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ID PMID Title PublicationDate abstract
19460761 Synovial tissue and serum biomarkers of disease activity, therapeutic response and radiogr 2010 Apr OBJECTIVES: To evaluate synovial tissue and serum biomarkers of disease activity, therapeutic response and radiographic progression during biological therapy for rheumatoid arthritis (RA). METHODS: Patients with active RA entered a randomised study of anakinra 100 mg/day, administered as monotherapy or in combination with pegsunercept 800 microg/kg twice a week. Arthroscopic synovial tissue biopsies were obtained at baseline and two further time points. Following immunohistochemical staining, selected mediators of RA pathophysiology were quantified using digital image analysis. Selected mediators were also measured in the serum. RESULTS: Twenty-two patients were randomly assigned: 11 received monotherapy and 11 combination therapy. American College of Rheumatology 20, 50 and 70 response rates were 64%, 64% and 46% with combination therapy and 36%, 9% and 0% with monotherapy, respectively. In synovial tissue, T-cell infiltration, vascularity and transforming growth factor beta (TGFbeta) expression demonstrated significant utility as biomarkers of disease activity and therapeutic response. In serum, interleukin 6 (IL-6), matrix metalloproteinase (MMP) 1, MMP-3 and tissue inhibitor of metalloproteinase 1 (TIMP-1) were most useful in this regard. An early decrease in serum levels of TIMP-1 was predictive of the later therapeutic outcome. Pretreatment tissue levels of T-cell infiltration and the growth factors vascular endothelial growth factor/TGFbeta, and serum levels of IL-6, IL-8, MMP-1, TIMP-1, soluble tumour necrosis factor receptor types I and II and IL-18 correlated with radiographic progression. CONCLUSIONS: Synovial tissue analysis identified biomarkers of disease activity, therapeutic response and radiographic progression. Biomarker expression in tissue was independent of the levels measured in the serum.
19419560 Class-switched B cells display response to therapeutic B-cell depletion in rheumatoid arth 2009 INTRODUCTION: Reconstitution of peripheral blood (PB) B cells after therapeutic depletion with the chimeric anti-CD20 antibody rituximab (RTX) mimics lymphatic ontogeny. In this situation, the repletion kinetics and migratory properties of distinct developmental B-cell stages and their correlation to disease activity might facilitate our understanding of innate and adaptive B-cell functions in rheumatoid arthritis (RA). METHODS: Thirty-five 'RTX-naïve' RA patients with active arthritis were treated after failure of tumour necrosis factor blockade in an open-label study with two infusions of 1,000 mg RTX. Prednisone dose was tapered according to clinical improvement from a median of 10 mg at baseline to 5 mg at 9 and 12 months. Conventional disease-modifying antirheumatic drugs were kept stable. Subsets of CD19+ B cells were assessed by flow cytometry according to their IgD and CD27 surface expression. Their absolute number and relative frequency in PB were followed every 3 months and were determined in parallel in synovial tissue (n = 3) or synovial fluid (n = 3) in the case of florid arthritis. RESULTS: Six of 35 patients fulfilled the European League Against Rheumatism criteria for moderate clinical response, and 19 others for good clinical response. All PB B-cell fractions decreased significantly in number (P < 0.001) after the first infusion. Disease activity developed independently of the total B-cell number. B-cell repopulation was dominated in quantity by CD27-IgD+ 'naïve' B cells. The low number of CD27+IgD- class-switched memory B cells (MemB) in the blood, together with sustained reduction of rheumatoid factor serum concentrations, correlated with good clinical response. Class-switched MemB were found accumulated in flaring joints. CONCLUSIONS: The present data support the hypothesis that control of adaptive immune processes involving germinal centre-derived, antigen, and T-cell-dependently matured B cells is essential for successful RTX treatment.
