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ID PMID Title PublicationDate abstract
18276742 Detection, identification and in vivo treatment responsiveness of bone morphogenetic prote 2009 Jan OBJECTIVE: To characterise the bone morphogenetic protein (BMP) target cells positive for phosphorylated (P)-SMAD1/5, in rheumatoid arthritis (RA) synovium. METHODS: Synovial biopsies were obtained by needle arthroscopy. Anti-P-SMAD1/5 antibodies were used for Western blot (WB) on protein extracts from RA and normal synovium and for immunostaining of synovial biopsy sections. Positive cells were further identified by double staining for CD3, CD20, CD68, CD138, CD90, alpha smooth muscle actin (SMA), endoglin (CD105) and von Willebrand factor (VWF). In sections from early patients with RA taken before and under antirheumatic treatment, the degree of inflammation and activation of the BMP pathway were quantified. RESULTS: P-SMAD1/5 protein was detected by WB in RA and to a lesser extent in normal synovium. Different P-SMAD1/5 positive cell populations were identified in RA synovium, mainly in perivascular and sublining cells. P-SMAD1/5 positive perivascular cells were alphaSMA positive and located around VWF positive endothelial cells. Some CD90 positive synovial fibroblasts were P-SMAD1/5 positive, as was part of the CD68 positive synovial cells but other cells of the haematopoietic lineage showed no SMAD1/5 phosphorylation. Treatment resulted in an absolute but not relative decrease in BMP activation in the synovium. CONCLUSION: BMP-activated cells belong to distinct stromal compartments in RA synovium and some of them express markers associated with the mesenchymal progenitor cell lineage. Antirheumatic treatment effectively downregulates synovial inflammation, but BMP activation in the synovium does persist albeit reduced.
18820827 The analysis of CIS, SOCS1, SOSC2 and SOCS3 transcript levels in peripheral blood mononucl 2008 Dec Being expressed in immune cells, cytokine-inducible SH2 protein (CIS) and suppressors of cytokine signaling proteins, SOCS1, SOCS2 and SOCS3, can regulate cytokine signaling and immune responses. To evaluate the possible expressional dysregulation of CIS, SOCS1, SOCS2 and SOCS3 in systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) patients, the transcript levels of these genes in peripheral blood mononuclear cells (PBMCs) from SLE and RA patients were determined and statistically compared with those in PBMCs from normal individuals. It was found that SLE patients with the active disease activity significantly express higher CIS transcript levels than normal individuals and SLE patients with the inactive disease activity, whereas the difference in SOCS1, SOCS2 and SOCS3 transcript levels between normal individuals and SLE patients is not statistically significant. However, transcript levels of these CIS/SOCS genes in RA patients were not significantly different from those in normal individuals, except that treatment with a TNF-alpha-blocking agent in RA patients appears to enhance the CIS transcript expression, but down-regulates the SOCS2 transcript expression in PBMCs. These data suggest that CIS can serve as an SLE disease marker and may be involved in the pathogenesis of SLE, and that TNF-alpha may play an important role in the regulation of CIS and SOCS2 gene expression in PBMCs in vivo.
18670735 Abatacept: a T-cell co-stimulation modulator for the treatment of rheumatoid arthritis. 2008 Nov Rheumatoid arthritis (RA) is a debilitating autoimmune disease that has traditionally been treated with disease-modifying anti-rheumatic drugs (DMARDs). In the European Union (EU), patients who fail to respond to traditional DMARDs may receive tumor necrosis factor-alpha (TNF-alpha) antagonists. However, approximately one-third of patients fail TNF-alpha antagonists due to adverse effects or lack of efficacy, and there are limited treatment options available to these patients. As knowledge of the underlying immunopathology of RA evolves, new strategies for inhibiting the inflammatory process have emerged. It is well known that activated T cells play a key role in orchestrating the immunopathological mechanisms of RA. Inhibiting the full activation of T cells is a rational strategy in the treatment of RA and represents a novel method of inhibiting disease activity, distinct from inflammatory cytokine blockade. Here, the safety and efficacy of abatacept, a selective T-cell co-stimulation modulator recently approved in the EU, is reviewed in patients with RA who have shown an inadequate response to TNF-alpha antagonists. In a randomized, placebo-controlled, double-blind, phase III trial of patients with an inadequate response to TNF-alpha antagonism, abatacept was effective in improving the signs and symptoms of RA, as well as patient-centered outcomes, such as fatigue, disability, and other mental and physical aspects of health-related quality of life. These improvements were sustained through 2 years during the open-label, long-term extension period. In this trial, abatacept demonstrated a safety and tolerability profile similar to placebo. Taken together, these data suggest that selective co-stimulation modulation with abatacept may be a viable option for patients who are refractory to both traditional therapies and TNF-alpha antagonists.
