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ID PMID Title PublicationDate abstract
18379788 High levels of Lymphotoxin-Beta (LT-Beta) gene expression in rheumatoid arthritis synovium 2008 Aug Lymphotoxin-Beta (LT-Beta) is implicated in lymphoid follicle development, production of pro-inflammatory cytokines, and can enhance the proliferation of fibroblasts and synoviocytes. The objective of this study was to investigate LT-Beta and LT-BetaReceptor (LT-BetaR) gene expression in RA patient synovium and blood samples compared with control individuals, and correlate with LT-Alpha and TNF-Alpha gene expression and disease parameters. RT-PCR was used to investigate the gene expression of LT-Beta, LT-BetaR, TNF-Alpha and LT-Alpha in the blood and synovium of RA patients and a control group of individuals. LT-Beta gene expression was significantly higher in RA patient synovium compared to control synovium (P = 0.005). There was a significant positive correlation between LT-Beta and LT-Alpha gene expression in both the synovium (P = 0.001) and blood (P = 0.002) of RA patients. LT-Beta gene expression was significantly higher in RA patient synovial samples that were inflamed to a moderately severe degree compared to those inflamed to a minimal degree (P = 0.02). Analysis of clinical variables revealed a significant positive correlation between LT-BetaR gene expression in RA patient synovium and Pain VAS Score (P = 0.01) and also HAQ Score (P = 0.01). Increased LT-Beta gene expression occurs in RA synovium and correlates with the degree of inflammation. LT-Beta may play a role in RA disease pathogenesis by contributing to a more intense inflammatory reaction in the synovium.
17068631 [Quantification of expression of leukotriene B4 inducing tumor necrosis factor-alpha and i 2006 Oct 18 OBJECTIVE: To investigate quantification of expression of LTB4 inducing IL-1beta and TNF-alpha at mRNA level in synovial membrane cells of rheumatoid arthritis. METHODS: Primary cultured synovial cells from RA patients were treated with exogenous LTB4, MK-886 (inhibitor of 5-lipoxygenase activating protein) and Bestatin(inhibitor of leukotriene A4 hydrolase) in the presence of LIT respectively, expressions of TNF-alpha and IL-1beta were detected at mRNA level by Real-time Quantitative PCR. RESULTS: Expressions of basic TNF-alpha (TNF-alpha/GAPDH) and IL-beta (IL-beta/GAPDH) at mRNA level in primary cultured synovial cells were 0.02 +/- 0.00 and 0.16 +/- 0.01 respectively. LTB4 (10(-9) mol/L-10(-8) mol/L) was shown to induce dose-dependent increase of mRNA expression of TNF-alpha. (7-15 times) and IL-1beta (1 time) , endogenous product of LTB4 by LIT significantly increased mRNA expressions of TNF-alpha (145 times) and IL-1beta (12 times) respectively. LIT-treated synoviocytes with addition of MK-886 (5-LOX exciting protein FLAP inhibitor) (1-10 micromol/L) were inhibited to secrete LTB4 dose-dependently, following the markedly down-regulated expressions of TNF-alpha (15%-66%) and IL-1beta (41%-71%) at mRNA level . Bestatin(100 mg/L) could also remarkably diminish LTB4-induced mRNA expressions of TNF-alpha(86%) and IL-1beta (79%). CONCLUSION: LTB4 of synovial membrance cells in rheumatoid arthritis could induce expressions of TNF-alpha and IL-1beta at mRNA level, and their expression at mRNA level had been quantified successfully. It is a beneficial help to quantify all kinds of cytokines in methodology.