20100935 Histone deacetylase inhibitors suppress inflammatory activation of rheumatoid arthritis pa 2010 Mar 1 Macrophages contribute significantly to the pathology of many chronic inflammatory diseases, including rheumatoid arthritis (RA), asthma, and chronic obstructive pulmonary disease. Macrophage activation and survival are tightly regulated by reversible acetylation and deacetylation of histones, transcription factors, and structural proteins. Although histone deacetylase (HDAC) inhibitors (HDACis) demonstrate therapeutic effects in animal models of chronic inflammatory disease, depressed macrophage HDAC activity in patients with asthma, chronic obstructive pulmonary disease, or RA may contribute to inflammation in these diseases, potentially contraindicating the therapeutic administration of HDACis. In this study, we directly examined whether HDACis could influence the activation of macrophages derived from the inflamed joints of patients with RA. We found that inhibition of class I/II HDACs or class III sirtuin HDACs potently blocked the production of IL-6 and TNF-alpha by macrophages from healthy donors and patients with RA. Two HDACis, trichostatin A and nicotinamide, selectively induced macrophage apoptosis associated with specific downregulation of the antiapoptotic protein Bfl-1/A1, and inflammatory stimuli enhanced the sensitivity of macrophages to HDACi-induced apoptosis. Importantly, inflammatory and angiogenic cytokine production in intact RA synovial biopsy explants was also suppressed by HDACis. Our study identifies redundant, but essential, roles for class I/II and sirtuin HDACs in promoting inflammation, angiogenesis, and cell survival in RA.
19404006 Jak inhibitor ; possibility and mechanism as a new disease modifying anti-rheumatic drug. 2009 Apr Treatment of rheumatoid arthritis (RA) has developed dramatically by the appearance of biologics. However the development of a new anti-rheumatic drug is necessary because of its issue on route of administration and expense. Recently, inhibitors targeting tyrosine kinase known as Janus kinase (Jak) has shown prominent effect on RA. Jak family is comprised by Jak1, Jak2, Jak3 and Tyk2 which is necessary for signal transduction for inflammatory cytokines. INCB18424 targeting Jak1/2 and CP690,550 targeting Jak3 has been developed and is now on phase II clinical study for RA. Results from those clinical studies have proven that these inhibitors can be effective as biologics with few side effects. However, it has been reported that inhibitors are less specific than it has been expect and that non-specificity can be important for its effect. Therefore, we think that the mechanism of inhibitors cannot be explained by its inhibition of a single kinase. Herein, we describe IL-10 overproduction by Jak3 and Stat6 deficient dendritic cell. We speculate that this is one possible mechanism of action for CP690,550 although as for its non-specificity we need further investigation to predict not only its effect but also its side effect in a long term administration.
21052674 Mycoplasmal lipid-associated membrane proteins and Mycoplasma arthritidis mitogen recognit 2011 Jul Mycoplasmal lipid-associated membrane proteins (LAMPs) and Mycoplasma arthritidis mitogen (MAM superantigen) are potent stimulators of the immune system. The objective of this work was to detect antibodies to MAM and LAMPs of Mycoplasma hominis and M. fermentans in the sera of patients affected by rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) to identify mycoplasmal products that can be involved in the etiopathogenesis of these autoimmune diseases. Serum samples from female RA and SLE patients and controls, recombinant MAM, and LAMPs of M. hominis PG21 and M. fermentans PG18 were used in Western blot assays. A similar frequency of sera from patients and controls reactive to MAM was detected. A larger number of M. hominis and M. fermentans LAMPs were recognized by sera from RA patients than controls, but no differences were detected between sera from SLE patients and controls. Among the LAMPs recognized by IgG antibodies from RA patients, proteins of molecular masses in a range of <49 and ≥20 KDa (M. hominis) and <102 and ≥58 KDa (M. fermentans) were the most reactive. These preliminary results demonstrate the strong reactivity of antibodies of RA patients with some M. hominis and M. fermentans LAMPs. These LAMPs could be investigated as mycoplasmal antigens that can take part in the induction or amplification of human autoimmune responses.
