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ID PMID Title PublicationDate abstract
15909082 [Cardiovascular manifestations in rheumatoid arthritis]. 2005 May Rheumatoid arthritis (RA) is a chronic inflammatory disease, characterized by a polyarticular joint inflammation which eventually leads to joint destruction and general disability. Besides these polyarticular manifestations, several systemic immune phenomena have been described. An increased mortality in RA patients is evident and is mainly caused by an increased cardiovascular risk. The correlation between disease activity and mortality highlighted the important role of the systemic inflammatory reaction in induction and progression of vascular damaging processes. Endothelial dysfunction and vascular inflammation are important, mechanisms in atherosclerosis and induced by conventional risk factors and systemic inflammation. It has been shown that the deleterious influence of conventional risk factors is aggravated by inflammatory mediators, mainly by pro-inflammatory cytokines. In addition, certain inflammatory mediators exert damaging effects to blood vessels. Especially CRP, merely considered as a risk indicating parameter in the past, has attracted remarkable attention. Also certain RA specific immune phenomena are of considerable proatherosclerotic potential. At least in part, they could be responsible for the excess mortality in RA patients. The newer TNFalpha blocking agents interfere with different mechanisms responsible for induction and perpetuation of atherosclerotic processes. Time will show whether they make a remarkable impact on the cardiovascular mortality in RA patients.
15660457 Rheumatoid arthritis initial therapy: unanswered questions. 2005 Jan Recent changes in the treatment of patients with rheumatoid arthritis (RA) are high lighted in this article,with emphasis on initial therapy in RA. Critical new concepts and developments are discussed: the importance of early treatment, increased use of combination disease modifying antirheumatic therapy as initial treatment and after failure of monotherapy, the role of the newer biological therapies, and the influence of comorbidity on morbidity and mortality.
16474855 Pharmacogenetics of therapies in rheumatoid arthritis. 2005 Dec Rheumatoid arthritis (RA) is an inflammatory, aggressive arthritis causing irreversible joint destruction and damage when left untreated. Disease-modifying antirheumatic drugs (DMARDs) are the mainstay of treatment for RA and ameliorate not only the clinical signs and symptoms but also joint damage associated with the disease. In recent years, biological therapies have been introduced for the treatment of RA, and the effectiveness of these agents in slowing the clinical and radiographic progression in RA has been established beyond question. However, there is significant variability in the response of patients with RA to these therapies. Moreover, the biological therapies are expensive, totaling several thousand dollars in yearly patient costs. Pharmacogenomics, the study of genetic variations in drug-metabolizing enzymes and their translation to differential responses to drugs, is a nascent but rapidly evolving field. The application of pharmacogenomics to therapies used in RA, particularly the new expensive biological agents, holds great promise for tailoring therapy with these agents based on a patient's genetics. Published literature on the pharmacogenetics of commonly used DMARDs and the emerging body of literature on the pharmacogenetics of the new biological therapies in RA are the focus of this review. As evident from the contents of this review, pharmacogenomics is an exciting field which is progressing productively and rapidly. Pharmacogenomic approaches offer powerful tools to optimize drug therapy in individual patients.
16200584 Association between PADI4 and rheumatoid arthritis: a replication study. 2005 Oct OBJECTIVE: The peptidylarginine deiminase type 4 gene (PADI4) was recently reported to be associated with rheumatoid arthritis (RA) in a Japanese population. The presence of a single-nucleotide polymorphism (SNP) located in intron 3 of PADI4 provided the strongest evidence of this association. Moreover, functional haplotypes that affect stability of transcripts were identified. However, subsequent research failed to confirm the observed association in a UK population. The present study was undertaken to further investigate the association of PADI4 with RA, using a series of population-based samples from subjects with the same ethnic background as the subjects in the original study. METHODS: DNA samples were obtained from 1,230 Japanese RA patients and 948 ethnically matched controls. Genotyping was performed using 5' allele discrimination assays. All samples were genotyped for 3 SNPs on PADI4 (padi4_94, padi4_104, and padi4_102), which comprised the reported haplotypes. Chi-square testing was performed for a case-control study and the PENHAPLO program was used for haplotype estimation. RESULTS: All tested SNPs were found to show significant differences in frequency between cases and controls (P = 0.010-0.0008), which confirmed the association observed in the original study. Odds ratios calculated for allele frequencies were 1.23, 1.21, and 1.36 in padi4_94, padi4_104, and padi4_102 respectively. CONCLUSION: Replication of association in individual samples strongly suggests that PADI4 is a true susceptibility gene for RA.
