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ID PMID Title PublicationDate abstract
21267729 [The future of methotrexate therapy and other folate inhibitors]. 2011 Feb Because of its good effectiveness and tolerability, methotrexate (MTX) has been the most important DMARD for the treatment of rheumatoid arthritis (RA) worldwide for many years. Thus the treatment of this disease is strongly based on the principle of folate inhibition. Recent years have brought new insights into the pharmacology and mechanisms of action of MTX. As a result, it now appears possible to further develop folate inhibitors to increase effectiveness and specificity. Polyglutamation of the drug, a metabolic step which appears to play a role both in terms of therapeutic effects and hepatic side effects, might be a possible starting point. Moreover, methods of targeted drug delivery intended to increase drug accumulation at the site of inflammation can increase the effectiveness of treatment and reduce toxicity. Albumin-coupled and liposomally-conjugated MTX, both of which inhibit inflammation in animal models more potently than MTX, are undergoing preclinical evaluation. It was recognized that activated synovial macrophages upregulate folate receptor ß (FR-ß) expression and that MTX can become active by this pathway. This finding makes it possible to develop new FR-ß-specific folate inhibitors with specificity for this pathophysiologically important cell population.
21881229 Emodin inhibits proinflammatory responses and inactivates histone deacetylase 1 in hypoxic 2011 Chronic inflammation of rheumatoid arthritis (RA) is promoted by proinflammatory cytokines and closely linked to angiogenesis. In the present study, we investigated the anti-inflammatory effects of emodin (1,3,8-trihydroxy-6-methyl-anthraquinone) isolated from the root of Rheum palmatum L. in interleukin 1 beta (IL-1β) and lipopolysaccharide (LPS)-stimulated RA synoviocytes under hypoxia. Emodin significantly inhibited IL-1β and LPS-stimulated proliferation of RA synoviocytes in a dose-dependent manner under hypoxic condition. Also, enzyme linked immunosorbent assay (ELISA) revealed that emodin significantly reduced the production of pro-inflammatory cytokines [tumor necrosis factor-alpha (TNF-α), IL-6 and IL-8], mediators [prostagladin E(2) (PGE(2)), matrix metalloproteinase (MMP)-1 and MMP-13] and vascular endothelial growth factor (VEGF) as an angiogenesis biomarker in IL-1β and LPS-treated synoviocytes under hypoxia. Consistently, emodin attenuated the expression of cyclooxygenase 2 (COX-2), VEGF, hypoxia inducible factor 1 alpha (HIF-1α), MMP-1 and MMP-13 at mRNA level in IL-1β and LPS-treated synoviocytes under hypoxia. Furthermore, emodin reduced histone deacetylase (HDAC) activity as well as suppressed the expression of HDAC1, but not HDAC2 in IL-1β and LPS-treated synoviocytes under hypoxia. Overall, these findings suggest that emodin inhibits proinflammatory cytokines and VEGF productions, and HDAC1 activity in hypoxic RA synoviocytes.
22747951 Validation of ACR/EULAR definition of remission in rheumatoid arthritis from RA practice: 2012 Jun 29 INTRODUCTION: In development of the American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) rheumatoid arthritis (RA) remission definitions using clinical trials data, one criterion used to compare different remission definitions was whether, compared with those not in remission, those in remission had evidence of later disease stability defined by x-ray and functional status. Validation of the RA remission criteria using observational study data is necessary before recommending their use in practice. METHODS: Using data from those who met RA criteria in the ESPOIR cohort, we matched each person in remission with a person not in remission and then carried out analyses comparing later stability of x-ray and health assessment questionnaire (HAQ) between the two groups. We compared the predictive validity of the same candidate definitions of remission evaluated in the ACR/EULAR process. To minimize potential bias and produce more stable results, we used a bootstrap resampling approach to select those not in remission, repeating the sample matching analysis process 500 times. RESULTS: Results were similar to those of clinical trials analyzed for the ACR/EULAR remission criteria. Specifically, the ACR/EULAR remission definitions using either an simple disease activity index (SDAI) ≤ 3.3, clinical disease activity index (CDAI) ≤ 2.8 or a definition of remission requiring tender joint count, swollen joint count, patient global assessment all ≤ 1 performed as well or better than other candidate definitions of remission in terms of predicting later x-ray and function stability. CONCLUSIONS: ACR/EULAR definitions of remission developed for trials are similarly valid in observational studies in RA and could be used in practice.
