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ID PMID Title PublicationDate abstract
20180721 Survival of primary total hip arthroplasty in rheumatoid arthritis patients. 2010 Feb BACKGROUND AND PURPOSE: There has been a limited amount of research on survival of total hip arthroplasties (THAs) in rheumatoid arthritis (RA). We therefore performed a population-based, nationwide study to compare the survival of primary THAs in RA patients and in osteoarthritis (OA) patients. We also wanted to identify predictors of THA failure in RA patients. METHODS: Using the Danish Hip Arthroplasty Registry, we identified 1,661 primary THAs in RA patients and 64,858 in OA patients, all of which were inserted between 1995 and 2008. The follow-up period was up to 14 years for both groups. RESULTS: Regarding overall THA survival, the adjusted RR for RA patients compared to OA patients was 0.81 (95% CI: 0.65-1.01). We found no difference in survival of cups between primary THAs in RA and OA patients. In contrast, there was better overall survival of stems in RA patients than in OA patients, both regarding revision due to aseptic loosening (adjusted RR = 0.58; 95% CI: 0.34-0.99) and for any reason (adjusted RR = 0.63; 95% CI: 0.45-0.88). In RA patients, males had a higher risk of revision than females concerning aseptic loosening of the stem, any revision of the stem, and any revision of both components. INTERPRETATION: The overall survival of primary THAs in RA patients is similar to THA survival in OA patients. Stem survival appeared to be better in RA patients, while survival of the total THA concept did not show any statistically significant differences between the two groups. In RA patients, males appear to have a greater risk of revision than females.
19332636 Changing patterns of tumor necrosis factor inhibitor use in 9074 patients with rheumatoid 2009 May OBJECTIVE: Patients with rheumatoid arthritis (RA) commonly switch between tumor necrosis factor (TNF) inhibitors after failing to control disease activity. Much of the clinical data that support switching to a second TNF agent when one agent fails to work has come from small, short-term studies. We utilized a US insurance claims database to determine patterns of use such as dose escalation, time to discontinuation, and switching between TNF inhibitors in patients with RA. METHODS: A retrospective analysis was performed using an insurance claims database in the US from 2000 to 2005. TNF inhibitor use, time to switch, dose escalation, and continuation times were analyzed in patients with RA. RESULTS: Nine thousand seventy-four patients with RA started TNF inhibitors during the period 2000 to 2005. Etanercept was the most commonly used TNF inhibitor; infliximab had the highest duration of continuation, about 50% at 2 years. In addition, infliximab showed higher rates of dose escalation compared to etanercept and adalimumab. For all TNF inhibitors, time to switching decreased from 2000 to 2005. CONCLUSION: TNF inhibitor use patterns changed from 2000 to 2005, with more frequent changes among the different TNF inhibitors and a shorter duration of treatment before the change. Only about 50% of TNF inhibitors are still continued at 2 years, reflecting the difference between randomized clinical trials and real-world experience.
19248109 Inhibition of interleukin-33 signaling attenuates the severity of experimental arthritis. 2009 Mar OBJECTIVE: Interleukin-33 (IL-33; or, IL-1F11) was recently identified as the ligand of the IL-1 family receptor T1/ST2. The aim of this study was to examine IL-33 production in human and mouse joints and to investigate the role of IL-33 and T1/ST2 in experimental arthritis. METHODS: IL-33 expression was examined in human synovial tissue, rheumatoid arthritis (RA) synovial fibroblasts, and arthritic mouse joints. Mice with collagen-induced arthritis (CIA) were treated with blocking anti-ST2 antibody or control antibody beginning at the onset of disease. Arthritis severity was assessed by clinical and histologic scoring. Draining lymph node (LN) cell responses were examined ex vivo, and joint messenger RNA (mRNA) was used for expression profiling. RESULTS: IL-33 was highly expressed in human RA synovium. In cultured synovial fibroblasts, IL-33 expression was strongly induced by IL-1beta and/or tumor necrosis factor alpha. Furthermore, IL-33 mRNA was detected in the joints of mice with CIA and increased during the early phase of the disease. Administration of a blocking anti-ST2 antibody at the onset of disease attenuated the severity of CIA and reduced joint destruction. Anti-ST2 antibody treatment was associated with a marked decrease in interferon-gamma production as well as with a more limited reduction in IL-17 production by ex vivo-stimulated draining LN cells. Finally, RANKL mRNA levels in the joint were reduced by anti-ST2 treatment. CONCLUSION: IL-33 is produced locally in inflamed joints, and neutralization of IL-33 signaling has a therapeutic effect on the course of arthritis. These observations suggest that locally produced IL-33 may contribute to the pathogenesis of joint inflammation and destruction.