17094333 Leflunomide in clinical practice. 2006 Jul Leflunomide (LEF) is a prodrug that is rapidly converted to its active metabolite A77 1726, that inhibits the novo pyrimidine nucleotide biosynthesis, mediated especially by the dihydroorotate dehidrogenase (DHODH). DMARD properties were documented in rheumatoid arthritis with efficacy, safety and limiting of radiological progression demonstrated in multiple studies. LEF has been also used in other autoimmune diseases, like Psoriatic Arthritis, Wegener granulomatosis, Systemic Lupus Erythematosus, Sarcoidosis and others. This article reviews the place of LEF in clinical practice and outlines its potential applications beyond the officially recognized indication: rheumatoid arthritis (RA).
17074105 [A retrospective clinical study of Rhupus syndrome]. 2006 Jul OBJECTIVE: To analyse the clinical features and pathogenesis of overlapping features of rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), termed 'Rhupus syndrome'. METHODS: Twenty-four patients with Rhupus syndrome were identified over the last two decades. The clinical features of these patients were described and the literatures about this disease were reviewed. RESULTS: Twenty-four patients (twenty-three women, one man) were enrolled with an average age of 45.5 years. The mean age at presentation was 36.8 years. Nineteen of the patients initially present with erosive RA and developed SLE over about 7.7 years. In 14 patients who had convincing personal histories, 4 had pregnancies, 2 had dysmenorrhea and one had ovary cyst before poly arthritis developed. Ten of these patients were associated with menopause during transitions from RA to SLE. Expression frequencies of RA associated antibodies were similar as other RA patients. SLE associated manifestations were moderate in Rhupus syndrome especially severe renal damage. Hematopoietic system manifestations were prominent in this population. CONCLUSIONS: Most of the Rhupus syndrome patients firstly presented with RA and showed less SLE associated severe damages. Sex hormone factor might be associated with the incidence of the disease.
16495318 The reliability, validity and sensitivity to change of the Chinese version of SF-36 in ori 2006 Aug OBJECTIVE: To assess the reliability, validity and sensitivity to change of a Chinese version of the 36-item Short-Form Health Survey (SF-36) in Chinese-speaking patients with rheumatoid arthritis (RA) in Singapore. METHODS: The psychometric properties of the Chinese Hong Kong standard version of the SF-36 were assessed in 401 RA patients. The construct validity of the Chinese SF-36 was assessed by comparison with the American College of Rheumatology (ACR) functional status, a validated Chinese Health Assessment Questionnaire (C-HAQ) and markers of RA activity and severity. RESULTS: The overall Cronbach's coefficient alpha was 0.921, reflecting excellent internal consistency. The instrument showed reasonable test-retest reliability except in the social functioning (SF) subscale. There was a significant ceiling effect in the role physical (RP), SF and role emotional (RE) subscales and a floor effect in the RP and RE subscales. Physical function (PF) and SF were strongly correlated with C-HAQ and patient's assessment of RA activity [Pearson's correlation coefficient (r) ranging from -0.41 to -0.53] and moderately correlated with ACR functional status (r = -0.35 and -0.3, respectively). Weak correlations were also found between the Chinese SF-36 and markers of RA activity, deformed joint count and radiographic damage. PF and SF were the subscales most responsive to change in quality of life (QOL). CONCLUSION: The Chinese SF-36 showed reasonable reliability, criterion validity and responsiveness with limitations in certain subscales. Overall, the physical domains and PF in particular may be the most ideal psychometric measures of QOL in RA.