21683623 Outcomes after the Stainsby procedure in the lesser toes: an alternative procedure for the 2011 Sep Clawing of the digits is a deformity seen both in patients with and without rheumatoid arthritis, resulting in pain and deformity in the forefoot. After failure of conservative treatment, the Stainsby procedure is one surgical option for severe clawing and metatarsalgia in both rheumatoid and nonrheumatoid feet. Results from the originating authors (G.D. Stainsby and P.J. Briggs) are consistent and reliable; however, there is little material outside of the originating center. This article reviews our experience in the Western Sussex Hospitals NHS Trust. Sixteen consecutive patients who underwent Stainsby procedure between 2006 and 2009 were reviewed. All operations were performed by a single consultant surgeon, the senior author (S.P.). All patients were scored using the Manchester Oxford Foot and Ankle score preoperatively and postoperatively. Minimum follow-up was 6 months, with a mean follow-up of 14 months. Significant improvements in all scores were seen postoperatively. Walking scores dropped from a mean of 22 preoperatively to 12.7 postoperatively (p = 0.007). Pain scores dropped from a mean of 13.3 to 7.1 (p = 0.001). Social scores dropped from a mean 11 to 6 (p = 0.001). Overall patient satisfaction was high. The Stainsby procedure has been shown to improve function and reduce pain in patients from its originating center in both rheumatoid and nonrheumatoid feet. This study demonstrates this simple technique is reproducible and effective in reducing morbidity.
20559723 Rheumatoid arthritis and renal light-chain deposition disease: long-term effectiveness of 2011 Sep A 68-year-old woman diagnosed with erosive rheumatoid arthritis (RA) was treated with intramuscular methotrexate 15 mg weekly and oral prednisone 5 mg daily. A favorable outcome of 6 years was followed by RA flare and nephrotic syndrome (NS). Renal biopsy revealed non-amyloid light-chain deposition disease. Laboratory analysis and bone marrow biopsy excluded monoclonal protein and plasma cell dyscrasia. Addition of subcutaneous etanercept, 25 mg twice weekly allowed rapid control of both arthritis and NS. To date, after over 7-year follow-up, RA is in clinical remission, 24-h albuminuria is consistently below 0.5 g, and serum creatinine is 0.9 mg/dl.
22493518 Autotaxin expression from synovial fibroblasts is essential for the pathogenesis of modele 2012 May 7 Rheumatoid arthritis is a destructive arthropathy characterized by chronic synovial inflammation that imposes a substantial socioeconomic burden. Under the influence of the proinflammatory milieu, synovial fibroblasts (SFs), the main effector cells in disease pathogenesis, become activated and hyperplastic, releasing proinflammatory factors and tissue-remodeling enzymes. This study shows that activated arthritic SFs from human patients and animal models express significant quantities of autotaxin (ATX; ENPP2), a lysophospholipase D that catalyzes the conversion of lysophosphatidylcholine to lysophosphatidic acid (LPA). ATX expression from SFs was induced by TNF, and LPA induced SF activation and effector functions in synergy with TNF. Conditional genetic ablation of ATX in mesenchymal cells, including SFs, resulted in disease attenuation in animal models of arthritis, establishing the ATX/LPA axis as a novel player in chronic inflammation and the pathogenesis of arthritis and a promising therapeutic target.
22143313 Comparative study of tibial posterior slope angle following cruciate-retaining total knee 2012 Apr PURPOSE: Pre- and postoperative tibial posterior slope angles (PSAs) were assessed in patients who underwent cruciate-retaining total knee arthroplasty (TKA). MATERIAL AND METHODS: A total of 386 cruciate retaining TKA were performed in 308 patients and retrospectively reviewed. Based on the prostheses, 202 cases using NexGen were classified as group I, 120 cases using PFC sigma as group II, and 64 cases using Vanguard as group III. Postoperative PSA of groups I, II, and III were compared. RESULTS: In groups I, II, and III, postoperative PSA was 6.0˚, 6.0˚, and 4.5˚, respectively (p < 0.001). Between preoperative measurement and final follow-up examination, mean knee score (59.7 to 97.3), function score (54.2 to 90.5), and range of motion (ROM; 126.7° to 132.2°) improved. These three values did not differ significantly among groups. CONCLUSIONS: The 3° slope of the Vanguard polyethylene insert caused the difference in PSAs. This design characteristic should be considered when using this implant in TKA.