18396440 Prolylcarboxypeptidase: a cardioprotective enzyme. 2009 Mar Prolylcarboxypeptidase (PRCP) is involved in regulating the blood flow through active tissues in order to preserve the internal environment. The expression of PRCP in tissues is determined by a number of pharmacological stimuli such as glucocorticoids and a combination of dexamethasone plus the mu-opioid receptor agonist [D-Ala2, N-Me-Phe4, Gly5-ol]-Enkephalin acetate. PRCP is an enzyme which is associated with preeclampsia, rheumatoid arthritis, and tonsillitis. The interplay between inward cellular signalling required for induced and basal transcription, and PRCP expression have not been mechanistically characterized. Molecules modulated by PRCP include angiotensin II (Ang II), angiotensin III (Ang III), alpha-MSH, and prekallikrein (PK), demonstrating its cardiovascular protective role. In addition to regulating vascular tone, PRCP may modulate proliferation, cell migration, and angiogenesis through regulating angiotensin molecules--and bradykinin--induced endothelium activation. The anti-hypertensive and proinflammatory properties of PRCP implicate that this enzyme may well be an accessible target for anti-inflammatory therapy.
19947184 Zinc and copper plasma concentrations in rheumatoid arthritis patients from a selected pop 2009 Jul 15 The importance of trace elements in chronic inflammatory diseases is related to their cofactor role in immune system functions and in different metabolic processes in articular tissues. The aim of this study was to compare serum levels of Cu, Zn and Zn/Cu ratio in Rheumatoid Arthritis (RA) patients with healthy volunteers in Sari Rheumatology clinic, 2007. Zn and Cu plasma concentrations were assayed using atomic absorption spectrophotometery in 40 selected RA patients sera based on sex and age compared with healthy volunteers. Statistical analysis was performed by SPSS 10 software using independent sample t-test. Zn plasma content in patient group was significantly lower (p = 0.02) than that in healthy group. Also, Cu plasma content showed no differences in comparison with healthy group (p = 0.15). Results showed no correlation between Cu and Zn plasma concentrations in patient group (p = 0.946). In contrast, significant positive correlation was found between Zn and Zn/Cu ratio (p = 0.000); but decreased Zn/Cu ratio was more influenced by diminished Zn concentration. The study showed that spreading of RA in Iranian Society is related to age, sex, career and nutrition of the patients. However, consumption of Zn and Cu supplements in RA patients may be suggested by future investigations.
19591008 The effects of hormone replacement therapy on autoimmune disease: rheumatoid arthritis and 2009 Oct Autoimmune diseases are generally more common in women than men; however, there is no simple explanation for this. Sex hormones, especially estrogen (but also prolactin and testosterone), play important roles in these diseases. Estrogens are generally considered to enhance autoimmunity and have multiple effects on the immune system through various cell types and molecular pathways. There is much evidence supporting the role of estrogen in the pathogenesis of systemic lupus erythematosus (SLE): the disease occurs much more frequently in women, especially during the years of child-bearing potential, and commonly flares during pregnancy. The relationship between estrogen and the development of SLE is complex, however. Exogenous estrogens have been historically avoided in women with SLE due to the widely held view that they could activate disease and their use remains controversial. Current evidence from prospective trials suggests that there may be a small increased risk of mild/moderate flares in women with SLE taking hormone replacement therapy (HRT), but the risk of major flare does not appear to be increased. In rheumatoid arthritis, HRT does not appear to be associated with an increased risk of disease flare and may actually improve disease activity. In all individuals with autoimmune disease, the risk of venous thrombosis associated with oral HRT is an important factor that should also be considered.