16786384 [Inflammatory spine disease as a cause of back pain]. 2006 Jun PURPOSE: The aim of this review is to evaluate the role of inflammatory spine disease in patients with chronic back pain. The contribution of imaging modalities for the diagnostic evaluation of back pain is discussed. MATERIAL AND METHODS: A systematic literature search based on the classification of seronegative spondyloarthropathies and rheumatoid arthritis was performed. The results of this search and the experiences in a large collective of rheumatological patients are analyzed. RESULTS: The prevalence of rheumatoid arthritis (1-2%) is comparable to that of spondyloarthropathies (1.9%). The etiology of these entities is not fully elucidated. Magnetic resonance imaging is increasingly used for early detection and surveillance of therapy with TNF-alpha antagonists. DISCUSSION: Bone marrow edema, which is only detectable with MRI, represents an early sign of inflammation. Therapy with TNF-alpha antagonists is based on clinical and laboratory criteria, and signs of inflammation in MRI. MRI is useful for assessment of the effectiveness of anti-inflammatory therapy.
16859535 Independent associations of anti-cyclic citrullinated peptide antibodies and rheumatoid fa 2006 Several recent publications have established a strong association between anti-cyclic citrullinated peptide antibody (anti-CCP)-positive rheumatoid arthritis (RA) and carriage of shared epitope (SE) alleles. Although anti-CCP have also been associated with more severe RA, the issue of whether this is independent of rheumatoid factor (RF) has not been addressed. To identify associations between RF, anti-CCP, SE status and radiological damage, we studied a large cross-sectional cohort with longstanding RA. Individuals (n = 872) enrolled in the study all fulfilled the American College of Rheumatology criteria for RA, had a minimum disease duration of 3 years, and at least one definite radiographic erosion was present in hands or feet. Radiographs were scored blind at study entry by a single musculoskeletal radiologist using a modified Larsen's score. Anti-CCP and RF levels were determined using enzyme-linked immunosorbent assay, and DRB1 typing was performed using polymerase chain reaction based methodology. Both anti-CCP and RF levels were strongly associated with radiographic severity (P < 0.0001). In subgroups stratified for both anti-CCP and RF status, evidence of independent associations of both antibodies with radiographic outcome was found (P < 0.0001). An association of SE alleles with radiographic severity was present only in RF-negative individuals. Anti-CCP positivity was associated with SE status with evidence of a gene-dose effect, most markedly in RF-negative individuals (P < 0.01). Anti-CCP and RF status are independent severity factors for RA, with SE alleles playing at most a secondary role. Our data support the view that previously described associations between SE and radiological severity, especially in RF-negative patients, may be indirect and due to an association with anti-CCP.
16320335 The disease activity score is not suitable as the sole criterion for initiation and evalua 2005 Dec OBJECTIVE: The Disease Activity Score (DAS) is widely used in clinical trials. A DAS of 5.1 defines the level of severe rheumatoid arthritis (RA) and is the criterion for the initiation of anti-tumor necrosis factor therapy in the UK and The Netherlands. In North America, similar rules are sometimes imposed. However, it is not known how accurately the DAS characterizes RA activity. The present study was undertaken to determine the concordance between DAS scores and physicians' assessments of RA activity, to investigate factors relating to discrepancies, and to assess the suitability of using the DAS in individual patients. METHODS: Six hundred sixty-nine RA patients were assessed using the DAS and other clinical measures. A physician's global estimate of RA activity was performed using an 11-point predefined scale and a standard definition of disease activity. RESULTS: The DAS and physician global assessment had substantially different distributions of values. The level of agreement (Kendall's tau-a) between DAS scores and physician global assessments was 49% (95% confidence interval 45-53%), Lin's coefficient of concordance was 0.62, and the Bland-Altman 95% limits of agreement were -3.17 and 3.99. These results suggest poor-to-moderate concordance between the 2 measures of disease activity. CONCLUSION: The DAS and the physician's assessment of RA activity do not approach, value, and weight RA variables to the same extent, suggesting that RA activity is not evaluated similarly by North American physicians and with the DAS. The scales do not have acceptable levels of concordance. There is too much inherent variability in the DAS and other RA scales (e.g., the Health Assessment Questionnaire) to recommend them as sole determinants of RA activity for clinical or regulatory purposes.