22079854 Evaluation of pulse wave velocity in systemic lupus erythematosus, rheumatoid arthritis an 2012 Jan OBJECTIVES: Connective tissue diseases involve characteristic inflammatory lesions in the cardiovascular system, in addition to other systems. The involvement of the cardiovascular system in the course of connective tissue diseases may result in serious morbidity and mortality. Pulse wave velocity which is an indicator of arterial dilatation capacity may predict cardiovascular risk of patients. Pulse wave velocity is inversely proportional to arterial dilatation capacity. Decreased dilatation capacity leads to a reduction in arterial blood pressure and flow dynamics and impairment in coronary perfusion. METHODS: In our study, we examined pulse wave velocity in frequent chronic inflammatory rheumatologic diseases: rheumatoid arthritis, systemic lupus erythematosus, and Behçet's disease. A total of 98 subjects participated in our study including 24 patients with newly diagnosed rheumatoid arthritis (4 males, 20 females; mean age 42.5 ± 11.5 years), 22 patients with newly diagnosed systemic lupus erythematosus (1 male, 21 females; mean age 35.8 ± 11.1 years), 33 patients with newly diagnosed Behçet's disease (26 males, 7 females; mean age 32.7 ± 8.0 years), and 19 healthy subjects in the control group (10 males, 9 females; mean age 36.2 ± 15.0 years). Aorta pulse wave velocity was determined by Complior Colson (Createch Industrie, Garges les Gonesses, France) device which allowed for pulse wave recording and automated measurement. RESULTS: Pulse wave velocity was higher in rheumatoid arthritis, systemic lupus erythematosus, and Behçet's disease groups compared to the control group. When all variables were included in the regression analysis only age was found to affect pulse wave velocity independently. CONCLUSION: Pulse wave velocity was found to be high in chronic inflammatory connective tissue diseases compared to the control group. However, no difference was found between groups. Age was determined as the most important independent variable in the regression analysis.
23234648 Citrullination enhances the pro-inflammatory response to fibrin in rheumatoid arthritis sy 2013 Aug OBJECTIVE: Fibrin deposits are characteristic of the synovial tissues in rheumatoid arthritis (RA). Once citrullinated, fibrin becomes an autoantigen and is thought to contribute in this way to perpetuate the disease. Our study aimed to analyse the responses of RA synovial fibroblasts (RASF) to native and citrullinated fibrin. METHODS: The transcriptome induced by fibrin in RASF was approached with whole-genome-based gene expression arrays. The upregulation of selected pro-inflammatory genes by fibrin was confirmed in additional primary cell cultures using quantitative PCR and ELISA. Citrullination reactions were carried out with recombinant human peptidylarginine deiminases (PAD) 2 and 4. RESULTS: In the whole-genome array native fibrin was found to modulate the gene expression profile of RASF, particularly upregulating mRNA levels of several pro-inflammatory cytokines. The induction of interleukin (IL)-6 and IL-8 by fibrin was confirmed in additional samples at both the mRNA and the protein level. Blocking and knockdown experiments showed the participation of toll-like receptor (TLR)4 in the induction of both cytokines. As compared with the native macromolecule, PAD2-citrullinated fibrin induced significantly higher expression of the pro-inflammatory cytokines in these cells. CONCLUSIONS: Our results suggest that fibrin mediates inflammatory responses in RASF via a TLR4 pathway. In this way, fibrin and particularly its citrullinated form may contribute to sustain the cytokine burst in RA.
21852254 Postmarketing surveillance of tocilizumab for rheumatoid arthritis in Japan: interim analy 2011 Dec OBJECTIVE: An interim analysis of an all-patient postmarketing surveillance programme in Japan to investigate the safety of tocilizumab for the treatment of rheumatoid arthritis (RA) in the real world. METHODS: This analysis included 3881 patients. Patients received 8 mg/kg of tocilizumab every 4 weeks, and were observed for 28 weeks. Data on baseline characteristics and adverse events (AE) were collected. RESULTS: Total and serious AE were reported as 167 and 27 events/100 patient-years, respectively. The most frequent AE and serious AE were infections. Logistic regression analysis identified the following risk factors for the development of serious infection: concurrent or medical history of respiratory disorders; prednisolone dose at baseline ≥5 mg/day; and age ≥65 years. Twenty-five patients died, and the standardised mortality ratio, with the Japanese general population in 2008 as reference, was 1.66, similar to the results from the Japanese cohort study for RA patients. CONCLUSIONS: Tocilizumab is acceptably safe in the real clinical setting. Tocilizumab needs to be used with consideration of the benefit-risk balance to avoid serious infections in elderly patients and those on high doses of corticosteroids or with a concurrent or medical history of respiratory disorders.
