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ID PMID Title PublicationDate abstract
22832945 Mechanisms of bone fragility in a mouse model of glucocorticoid-treated rheumatoid arthrit 2012 Nov OBJECTIVE: Glucocorticoid (GC) therapy is associated with increased risk of fracture in patients with rheumatoid arthritis (RA). To elucidate the cause of this increased risk, we examined the effects of chronic erosive inflammatory arthritis and GC treatment on bone quality, structure, and biomechanical properties in a murine model. METHODS: Mice with established arthritis and expressing human tumor necrosis factor α (TNFα) transgene (Tg) and their wild-type (WT) littermates were continually treated with GC (prednisolone 5 mg/kg/day via subcutaneous controlled-release pellet) or placebo for 14, 28, or 42 days. Microstructure, biomechanical properties, chemical composition, and morphology of the tibiae and lumbar vertebral bodies were assessed by micro-computed tomography, biomechanical testing, Raman spectroscopy, and histology, respectively. Serum markers of bone turnover were also determined. RESULTS: TNF-Tg and GC treatment additively decreased mechanical strength and stiffness in both the tibiae and the vertebral bodies. GC treatment in the TNF-Tg mice increased the ductility of tibiae under torsional loading. These changes were associated with significant alterations in the biochemical and structural composition of the mineral and organic components of the bone matrix, a decrease in osteoblast activity and bone formation, and an increase in osteoclast activity. CONCLUSION: Our findings indicate that the concomitant decrease in bone strength and increase in bone ductility associated with chronic inflammation and GC therapy, coupled with the significant changes in the bone quality and structure, may increase the susceptibility of the bone to failure under low-energy loading. This may explain the mechanism of symptomatic insufficiency fractures in patients with RA receiving GC therapy who do not have radiographic manifestations of fracture.
22390545 Hypogalactosylation of serum N-glycans fails to predict clinical response to methotrexate 2012 Mar 5 INTRODUCTION: Rheumatoid arthritis (RA) is associated with hypogalactosylation of immunoglobulin G (IgG). We examined whether a proxy measure for galactosylation of IgG N-glycans could predict response to therapy or was differentially affected by methotrexate (MTX) or TNF blockade. METHODS: Using a previously defined normal phase high-performance liquid chromatography approach, we ascertained the galactosylation status of whole serum N-glycans in two well-defined RA clinical cohorts: the Autoimmune Biomarkers Collaborative Network (n = 98) and Nested I (n = 64). The ratio of agalactosylated to monogalactosylated N-glycans in serum (sG0/G1) was determined before and during therapy with MTX or TNF inhibition and correlated with anticitrullinated peptide antibody (ACPA) status and clinical response as assessed by 28-joint Disease Activity Score utilizing C-reactive peptide and European League Against Rheumatism response criteria. RESULTS: RA patients from both cohorts exhibited elevation of sG0/G1 at baseline. Improvement in clinical scores correlated with a reduction in sG0/G1 (Spearman's ρ = 0.31 to 0.37; P < 0.05 for each cohort). However, pretreatment sG0/G1 was not predictive of clinical response. Changes in sG0/G1 were similar in the MTX and TNF inhibitor groups. Corrected for disease activity, ACPA positivity correlated with higher sG0/G1. CONCLUSIONS: Baseline serum N-glycan hypogalactosylation, an index previously correlated with hypogalactosylation of IgG N-glycans, did not distinguish patients with rheumatoid arthritis who were likely to experience a favorable clinical response to MTX or TNF blockade. Clinical improvement was associated with partial glycan normalization. ACPA-positive patients demonstrated enhanced N-glycan aberrancy compared with ACPA-negative patients.
21965824 Multicentric evaluation of a second generation assay to detect antiviral citrullinated pep 2011 Dec AIMS: A novel immunoenzymatic assay using viral citrullinated peptides derived from Epstein-Barr virus-encoded proteins (viral citrullinated peptide 2 (VCP2)) has been developed and evaluated by means of a multicentre collaborative study. METHODS: Three hundred nine sera from patients with established rheumatoid arthritis (RA), 36 with early arthritis, 12 with juvenile arthritis and 453 controls were tested for VCP2 and cyclic citrullinated peptide (CCP) antibodies. RESULTS: The VCP2 assay showed 78.3% sensitivity and 97.1% specificity. VCP2 and CCP had a high concordance rate in patients with RA (88%) and controls (97%). However, 36 RA sera were positive in the CCP assay but negative on VCP2, and two RA sera reacted only on VCP2. CONCLUSIONS: The new VCP2 assay is endowed with high sensitivity and specificity. VCP2-positive RA sera are mostly but not completely contained in the CCP-positive population. Studies are in progress to establish whether the VCP2 assay can detect clinically distinct subsets of patients with RA.