17324968 All-cause and cause-specific mortality in rheumatoid arthritis are not greater than expect 2007 Jul BACKGROUND: Mortality is increased in rheumatoid arthritis (RA), mainly because of cardiovascular (CV) events, cancer and infections. Recent data suggest that treatment with tumour necrosis factor (TNF) antagonists may affect this trend. OBJECTIVE: To assess whether treatment with TNF antagonists is associated with reduction in CV events, cancer and infection rates, and in mortality in patients with RA treated and not treated with TNF antagonists. METHODS: BIOBADASER is a registry for active long-term follow-up of safety of biological treatments in patients with RA. It includes 4459 patients with RA treated with TNF antagonists. EMECAR is an external RA cohort (n = 789) established to define the characteristics of the disease in Spain and to assess comorbidity. The incidence density (ischaemic heart disease) of CV events, cancer and infections was estimated and compared. The standardised mortality ratio was compared with the rate in the general population. A propensity score was used to match cohorts by the probability of being treated. RESULTS: Rates of CV and cancer events are significantly higher in EMECAR than in BIOBADASER (RR 5-7 for different CV events, and RR 2.9 for cancer), whereas the rate of serious infections is significantly higher in BIOBADASER (RR 1.6). Mortality ratio of BIOBADASER by EMECAR is 0.32 (0.20-0.53) for all causes of death, 0.58 (0.24-1.41) for CV events, 0.52 (0.21-1.29) for infection and 0.36 (0.10-1.30) for cancer-related deaths. CONCLUSION: Morbidity, other than infection, and mortality are not higher than expected in patients with RA treated with TNF antagonists.
16502118 Risk factors for vertebral fracture in menopausal or postmenopausal Japanese women with rh 2006 The occurrence of vertebral fracture was examined cross-sectionally and longitudinally over a 4-year interval in 117 menopausal and postmenopausal Japanese women with rheumatoid arthritis (RA), whose ages ranged from 50 to 64 years. Patients treated with bisphosphonate were excluded. Vertebral fracture was diagnosed by lateral thoracic and lumbar spine radiography at the start and end of a 4-year period. Bone mineral density (BMD) at L2-L4 according to dual-energy X-ray absorptiometry (DXA), the administration of corticosteroids or methotrexate, and urinary excretion of N-telopeptide of type I collagen (NTx) were also recorded. In the cross-sectional study, the prevalence of vertebral fracture in the initial radiographs of RA patients was 21%, while it was 5% in healthy age-matched controls. Among RA patients treated with corticosteroids, 33% had vertebral fracture, which was a significantly higher prevalence than that in RA patients without steroid administration. In the longitudinal study, vertebral fracture prevalence was also increased in patients more than 60 years old. RA patients having steroid treatment and a BMD/YAM (young adult mean) ratio below 70% had higher risk of vertebral fracture than patients with a BMD/YAM ratio of 70%-80%, which in turn exceeded the risk with a BMD of 80% or more. No adverse effect of low-dose methotrexate on vertebral fracture was found. Urinary NTx was high in RA patients, as reported previously, and did not differ between patients with or without new fracture after 4 years. In conclusion, Japanese RA patients more than 60 years old who were treated with corticosteroid or had a BMD below 80% had high risk of vertebral fracture.