21961966 Association of programmed cell death-1 (PDCD-1) gene polymorphisms with rheumatoid arthrit 2011 Sep OBJECTIVES: Programmed cell death 1 (PDCD-1, also named PD-1, CD279, and SLEB2), a negative T cell regulator to maintain peripheral tolerance, induces negative signals to T cells during interaction with its ligands and is therefore a candidate gene in the development of autoimmune diseases such as rheumatoid arthritis (RA). Herein, we investigate the association of PDCD-1 polymorphisms with the risk of RA among Iranian patients and healthy controls. METHODS: Genomic DNA was extracted from the whole blood samples using DNA Purification kit (DNG-plus). Using the PCR- RFLP method, 3 PDCD-1 SNPs, including PD1.1G/A, PD1.3G/A, and PD1.9C/T were genotyped in 120 RA patients as well as 188 healthy controls. The genotype and allele frequencies of these SNPs were analysed by statistical tests for the significant association between RA patients and controls. Haplotype constructions of these SNPs were performed. Clinical diagnosis of the RA patients was confirmed by the Rheumatology Research Centere of Tehran University of Medical Sciences. RESULTS: Our study revealed that PD1.1 A allele at position -538 in the promoter region of PDCD-1 gene is associated with an increased risk of RA disease compared to controls (2.9% vs. 0.7%, OR= 3.735, 95% CI= 0.956-14.588, p=0.046). There were no significant differences in other alleles and genotypes of PDCD-1 SNPs between RA cases and controls. CONCLUSIONS: Our results indicate that among the polymorphisms which we evaluated only the PD1.1A allele in the promoter region of PDCD-1 gene is significantly associated with RA susceptibility in Iranian patients.
21338307 Comparative quality of life in patients with depression and rheumatoid arthritis. 2011 We assessed the inter-relationships between the Short Form 36 (SF-36) physical and mental function in 220 patients with onset cases of mild and moderate depression and 913 adults with early and established rheumatoid arthritis (RA) through secondary analysis and compared both scores with the UK general population norms. In depression and RA the SF-36 total scores showed significant impairment across the spectrum of both domains compared with age-specific UK normative score. In RA mental health and role, mental scores were highly correlated with other SF-36 domains. In depression there was little evidence of such inter-relationships. Mental health and role mental domains were lowest in active RA (disease activity scores (DAS28) over 5.1). They had strong correlations with the vitality and social function SF-36 sub-scores and weak correlations with the physical function and role emotional sub-scores. Patients with long-term conditions require comprehensive care. At present it is unclear how best to combine treatment of RA synovitis with the management of mental health problems. Mental health symptoms are present from the earliest stages of RA and it may be appropriate to initiate multidisciplinary care as soon as practicable, although its efficacy requires a further detailed study across primary and secondary care.
22244520 Six-transmembrane epithelial antigen of prostate 4 (STEAP4) is expressed on monocytes/neut 2012 Jan OBJECTIVES: Human six-transmembrane epithelial antigen of prostate 4 (STEAP4) is one of the STEAP family as a homologue of mouse tumour necrosis factor-α-induced adipose-related protein (TIARP). Recently, we reported that the TIARP gene expression was remarkably increased in spleen and joints of glucose-6-phosphate isomerise (GPI)-induced arthritis model, suggesting pivotal association to arthritis. The aim of the present study was to assess the expression, localisation and function of STEAP4 in peripheral blood of patients with rheumatoid arthritis (RA). METHODS: Peripheral blood was obtained from seven patients with RA, the surface expression of STEAP4 was detected by flow cytometry. The number of neutrophils was compared with the expression of STEAP4 mRNA derived from peripheral blood of patients with RA. Neutrophils were introduced by HL60 with retinoic acid, and were transfected with GFP-STEAP4 plasmid DNA, then the migration of neutrophil-like HL60 was determined by transwell assay. In addition, the fluctuation of STEAP4 mRNA was analysed before and after treatment with infliximab in 40 patients with RA. RESULTS: STEAP4 was expressed on monocytes and neutrophils in peripheral blood in RA. The number of neutrophils and expression of STEAP4 mRNA was positively correlated. Migration of neutrophil-like HL60 was down-regulated by over-expression of STEAP4. Expression of STEAP4 Mrna was significantly decreased after infliximab treatment in patients with RA, especially in good responders. CONCLUSIONS: STEAP4 is expressed on monocytes and neutrophils in peripheral blood, regulates cell migration, is down-regulated by TNF antagonist, and might be a possible predictor of response to TNF antagonist.