21885483 Serum hepcidin: a direct link between anemia of inflammation and coronary artery atheroscl 2011 Oct OBJECTIVE: To investigate the role of hepcidin as an inducer of anemia of inflammation in patients with rheumatoid arthritis (RA), and its correlation to coronary artery atherosclerosis. METHODS: Our study included 60 patients with RA and 20 healthy controls. Anemic RA patients with serum transferrin receptors/log ferritin (sTfR-F) index value < 1.5 were classified as having pure anemia of chronic disease (ACD), and patients with sTfR-F index value > 1.5 were classified as having anemia of chronic disease with coexistent iron deficiency anemia (ACD+IDA). Measurements were taken for Disease Activity Score for 28 joints (DAS28), Modified Health Assessment Questionnaire (MHAQ), erythrocyte sedimentation rate (ESR), high sensitivity C-reactive protein (hsCRP), rheumatoid factor (RF), lipid profile, serum interleukin 6 (IL-6), tumor necrosis factor-α, iron studies, and serum hepcidin. Coronary calcium score (CCS) was measured using multislice spiral computed tomography as a marker of atherosclerosis. RESULTS: Serum hepcidin was found to be higher in anemic patients with RA than in controls (p < 0.001), and higher in the pure ACD subgroup than in the ACD+IDA subgroup (p < 0.001). Hepcidin concentration was positively correlated with disease duration, ESR, hsCRP, RF, DAS28, MHAQ, serum ferritin, IL-6, and mean CCS and inversely correlated with hemoglobin, sTfR, and the sTfR-F index. CONCLUSION: Hepcidin can be considered a key inducer of anemia of inflammation in patients with RA. This inflammation was proved to be directly linked to coronary artery atherosclerosis. The correlations between serum hepcidin with disease activity and IL-6 raise the possibility of using it as a surrogate marker for disease activity.
22105995 TLR2 expression is regulated by microRNA miR-19 in rheumatoid fibroblast-like synoviocytes 2012 Jan 1 Resident cells, such as fibroblast-like synoviocytes (FLS), play a crucial role in rheumatoid arthritis (RA). They are implicated in the inflammatory response and play a key role in osteoarticular destruction. Moreover, RA FLS spread RA to unaffected joints. Pathogen-associated molecular patterns and damage-associated molecular patterns have been found to activate RA FLS by interacting with pattern recognition receptors, such as TLR. RA FLS express a large number of TLR, and TLR2 was demonstrated to be involved in RA inflammation. Because microRNA have emerged as important controllers of TLR expression and signaling, the aim of this study was to evaluate their potential involvement in the control of TLR2 expression by RA FLS. We first showed that Tlr2 expression is strongly upregulated in RA FLS in response to TLR2 ligands. Using a microRNA microarray analysis, we identified one miRNA in activated RA FLS, miR-19b, which was downregulated and predicted to target Tlr2 mRNA. Downregulation of miR-19b and miR-19a, which belongs to the same cluster, was confirmed by real-time quantitative PCR. Transfection of RA FLS with miR-19a/b mimics decreased TLR2 protein expression. In parallel, we found that both IL-6 and matrix metalloproteinase 3 secretion was significantly downregulated in activated FLS transfected with either mimic. Moreover, using a luciferase assay, we showed that miR-19a/b directly target Tlr2 mRNA. Taken together, our data point toward an important role for miR-19a/b in the regulation of IL-6 and matrix metalloproteinase 3 release by controlling TLR2 expression, as well as provide evidence that miR-19a/b can act as negative regulators of inflammation in humans.
21420089 TNFA -308 (rs1800629) polymorphism is associated with a higher risk of cardiovascular dise 2011 May OBJECTIVE: To assess the influence of the TNFA rs1800629 (G > A) polymorphism in the risk of cardiovascular (CV) disease and subclinical atherosclerosis in patients with rheumatoid arthritis (RA). METHODS: 587 patients fulfilling the 1987 American College of Rheumatology classification criteria for RA were studied. Patients were genotyped for the TNFA rs1800629 polymorphism using predesigned TaqMan single nucleotide polymorphism genotyping assay. Also, HLA-DRB1 genotyping was performed using molecular based methods. Carotid artery intima-media thickness, flow-mediated endothelium-dependent and endothelium independent vasodilatation, used as surrogate markers of subclinical atherosclerosis, were measured in a subgroup of patients. RESULTS: We observed a higher frequency of carriers of the minor allele A among the patients with CV disease (with 37.6% vs. without 27.9%, p = 0.06, OR 1.56 [95% confidence interval-CI 0.95-2.54]). Carriers of the minor allele A exhibited a higher risk of CV events after adjustment for demographic and traditional CV risk factors (p = 0.023, HR 1.72 [95% CI 1.076-2.74]). Also, a significant interaction between this polymorphism and the presence of the rheumatoid shared epitope (SE) was observed (p = 0.024). Due to this, the association between carriers of the minor allele A and CV disease was only present in carriers of the SE, even after adjustment (p = 0.001, HR 2.43 [95% CI 1.41-4.19]). No significant association between the TNFA variant and the surrogate markers of subclinical atherosclerosis was observed. CONCLUSION: Our results show that TNFA rs1800629 gene polymorphism is associated with predisposition to CV complications in patients with RA. This predisposition is restricted to individuals carrying the rheumatoid SE.