20346233 Visfatin, resistin, hsCRP and insulin resistance in relation to abdominal obesity in women 2010 Jan OBJECTIVES: The increasing incidence of overweight and obesity in modern societies, and the demonstration that adipose tissue produces numerous cytokines, increases interest of investigators in the associations between adipose tissue, adipokines, CRP and insulin resistance in rheumatoid arthritis (RA) and their possible role in the pathogenesis of this disease.The purpose of the study was to investigate serum levels of visfatin, resistin, hsCRP and insulin resistance in relation to abdominal obesity in patients with RA. METHODS: Serum levels of visfatin, resistin, hsCRP and glucose metabolism parameters were measured in 46 women with RA - 22 without abdominal obesity and 24 with abdominal obesity. RESULTS: Patients with RA and abdominal obesity showed significant lower visfatin levels (1.00+/-0.93 vs. 1.44+/-0.85 ng/ml; p<0.05) in comparison to those without abdominal obesity. We found significant correlations between levels of visfatin and resistin (r=0.41; p<0.01); and between resistin levels and hsCRP levels (r=0.41; p<0.01); resistin levels and leucocytes count (r=0.36; p<0.05); and resistin levels and ESR (r=0.30; p<0.05), in the whole investigated group. Visfatin as well as resistin did not correlate with anthropometric parameters or insulin resistance in whole patients with RA. CONCLUSIONS: In patients with RA and abdominal obesity, in comparison to patients without abdominal obesity, significantly lower visfatin levels have been demonstrated. Resistin was associated with laboratory markers of inflammation. Positive correlation between levels of visfatin and resistin may suggest that visfatin plays a role in inflammation in RA.
19685204 Infliximab treatment reduces the serum levels of interleukin-23 in patients with rheumatoi 2009 In this study, we investigated the effect of the antitumor necrosis factor alpha (anti-TNF-alpha) antibody, infliximab, combined with methotrexate (MTX) and MTX alone on the serum levels of interleukin (IL)-23 and IL-17 in rheumatoid arthritis (RA) patients. Infliximab combined with MTX was administered to 26 patients with RA (infliximab group), and MTX alone was given to 20 patients with RA (MTX group). We evaluated clinical and laboratory parameters, including the Disease Activity Scores of 28 joints (DAS28) and serum levels of IL-23 and IL-17 at baseline and at 14 and 30 weeks after the initial treatment with these drugs. Single regression analysis was performed between the levels of serum IL-23 and other clinical and laboratory parameters at baseline before the initial treatment with infliximab or MTX. A significant reduction of DAS28 scores was observed in both the infliximab and the MTX group at 14 and 30 weeks after the initial treatment. A significant decrease in serum levels of IL-23 was observed in the infliximab group but not in the MTX group at 14 and 30 weeks after the initial treatment. Serum IL-17 levels did not show a significant change during the follow-up period. At baseline, before the initial treatment with infliximab or MTX, serum IL-23 levels showed a significant correlation with DAS28 and the number of swollen joints. This study indicated that the reduction of serum IL-23 levels in RA patients was a novel action of infliximab.
21188453 A multicentre trial of bucillamine in the treatment of early rheumatoid arthritis (SNOW st 2011 Jun In this study, we enrolled early rheumatoid arthritis (RA) patients at multiple institutes who fulfilled the American Rheumatism Association 1987 revised criteria for the classification of RA, and followed the clinical results of disease-modifying anti-rheumatic drug (DMARD) treatment prospectively. With the aim of developing therapeutic guidelines using the disease activity score 28 (DAS28) as disease indices, we investigated the usefulness of bucillamine (BUC), one of the most widely used DMARDs in Japan. Eighty-one patients with early RA who had not previously been treated with DMARDs were suitable for BUC therapy as first-choice treatment. After 24 months of treatment, at least moderate improvement was seen in 87.5% of patients using the DAS28 erythrocyte sedimentation rate (ESR). After 24 months of BUC therapy, 7 patients (43.8%) met the remission criterion of DAS28 (ESR) <2.6. The 24-month BUC continuation rate was 60.5% (49/81, monotherapy + combination therapy), of which 59.2% (29/49) were on BUC monotherapy. From the efficacy and safety viewpoints alike, BUC was useful as first-choice treatment for early RA.