20604892 Association of the PTPN22 gene (-1123G > C) polymorphism with rheumatoid arthritis in Chin 2010 Oct This study aimed at examining the association of the single nucleotide polymorphism (SNP) in the protein tyrosine phosphatase gene (PTPN22) with the risk of rheumatoid arthritis (RA) in a Chinese population. A total of 200 RA patients and age and gender-matched healthy controls were recruited. Their genotypes and allelic frequency were determined by the TaqMan-MGB probe-based polymerase chain reaction (PCR). The frequencies of the CC genotype and C allele in RA patient group were significantly higher than that of controls (P < 0.01 or P < 0.05) with an odds ratio of 1.67, respectively. These data suggest, the CC genotype and C allele of the -1123G > C in the PTPN22 gene are associated with an increased risk for RA in Chinese population. Therefore, the CC genotype and C allele of the -1123G > C in the PTPN22 gene may be used as a genetic marker for the predisposition of RA in Chinese.
19365401 TNF-alpha-308 G/A polymorphism and responsiveness to TNF-alpha blockade therapy in moderat 2009 Jun Although tumor necrosis factor-alpha (TNF-alpha) blockade is a very effective therapy for rheumatoid arthritis (RA), not all patients achieve a favorable outcome. The objective of this study was to determine if the common TNF-alpha variant -308(A) predicts poor response to TNF-alpha inhibitors in RA patients using meta-analysis. Studies were identified using MEDLINE and EMBASE. Data were extracted based on DAS28 or achieving at least American College of Rheumatology 20 response. A total of nine studies met the inclusion criteria representing a total of 692 RA patients. There was no significant heterogeneity among study effect sizes (P=0.36). The frequency of the A allele was 22% (119/531) in responders and 37% (60/161) in non-responders. The odds of having the A allele was lower in responders versus non-responders (odds ratio (OR)=0.43, 95% confidence intervals (CI): 0.28-0.68, P=0.000245), irrespective of the TNF-alpha inhibitor prescribed, indicating that the -308(A) variant predicts poor response to TNF-alpha inhibitors. The clinical utility of prospectively genotyping for this variant when initiating anti-TNF-alpha therapy for RA should now be formally assessed.
20131283 Birth outcomes in women who have taken leflunomide during pregnancy. 2010 May OBJECTIVE: In preclinical reproductive studies, leflunomide was found to be embryotoxic and teratogenic. Women treated with leflunomide are advised to avoid pregnancy; those who become pregnant are advised to reduce fetal exposure through a cholestyramine drug elimination procedure. The present study was undertaken to investigate pregnancy outcomes in women who received leflunomide and were treated with cholestyramine during pregnancy. METHODS: Sixty-four pregnant women with rheumatoid arthritis (RA) who were treated with leflunomide during pregnancy (95.3% of whom received cholestyramine), 108 pregnant women with RA not treated with leflunomide, and 78 healthy pregnant women were enrolled in a prospective cohort study between 1999 and 2009. Information was collected via interview of the mothers, review of medical records, and specialized physical examination of infants. RESULTS: There were no significant differences in the overall rate of major structural defects in the exposed group (3 of 56 live births [5.4%]) relative to either comparison group (each 4.2%)(P = 0.13). The rate was similar to the 3-4% expected in the general population. There was no specific pattern of major or minor anomalies. Infants in both the leflunomide-exposed and non-leflunomide-exposed RA groups were born smaller and earlier relative to infants of healthy mothers; however, after adjustment for confounding factors, there were no significant differences between the leflunomide-exposed and non-leflunomide-exposed RA groups. CONCLUSION: Although the sample size is small, these data do not support the notion that there is a substantial increased risk of adverse pregnancy outcomes due to leflunomide exposure among women who undergo cholestyramine elimination procedure early in pregnancy. These findings can provide some reassurance to women who inadvertently become pregnant while taking leflunomide and undergo the washout procedure.