22887851 Impact of tocilizumab therapy on antibody response to influenza vaccine in patients with r 2012 Dec OBJECTIVES: We assessed the influence of tocilizumab (TCZ), a humanised monoclonal anti-interleukin-6 receptor antibody, on antibody response following influenza vaccination in patients with rheumatoid arthritis (RA). METHODS: A total of 194 RA patients received inactive trivalent influenza vaccination (A/H1N1, A/H3N2 and B/B1 strains). All patients were classified into the TCZ (n=62), TCZ+methotrexate (MTX) (n=49), MTX (n=65) and RA control (n=18) groups. Antibody titres were measured before and 4-6 weeks after vaccination using the haemagglutination inhibitory assay. RESULTS: For the A/H1N1 and A/H3N2 strains, the TCZ and TCZ+MTX groups achieved fold increases of 9.9-14.5, postvaccination seroprotection rates greater than 70% and seroresponse rates greater than 40%. For the B/B1 strain, seroresponse rates were approximately 30%, but fold increases and seroprotection rates were 5.0-5.4 and greater than 70%, respectively, in these treatment groups. MTX had a negative impact on vaccination efficacy, but adequate responses for protection were nevertheless demonstrated in the MTX group. Neither severe adverse effects nor RA flares were observed. CONCLUSIONS: TCZ does not hamper antibody response to influenza vaccine in RA patients. Influenza vaccination is considered effective in protecting RA patients receiving TCZ therapy with or without MTX.
22052070 Contrast-enhanced ultrasonography is more sensitive than grayscale and power Doppler ultra 2011 Dec PURPOSE: To evaluate wrist and finger joints in patients with rheumatoid arthritis (RA) by grayscale, power Doppler (PD) and contrast-enhanced musculoskeletal ultrasonography (US) and to compare these findings with MRI, clinical (DAS28) and laboratory (ESR; CRP) data. MATERIALS AND METHODS: US was performed at baseline (t0) and after three, six and twelve (t12) months before and after a change of medical treatment. MRI was carried out at t0 and t12 and used as the reference method. Contrast-enhanced US was used to assess one clinically most affected joint region. Different semiquantitative synovitis scores were calculated by grayscale and PD US. RESULTS: Contrast-enhanced US results evaluated by enhancement, slope and semi-quantitative assessment significantly correlated to each other, to grayscale US, CRP, as well as to MRI with the highest correlation coefficients for the used contrast-enhanced US modes (r = 0.56, r = 0.55, r = 0.57; each p < 0.05). Sum scores evaluated by grayscale US showed that synovial inflammation in finger joints was detected significantly more frequently in the palmar aspect than on the dorsal side (p = 0.001). Using power Doppler US, the wrists were significantly more inflamed from dorsal than on the palmar side (p = 0.0004). Significant longitudinal correlations between grayscale and power Doppler US scores were detected. CONCLUSION: Grayscale, power Doppler and contrast-enhanced US are accurate tools for the detection and follow-up of synovitis in RA wrist and finger joints, with contrast-enhanced US being most sensitive compared to MRI. All imaging methods reflected a good response to TNFα blocking therapy.