18388515 Is there a future for small molecule drugs in the treatment of rheumatic diseases? 2008 May PURPOSE OF REVIEW: In this review, we outline the landscape of recent developments regarding small molecule compounds for the treatment of inflammatory disorders by discussing drug candidates currently in the pipeline. We also stress the fact that novel techniques are available to evaluate the safety of new therapeutics at an early stage of development. RECENT FINDINGS: Regulation of signal transduction has evolved into an important field of drug research, and small molecule inhibitors of a number of pathways are tested as new anti-inflammatory agents. For rheumatic diseases, specific Jak3 and Syk inhibitors are, so far, the most successful compounds due to their good efficacy, representing a significant advantage over p38 mitogen-activated protein kinase inhibitors. Additional benefit in the treatment of inflammatory diseases may be provided by targeting CD80, IL-12/IL-23, AP-1 transcription factor and receptors modulating cellular activation like chemokine receptors, Toll-like receptors and adenosine A3 receptor. SUMMARY: There is a big hope that novel small molecule drugs, which are rationally designed, based on scientific advancements and biotechnological improvements, will achieve or even exceed efficacy of protein drugs. Thereby, new therapeutic alternatives would be given, and chances for improved outcomes in the care of rheumatic patients provided.
16421641 [Risk of infection during treatment with tumor necrosis factor-alpha inhibitors]. 2006 Feb Tumor necrosis factor-alpha (TNF) is essential for immune defense. TNF plays a major role in the recruitment of inflammatory cells to the site of infection and in the formation and maintenance of granulomas. In addition, it plays a primary and detrimental role in chronic autoimmune diseases. Drugs that inhibit TNF are effective in the treatment of inflammatory rheumatic and autoimmune diseases. However, the three currently available TNF antagonists (etanercept, infliximab and adalimumab) decrease host resistance to granulomatous diseases such as tuberculosis. The incidence of tuberculosis in patients treated with TNF antagonists is higher than in the general population. There are a number of case reports describing the association of TNF-antagonists and the presentation of other infectious diseases such as histoplasmosis, listeriosis, coccidioidomycosis, candidiasis and aspergillosis. These case reports, however, are anecdotal. Nonetheless, patients treated with TNF antagonists are immunocompromised and infectious diseases are most likely more frequent and may present differently than expected. In this review, we describe the role of TNF in constraining infectious diseases, the difference between the three available TNF antagonists, and we discuss the relevant clinical data published in the literature as related to the risk of anti-TNF therapy for infectious diseases.
17469108 Mycobacterial Hsp65-IgG-expressing tolerogenic B cells confer protection against adjuvant- 2007 May OBJECTIVE: Tolerization of T cells directed against a target autoantigen is a desired goal of experimental approaches for the treatment of autoimmune diseases, and novel and improved methods of tolerance induction are continuously being sought. Because most traditional methods of tolerance induction using soluble antigen are effective in the prevention of autoimmunity but fail to control established disease, this study was carried out to explore an innovative tolerogenic approach for the treatment of ongoing disease, using the rat adjuvant-induced arthritis (AIA) model of human rheumatoid arthritis. METHODS: Lewis (RT.1(l)) rats were injected subcutaneously with heat-killed Mycobacterium tuberculosis H37Ra to induce AIA. Before or after AIA induction, Lewis rats were treated intraperitoneally (IP) with tolerogenic B cells expressing a fusion construct of mycobacterial 65-kd heat-shock protein (Hsp65) and IgG heavy-chain. For comparison, control rats were treated IP with ovalbumin (OVA)-IgG-expressing B cells or soluble mycobacterial Hsp65, and the effects on AIA were observed. We also tested the immune response to mycobacterial Hsp65 in B cell-tolerized rats. RESULTS: Administration of tolerogenic mycobacterial Hsp65-expressing B cells as well as soluble mycobacterial Hsp65, but not OVA-expressing B cells, resulted in a significant decrease in the severity of subsequent AIA. However, in rats with established disease, only the B cell regimen of mycobacterial Hsp65, but not the soluble antigen, suppressed ongoing AIA. CONCLUSION: Mycobacterial Hsp65-IgG-expressing B cells can successfully attenuate the progression of AIA. This study introduces a promising approach for the treatment of arthritis that should be further explored.