19773287 The time has come to limit the placebo period in rheumatoid arthritis trials to 3 months: 2010 Jan BACKGROUND: Most registration trials in rheumatoid arthritis (RA) include a placebo arm in the setting of an incomplete response to disease-modifying antirheumatic treatment (DMARD-IR). A minimum duration of 6 months is required despite serious methodological and ethical shortcomings. OBJECTIVE: To study whether a 3-month placebo period is sufficient to prove efficacy. METHODS: Meta-analysis of placebo- or active control trials of biological agents in DMARD-IR RA, comparing the contrast in ACR response between experimental and control groups at 3 and 6 months. RESULTS: Twenty trials yielded 15 placebo and 18 active control contrasts (>10,000 patients). At 3 months active treatment showed a highly significant contrast with placebo for ACR20 and ACR50 in every instance. As all groups improved further the mean contrast at 6 months was unchanged. For ACR70 the contrast was clearly greater at 6 months owing to further improvement only in the experimental groups. In active control trials contrasts were smaller, and for ACR50 and ACR70 these decreased somewhat owing to "catch-up" responses in the control groups. CONCLUSION: The placebo phase of registration trials for RA can be limited to 3 months. An accompanying viewpoint proposes that patients receiving placebo should then be switched to standard of care, allowing a more valid and comprehensive assessment, including safety.
19287198 Association of TBX21 polymorphisms in a Korean population with rheumatoid arthritis. 2009 Jan 31 TBX21 (T-bet) is a member of the T-box family of transcriptional factors that contain a conserved DNA binding domain. TBX21 is a critical regulator of the commitment to the Th1 lineage and IFN-gamma production. Th1 and Th2 cells cross-regulate the differentiation of each other, and in this way TBX21 could be an attractive candidate gene for treating autoimmune disease such as rheumatoid arthritis (RA). In present study, we analyzed the genotypic frequencies of six polymorphisms of the TBX21 gene between the 367 RA patients and the 572 healthy controls. We showed that the g.-1514T>C and c.99C>G polymorphisms are suggestively associated with RA susceptibility. It is interesting that the genotypic frequencies of the TBX21 polymorphisms (g.-1514T>C and c.2103A>C) in the male RA patients were significantly different from the male control group (P=0.0016 and 0.045, respectively). We also found that the g.-1514T>C and c.2103A>C polymorphisms of the TBX21 gene in the male RA patients have significant association with the levels of anti-CCP (P=0.05) and rheumatoid factor (P=0.03), respectively. These results suggest that the polymorphisms of the TBX21 gene might be associated with the susceptibility to male RA patients.
20401484 Feasibility study of semi-automated measurements of finger joint space widths. 2011 Oct The purpose of this study is to evaluate technical feasibility based on image capturing conditions (film-focus distance (FFD), film sensitivity, film brand, exposure level and tube voltage) that potentially alter radiographs and consequently may influence the semi-automated measurement of joint space distance (JSD) by computer-aided joint space analysis (CAJSA) in rheumatoid arthritis and osteoarthritis. The radiographs of a left hand (deceased man) were acquired under systematically changing image capturing conditions (exposure level: 4-8 mAs; FFD: 90-130 cm; film sensitivity: 200/400 and tube voltage: 40-52 kV with different image modalities: conventional radiographs, original digital radiographs, digital print-outs). All JSD-measurements were performed with the CAJSA-technology (Radiogrammetry Kit, Version 1.3.6; Sectra; Sweden) at the metacarpal-phalangeal articulation. JSD-analysis was not influenced by changes of FFD, exposure level, film sensitivity or film brand. JSD showed significant variation caused by tube voltage (conventional: CV = 1.913% for Agfa and CV = 2.448% for Kodak; digital: CV = 0.741% for Philips print-outs and CV = 0.620% with original digital images versus CV = 2.185% for Siemens print-outs and 0.951% with original digital images). Computer-aided joint space analysis for JSD-measurements is unaffected by the following image capturing parameters: film-focus distance, film sensitivity, film brand and exposure level. An influence of tube voltage was detected in a lesser extent for original digital images compared to the printed digital as well as conventional versions. Consequently, a standardized tube voltage is essential for accurate reproductions of CAJSA-measurements in rheumatoid arthritis and osteoarthritis.