16247585 A study on vascular endothelial growth factor and endothelin-1 in patients with extra-arti 2006 May Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease associated with a wide range of extra-articular manifestations. Recent studies emphasise a key inflammatory role of the endothelial cells, either by overexpression of inflammatory mediators or by the proliferation of new blood vessels, in the disease process leading to the systemic organ involvement. To evaluate the relationship between internal organ manifestations and immunological markers of endothelial activation, serum levels of vascular endothelial growth factor (VEGF) and endothelin-1 (ET-1) were determined by an enzyme-linked immunosorbent assay in 64 RA patients and in 32 healthy controls. In comparison with a control group, higher serum concentrations of VEGF and ET-1 (p<0.001) in RA patients were demonstrated. A comparison between both RA groups with (20 patients) and without systemic involvement (44 patients) showed significantly higher concentrations of VEGF (p<0.05) and ET-1 (p<0.01) in the sera of patients with systemic manifestation. Moreover, a significant positive correlation between VEGF and ET-1 (r=0.475, p<0.001) in RA patients was found. A positive correlation between VEGF and Disease Activity Score (DAS) 28 index (r=0.39, p<0.005) as well as erythrocyte sedimentation rate (ESR) (r=0.564, p<0.0001) and C-reactive protein was found. ET-1 serum level correlated significantly with ESR (r=0.326, p<0.05) and DAS 28 index (r=0.307, p<0.05). These results suggest that the elevated serum levels of VEGF and ET-1 are associated with systemic organ involvement in RA patients and may play a key role in the pathogenesis of extra-articular manifestation of the disease.
18592987 [Lung cancer associated with rheumatoid arthritis and usual interstitial pneumonia]. 2008 Jun To assess the effects of usual interstitial pneumonia (UIP) and smoking in rheumatoid arthritis (RA) patients regarding lung cancer risk, we studied 86 RA patients (14 patients with lung cancer, 58 patients with UIP (RA/ UIP), and 14 patients with both). Among the 28 RA patients with lung cancer, 14 patients (50%) had UIP. Compared to the lung cancer patients without UIP, the proportion of smokers (92.6 vs 50%, p = 0.0328) and total pack-years of smoking (57.1 +/- 37.1 vs 19.5 +/- 21.9, p = 0.003) were significantly higher in lung cancer patients with UIP. There was no significant difference in age, sex, and histological type and location of lung cancer between these two groups. Among the 72 RA/UIP patients, 14 patients (19.4%) had lung cancer. Compared to RA/UIP-only patients, the proportion of smokers (92.6 vs 46.6%, p = 0.002) and total pack-years of smoking (57.1 +/- 37.1 vs 25.4 37.4, p = 0.006) were significantly higher in RA/UIP patients with lung cancer. There was no significant difference in age, sex, and the duration of RA between these two groups. The odds ratio of smoking and total pack-years of smoking over 20 for the development of lung cancer in RA/UIP patients were 14.93 and 21.27, and the differences were statistically significant (p = 0.002 and p < 0.001, respectively). CONCLUSION: 50% of RA patients with lung cancer had RA/UIP and 19.4% of RA/UIP patients had lung cancer. These findings suggest that RA/UIP may be associated with increased risk of development of lung cancer in RA patients. In an RA cohort study to assess the development of lung cancer, RA patients should be divided into two groups, one with RA/UIP and another without RA/UIP. Smokers with RA/UIP should be recommended to cease smoking.
17417991 A low prevalance of purified protein derivative test positivity in Turkish patients with r 2007 Jan OBJECTIVES: In this study, we aimed to evaluate the frequency of purified protein derivative (PPD) skin test positivity and associated clinical features in RA patients. MATERIALS AND METHODS: We included 94 (80 F, 14 M, mean age: 55.8) consecutive RA patients with a disease duration of 8.7 years. PPD test was performed in all RA patients; clinical features were recorded down; chest x-ray, pulmonary function tests and HRCT were available in all cases. As the control group, we included data of 21 SLE, 44 AS, 27 OA, 16 gouty arthritis and 18 vasculitis patients. RESULTS: The frequencies of PPD positivity in RA (29.8%) and SLE (19%) patients were lower than in patients with AS (65.9%), gouty arthritis (68.8%) and OA (63%) (all p values < 0.01). PPD-positive RA patients were more frequently smokers (p = 0.005) and had a higher rate of RF seropositivity (p = 0.04) than PPD-negatives. PPD was less frequently positive in erosive RA disease (p = 0.033). Chest x-rays and HRCT abnormalities were detected in 41.8% and 62.7% of RA patients, respectively. Frequencies of chest x-ray and HRCT abnormalities in PPD-positive and PPD-negative patients were not different from each other (p > 0.05). CONCLUSION: In our country in which tuberculosis is relatively frequent -contrary to the situation in AS patients- we observed a lower frequency of PPD positivity in RA and SLE patients compared to patients with other rheumatic diseases. We did not find any relationship between PPD positivity and the frequency of chest x-ray, HRCT abnormalities.