19095031 Construction and characterization of a novel DNA vaccine that is potent antigen-specific t 2009 Jan 29 Currently available treatments for rheumatoid arthritis (RA) are often ineffective in ameliorating the progression of disease, particularly the invasive destruction of articular cartilage and bone, and RA remains incurable. Therefore, vaccinotherapy of RA with an antigen-specific tolerizing DNA vaccine may offer new promise for overcoming this difficulty. Using recombinant technology, the DNA sequences encoding chicken type II collagen (CCOL2A1) with deleted N-propeptides were obtained from the plasmid pPIC9K/pCalpha(1)(II), and then cloned into pcDNA3.1(+). The resulting recombinant plasmid pcDNA-CCOL2A1 was produced in Escherichia coli, purified, characterized and used as a tolerizing DNA vaccine for the treatment of collagen-induced arthritis (CIA). Therapeutic efficacy and potential action mechanisms of pcDNA-CCOL2A1 tolerizing DNA vaccine against CIA were studied. Here we demonstrate that a single intravenous treatment with novel tolerizing DNA vaccine pcDNA-CCOL2A1 can induce potent immune tolerance against CIA. The efficacy of this therapy was verified by clinical visual scoring, radiographic X-ray, histopathological examination, and anti-CII IgG levels. Furthermore, the action mechanism behind this efficacy can be at least partially attributed to increased CD4(+)CD25(+) T regulatory cells, which specifically down-modulate the T lymphocyte proliferative response to CCII, induce a shift of Th1 to Th2 cells, as well as down-regulate Th1-cytokine TNF-alpha, while up-regulating both Th2-cytokine IL-10 and Th3-cytokine TGF-beta. More importantly, pcDNA-CCOL2A1 alone seems to be as effective as the current "golden standard" treatment, methotrexate (MTX). Taken together, these results suggest that we have successfully developed a novel tolerizing DNA vaccine encoding CCII, which is the first description of a tolerizing DNA vaccine encoding CCII for antigen-specific tolerizing therapy but not prophylactic against CIA.
19603104 Osteopontin is associated with increased arterial stiffness in rheumatoid arthritis. 2009 Nov Rheumatoid arthritis (RA) patients are characterized by increased arterial stiffness, an independent predictor of cardiovascular risk. It has been suggested that osteopontin (OPN), a cytokine involved in RA pathogenesis, might have vascular effects. To study a possible relationship between OPN and arterial stiffness, aortic pulse wave velocity (PWV) was measured by tonometry in 69 patients (41 with RA, 28 with systemic sclerosis [SSc]) and 18 healthy controls. Plasma OPN levels, oxidative stress markers, and endothelin 1 (ET-1) were assessed. OPN levels were significantly (P < 0.05) higher in RA (median 9.93, range 4.36-47.80 ng/mL) than in SSc (4.3, 2.1-19.7 ng/mL) or controls (5.2, 4.1-9.4 ng/mL). In RA patients, log-OPN was related to log-C-reactive protein (log-CRP) (r = 0.30, P < 0.05), age (r = 0.38, P < 0.01), Health Assessment Questionnaire (HAQ) (r = 0.58, P < 0.0001), and inversely related to total cholesterol (r = -0.33, P < 0.05) and apolipoprotein A (apoA) (r = -0.58, P < 0.001), but not to oxidative stress markers and ET-1. PWV was similar in RA (median 8.1, range 4.7-16.4 m/s) and SSc (median 8.7, range 7.1-13.1 m/s), but significantly greater (P < 0.01) than controls (median 7.5, range 4.1-10.4 m/s). Aortic PWV was related to log-OPN (r = 0.40, P < 0.01) only in RA patients. It also was related to age (r = 0.34, P < 0.05), mean blood pressure (r = 0.44, P < 0.001), and HAQ (r = 0.48, P < 0.001). In multiple regression analysis (r(2) = 0.36), including confounders, log-OPN remained a significant predictor (P < 0.05) of PWV in RA. Elevated plasma OPN levels are associated with increased arterial stiffness in RA patients, suggesting that this protein might represent a bridge protein between inflammation and the consequent joint damage and cardiovascular risk in RA patients.
19459571 [Biologic therapy of rheumatoid arthritis]. 2009 Mar Rheumatoid arthritis (RA) and juvenile idiopathic/rheumatoid arthritis (JIA) are chronic, inflammatory, systemic, autoimmune diseases characterized by chronic arthritis leading to progressive joint erosions. The individual functional and social impact of rheumatoid arthritis is of great importance. Disability and joint damage occur rapidly and early in the course of the disease. The remarkably improved outcomes have been achieved initiating biologic therapy with close monitoring of disease progression. Biologic agents are drugs, usually proteins, which can influence chronic immune dysregulation resulting in chronic arthritis. According to the mechanism of action these drugs include: 1) anti-TNF drugs (etanercept, infiximab, adalimumab); 2) IL-1 blocking drugs (anakinra); 3) IL-6 blocking drugs (tocilizumab); 4) agents blocking selective co-stimulation modulation (abatacept); 5) CD 20 blocking drugs (rituximab). Biologics targeting TNF-alpha with methotrexate have revolutionized the treatment of RA, producing significant improvement in clinical, radiographic, and functional outcomes not seen previously. The new concept of rheumatoid arthritis treatment defines early diagnosis, early aggressive therapy with optimal doses of disease modifying antirheumatic drugs (DMARDs) and, if no improvement has been achieved during six months, early introduction of biologic drugs. The three-year experience of biologic therapy in Serbia has shown a positive effect on disease outcome.