18794858 Functional SNPs in CD244 increase the risk of rheumatoid arthritis in a Japanese populatio 2008 Oct Rheumatoid arthritis is a chronic autoimmune inflammatory disease with a complex genetic etiology. Members of the signaling lymphocyte activation molecule (SLAM) family carry out pivotal functions in innate immunity and in conventional lymphocytes. We identified a linkage disequilibrium block associated with rheumatoid arthritis in the chromosome 1q region containing multiple SLAM family genes. In this block, the association peaked at two functional SNPs (rs3766379 and rs6682654) in CD244 in two independent rheumatoid arthritis cohorts from Japan (P = 3.23 x 10(-8) and P = 7.45 x 10(-8)). We also identified a Japanese cohort with systemic lupus erythematosus that had a similar genotype distribution as the rheumatoid arthritis cohorts. We demonstrated that the rheumatoid arthritis-susceptible alleles of rs3766379 and rs6682654 and their haplotype increased their expression in luciferase and allele-specific transcript quantification assays. CD244 is a genetic risk factor for rheumatoid arthritis and may have a role in the autoimmune process shared by rheumatoid arthritis and systemic lupus erythematosus.
18194893 Temporomandibular joint disorders in patients with rheumatoid arthritis. 2007 Dec BACKGROUND: Temporomandibular joint disorders (TMD) are not uncommon in patients with rheumatoid arthritis (RA). However, the extent of involvement and its clinical relevance have not been well characterized. This study evaluated the correlation between the severity of RA-related TMD and RA, as well as determined the potential predictors for early identification and management of TMD in RA patients. METHODS: We sequentially recruited 56 adult RA patients from our Arthritis Clinic. TMD and RA were surveyed, clinically by questionnaires and physical examinations, and radiologically by tomography in TMD and conventional radiography in RA. The patients were stratified into no, mild and severe TMD groups according to the physical and tomographic examinations. The correlation of the severity of TMD and RA were evaluated. The relative importance of relevant predictors of severe TMD was analyzed by a logistic regression model. RESULTS: Physical and radiologic temporomandibular joint abnormalities were found to be highly prevalent (85.7% and 74.5%) in these patients, and the occurrence increased to as much as 92.9% when the 2 data sets were combined. More than half of the patients had severe TMD presenting with debilitating symptoms or with a significant degree of bony destruction. The severity of TMD was variably correlated with RA severity. The score of hand-joint space narrowing was found to be the most influential predictor of severe TMD by logistic regression analysis. CONCLUSION: There was a high prevalence of TMD in RA patients. The severity of TMD variably correlated with RA severity. Clinically, a high score of hand-joint space narrowing may serve as an early indicator of RA patients at risk of severe TMD. This may facilitate early management and prevent the functional impairment of the temporomandibular joint.
18799094 HLA-DRB1*0404 is strongly associated with high titers of anti-cyclic citrullinated peptide 2008 Jul OBJECTIVE: To test whether the presence of RA associated HLA-DRB1*0101, HLA-DRB1*0401 and HLA-DRB1*0404 alleles individually influences anti-cyclic citrullinated peptide antibodies (anti-CCP) production. METHODS: The frequency of anti-CCP antibodies was calculated in the sera of 260 RA patients expressing either two (double dose genotypes SE+/SE+), one (single dose genotypes SE+/SE-) or no RA associated HLA-DR alleles (SE-/SE-). Anti-CCP antibodies titers were also determined. RESULTS: RA associated HLA-DR alleles are not mandatory for production of anti-CCP. We found that 68% of SE-/SE- patients were anti-CCP positive. There was no significant difference in anti-CCP between SE negative patient (SE-/SE-) and patients expressing at least one SE (SE+/SE+ and SE+/SE-) (p=0.140). We observed no statistical difference in anti-CCP between RA patients expressing one or two SE (82% vs. 77%, p=0.577). Among SE+/SE-patients, HLA-DRB1*0404 was associated with anti-CCP with a statistically significant difference compared with SE negative patients (90% anti-CCP positive, p=0.02). HLA-DRB1*0404 was also associated with high titers of anti CCP with a statistically significant difference compared with HLA-DRB1*0401 and HLA-DRB1*0101 patients (p=0.025). CONCLUSIONS: The RA-associated HLA-DRB1*0404 allele was the most strongly associated with the presence of anti-CCP in RA sera. Moreover, HLA-DRB1*0404 patients had higher titers of anti CCP than patients with other RA associated HLA-DR alleles.