22133036 The influence of methotrexate on the gene expression of the pro-inflammatory cytokine IL-1 2011 Nov OBJECTIVES: Methotrexate (MTX) is a cornerstone in the treatment of rheumatoid arthritis (RA). Among its anti-proliferative activity, the anti-inflammatory mechanisms of MTX seem to play a major role in the treatment of RA. MTX reduces the production of pro-inflammatory cytokines such as interleukin (IL)-1, IL-2, IL-6 and interferon (INF)-γ, while the gene expression of anti-inflammatory Th2 cytokines like IL-4 and IL-10 is increased - altogether resulting in the anti-inflammatory effect. As little is known about the impact of MTX on other cytokines involved in the pathogenesis of RA, the present trial investigated the effect of MTX on IL-12A and IL-18 gene expression by peripheral blood mononuclear cells (PBMCs). For comparison, the effect on IL-6 and tumour necrosis factor (TNF) was analysed. METHODS: Using real-time PCR, mRNA concentrations of pro-inflammatory cytokines were determined in PBMCs from 17 patients before and during MTX therapy. Furthermore, gene expression was correlated with clinical and pharmacokinetic parameters such as methotrexate polyglutamate concentrations (Spearman's correlation coefficient). To eliminate concomitant corticosteroids as confounding factor, a subgroup analysis for methotrexate without corticosteroids was performed in 6 patients. RESULTS: MTX statistically significantly reduced the mRNA expression of IL-12A by PBMCs in rheumatoid arthritis patients (Wilcoxon-test for paired samples, p<0.046). Consistent with other reports, IL-6 was reduced under MTX treatment. Although the combination of MTX and corticosteroids significantly reduced the gene expression of IL-18, this key molecule was unaffected by MTX without corticosteroids. Our results were further supported by a negative correlation of methotrexate polyglutamate concentrations and the mRNA expression of the pro-inflammatory cytokines IL-6 and IL-12A. CONCLUSIONS: We describe a novel effect of MTX reducing the gene expression of IL-12A independently of corticosteroid application in patients. This impact was further enhanced by a reduction of IL-12A-producing lymphocytes and neutrophils under MTX treatment. These results expand the understanding of the mechanism of action of the most widely used drug in RA.
21345204 Early changes in bone mineral density measured by digital X-ray radiogrammetry predict up 2011 Feb 23 INTRODUCTION: Changes in bone mineral density (BMD) in the hand as evaluated by digital X-ray radiogrammetry (DXR) of the second to fourth metacarpal bones has been suggested to predict future joint damage in patients with rheumatoid arthritis (RA). This study's objective was to investigate whether DXR-BMD loss early in the course of the disease predicts the development of joint damage in RA patients followed for up to 20 years. METHODS: A total of 183 patients (115 women and 68 men) with early RA (mean disease duration, 11 months) included from 1985 to 1989 were followed prospectively (the Lund early RA cohort). Clinical and functional measures were assessed yearly. Joint damage was evaluated according to the Larsen score on radiographs of the hands and feet obtained in years 0 to 5 and years 10, 15 and 20. These radiographs were digitized, and BMD of the second to fourth metacarpal bones was evaluated by DXR. Early DXR-BMD change rate (that is, bone loss) per year calculated from the first two radiographs obtained on average 9 months apart (SD ± 4.8) were available for 135 patients. Mean values of the right and left hand were used. RESULTS: Mean early DXR-BMD loss during the first year calculated was -0.023 g/cm2 (SD ± 0.025). Patients with marked bone loss, that is, early DXR-BMD loss above the median for the group, had significantly worse progression of joint damage at all examinations during the 20-year period. CONCLUSIONS: Early DXR-BMD progression rate predicted the development of joint damage evaluated according to Larsen score at year 1 and for up to 20 years in this cohort of early RA patients.