19581389 Investigation of the influence of CYP1A2 and CYP2C19 genetic polymorphism on 2-Cyano-3-hyd 2009 Oct Leflunomide is a disease-modifying antirheumatic drug used for the treatment of rheumatoid arthritis (RA). Cytochromes P450, mainly CYP1A2 and CYP2C19, may be involved in the transformation of leflunomide to leflunomide metabolite (A77 1726, 2-cyano-3-hydroxy-N-[4-(trifluoromethyl)phenyl]-2-butenamide). The aim of this study was to investigate whether genetic polymorphisms in CYP1A2 and CYP2C19 influence leflunomide pharmacokinetics, treatment response, and the occurrence of adverse drug reactions (ADRs). The study included 67 patients with RA and 4 patients with polyarthritis resembling RA and psoriasis treated with leflunomide. A77 1726 steady-state plasma concentrations were determined by validated high-performance liquid chromatography with UV detection. A population pharmacokinetic model was developed to estimate the oral clearance (CL/F) and volume of distribution (V/F). A genotyping approach was used to determine C-163A, C-729T, and T-739G in the CYP1A2 gene as well as single nucleotide polymorphisms that characterize CYP2C19*2, *3, *4, and *17 alleles. A large interindividual variability in trough A77 1726 steady-state plasma concentrations was observed (from 1.9 to 156.9 mg/l). A77 1726 CL/F was 71% higher in carriers of the CYP2C19*2 allele compared with noncarriers. The A77 1726 average steady-state plasma concentration was associated with the treatment response. Patients with a greater decrease in C-reactive protein (CRP) had higher average steady-state plasma A77 1726 concentrations: 49.7 +/- 39.0 mg/l in patients with DeltaCRP of more than 8.5 mg/l compared with 24.8 +/- 13.7 mg/l in patients with DeltaCRP of
19132792 Cartilage and bone biomarkers in rheumatoid arthritis: prediction of 10-year radiographic 2009 Feb OBJECTIVE: As current predictors of joint destruction have low specificity, serological biomarkers reflecting bone and cartilage destruction have been proposed as tools in assessing prognosis of rheumatoid arthritis (RA). We examined whether serum concentrations of a panel of biomarkers could predict radiographic progression in patients with RA. METHODS: A cohort of 238 patients with RA was followed longitudinally for 10 years with collection of clinical data and serum samples. These analyses focus on the 136 patients with radiographs of the hands available at baseline and at 5 and/or 10 years. Radiographs were scored according to the van der Heijde-modified Sharp score (SHS). Baseline sera were analyzed for receptor activator of nuclear factor-kappaB ligand (RANKL), osteoprotegerin (OPG), human cartilage glycoprotein-39 (YKL-40), C2C, collagen cross-linked C-telopeptide (CTX-I), and cartilage oligomeric matrix protein (COMP). Multivariate linear and logistic regression analyses were used to identify predictors of radiographic progression. RESULTS: Baseline CTX-I levels were higher in progressors [0.41 ng/ml (interquartile range 0.31-0.75)] than in nonprogressors [0.32 ng/ml (IQR 0.21-0.49)], and were independently associated with 10-year change in radiographic damage score [ss = 16.4 (IQR 5.7-27.1)]. We found no association between radiographic progression and baseline serum levels of RANKL, OPG, C2C, YKL-40, or COMP. CONCLUSION: This longterm followup study of patients with RA indicates a relationship between elevated CTX-I levels in serum and subsequent joint destruction. This association was, however, weak, and our study does not support that serum CTX-I or any of the other tested biomarkers will serve as more useful prognostic markers than current predictors such as anti-cyclic citrullinated peptide, radiographic damage early in the disease course, and signs of inflammation.