17929131 Inhibition of nuclear factor-kappaB by hyaluronan in rheumatoid chondrocytes stimulated wi 2007 The aim of this study was to examine the inhibitory effect of high molecular weight hyaluronan (HA) on nuclear factor (NF)-kappaB activation by COOH-terminal heparin-binding fibronectin fragment (HBFN-f) in rheumatoid arthritis (RA) chondrocytes. When RA chondrocytes in monolayer or cartilage explants were cultured with HBFN-f, the fragment stimulated the phosphorylation and nuclear translocation of NF-kappaB, leading to nitric oxide (NO) production in association with inducible form of NO synthase (iNOS) up-regulation. Inhibition studies with NF-kappaB inhibitors indicated the requirement of NF-kappaB for HBFN-f-induced NO production. Pretreatment with 2700 kDa HA resulted in significant suppression of NF-kappaB activation by HBFN-f. HA also inhibited HBFN-f-stimulated NO production with down-regulation of iNOS. The present study clearly demonstrated that high molecular weight HA suppressed HBFN-f-activated NF-kappaB in RA chondrocytes. HA could down-regulate the catabolic action of fibronectin fragments like HBFN-f in RA joints as a potent NF-kappaB inhibitor.
16485108 Serum levels of cartilage oligomeric matrix protein (COMP): a rapid decrease in patients w 2006 Sep To examine the influence of intravenous steroid-treatment (IST) on serum levels of Cartilage oligomeric matrix protein (COMP) in patients with active rheumatoid arthritis (RA). Serum levels of COMP and C-reactive protein (CRP) were measured in 12 patients with highly active RA (Steinbrocker stages II-IV) and in 5 patients with highly active reactive arthritis (ReA) (positive testing for HLA-B27) before starting daily IST. Patients received a total steroid dosage between 100 and 500 mg of prednisolone. COMP was measured by a commercially available sandwich-type ELISA-kit developed by AnaMar Medical AB, Sweden. Statistical evaluation was calculated by paired t test. In the RA group, COMP levels ranged from 6.3 to 19.4 U/l (mean 12.9 U/l), CRP from 5 to 195 mg/l (mean 77.8 mg/l), the COMP levels of the ReA group ranged from 5.1 to 7.4 U/l (mean 7.9 U/l), the CRP levels from 13 to 126 mg/l (mean 49 mg/l). We found a significant difference between the initial COMP levels in RA+ and ReA patients (P<0.005). In contrast to the ReA group, serum-COMP levels of RA+ patients (P<0.004) and the VAS (P<0.0001) decreased significantly within 2-10 days after the first treatment with steroids. The CRP levels remained unchanged in both groups. Our results indicate that the intravenous treatment with steroids in patients with highly active RA leads to a significant decrease of cartilage degradation. COMP seems to be a valuable parameter not even as a prognostic factor, but as a marker for monitoring the therapy response in patients with RA.
18578108 Confirmation of the validity of the HAQ-DI in two populations living with chronic illnesse 2008 The assessment of functional health in chronic illnesses such as HIV/AIDS and rheumatoid arthritis is central to the measurement of health-related quality of life. The purpose of this article is to report the testing and comparison of the measurement structure of the Health Assessment Questionnaire-Disability Index (HAQ-DI), a measure of functional health, in 917 persons living with HIV/AIDS and 901 individuals with rheumatoid arthritis. The samples come from data collected as part of the Arthritis, Rheumatism, and Aging Medical Information System (ARAMIS) and AIDS Time-Oriented Health Outcome Study (ATHOS) projects. Using confirmatory factor analysis (CFA), the hypothesized structure represented by a general factor (functional health) and eight measured items was tested separately. Based on the fit indexes, the model fit the ATHOS data (chi2 = 36.933, p < .0117; CFI = 1.000; SRMR = 0.025). After correlating the error terms for two of the measured items, the model also fit the ARAMIS data (chi2 = 302.34, p = .0000; CFI = 0.937; SRMR = 0.041). This analysis provides further support of the construct validity of the HAQ-DI for persons living with HIV/AIDS or rheumatoid arthritis.