19824913 Expression and function of the NALP3 inflammasome in rheumatoid synovium. 2010 Feb The NACHT, LRR and PYD domains containing protein (NALP3) inflammasome is a key regulator of interleukin-1 beta (IL-1 beta) secretion. As there is strong evidence for a pro-inflammatory role of IL-1 beta in rheumatoid arthritis (RA) and in murine models of arthritis, we explored the expression of the different components of the NALP3 inflammasome as well as other nucleotide oligomerization domain (NOD)-like receptors (NLRs) in synovium obtained from patients with RA. The expression of NLRs was also studied in fibroblast lines derived from joint tissue. By immunohistology, NALP3 and apoptosis-associated speck-like protein containing a CARD domain (ASC) were expressed in myeloid and endothelial cells and B cells. T cells expressed ASC but lacked NALP3. In synovial fibroblast lines, NALP3 expression was not detected at the RNA and protein levels and stimulation with known NALP3 agonists failed to induce IL-1 beta secretion. Interestingly, we were unable to distinguish RA from osteoarthritis synovial samples on the basis of their basal level of RNA expression of known NLR proteins, though RA samples contained higher levels of caspase-1 assayed by enzyme-linked immunosorbent assay. These results indicate that myeloid and endothelial cells are the principal sources of inflammasome-mediated IL-1 beta production in the synovium, and that synovial fibroblasts are unable to activate caspase-1 because they lack NALP3. The NALP3 inflammasome activity does not account for the difference in level of inflammation between RA and osteoarthritis.
20833179 Evaluation of heterophilic antibody blocking agents in reducing false positive interferenc 2010 Oct 31 IL-17AA, IL-17FF, and IL-17AF are proinflammatory cytokines that have been implicated in the pathogenesis of autoimmune diseases such as rheumatoid arthritis (RA). In order to measure the levels of these cytokines in synovial fluid and serum samples from RA patients, immunoassays specific for IL-17AA, FF, and AF were developed. Although these assays could tolerate up to 50% pooled normal human serum, false positive reactivity was problematic in patient samples suggesting interference from heterophilic antibodies. We therefore evaluated the ability of several commercially available heterophilic antibody blocking agents to reduce false positive reactivity by testing them against samples that were confirmed as false positives in the IL-17AA, FF, and AF assays. Several of the blockers performed well, including HBR-1, HBR-9, HBR-11, HBR-Plus, Serum Cytokine Assay Diluent, and IIR. We chose to move forward using IIR blocker for sample analysis and verified that IIR had no effect on the assay standard curves and did not affect IL-17 quantitation in plasma from ex vivo stimulated human whole blood. IL-17FF and IL-17AF were below the limits of quantitation of the assays (12.3 and 10.5pg/ml, respectively) in synovial fluid and serum samples from patients with RA and osteoarthritis (OA). For the more sensitive IL-17AA assay (1.6pg/ml limit of quantitation), low levels of IL-17AA were measurable in 48% of RA synovial fluid samples (mean, 7.9pg/ml; median, <1.6pg/ml; range, <1.6-29.7pg/ml; n=23) but not in synovial fluid from patients with OA (n=33). For serum samples, however, IL-17AA was below the limit of detection for both RA and OA patients. When these same serum samples were analyzed in the absence of a heterophilic antibody blocker, false positive reactivity yielded apparent mean IL-17AA levels of 43.3pg/ml (28% positive; n=50) and 14.8pg/ml (12% positive; n=50) for RA and OA patients, respectively, results that could potentially be interpreted as consistent with disease biology. These studies demonstrate the importance of ensuring that HAb interference is well controlled, particularly when measuring low concentrations of cytokines in samples from patients with autoimmune disease.