20673615 Effects of extensor synovectomy and excision of the distal ulna in rheumatoid arthritis on 2010 Sep PURPOSE: Objective outcomes data after excision of the distal ulna in rheumatoid arthritis are lacking. The aim of this study was to evaluate the functional results of this surgery in the long term. METHODS: We prospectively collected data on range of motion (22 wrists), visual analog pain scores (14 wrists), and grip strength measured using a Jamar dynamometer (20 hands) in a group of 23 patients (26 wrists) preoperatively and at 3 months, 12 months, and a minimum of 5 years postoperatively (range, 5.3-10.4 y). The Jebsen-Taylor hand function test was administered to 9 patients at the same time points. A subgroup of patients also underwent extensor carpi radialis longus to extensor carpi ulnaris tendon transfer (11 wrists). RESULTS: At one year, there were improvements in wrist pronation and supination, which were maintained at final follow-up. Active radial deviation decreased significantly at 3 months (p = .01) and one year (p = .02); this remained reduced at final follow-up (not significant). Wrist extension and active ulnar deviation showed slight improvements by one year, but reduced to levels below that measured preoperatively by final follow-up. Wrist flexion was significantly reduced at all time points postoperatively. Grip strength showed improvement from 10.0 kg (standard deviation [SD] 4.1 kg) preoperatively to 12.5 kg (SD 4.6 kg) 1 year after surgery and returned to preoperative levels (9.5 kg, SD 5.6 kg) by final follow-up. Wrist pain was significantly reduced from a mean score of 5 (SD 4) preoperatively to 2 (SD 2) postoperatively (p = .01). The Jebsen-Taylor hand function test showed improvements in writing and card turning. CONCLUSIONS: In the long term, excision of the distal ulna in rheumatoid patients results in an improvement in some aspects of hand function. There is a significant (p = .01) reduction in wrist pain but a reduction of wrist flexion. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV.
19490633 Nerve growth factor and receptor expression in rheumatoid arthritis and spondyloarthritis. 2009 INTRODUCTION: We previously described the presence of nerve growth factor receptors in the inflamed synovial compartment. Here we investigated the presence of the corresponding nerve growth factors, with special focus on nerve growth factor (NGF). METHODS: mRNA expression levels of four ligands (NGF, brain derived growth factor (BDNF), neurotrophin (NT)-3, NT-4) and their four corresponding receptors (tyrosine kinase (trk) A, trkB, trkC, NGFRp75) were determined in the synovial fluid (SF) cells of 9 patients with rheumatoid arthritis (RA) and 16 with spondyloarthritis (SpA) and compared with 7 osteoarthritis (OA) patients. NGF was also determined in synovial tissue (ST) biopsies of 10 RA and 10 SpA patients. The production of NGF by monocytes and lymphocytes was assessed by flow cytometry of SF cells, synovial tissue derived fibroblast-like synoviocytes (FLS) were assessed by ELISA on culture supernatant. RESULTS: SF cell analysis revealed a clear BDNF and NGF mRNA expression, with significantly higher NGF expression in RA and SpA patients than in the OA group. NGF expression was higher in ST samples of RA as compared to SpA. Using intracellular FACS analysis, we could demonstrate the presence of the NGF protein in the two inflammatory arthritis groups on both CD3+ T lymphocytes and CD14+ cells, i.e. monocytes/macrophages, whereas cultured FLS did not produce NGF in vitro. CONCLUSIONS: Neurotrophins and especially NGF are expressed in the synovial fluid and tissue of patients with peripheral synovitis. The presence of neurotrophins as well as their receptors, in particular the NGF/trkA-p75 axis in peripheral synovitis warrants further functional investigation of their active involvement in chronic inflammatory arthritis.