17504820 Caspase 7 influences susceptibility to rheumatoid arthritis. 2007 Aug OBJECTIVE: The aim of this study was to investigate the possible role of the caspase 7 (CASP7) in susceptibility to rheumatoid arthritis (RA). METHODS: Genotyping of three single nucleotide polymorphisms (SNPs) of the CASP7 gene: rs11593766 (G/ T), rs2227310 (C/G) and rs2227309 (G/A) was performed in a total of 906 RA patients and 528 matched healthy controls using TaqMan assays. All the subjects were of Spanish Caucasian origin. A relative quantification of mRNA encoding the non-functional variant of procaspase 7 (isoform beta) vs functional isoforms was performed in total RNA from 32 healthy individuals using real-time PCR. RESULTS: Only the rs2227309 SNP was found to be associated with susceptibility to RA. Frequency of the G allele was significantly higher among RA patients [overall frequency of the G allele 74.0% in cases vs 68.4% in controls, P = 0.001, Odds ratio (OR) = 1.32, 95% Confidence intervals (95% CI) 1.11-1.56] and a higher frequency of GG homozygous individuals was found in the RA patient group (overall frequency of GG genotype 56.0% in cases and 46.4% in controls, P = 0.0005, OR = 1.47, 95%CI 1.18-1.83). A statistically significant deviation was observed to compare the relative expression of the procaspase 7 isoform beta in samples from individuals stratified according their rs2227309 genotypes (AA + AG: 1.36 +/- 0.55, n = 19, vs GG: 2.35 +/- 0.74, n = 13; P = 0.0002). CONCLUSION: Our results support involvement of the CASP7 gene in the susceptibility to RA. The higher production of the no functional variant of CASP7 by individuals with a particular genotype could be the basis of this association.
16641046 Killer cell immunoglobulin-like receptor gene's repertoire in rheumatoid arthritis. 2006 Mar OBJECTIVE: To investigate the role of the killer cell immunoglobulin-like receptor (KIR) gene's repertoire in the pathogenesis of rheumatoid arthritis (RA) in Taiwan. METHODS: KIR genotypes were determined in 122 patients with RA and 96 healthy controls by the sequence-specific primer polymerase chain reaction (SSP-PCR) method. Human leucocyte antigen (HLA)-C genotyping was also performed simultaneously in 72 patients and 66 controls by the SSP-PCR method. RESULTS: The total carriage frequency of KIR 2DS4 regardless of corresponding HLA-Cw4 was significantly increased in RA patients compared with controls [p<0.001, odds ratio (OR) = 1.9, 95% confidence interval (CI) = 1.1-3.4, Pc<0.01]. The total carriage frequency of KIR 2DL1 regardless of corresponding HLA-C also tended to be increased in RA patients (p<0.02, OR = 2.1, 95% CI = 1.2-3.9, Pc = not significant). The frequency of KIR 2DS4 with corresponding HLA-Cw4 was increased in RA patients in comparison with controls (p = 0.02, OR = 3.2, 95% CI = 1.1-9.4). Moreover, the association of RA with KIR 2DS4 depended on the presence of the corresponding HLA-Cw4. CONCLUSIONS: KIR 2DS4 may be a risk factor for susceptibility to RA in Taiwan.
16628200 MIF: a new cytokine link between rheumatoid arthritis and atherosclerosis. 2006 May Macrophage migration inhibitory factor (MIF) is well established as a key cytokine in immuno-inflammatory diseases such as rheumatoid arthritis. Inflammation is now also recognized as having a crucial role in atherosclerosis, and recent evidence indicates that MIF could also be important in this disease. Here, we review the role of MIF in rheumatoid arthritis and atherosclerosis, discuss the ways in which MIF and its relationship with glucocorticoids could link these diseases, and consider the potential of MIF as a new therapeutic target for small-molecule and antibody-based anti-cytokine drugs.