17328048 Expression and proinflammatory role of proteinase-activated receptor 2 in rheumatoid synov 2007 Mar OBJECTIVE: Serine proteinases activate the G protein-coupled receptor, proteinase-activated receptor 2 (PAR-2), via cleavage and exposure of a tethered ligand. PAR-2 is known to exert proinflammatory actions in a murine model of arthritis, since PAR-2-deficient mice exhibit strikingly reduced articular inflammation. This study was undertaken to examine synovial PAR-2 expression and to determine the effect of a novel PAR-2 antagonist on synovial cytokine production, in order to investigate the hypothesis that PAR-2 plays a critical role in the pathogenesis of rheumatoid arthritis (RA). METHODS: Using a monoclonal antibody to human PAR-2, expression in RA synovium and cultured synovial fibroblasts was characterized. The novel PAR-2 antagonist, ENMD-1068, was added to primary cultures of RA synovial tissue, from which spontaneous cytokine release was measured. RESULTS: PAR-2 was substantially up-regulated in RA synovium compared with control synovial tissue from patients with osteoarthritis or seronegative inflammatory arthritis, neither of which exhibited significant PAR-2 expression. Importantly, spontaneous release of tumor necrosis factor alpha and interleukin-1beta from RA synovium was substantially inhibited by ENMD-1068, in a dose-dependent manner. CONCLUSION: These findings identify PAR-2 as a novel upstream regulator of proinflammatory cytokine production in RA and indicate its potential as a novel therapeutic target in inflammatory arthritis.
17907167 Disease activity early in the course of treatment predicts response to therapy after one y 2007 Oct OBJECTIVE: To assess whether disease activity levels at treatment initiation or during the first 3 months of therapy predict disease activity at 1 year after treatment initiation. METHODS: Pooled patient data from early rheumatoid arthritis (RA) clinical trials (n = 1,342) of methotrexate (MTX), tumor necrosis factor (TNF) inhibitor monotherapy (adalimumab and etanercept), and the combination of the two (adalimumab or infliximab plus MTX) were used for the primary analyses. Pooled data from clinical trials of MTX and of TNF inhibitor plus MTX in late RA (n = 712) were used for validation of the results. Disease activity was primarily assessed using the Simplified Disease Activity Index (SDAI); in addition, we calculated the Disease Activity Score 28-joint assessment (DAS28) and the Clinical Disease Activity Index (CDAI). Associations of disease activity measures at baseline and at 1, 2, 3, and 6 months with disease activity values or disease activity states at 1 year were performed using Spearman's rank correlation, analysis of variance, and diagnostic testing procedures, including receiver operating characteristic (ROC) curve analyses, and probit analysis. RESULTS: Correlations with SDAI values at end point were significant (P < 0.0001) at baseline, and increased to r = approximately 0.6 at 3 months. The area under the ROC curve indicated a high diagnostic test yield with respect to the 1-year outcome (area under the ROC curve approximately 0.8). At all time points, including baseline, the group of patients who achieved remission at 1 year had lower average SDAI values than did those whose disease activity was high at 1 year. The groups achieving low or moderate disease activities at 1 year had SDAI values lying between. Baseline disease activity was less associated with disease activity at the end point for treatment with TNF inhibitor plus MTX, indicating its effectiveness over a broader range of baseline disease activity, but the association with end point disease activity was similar to that in the MTX treatment group at 1 month after treatment initiation. The data were similar when scores on the DAS28 and CDAI were used and were fully validated in the independent cohort of patients with late RA. CONCLUSION: The level of disease activity at baseline and especially during the first 3 months of treatment is significantly related to the level of disease activity at 1 year. Patients who reach a moderate or low disease activity status after 3-6 months of therapy may require switching to alternative therapies. Our findings indicate that intensive and dynamic treatment strategies that include a closer look at disease activity at 3 months in patients with early and late RA is warranted.