22226312 Monitoring improvement in health during homeopathic intervention. Development of an assess 2012 Jan INTRODUCTION: Hering's 'Law of Cure' is considered important in homeopathy and thought to predict a positive outcome to treatment. No formal outcome measures are currently available to monitor response to homeopathic treatment on the basis of these assumptions. We describe a simple assessment tool, the Hering's Law Assessment Tool (HELAT) to identify and differentiate patient responses to homeopathic treatment as corresponding to Hering's Law from other symptomatic responses. We describe the development of the tool and assess its face, content and predictive validity. METHOD: The HELAT was initially developed through literature review, discussion between homeopaths and clinical experience. In phase one, the tool was reviewed by three experienced homeopaths to assess face and content validity. In phase two, we tested its predictive validity by hypothesizing that the HELAT total score may predict changes in a clinical response (using standard validated rheumatological outcome, the American College of Rheumatology (ACR)20%) in 32 patients with rheumatoid arthritis receiving homeopathic intervention over 24 weeks as part of a clinical trial. RESULTS: The HELAT was piloted and changed to improve face and content validity and the final version was then employed for phase two as a predictor of outcome. HELAT total score predicted patient's clinical response (ACR20) [B = 1.142, SE = 0.462, P = 0.013] which was independent of practitioner assessing the patients treatment response [B = 1.04, SE = 1.01, P = 0.302]. CONCLUSION: The initial data suggests that the HELAT may hold promise for a potential clinical and research outcome measure in homeopathy. Further work is now needed to formally assess its reliability and validity for potential use in clinical practice and trials.
21267733 [Combination therapy using methotrexate with DMARDs or biologics--current status]. 2011 Feb Methotrexate (MTX) is the most frequently used drug in combination treatment with disease-modifying antirheumatic drugs (DMARDs) and biologics in rheumatoid arthritis. DMARD combinations are usually the second step after unsuccessful MTX monotherapy. Evidence-based combinations of MTX+leflunomide, MTX+cyclosporine and triple combination MTX+sulphasalazine+hydroxychloroquine (complemented by glucocorticoids) showed the best results.In the case of insufficient response to the DMARD combination, MTX should be used in combination with a biologic. To date, the most frequent biologic treatment is with TNF inhibitors, but studies have shown that all biologics (with the exception of Anakinra) have comparable success rates. The combination of MTX plus abatacept, MTX plus rituximab and MTX plus tocilizumab are very promising, both clinically and in terms of blocking radiological progression. The efficacy of biological therapy is generally better using MTX combination than monotherapy.The safety of MTX combination treatment with DMARDs is not significantly lower than that of the individual substances; therefore, the required safety controls are also the same.
23011358 A phase 3 randomized, double-blind, multicenter comparative study evaluating the effect of 2013 Jul OBJECTIVES: The aim of this phase 3, double-blind study was to compare the radiographic and clinical effects of etanercept (ETN) versus methotrexate (MTX) over 52 weeks in Japanese subjects with active rheumatoid arthritis. METHODS: The study population comprised 550 subjects with inadequate response to ≥1 disease-modifying anti-rheumatic drugs who were randomized to treatment groups of ETN 25 mg twice weekly (BIW; n = 182), ETN 10 mg BIW (n = 192), or MTX (≤8.0 mg/week; n = 176). RESULTS: Of the 550 subjects initially enrolled in the three treatment groups, 21.6% discontinued the study; a significantly higher proportion of those who withdrew from the study due to lack of efficacy were in the MTX (21.6%) group compared with the ETN 25 mg (3.3%) and ETN 10 mg (6.8%) groups (P < 0.001). Mean change from baseline in the modified total Sharp score at week 52 (primary endpoint) was significantly lower in the ETN 25 mg [3.33; standard error (SE), 0.73] and ETN 10 mg (5.19; SE 0.93) groups than in the MTX group (9.82; SE 1.16; P < 0.0001 vs. either ETN group). Compared with subjects receiving MTX, significantly higher percentages of subjects treated with ETN 25 and 10 mg achieved American College of Rheumatology (ACR) ACR20 and ACR50 response rates at all time points (P < 0.01). ETN was well-tolerated, with no unexpected safety findings. CONCLUSIONS: ETN 25 mg BIW and ETN 10 mg BIW slowed radiographic progression and improved clinical outcomes more effectively than MTX in this Japanese population.