16968121 A new arthritis therapy with oxidative burst inducers. 2006 Sep BACKGROUND: Despite recent successes with biological agents as therapy for autoimmune inflammatory diseases such as rheumatoid arthritis (RA), many patients fail to respond adequately to these treatments, making a continued search for new therapies extremely important. Recently, the prevailing hypothesis that reactive oxygen species (ROS) promote inflammation was challenged when polymorphisms in Ncf1, that decrease oxidative burst, were shown to increase disease severity in mouse and rat arthritis models. Based on these findings we developed a new therapy for arthritis using oxidative burst-inducing substances. METHODS AND FINDINGS: Treatment of rats with phytol (3,7,11,15-tetramethyl-2-hexadecene-1-ol) increased oxidative burst in vivo and thereby corrected the effect of the genetic polymorphism in arthritis-prone Ncf1(DA) rats. Importantly, phytol treatment also decreased the autoimmune response and ameliorated both the acute and chronic phases of arthritis. When compared to standard therapies for RA, anti-tumour necrosis factor-alpha and methotrexate, phytol showed equally good or better therapeutic properties. Finally, phytol mediated its effect within hours of administration and involved modulation of T cell activation, as injection prevented adoptive transfer of disease with arthritogenic T cells. CONCLUSIONS: Treatment of arthritis with ROS-promoting substances such as phytol targets a newly discovered pathway leading to autoimmune inflammatory disease and introduces a novel class of therapeutics for treatment of RA and possibly other chronic inflammatory diseases.
16447236 A new classification of HLA-DRB1 alleles differentiates predisposing and protective allele 2006 Feb OBJECTIVE: A new classification of HLA-DRB1 alleles supporting the shared epitope hypothesis of rheumatoid arthritis (RA) susceptibility was recently introduced. We investigated the relevance of this classification in terms of the structural severity of RA. METHODS: The study group comprised 144 patients who were included in a prospective longitudinal cohort of French Caucasoid patients with early RA. Progression of the total radiographic damage score (Sharp/van der Heijde method) was used to quantify the structural severity of RA after 4 years of followup. HLA-DRB1 typing and subtyping were performed by polymerase chain reaction, using a panel of sequence-specific oligonucleotide probes. HLA-DRB1 alleles were classified according to the above-mentioned new system. The association between the HLA-DRB1 allele groups (S1, S2, S3P, S3D, and X) and the structural severity of RA was analyzed with nonparametric statistical tests. RESULTS: The presence of S2 alleles (HLA-DRB1*0401 and HLA-DRB1*1303) was associated with severe forms of RA (P = 0.004); a significant dose effect was observed (P = 0.01). The presence of S3D alleles (HLA-DRB1*11001, HLA-DRB1*1104, HLA-DRB1*12, and HLA-DRB1*16) was associated with benign forms of RA (P < 0.0001), and a significant dose effect was observed (P < 0.01). CONCLUSION: The studied classification of HLA-DRB1 alleles is relevant in terms of RA outcomes. Compared with a previously described classification system, this system differentiates predisposing (S2) and protective (S3D) alleles for RA structural severity, which, respectively, correspond to KRRAA and DRRAA amino acid patterns at position 70-74 of the third hypervariable region of the HLA-DRbeta chain.
16146609 [Observation on effect of double filtration plasmapheresis on patients with active rheumat 2005 Sep OBJECTIVE: To investigate the effect of filtration plasmapheresis (DFPP) on blood contents of rheumatoid factor (RF), C reactive protein (CRP), and erythrocyte sedimentation rate (ESR) in patients with rheumatoid arthritis (RA) in active stage, and to appraise the therapeutic effect of DFPP on RA. METHODS: The changes in contents of blood RF, CRP, ESR before and after DFPP were compared. The treatment was given for 2-3 times, and the activity of RA and the appearance of filtrate plasma were compared before and after the treatment. RESULTS: There were dramatic reductions of the levels of RF, CRP, ESR after single DFPP by 22.55%, 57.08% and 50.48%, respectively, compared with those before the treatment (all P<0.001). The color of the filtrate was green in RA in active stage. The cases with dark green filtrate had higher active indexes (pain, tenderness, swelling) and blood contents of CRP and ESR than those with green or yellow-green ones (all P<0.001). CONCLUSION: DFPP can remarkably reduce the level of RF, CRP, ESR of blood. The filtrate of RA in active stage appeared green. There is a relationship between the activity of RA and the color of filtrates.