16947774 Tumor necrosis factor alpha antagonist use and cancer in patients with rheumatoid arthriti 2006 Sep OBJECTIVE: Concerns persist about a possible association between tumor necrosis factor alpha (TNFalpha) antagonist treatment and development of cancers in patients with rheumatoid arthritis (RA). This study was undertaken to estimate the association between treatment with biologic disease-modifying antirheumatic drugs (DMARDs) and development of cancer in patients with RA. METHODS: We conducted a cohort study pooling administrative databases from 2 US states and 1 Canadian province. A cohort of patients who had received a diagnosis of RA on > or =1 occasion and had been prescribed DMARDs was identified. We categorized patients with a prescription for a biologic DMARD as biologic DMARD users, and those with a prescription for methotrexate (MTX) but no biologic DMARD as MTX users. We used time-varying propensity scores to adjust for the large number of possible confounders and stratified proportional hazards regression to estimate the effects of biologic DMARDs on cancer. The primary end points were hematologic malignancies (lymphoma, multiple myeloma, and leukemia) and common solid tumors (colorectal, lung, stomach, breast, prostate, uterine, ovarian, urinary tract/bladder, and melanoma). RESULTS: The pooled cohort included 1,152 biologic DMARD users and 7,306 MTX users. We identified 11 hematologic malignancies and 46 solid tumors during 2,940 person-years of biologic DMARD use, and 88 hematologic malignancies and 558 solid tumors during 30,300 person-years of MTX use. Comparing biologic DMARD users with MTX users, the propensity score-adjusted pooled hazard ratio was 1.37 (95% confidence interval 0.71-2.65) for hematologic malignancies and 0.91 (95% confidence interval 0.65-1.26) for solid tumors. CONCLUSION: Our results indicate that users of biologic agents are unlikely to have a substantial increase in the risk of hematologic malignancies and solid tumors as compared with MTX users. Despite the use of large combined data sets, studying the effect of an infrequent exposure (biologic DMARDs) on rare diseases (hematologic malignancies) remains a challenge.
18230628 Lymphotoxin 252A>G polymorphism is common and associates with myocardial infarction in pat 2008 Nov OBJECTIVE: Cardiovascular disease (CVD) is more prevalent and more likely to lead to death in patients with rheumatoid arthritis (RA). Single nucleotide polymorphisms of the genes for lymphotoxin-A (LT-A) and its regulatory protein galectin-2 (LGALS2) have been implicated as genetic risk factors for acute cardiovascular events in the general population: we hypothesised that their risk alleles/genotypes (a) may be more frequent among patients with RA compared with non-RA controls (thus explaining some of the increased CVD in RA), and (b) may be more frequent among patients with RA with prevalent CVD compared with patients with RA without CVD. METHODS: Genomic DNA samples were collected from 388 patients with RA and 399 local population controls without RA. LT-A gene intron 1 252A>G and LGALS2 intron 1 3279C>T single nucleotide polymorphisms were identified using real-time polymerase chain reaction and melting curve analysis. RESULTS: LT-A 252GG homozygotes were significantly more prevalent among patients with RA compared with controls (19.8% vs 11.8%, p = 0.002; OR(GG/GA,AA) = 1.85, 95% CI 1.25 to 2.75, p = 0.002). Patients with RA possessing LT-A 252 GG were significantly more likely to have had a myocardial infarction compared with those with LT-A 252 AA or GA (13% vs 5.5%, p = 0.02; adjusted OR(GG/GA,AA) = 3.03, 95% CI 1.2 to 7.68, p = 0.002). The frequency of LGALS2 polymorphisms was similar between RA and controls and was not associated with CVD among patients with RA. CONCLUSIONS: The LT-A 252GG genotype occurs more frequently among patients with RA than the general population. In RA, this genotype appears to associate with increased likelihood of suffering an myocardial infarction.