19699293 Convergent Random Forest predictor: methodology for predicting drug response from genome-s 2009 Dec Biomarker development for prediction of patient response to therapy is one of the goals of molecular profiling of human tissues. Due to the large number of transcripts, relatively limited number of samples, and high variability of data, identification of predictive biomarkers is a challenge for data analysis. Furthermore, many genes may be responsible for drug response differences, but often only a few are sufficient for accurate prediction. Here we present an analysis approach, the Convergent Random Forest (CRF) method, for the identification of highly predictive biomarkers. The aim is to select from genome-wide expression data a small number of non-redundant biomarkers that could be developed into a simple and robust diagnostic tool. Our method combines the Random Forest classifier and gene expression clustering to rank and select a small number of predictive genes. We evaluated the CRF approach by analyzing four different data sets. The first set contains transcript profiles of whole blood from rheumatoid arthritis patients, collected before anti-TNF treatment, and their subsequent response to the therapy. In this set, CRF identified 8 transcripts predicting response to therapy with 89% accuracy. We also applied the CRF to the analysis of three previously published expression data sets. For all sets, we have compared the CRF and recursive support vector machines (RSVM) approaches to feature selection and classification. In all cases the CRF selects much smaller number of features, five to eight genes, while achieving similar or better performance on both training and independent testing sets of data. For both methods performance estimates using cross-validation is similar to performance on independent samples. The method has been implemented in R and is available from the authors upon request: Jadwiga.Bienkowska@biogenidec.com.
20884744 Lung diseases directly associated with rheumatoid arthritis and their relationship to outc 2011 Jun The outcome and cause of death of each lung disease directly associated with rheumatoid arthritis (RA-LD) have been poorly investigated. A retrospective study was conducted of 144 patients with RA-LD, in whom the median follow-up period after the initial visit for a respiratory examination was 4.5 yrs. A total of 57 patients were identified with usual interstitial pneumonia (UIP), 31 with bronchiectasis, 16 with nonspecific interstitial pneumonia (NSIP), 11 with bronchiolitis, five with organising pneumonia (OP), five with diffuse alveolar damage (DAD) and 19 with combined disease. The 5-yr survival rates were 36.6% in the UIP group, 87.1% in the bronchiectasis group, 93.8% in the NSIP group, 88.9% in the bronchiolitis group, 60.0% in the OP group and 20.0% in the DAD group. Survival of patients with DAD was worse than that of patients with UIP. Overall, survival of patients with UIP was worse than that of patients with bronchiectasis, NSIP or bronchiolitis. Of the 144 patients, 71 (49.3%) died, of whom 58 (81.7%) died due to respiratory lesions. Of patients with RA-LD, patients with DAD experienced the highest mortality, and the survival of patients with UIP was worse than that of patients with NSIP.
20433955 Strategies after the failure of the first anti-tumor necrosis factor alpha agent in rheuma 2010 Jun During the last two decades fundamental changes have taken place in the treatment of patients with rheumatoid arthritis (RA). The effective establishment of methotrexate as the anchor drug and the introduction of new drugs, in particular anti-tumor necrosis factor (TNF) alpha blockers and the novel biologics have made the goal of remission feasible for plenty of RA patients. However, almost 14-38% of patients do not respond to first-line anti-TNF-alpha treatment at all and as many as 40% discontinue these drugs within a year and 50% within 2 years. Currently, no recommendations exist as regards the treatment of RA patients after TNF-alpha-antagonist failure. In this review the issue of anti-TNF-alpha therapy failure is discussed. Further, the various options for overcoming the apparent failure are explored according to evidence from the published literature.