16870093 Glutathione S-transferase gene polymorphisms in Japanese patients with rheumatoid arthriti 2006 May OBJECTIVE: To investigate the role of polymorphisms of the glutathione S-transferase M1 (GSTM1), GSTT1, and GSTP1 genes in determining susceptibility to rheumatoid arthritis (RA) and association with the clinical features. METHODS: Polymorphisms of the GSTM1, GSTT1, and GSTP1 genes in 108 Japanese patients with RA and in 143 healthy controls were analyzed by polymerase chain reaction (PCR) or PCR-restriction fragment length polymorphism. RESULTS: The frequency of the GSTM1 null genotype was significantly higher among RA patients than among control subjects (60.2% and 44.1%, respectively. P = 0.011). Moreover, the female patients with GSTM1 homozygous null genotype showed significantly higher serum MMP-3 level than the female patients with non-null genotype (P = 0.030). Frequencies of the GSTT1 and GSTP1 gene polymorphism were not different between RA patients and controls. CONCLUSION: The GSTM1 homozygous null genotype could be a genetic factor that determines susceptibility to RA and may have influence on the disease process.
16226480 Human leukocyte antigen DRB1*04 is associated with rheumatoid arthritis in Kuwaiti patient 2006 Jan OBJECTIVES: Rheumatoid arthritis (RA) is a common, complex autoimmune disease known to be associated with inheritance of certain human leukocyte antigen (HLA)-DR alleles in different populations. This study investigated the association of DRB1 alleles in Kuwaiti patients with RA. MATERIALS AND METHODS: DRB1 alleles were analyzed in 47 Kuwaiti patients and 70 ethnically matched controls using a DNA-based sequence specific primer (SSP) method. RESULTS: The frequency of DRB1*04 allele was higher in patients compared to the controls (P < 0.012). The association with of HLA-DRB1*04 allele in our patients with RA was accounted for mainly by the seropositive group of patients (P < 0.05). Moreover, five patients were homozygous for DRB1*4 compared to none in the controls. None of the other DRB1 alleles tested was significantly higher in the patients. All patients homozygous for the DRB1*04 allele were females. There was no statistically significant difference in the frequency of DRB1*04 allele in patients classified according to presence of erosive disease or extra-articular manifestations. CONCLUSION: Our results indicate that in Kuwaiti patients, RA is associated with the presence of DRB1*04 allele. The lack of association with severity or the phenotype of RA is not surprising since this is a hospital-based study where patients tend to have a more severe disease.
15736039 Expression pattern of cell cycle-related gene products in synovial stroma and synovial lin 2005 Apr OBJECTIVE: To investigate the expression pattern of cell cycle related gene products in active and quiescent Rheumatoid arthritis (RA). METHODS: Synovial tissue from 20 patients with active proliferative RA and 28 patients with RA in remission was immunohistochemically examined for expression of p53, p63, p21, p27, p16, cyclin D1, CDK4, RB, E2F, Ki-67 on tissue microarrays and by DNA flow cytometry for cell cycle phases. RESULTS: Elevated expression of p53 and p27 was found in synovial lining and in stromal cells in proliferative active RA. In the remission stage this finding was confined to the synovial lining. Most of the cells were in the G0-phase. Ki-67 proliferation index was maximum 10% in synovial cells. CONCLUSION: The p53 pathway is activated in synovial cells in active RA as well as in quiescent stage of disease. Differences in the spatial expression pattern of proteins involved in the p53 pathway in RA in remission compared to actively proliferating RA reflect the phasic nature of the disease and support in our opinion the concept of adaptive role of p53 pathway in RA.
15777203 Signal transduction by IL-2 and its receptors as target in treatment of rheumatoid arthrit 2005 Mar Rheumatoid arthritis (RA) is a chronic and destructive arthropathy with systemic features, the etiopathogenesis of which remains unclear. It is characterized by relapsing and remitting inflammation and hyperplasia of synovial cells. Proinflammatory cytokines, such as interleukin-2 (IL-2), play an important role in maintaining cartilage damage and severe destruction of the joints due to an uncontrolled activation of cellular immunity. An imbalance between proinflammatory and anti-inflammatory mediators is likely to contribute to the chronicity of the disease. Therefore, insight into the activation state of T-cells in different stages of the disease may be important to understand pathogenetic mechanisms underlying RA and could be a lead for the design of future therapeutic strategies. Because of the central role of the IL-2/IL-2 receptor (IL-2R) system in mediation of the immune system, monitoring and manipulation of this system has important diagnostic and therapeutic implications. New approaches in RA therapy with anticytokine agents, which block cytokines and their receptors, are now used as antirheumatic drugs in clinical practice.