16269464 Organ messenger ribonucleic acid and plasma proteome changes in the adjuvant-induced arthr 2006 Feb Two receptors [estrogen receptor (ER)alpha and ERbeta] mediate the manifold effects of estrogens throughout the body. Although a clear role has been established for ERalpha in the classical effects of estrogen activity, the physiological role of ERbeta is less well understood. A small-molecule ERbeta selective agonist, ERB-041, has potent antiinflammatory activity in the Lewis rat model of adjuvant-induced arthritis. To characterize the response of target organs and pathways responsible for this antiinflammatory effect, mRNA expression profiling of the spleen, lymph node, and liver was performed, in conjunction with a global analysis of the plasma proteome. We find that the expression of a large number of genes and proteins are altered in the disease model and the majority of these are partially or fully reversed by ERB-041 treatment. Regulated pathways include the acute-phase response, eicosanoid synthesis, fatty acid metabolism, and iron metabolism. In addition, many of the regulated genes and proteins are known to be dysregulated in human rheumatoid arthritis, providing further evidence that the manifestations of the Lewis rat adjuvant-induced arthritis model bear similarity to the human disease.
17982198 [Efficacy of anti-cytokines and anti-RANKL antibody for treatment of RA and osteoporosis]. 2007 Nov Rheumatoid arthritis (RA) is characterized by inflammatory synovitis, erosive arthritis and joint destruction. Recent evidence indicates that inflammatory cytokines such as TNF-alpha or IL-6 plays a pathological role in joint destruction and osteoporosis and that anti-cytokine therapy or anti-RANKL antibody provides significant protection against the process.
18050384 Clinical and ultrasonographic monitoring of response to adalimumab treatment in rheumatoid 2008 Jan OBJECTIVE: To evaluate by clinical, laboratory, and sonographic assessment the effects of adalimumab therapy in patients with rheumatoid arthritis (RA) over 24 months of treatment. METHODS: Twenty-five patients with RA were commenced on adalimumab therapy. Before the beginning of the therapy (Time 0) and after 3 (T1), 12 (T2), and 24 (T3) months we evaluated erythrocyte sedimentation rate, C-reactive protein, physician and patient visual analog scale for disease activity, number of tender and swollen joints, Health Assessment Questionnaire, and Disease Activity Score in 28 joints. In addition, musculoskeletal ultrasound (US) was performed bilaterally in the 2nd and 5th metacarpophalangeal, 3rd interphalangeal, wrist, and knee joints and in the tendon sheaths and bursae of those areas. A semiquantitative score (0 3) was used to indicate the presence of a localized inflammatory process and/or structural damage. The summed total was used as an indicator of global change in each joint (single joint score). The sum of the single joint scores was used as an indicator of overall polyarticular involvement in each patient (total score). RESULTS: Patients who did not submit to the planned examinations strictly on time were excluded from the study. Then 25 patients were examined at T0 and T1, 20 at T2, and 9 at T3. All clinical and laboratory measures as well as the US scores were significantly reduced during the followup. CONCLUSION: A positive response to treatment with adalimumab was demonstrated by clinical, laboratory, and US evaluation by both short- and longterm followup.
16870100 Short-term adalimumab therapy improves endo-thelial function in patients with rheumatoid a 2006 May OBJECTIVE: Endothelial dysfunction has been found in patients with rheumatoid arthritis (RA). In this study we aimed to assess whether adalimumab, a fully human monoclonal antibody directed against TNF-alpha, was able to improve endothelial function in RA patients with long-standing disease refractory to infliximab. METHODS: Eight RA patients (7 women; range: 24- 74 years) were studied. They had been treated with the chimeric monoclonal anti-TNF-alpha antibody-infliximab for at least 1 year and were switched to adalimumab therapy because of loss of efficacy following periodical treatment with infliximab. Endothelial dependent (EDV) and independent vasodilatation (EIV) were measured by brachial ultrasonography. Patients were assessed prior to (day 0) and at day 2, and weeks 2 and 12 after the onset of adalimumab therapy. RESULTS: Following adalimumab administration a rapid increase in the percentage (%) of EDV was found in all patients (mean +/- SD: 10.1 +/- 5.1% at day 2 compared to 5.8 +/- 4.1% at day 0). At weeks 2 and 12 the %EDV was also significantly increased compared to day 0. All patients showed decrease in the disease activity score 28 and C-reactive protein levels (P = 0.012). Moreover, at week 12 the atherogenic index was reduced in all patients (P = 0.012). CONCLUSION: Our study confirms that short-term adalimumab therapy yields an active and positive effect on endothelial function in long-standing RA patients with severe disease. This observation emphasizes the potential role of the TNF-alpha blockade in the mechanisms implicated in the development of atherogenesis in RA.