18388156 Rituximab inhibits structural joint damage in patients with rheumatoid arthritis with an i 2009 Feb OBJECTIVE: To determine if treatment with a B cell-targeted therapy can inhibit the progression of structural joint damage in patients with rheumatoid arthritis (RA), exhibiting an inadequate response to tumour necrosis factor (TNF) inhibitors. METHODS: In this phase III study, patients with an inadequate response to a TNF inhibitor and receiving methotrexate were randomised to rituximab or placebo. Radiographs were obtained at baseline, week 24 and week 56 after randomisation. Patients with an inadequate response to their randomised therapy could receive rescue medication from week 16. From week 24, eligible patients from both treatment arms could receive open-label rituximab. Patients were analysed according to their original treatment group. Radiographs were scored using the Genant-modified Sharp method. The primary radiographic endpoint was change in total Genant-modified Sharp score at week 56. RESULTS: Rituximab treatment caused significant reduction in joint damage progression compared with placebo. The mean change from baseline in the total Genant-modified Sharp score at week 56 was significantly lower for patients treated with rituximab than for patients treated with placebo (1.00 vs 2.31; p = 0.005), and was supported by changes in erosion score (0.59 and 1.32 for rituximab plus methotrexate vs placebo plus methotrexate, respectively; p = 0.011) and joint space narrowing score (0.41 and 0.99, respectively; p<0.001). CONCLUSIONS: This study provides the first evidence that a B cell-targeted therapy-rituximab-can significantly inhibit the progression of structural joint damage in patients with RA with long-standing, active and treatment-resistant disease.
18388148 Messenger ribonucleic acid expression profile in peripheral blood cells from RA patients f 2008 Jun OBJECTIVES: We monitored the mRNA expression profiles of peripheral blood cells during treatment with a TNF-alpha inhibitor, infliximab, in patients with RA. Using a DNA microarray analysis, we demonstrated a unique set of genes, with distinct baseline and post-treatment changes in expression between responders and non-responders to infliximab treatment. METHODS: Using a customized low-density cDNA microarray with 747 genes and a reliable data collection system, we monitored the mRNA expression profiles of whole blood cells from 18 RA patients before and after the infusion of infliximab for up to 22 weeks. The clinical response to treatment with infliximab was determined using the ACR response criteria, the disease activity score of 28 joints (DAS28), and individual clinical parameters. The patients were classified as responders or non-responders based on their ACR50% response at 22 weeks. RESULTS: Approximately 15% of the total genes were found to exhibit a >1.5-fold change, compared with their reference values, at one or more time points during the 22 weeks of infliximab therapy. The expression of inflammatory genes, such as IFN-related genes, was strongly correlated with the serum level of CRP and the DAS28. The increased expression of inflammatory genes in responders was normalized within 2 weeks and then remained at a normal level during the treatment period. In contrast, in the non-responders, the elevated expression at baseline, although it was significantly decreased at 2 weeks, returned to the baseline level after 14 weeks. In addition to inflammatory genes, we identified several groups of genes with distinct differences in expression between the responders and non-responders. CONCLUSIONS: Our results suggest that a customized low-density microarray is useful for monitoring mRNA expression profiles in peripheral blood cells, enabling us to identify a unique set of genes with differentially regulated expressions in responders and non-responders to a TNF inhibitor among patients with RA.