18445623 Preferential decrease in IgG4 anti-citrullinated protein antibodies during treatment with 2009 Apr OBJECTIVE: To investigate the dynamics of IgG1 and IgG4 anti-citrullinated protein antibody (ACPA) subclasses during anti-tumour necrosis factor (TNF) treatment in patients with rheumatoid arthritis (RA). METHODS: IgG, IgG1 and IgG4 ACPA levels were determined by ELISA on anti-citrullinated fibrinogen (ACF) and IgG1 : IgG4 ACPA ratios were calculated. A pilot study was performed in 28 ACF-positive patients treated with infliximab for one year. Confirmation of the results was obtained using a cohort of 180 consecutive patients treated with adalimumab for 28 weeks. RESULTS: The median reduction in ACF levels was 31% for total IgG, 29% for IgG1, 40% for IgG4 and 22% for the IgG4 : IgG1 ACF ratio in the infliximab cohort. In adalimumab-treated patients, ACF levels declined 14% for total IgG and IgG1, and 36% for IgG4 ACF; the IgG4 : IgG1 ratio was reduced by 24% (all percentage values p<0.05). The decrease in antibody levels was correlated with the clinical response; European League Against Rheumatism good responders had the greatest decline in antibody levels and this effect was most pronounced for IgG4 (48% reduction). The IgG4 : IgG1 ACF ratio preferentially decreased in patients with adequate therapeutic adalimumab levels. CONCLUSION: ACPA subclass distribution is modulated by effective anti-inflammatory treatment. The preferential decline of IgG4 ACPA, reflected by the decreased IgG4 : IgG1 ratio, suggests a beneficial effect of anti-TNF treatment on chronic antigenic stimulation by citrullinated proteins. This effect may be directly anti-TNF mediated or the result of effective dampening of the inflammation in the rheumatoid joint.
18830734 Endothelial nitric oxide synthase T-786C polymorphism in rheumatoid arthritis: association 2009 Feb Several genetic factors were implicated in the pathogenesis of rheumatoid arthritis (RA). A case-control study was carried out to verify the associations of T-786C polymorphism in the promoter region of the endothelial nitric oxide synthase (eNOS) gene with RA. One hundred and five consecutive RA patients and 100 healthy controls were genotyped. The distribution of the T-786C genotype and alleles did not differ significantly between RA patients and controls. Nevertheless, the frequency of extraarticular manifestations was significantly greater among the carriers of the C/C genotype than among carriers of the T/C and T/T genotypes (P = 0.022). The C/C genotype was significantly associated with extraarticular manifestations compared with the T/T and T/C genotypes taken together (OR = 4.9, 95% CI = 1.3-18.9). The C allele was significantly associated with extraarticular manifestations of RA (P(corr) = 0.032). The results suggested the existence of an association between the T-786C polymorphism of the eNOS gene and extraarticular manifestations of RA.
19054829 Elevated synovial expression of triggering receptor expressed on myeloid cells 1 in patien 2009 Nov OBJECTIVE: To determine whether synovial expression of triggering receptor expressed on myeloid cells 1 (TREM-1) is upregulated in patients with distinct types of inflammatory or non-inflammatory arthritis. METHODS: Synovial fluid (SF) samples were analysed for levels of soluble TREM-1 (sTREM; n = 132), tumour necrosis factor alpha (TNFalpha, n = 78) and leucocyte TREM-1 messenger RNA (n = 48). Synovial tissue from four rheumatoid arthritis (RA) patients, two patients with Crohn's-associated arthritis, one patient with ankylosing spondylitis and one patient with osteoarthritis were examined for TREM-1 expression by immunohistology, and three of the RA samples were also analysed by Western blotting. RESULTS: Synovial fluid sTREM-1 levels in septic arthritis and RA were similar to each other and were each greater than those in gouty arthritis, non-septic/non-RA inflammatory arthritis and non-inflammatory arthritis. Synovial fluid TNFalpha and sTREM-1 levels correlated with each other, and sTREM-1 and leucocyte TREM-1 mRNA levels each correlated with SF leucocyte counts. TREM-1 in RA was expressed in situ in synovial tissue by cells of myelomonocytic lineage but was not detectably expressed in control osteoarthritis synovial tissue. CONCLUSIONS: Synovial TREM-1 expression is increased in septic arthritis and RA. In patients with acute inflammatory arthritis, elevated SF sTREM-1 levels may point the clinician to a diagnosis of septic arthritis or RA. In RA patients, targeting TREM-1 may have therapeutic benefits by reducing local proinflammatory cytokine and chemokine release.