17134501 Effect of infliximab on mRNA expression profiles in synovial tissue of rheumatoid arthriti 2006 We examined the gene expression profiles in arthroscopic biopsies retrieved from 10 rheumatoid arthritis patients before and after anti-TNF treatment with infliximab to investigate whether such profiles can be used to predict responses to the therapy, and to study effects of the therapy on the profiles. Responses to treatment were assessed using European League Against Rheumatism response criteria. Three patients were found to be good responders, five patients to be moderate responders and two patients to be nonresponders. The TNF-alpha status of the biopsies from each of the patients before treatment was also investigated immunohistochemically, and it was detected in biopsies from four of the patients, including all three of the good responders. The gene expression data demonstrate that all patients had unique gene expression signatures, with low intrapatient variability between biopsies. The data also revealed significant differences between the good responding and nonresponding patients (279 differentially expressed genes were detected, with a false discovery rate < 0.025). Among the identified genes we found that MMP-3 was significantly upregulated in good responders (log2 fold change, 2.95) compared with nonresponders, providing further support for the potential of MMP-3 as a marker for good responses to therapy. An even more extensive list of 685 significantly differentially expressed genes was found between patients in whom TNF-alpha was found and nonresponders, indicating that TNF-alpha could be an important biomarker for successful infliximab treatment. Significant differences were also observed between biopsies taken before and after anti-TNF treatment, including 115 differentially expressed genes in the good responding group. Interestingly, the effect was even stronger in the group in which TNF-alpha was immunohistochemically detected before therapy. Here, 1,058 genes were differentially expressed, including many that were novel in this context (for example, CXCL3 and CXCL14). Subsequent Gene Ontology analysis revealed that several 'themes' were significantly over-represented that are known to be affected by anti-TNF treatment in inflammatory tissue; for example, immune response (GO:0006955), cell communication (GO:0007154), signal transduction (GO:0007165) and chemotaxis (GO:0006935). No genes reached statistical significance in the moderately responding or nonresponding groups. In conclusion, this pilot study suggests that further investigation is warranted on the usefulness of gene expression profiling of synovial tissue to predict and monitor the outcome of rheumatoid arthritis therapies.
17763921 Rheumatoid arthritis, periodontal disease and coronary artery disease. 2008 Apr Rheumatoid arthritis (RA), periodontal disease (PD), and coronary artery disease (CAD) are common chronic inflammatory diseases. RA is associated with accelerated vascular risk resulting in an increased prevalence of CAD with attendant early mortality and excess morbidity. RA and PD have a common pathobiology. Accordingly, the aim of this study was to evaluate the association between RA, PD, and CAD and the influence of systemic inflammatory factors. A total of 100 active RA patients of which 50 had established CAD and 50 had no CAD were assessed for PD. All subjects underwent a clinical, cardiac, dental, laboratory, and radiological evaluation. Blood samples were obtained, and the level of high sensitivity C-reactive protein (hs-CRP), total white blood counts (WBC), erythrocyte sedimentation rate (ESR), fibrinogen and tumor necrosis factor (TNF) alpha, total cholesterol (TC), and high density lipoprotein (HDL) were assayed. The findings of this study demonstrated an association between RA, PD, and CAD. The RA patients with CAD had significantly more PD than RA patients without CAD. The inflammatory markers, hsCRP, ESR, WBC, fibrinogen, and TNF-alpha, were raised in all patients but were significantly higher in RA patients with CAD who also had PD. HDL levels were lower in RA patients with CAD when compared to RA patients without CAD. Evidence from this study shows an association between RA, PD, CAD, and systemic levels of the inflammatory mediators. The implication is that inflammation may be the central link between the chronic inflammatory, autoimmune disorders, and atherosclerosis.