18163485 Atacicept in patients with rheumatoid arthritis: results of a multicenter, phase Ib, doubl 2008 Jan OBJECTIVE: Atacicept is a recombinant fusion protein that binds and neutralizes B lymphocyte stimulator and a proliferation-inducing ligand. The purpose of this study was to investigate the tolerability, pharmacokinetics, and pharmacodynamics of atacicept treatment in patients with rheumatoid arthritis (RA) and to collect exploratory data on clinical outcomes. METHODS: In this multicenter, phase Ib, randomized, placebo-controlled, dose-escalating trial, 73 patients were enrolled into 6 escalating-dose cohorts. Patients received atacicept or placebo as single doses (70, 210, or 630 mg) or as repeated doses given at 2-week intervals (3 doses of 70 mg, 3 doses of 210 mg, or 7 doses of 420 mg), followed by 10 weeks of trial assessments, with a followup assessment at 3 months after the final dose. RESULTS: Atacicept was well tolerated, with few differences between treatment groups and no obvious safety concerns. The pharmacokinetics profile was nonlinear, but was consistent and predictable across all doses and regimens. Treatment-related decreases in immunoglobulin (particularly IgM) and rheumatoid factor levels were evident, and a clear decrease in anti-citrullinated protein antibodies was observed in the cohort that received 7 doses of 420 mg. The B cell response was biphasic, with an initial transient increase (dominated by memory B cells) followed by a dose-related decrease (dominated by mature B cells). Clinical assessments showed trends toward improvement with the 3-month treatment. Little effect on the erythrocyte sedimentation rate or C-reactive protein levels was seen. CONCLUSION: Atacicept was well tolerated both systemically and locally. The results demonstrated that the biologic activity of atacicept was consistent with its mechanism of action.
18214571 The patient-based outcome of upper-extremity surgeries using the DASH questionnaire and th 2008 Aug The Disabilities of the Arm, Shoulder and Hand (DASH) is a standardized patient-based outcome measure, which assesses integrated upper-extremity disorders. The objectives of this study were to investigate subjective outcome after upper-extremity surgeries for the patients with rheumatoid arthritis (RA) using the DASH questionnaire (Japanese version) and to investigate the influence of disease activity on the surgical outcome using the Disease Activity Score (DAS) 28-CRP(4). Approximately 127 surgical procedures for the upper extremities in 127 patients with RA were recruited in this study. Surgeries were performed in 4 shoulders, 35 elbows, 60 wrists and 28 hands. The DASH score (disability/symptom score) was investigated just before surgery and at follow-up. The mean follow-up period after the surgery was 15 months on average (range, 6 to 24 months). The preoperative DASH score (disability/symptom score) 50 +/- 23 (mean +/- SD) decreased significantly to 38 +/- 23 at the follow-up (n = 127, p < 0.01). Standardized response mean and effect size revealed a medium effect of -0.6 and -0.5. Patients with various degrees of disease activity improved and the improvements per se were comparable of preoperative disease activity and postoperative response to medical treatment. A favorable subjective outcome of rheumatoid upper-extremity surgeries can be anticipated under the good control of disease activity.
17136313 Absence of antibody to cyclic citrullinated peptide in sera of non-arthritic patients with 2007 Jul The objective of this study was to investigate if antibody to cyclic citrullinated peptide (anti-CCP) is detected in sera of patients with chronic hepatitis B virus (HBV) infection. Serum anti-CCP and IgA, IgG, and IgM rheumatoid factor (RF) isotypes were measured by enzyme-linked immunosorbent assay on 176 non-arthritic patients with HBV infection. IgA RF, IgG RF, and IgM RF were detectable in 29.5, 21, and 18.8% of the tested sera, respectively, with a total seropositivity rate of 42.7%. Marginally elevated anti-CCP was detected in one patient (0.6%). By regression analysis, there was no statistically significant association between the serum levels of anti-CCP and serum IgA, IgG, or IgM RF (R (2) = 0.033, with respective p values of 0.224, 0.297, and 0.334). In conclusion, anti-CCP was rarely detected in non-arthritic patients with HBV infection in contrast to RF. Thus, testing for anti-CCP may be a useful tool for the diagnosis of rheumatoid arthritis in this population.