared to control individuals. These differential levels of DRB1 gene expression were not influenced in any way by clinical, biological or therapeutic features of the patients. Various amounts of DRB1 mRNA may be related to variations of the density of DR molecules on B cells and consequently could influence the response of CD4 T cells. This particular regulation of DRB1 gene expression in RA patients could therefore represent one of the molecular mechanisms involved in the association of HLA DRB1 genes to RA.
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PMID:HLA-DRB1 gene transcripts in rheumatoid arthritis. 1135 53

To investigate the role of HLA-DQA1 genotypes and their interaction with HLA-DRB1 in the pathogenesis of rheumatoid arthritis (RA) in Taiwan, HLA-DQA1 was determined in 71 patients with RA and 108 healthy controls by SSP-PCR method. HLA-DRB1 and HLA-DQA1 were simultaneously detected in 55 RA patients and 101 healthy controls. PCR/SSOP method was used to determine the HLA-DRB1 genotypes, and the subtypes of HLA-DR4 were determined by cloning and sequencing. The phenotypic frequency of HLA-DQA1*0301 was significantly lower in RA than in controls, and, in contrast, the HLA-DQA1*0302 and DQA1*0303 were significantly higher in RA than in controls. The associations of DQA1*0301, *0302, and *0303 with RA were independent of DR4 and DRB1*0405. Moreover, the interactions between HLA-DR4 and HLA-DQA1*0302 or DQA1*0303 could enhance the development of RA. We also found that the prevalence of bone erosion and seropositivity of rheumatoid factor (RF) were significantly higher in HLA-DQA1*0303 positive RA patients than in healthy controls. HLA-DQA1*0302 and DQA1*0303 are the risk factors for susceptibility to RA, while HLA-DQA1*0301 is a protective factor. A synergistic effect for the susceptibility to RA can be found between HLA-DR4 and HLA-DQA1*0302 or DQA1*0303. We also found that the HLA-DQA1*0303 was related to bone erosion and seropositivity of RF in RA patients.
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PMID:HLA-DQA1 genotyping in patients with rheumatoid arthritis in Taiwan. 1148 29

Rheumatoid arthritis results from a T cell-driven inflammation in the synovial membrane that is frequently associated with the formation of tertiary lymphoid structures. The significance of this extranodal lymphoid neogenesis is unknown. Microdissection was used to isolate CD4 T cells residing in synovial tissue T cell/B cell follicles. CD4 T cells with identical TCR sequences were represented in independent, nonadjacent follicles, suggesting recognition of the same Ag in different germinal centers. When adoptively transferred into rheumatoid arthritis synovium-SCID mouse chimeras, these CD4 T cell clones enhanced the production of IFN-gamma, IL-1beta, and TNF-alpha. In vivo activity of adoptively transferred CD4 T cells required matching of HLA-DRB1 alleles and also the presence of T cell/B cell follicles. HLA-DRB1-matched synovial tissues that were infiltrated by T cells, macrophages, and dendritic cells, but that lacked B cells, did not support the activation of adoptively transferred CD4 T cell clones, raising the possibility that B cells provided a critical function in T cell activation or harbored the relevant Ag. Dependence of T cell activation on B cells was confirmed in B cell depletion studies. Treatment of chimeric mice with anti-CD20 mAb inhibited the production of IFN-gamma and IL-1beta, indicating that APCs other than B cells could not substitute in maintaining T cell activation. The central role of B cells in synovial inflammation identifies them as excellent targets for immunosuppressive therapy.
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PMID:T cell activation in rheumatoid synovium is B cell dependent. 1159 2

Conflicting data have been published on the value of the shared epitope (SE) hypothesis in predicting disease outcome in rheumatoid arthritis (RA). Recently we have proposed an alternative hypothesis, referred to as the RA protection (RAP) model. In this model, the HLA-DQ loci carry predisposition while HLA-DRB1 alleles encoding the motif DERAA provide protection against severe RA. In the present study, we have compared the respective values of the models in predicting both remission and erosions in early RA patients. We made use of an early arthritis clinic in which 158 RA patients and 138 patients with undifferentiated arthritis were enrolled. Patients were typed for HLA-DQ and -DR using high resolution DNA typing methods. Homozygosity for predisposing HLA-DQ alleles was associated with no remission and high erosion score. The presence of DERAA-bearing DRB1 alleles was negatively associated with erosions in otherwise predisposed individuals and increased the chance of being in remission. We found that the RAP model was significantly better than the SE model in predicting remission rate and erosion scores at one and two years in early RA patients. We conclude that HLA polymorphism does not only affect RA susceptibility, but also protects against severe disease at early stage.
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PMID:Human leukocyte antigen-DQ and DR polymorphisms predict rheumatoid arthritis outcome better than DR alone. 1170 83

In most ethnic groups genetic susceptibility to rheumatoid arthritis (RA) is associated with certain HLA-DRB1 alleles encoding a similar sequence motif called the 'shared epitope' (SE) spanning amino acid positions 70 to 74 in the third diversity region of the outermost domain of the HLA-DRB1 molecule. We examined the association of the SE and RA in 83 Colombian women with established RA and 90 healthy controls. The group HLA-DRB1*04 was associated with RA with respect to controls (47% vs 18%, respectively. OR: 4.1, 95%CI: 2.1-8.2, P < 0.001). HLA-DRB1 alleles carrying the SE QRRAA, but not those carrying QKRAA or RRRAA, were associated with disease (OR: 3.7, 95%CI: 1.73-7.83, P = 0.0009). This association was stronger among HLA-DRB1*04 carriers (OR: 23, 95%CI: 1.3-414, P = 0.002). In our population, the SE QRRAA expressed in DRB1*04 alleles appears critical in identifying women with increased susceptibility to RA.
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PMID:Rheumatoid arthritis association in Colombian population is restricted to HLA-DRB1*04 QRRAA alleles. 1185 65


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