22753652 Procalcitonin is a specific marker for detecting bacterial infection in patients with rheu 2012 Aug OBJECTIVE: Rheumatoid arthritis (RA) is a chronic inflammatory disease accompanied by many complications, and serious infections are associated with many of the advanced therapeutics used to treat it. We assessed serum procalcitonin (PCT) levels to distinguish bacterial infection from other complications in patients with RA. METHODS: One hundred eighteen patients experiencing an RA flare, noninfectious complication of RA or its treatment, nonbacterial infection, or bacterial infection were studied. Serum PCT concentrations were determined with a chemiluminescent enzyme immunoassay. RESULTS: All patients experiencing an RA flare showed negative PCT levels (≤ 0.1 ng/ml; n = 18). The PCT level was higher in the bacterial infection group (25.8% had levels ≥ 0.5 ng/ml) than in the other 3 groups (0.0-4.3% had levels ≥ 0.5 ng/ml) and the difference was significant among groups (p = 0.003). Conversely, no statistically significant difference was observed among the groups with C-reactive protein (CRP) concentration ≥ 0.3 mg/dl (p = 0.513), white blood cell (WBC) count > 8500/mm(3) (p = 0.053), or erythrocyte sedimentation rate (ESR) > 15 mm/h (p = 0.328). The OR of high PCT level (≥ 0.5 ng/ml) for detection of bacterial infection was 19.13 (95% CI 2.44-149.78, p = 0.005). Specificity and positive likelihood ratio of PCT ≥ 0.5 ng/ml were highest (98.2% and 14.33, respectively) for detection of bacterial infection, although the sensitivity was low (25.8%). CONCLUSION: Serum PCT level is a more specific marker for detection of bacterial infection than either CRP, ESR, or WBC count in patients with RA. High PCT levels (≥ 0.5 ng/ml) strongly suggest bacterial infection. However, PCT < 0.5 ng/ml, even if < 0.2 ng/ml, does not rule out bacterial infection and physicians should treat appropriately.
22792215 ACPA-negative RA consists of two genetically distinct subsets based on RF positivity in Ja 2012 HLA-DRB1, especially the shared epitope (SE), is strongly associated with rheumatoid arthritis (RA). However, recent studies have shown that SE is at most weakly associated with RA without anti-citrullinated peptide/protein antibody (ACPA). We have recently reported that ACPA-negative RA is associated with specific HLA-DRB1 alleles and diplotypes. Here, we attempted to detect genetically different subsets of ACPA-negative RA by classifying ACPA-negative RA patients into two groups based on their positivity for rheumatoid factor (RF). HLA-DRB1 genotyping data for totally 954 ACPA-negative RA patients and 2,008 healthy individuals in two independent sets were used. HLA-DRB1 allele and diplotype frequencies were compared among the ACPA-negative RF-positive RA patients, ACPA-negative RF-negative RA patients, and controls in each set. Combined results were also analyzed. A similar analysis was performed in 685 ACPA-positive RA patients classified according to their RF positivity. As a result, HLA-DRB1*04:05 and *09:01 showed strong associations with ACPA-negative RF-positive RA in the combined analysis (p = 8.8×10(-6) and 0.0011, OR: 1.57 (1.28-1.91) and 1.37 (1.13-1.65), respectively). We also found that HLA-DR14 and the HLA-DR8 homozygote were associated with ACPA-negative RF-negative RA (p = 0.00022 and 0.00013, OR: 1.52 (1.21-1.89) and 3.08 (1.68-5.64), respectively). These association tendencies were found in each set. On the contrary, we could not detect any significant differences between ACPA-positive RA subsets. As a conclusion, ACPA-negative RA includes two genetically distinct subsets according to RF positivity in Japan, which display different associations with HLA-DRB1. ACPA-negative RF-positive RA is strongly associated with HLA-DRB1*04:05 and *09:01. ACPA-negative RF-negative RA is associated with DR14 and the HLA-DR8 homozygote.