19906833 Initiation of rheumatoid arthritis treatments and the risk of serious infections. 2010 Jan OBJECTIVE: In clinical trials of RA patients on traditional DMARDs, the addition of TNF-alpha antagonists increased infections compared with addition of placebo. Our objective was to compare serious infections following initiation of different RA regimens. Prior comparative studies of DMARD initiation have yielded conflicting results. METHODS: We estimated hospitalization rates for infections following initiation of TNF-alpha antagonists, other DMARDs and oral glucocorticoids in Tennessee Medicaid-enrolled RA patients (1995-2005). Exposure time was measured using pharmacy information and infections were identified using validated definitions. Initiation of RA regimens was compared using Cox regression models with MTX as the reference. Sensitivity analyses excluded glucocorticoid users, applied a first exposure carried forward approach, restricted observations to 2002-05 and first episodes of use and explored effects of unmeasured confounders. RESULTS: We identified 28 906 new episodes of medication use, including TNF-alpha antagonists (8%), MTX alone (15%) and glucocorticoids alone (57%). Compared with MTX initiation, TNF-alpha antagonist initiation did not significantly increase the risk of hospitalizations for pneumonia [adjusted hazard ratio (aHR) 1.61; 95% CI 0.85, 3.03] or any infection (aHR 1.31; 95% CI 0.78, 2.19). Initiation of LEF, SSZ or HCQ did not increase serious infections, compared with MTX. Both initiation and concurrent glucocorticoid use were associated with a dose-dependent increase in serious infections. Sensitivity analyses showed consistent results. CONCLUSIONS: Compared with initiation of MTX alone, initiation of TNF-alpha antagonists was not associated with a large increase in the risk of serious infections. Glucocorticoid use was associated with a dose-dependent increase in the risk of these infections.
20537173 Peptidyl arginine deiminase type IV (PADI4) haplotypes interact with shared epitope regard 2010 INTRODUCTION: Anti-cyclic citrullinated peptide autoantibodies (anti-CCP) are the most specific serologic marker for rheumatoid arthritis (RA). Genetic polymorphisms in a citrullinating (or deiminating) enzyme, peptidyl arginine deiminase type IV (PADI4) have been reproducibly associated with RA susceptibility in several populations. We investigated whether PADI4 polymorphisms contribute to anti-CCP-negative as well as -positive RA, whether they influence disease severity (erosive joint status), and whether they interact with two major risk factors for RA, Human Leukocyte Antigen-DRB1 (HLA-DRB1) shared epitope (SE) alleles and smoking, depending on anti-CCP and erosive joint status. METHODS: All 2,317 unrelated Korean subjects including 1,313 patients with RA and 1,004 unaffected controls were genotyped for three nonsynonymous (padi4_89, padi4_90, and padi4_92) and one synonymous (padi4_104) single-nucleotide polymorphisms (SNPs) in PADI4 and for HLA-DRB1 by direct DNA sequence analysis. Odds ratios (OR) were calculated by multivariate logistic regression. Interaction was evaluated by attributable proportions (AP), with 95% confidence intervals (CI). RESULTS: A functional haplotype of the three fully correlated nonsynonymous SNPs in PADI4 was significantly associated with susceptibility to not only anti-CCP-positive (adjusted OR 1.73, 95% CI 1.34 to 2.23) but also -negative RA (adjusted OR 1.75, 95% CI 1.15 to 2.68). A strong association with both non-erosive (adjusted OR 1.62, 95% CI 1.29 to 2.05) and erosive RA (adjusted OR 1.62, 95% CI 1.14 to 2.31) was observed for PADI4 haplotype. Gene-gene interactions between the homozygous RA-risk PADI4 haplotype and SE alleles were significant in both anti-CCP-positive (AP 0.45, 95% CI 0.20 to 0.71) and -negative RA (AP 0.61, 95% CI 0.29 to 0.92). Theses interactions were also observed for both non-erosive (AP 0.48, 95% CI 0.25 to 0.72) and erosive RA (AP 0.46, 95% CI 0.14 to 0.78). In contrast, no interaction was observed between smoking and PADI4 polymorphisms. CONCLUSIONS: A haplotype of nonsynonymous SNPs in PADI4 contributes to development of RA regardless of anti-CCP or erosive joint status. The homozygous PADI4 haplotype contribution is affected by gene-gene interactions with HLA-DRB1 SE alleles.