19782532 Exercise echocardiography in rheumatoid arthritis: a case-control study. 2009 Nov BACKGROUND: Rheumatoid arthritis (RA) is associated with increased cardiovascular risk. METHODS: To assess the role of exercise echocardiography (EE) in the evaluation of patients with RA, follow-up (mean, 6.7+/-3.7 years) was retrospectively obtained in 159 patients with RA who underwent EE. Patients were matched for age, gender, and cardiovascular risk factors with 454 controls who underwent EE. RESULTS: Patients with RA were more likely to have positive results for ischemia on EE (odds ratio, 2.32; 95% confidence interval, 1.48-3.64; P=.0003). Rest and exercise wall motion score indexes were higher in the RA group (1.14+/-0.33 and 1.22+/-0.39, respectively, vs 1.06+/-0.18 and 1.10+/-0.24 in controls; P < .005 for each). Logistic regression adjusted for age revealed an increased odds ratio for myocardial ischemia of 1.06 (95% confidence interval, 1.02-1.11; P=.005) per year of RA. Five-year all-cause mortality in subjects with RA with myocardial ischemia on EE was 14.9%, compared with 4.3% in RA subjects without ischemia (P=.028). CONCLUSION: RA was associated with a 2-fold increased risk for myocardial ischemia on EE; risk increased with the duration of RA. Mortality was increased in patients with RA with ischemia on EE.
20721827 CH-1504, a metabolically inert antifolate for the potential treatment of rheumatoid arthri 2010 Aug CH-1504, being developed by Chelsea Therapeutics Inc under license from the University of South Alabama, is an orally available, metabolically inert antifolate, for the potential treatment of rheumatoid arthritis (RA). CH-1504 is an analog of methotrexate (MTX) but differs from the classical antifolates because of an improved safety and tolerability profile. A significant proportion of the toxicity profile of MTX can be attributed to its polyglutamylated and hydroxylated metabolites; therefore, metabolism-blocked antifolates, such as CH-1504, have been designed to prevent the accumulation of toxic metabolites. Preclinical studies and phase II clinical trials indicated that CH-1504 and MTX inhibit dihydrofolate reductase activity with equal potency. In a phase II, proof-of-concept trial in patients with RA, CH-1504 was associated with improved tolerability and reduced hepatotoxicity as compared with MTX; in addition, improvements in the American College of Rheumatology response rates were similar following treatment with either CH-1504 or MTX. Furthermore, Chelsea Therapeutics are developing the L-isomer of CH-1504, CH-4051, which displays improved in vitro potency over with racemate and appears to be Chelsea Therapeutics' preferred candidate for future development. Inert antifolates appear to be a promising drug class for the treatment of RA because the disease-modifying properties of MTX are retained, but the therapeutic window of the inert antifolates is improved. However, further trials are required to establish the efficacy and long-term safety in a wider population of patients with RA.
20597966 Risk factors and early detection of atherosclerosis in rheumatoid arthritis. 2010 Sep BACKGROUND: Patients with rheumatoid arthritis (RA) have an increased morbidity and mortality due to cardiovascular disease (CVD). This cannot be explained alone by the increased prevalence of traditional cardiovascular risk factors like smoking and hypertension. Other factors therefore seem to be involved in the pathogenesis of atherosclerosis in RA. METHODS: Literature was searched for epidemiology and pathophysiology of atherosclerosis in RA, with special focus on the role of advanced glycation end products (AGE's), endothelial activation, endothelial dysfunction and premature atherosclerosis as measured by intima media thickness (IMT). Finally, a literature search was performed on therapeutic strategies to prevent atherosclerosis in RA. RESULTS: In RA increased AGE accumulation, endothelial activation, endothelial dysfunction and premature atherosclerosis can be identified. Treatment of RA activity by multiple disease modifying anti rheumatic drugs (DMARD's) has shown to be effective in reducing premature atherosclerosis in RA. CONCLUSION: Cardiovascular disease is increased in RA. Tight disease control and treatment of other risk factors is recommended to prevent morbidity and mortality due to CVD in RA.