15852253 What are the links between Epstein-Barr virus, lymphoma, and tumor necrosis factor antagon 2005 Apr EPSTEIN-BARR VIRUS (EBV) AND RHEUMATOID ARTHRITIS (RA): Patients with (RA) have slightly impaired EBV specific immunity. EBV AND LYMPHOMA: EBV contributes to the development of lymphoma, especially in immunosuppressed patients. LYMPHOMA IN RA: The incidence of lymphoma is increased (2-fold) in patients with active RA. TUMOR NECROSIS FACTOR (TNF) ANTAGONISM, LYMPHOMA, AND RA: The risk to develop lymphoma in patients with RA under TNF inhibitors is slightly higher than that of patients with active RA who do not receive TNF inhibitors. As already demonstrated in the case of posttransplantation lymphoma, EBV load monitoring in patients with RA under TNF inhibitors might allow predicting and preventing the emergence of lymphoma.
16646982 Validation of the reshaped shared epitope HLA-DRB1 classification in rheumatoid arthritis. 2006 Recently, we proposed a classification of HLA-DRB1 alleles that reshapes the shared epitope hypothesis in rheumatoid arthritis (RA); according to this model, RA is associated with the RAA shared epitope sequence (72-74 positions) and the association is modulated by the amino acids at positions 70 and 71, resulting in six genotypes with different RA risks. This was the first model to take into account the association between the HLA-DRB1 gene and RA, and linkage data for that gene. In the present study we tested this classification for validity in an independent sample. A new sample of the same size and population (100 RA French Caucasian families) was genotyped for the HLA-DRB1 gene. The alleles were grouped as proposed in the new classification: S1 alleles for the sequences A-RAA or E-RAA; S2 for Q or D-K-RAA; S3D for D-R-RAA; S3P for Q or R-R-RAA; and X alleles for no RAA sequence. Transmission of the alleles was investigated. Genotype odds ratio (OR) calculations were performed through conditional logistic regression, and we tested the homogeneity of these ORs with those of the 100 first trio families (one case and both parents) previously reported. As previously observed, the S2 and S3P alleles were significantly over-transmitted and the S1, S3D and X alleles were under-transmitted. The latter were grouped as L alleles, resulting in the same three-allele classification. The risk hierarchy of the six derived genotypes was the same: (by decreasing OR and with L/L being the reference genotype) S2/S3P, S2/S2, S3P/S3P, S2/L and S3P/L. The homogeneity test between the ORs of the initial and the replication samples revealed no significant differences. The new classification was therefore considered validated, and both samples were pooled to provide improved estimates of RA risk genotypes from the highest (S2/S3P [OR 22.2, 95% confidence interval 9.9-49.7]) to the lowest (S3P/L [OR 4.4, 95% confidence interval 2.3-8.4]).
16932734 Mechanisms of disease: Genetic susceptibility and environmental triggers in the developmen 2006 Aug Rheumatoid arthritis (RA) is a complex disease in which environmental agents are thought to interact with genetic factors that influence susceptibility. This interaction triggers immunologic events that eventually result in the clinical signs of arthritis. Knowledge of the chain of etiological events that lead to the development of RA is incomplete. In this review, we describe the experimental approaches that are used to address the issue of gene-environment interactions in the etiology of RA, and discuss relevant examples of such interactions. We focus on how smoking, the best-known environmental risk factor for RA, interacts with HLA-DR shared epitope genes, the main genetic risk factors for RA, and result in a high risk of RA in individuals exposed to both of these risk factors. From these and other related findings, we can begin to define the distinct environmental risk factors (such as smoking) that in certain genetic contexts (for example, the presence of HLA-DR shared epitope alleles) can trigger immune reactions (such as autoantibodies to citrullinated peptides) many years before onset of RA, and consider how these immune reactions might contribute to clinical symptoms in a subset of affected patients. Increased knowledge about these and other events involved in the development of RA should enable the design of new tools for suppressing RA pathogenesis before the onset of disease.