17335569 Tumor necrosis factor alpha and adalimumab differentially regulate CD36 expression in huma 2007 In chronic inflammatory diseases, such as rheumatoid arthritis, inflammation acts as an independent cardiovascular risk factor and the use of anti-inflammatory drugs, such as anti-tumor necrosis factor alpha (anti-TNFalpha), may decrease this risk. The phagocytosis of oxidized low density lipoproteins (LDLs) accumulated in the subendothelium by mononuclear cells influences atherosclerosis and depends on CD36 expression. We investigated the role of TNFalpha and adalimumab, a human anti-TNFalpha monoclonal antibody widely used in human pathology, in CD36 expression in human monocytes. Human monocytes were prepared by adherence from whole-blood buffy-coat fractions from healthy donors. CD36 expression was assessed by RT-PCR and flow cytometry, with various TNFalpha or adalimumab concentrations. Implication of peroxisome proliferator-activated receptor (PPAR)gamma in the regulation of CD36 expression was assessed using specific inhibitor or gel shift assays. The impact of redox signaling was investigated using quantification of reactive oxygen species, antioxidant and a NADPH oxidase inhibitor. The F(ab')2 fragment of adalimumab was isolated and its effect was analyzed. TNFalpha inhibits both CD36 membrane expression and mRNA expression. This inhibition involves a reduction in PPARgamma activation. In contrast, adalimumab increases both CD36 membrane expression and mRNA expression. This induction is independent of the Fc portion of adalimumab and involves redox signaling via NADPH oxidase activation. CD36 expression on human monocytes is inhibited by TNFalpha and independently increased by adalimumab. These data highlight that pro-inflammatory cytokines and their specific neutralization influence the expression of cellular receptors implicated in atherosclerosis. Further studies are needed to investigate the clinical implications of these results in accelerated atherosclerosis observed in rheumatoid arthritis.
18465453 Charting the possible impact of national guidelines on the management of rheumatoid arthri 2008 May OBJECTIVE: To identify temporal trends in the prescription of disease-modifying antirheumatic drugs (DMARDs) in patients with early rheumatoid arthritis (RA). METHODS: Using data from the Swedish RA register (n = 2,584), we analysed the proportion of RA patients prescribed DMARDs at their first consultation between 1997 and 2001. Statistical process control (SPC) was used to chart and analyse major changes in prescription behaviour, while more traditional time series analysis methods (i.e. regression) were used to corroborate the nature of any trend. RESULTS: The SPC method identified an upward shift in the prescription of DMARDs in July 1998 and a change in the process by October 1998. Time series analysis confirmed an increasing trend in DMARD prescription over the period as a whole and the trend was statistically significant (p
16652441 B cell targeted therapies: safety considerations. 2006 May Reported data from recent clinical trials have contributed substantially to our growing understanding of the potential effectiveness and safety of B cell targeted therapy in the treatment of rheumatic diseases. Trials with rituximab, an anti-CD20 monoclonal antibody that depletes mature B cells, have amassed the most data of any B cell targeted therapy to date. A number of other B cell directed therapies are under investigation. Interestingly, although they may share a common target, the different agents have quite distinct mechanisms of action, and therefore their efficacy and safety profiles may differ. A common concern with all B cell directed therapies is the potential effect these agents may have on humoral immunity. The safety profile of rituximab in the oncology setting is well known, based on a database of well over 370,000 patients. Phase II trials of rituximab in rheumatoid arthritis (RA) have begun to examine safety issues specifically in the RA population, including issues surrounding longterm and repeated treatment safety profiles. Questions about the longterm safety of B cell therapy remain to be clarified: What will be the safety profile for repeated treatment courses? What will be the safety profile when B cell targeted therapies are used in sequence or in conjunction with other agents? Answers to these important questions are likely to come from careful observations by treating clinicians, data from registries, and longterm followup of patients enrolled in clinical trials.