21134963 Clinical significance of high levels of soluble tumour necrosis factor-α receptor-2 produ 2011 Apr OBJECTIVES: We investigated whether serum levels of an alternatively spliced soluble (s)TNF receptor-2 (DS-TNFR2) affected the clinical response to anti-TNF-α therapy, classical DMARDs or radiological evidence of disease progression in patients with RA. METHODS: We included 116 patients with RA. Cohort 1: 52 DMARD-naïve early RA patients [mean (s.d.) disease duration 8.5 (6.2) months] who started gold salts and MTX therapies. Cohort 2: 64 MTX-resistant established RA patients [144 (107) months] who started infliximab therapy. We evaluated the European League Against Rheumatism (EULAR) response to therapy and the serum levels of DS-TNFR2, sTNFR2 and ACPAs at baseline and at 12 months. In Cohort 1, radiological progression and levels of MMP-1 were also determined. RESULTS: In Cohort 1, 40% of patients had high baseline levels (HL > 50 ng/ml) of DS-TNFR2 with significantly higher RF and ACPA levels than patients with normal levels (NL ≤ 50 ng/ml) of DS-TNFR2. The EULAR response to DMARDs was similar in HL and NL patients. Radiographic progression was observed in 23.5% of all patients after 12 months. In Cohort 2, 26.6% of patients had HL of DS-TNFR2 with significantly higher RF and ACPA levels than patients with NLs. The EULAR response from 6 to 30 weeks was prolonged in the HL group compared with the NL group. CONCLUSIONS: Patients with HL of DS-TNFR2 maintained a prolonged therapeutic response to anti-TNF-α therapy and had proportionally less radiographic progression compared with patients with NLs.
22357327 Grip strength characteristics using force-time curves in rheumatoid hands. 2013 Feb The use of force-time curves in rheumatoid hands was investigated to assess peak force, average force, total grip time, area under the curve, and variability of the plateau region of the curves to identify the impact of different rheumatoid hand deformities on grip strength. We studied 43 patients - 10 men and 33 women - with established rheumatoid arthritis affecting their hands. Mean age was 61 years and mean duration of hand involvement was 13 years. Of the 86 hands, 38 had no finger deformity, eight had metacarpophalangeal joint ulnar deviation without any additional finger deformities, 16 had swan neck deformities, and 10 had boutonnière deformities. Fourteen hands had a combination of deformities. The hands with combined deformities were the weakest, had poor grip strength (34.7 N, SE 8), and were able to sustain grip for only a short time (22 sec, SE 3). Swan neck deformity also profoundly affects the magnitude (49.8 N, SE 7) and sustainability of grip (15 sec, SE 2). Even when only one finger had a swan neck deformity the mean strength was poor at 45 N. Swan neck deformity causes greater loss of strength than boutonnière deformity (82.7 N, SE 15). The strongest rheumatoid hands were those with only ulnar deviation deformities (90.8 N, SE 14). The area under the curve best predicted disability assessed using the Patient Evaluation Measure.
22368231 Fcγ receptor type IIIA polymorphism influences treatment outcomes in patients with rheuma 2012 Jun OBJECTIVE: To assess the association between a single nucleotide polymorphism in the gene of FCGR3A and the response to treatment with rituximab (RTX) in rheumatoid arthritis (RA). METHODS: SMART is a randomised open trial assessing two strategies of re-treatment in patients responding to 1 g infusion of RTX with methotrexate on days 1 and 15 after failure, intolerance or contraindication to tumour necrosis factor (TNF) blockers. Among the 224 patients included, 111 could be genotyped and were included in an ancillary study of SMART. Univariate and multivariate analyses adjusted on disease activity score on 28 joints were performed to assess whether FCGR3A-158V/F polymorphism was associated with European League Against Rheumatism response at week 24. RESULTS: Among the 111 patients, 90 (81%) were responders of whom 30 (27%) were good responders. V allele carriage was significantly associated with a higher response rate (91% of responders vs 70%, OR 4.6 (95% CI 1.5 to 13.6), p=0.006). These results were also confirmed in rheumatoid factor-positive patients (93% vs 74%, p=0.025). In multivariate analysis, V allele carriage was independently associated with response to RTX (OR 3.8 (95% CI 1.2 to 11.7), p=0.023). CONCLUSION: The 158V/F polymorphism of FCGR3A seems to influence the response to RTX in patients with RA after failure, intolerance or contraindication to TNF blockers.
21113640 Increased level of heme oxygenase-1 in rheumatoid arthritis synovial fluid. 2011 Apr We investigated the expression and localization of heme oxygenase-1 (HO-1) in synovial fluid and synovial tissue, and examined the stimulation of HO-1 production in rheumatoid synovial fibroblasts (RASFs). Synovial fluid samples were obtained from knee joints of 20 rheumatoid arthritis (RA) and 20 osteoarthritis (OA) patients, and concentration of HO-1 and matrix metalloproteinase-3 (MMP-3) were measured by enzyme-linked immunosorbent assay (ELISA). Synovial tissues obtained from RA or OA patients during total knee arthroplasty (TKA) were used for immunohistochemical analysis of HO-1. HO-1 production by RASFs in response to various cytokines was examined by ELISA. HO-1 levels in synovial fluid were higher in the RA group than in the OA group with significant difference (P < 0.001), and correlated with serum C-reactive protein (CRP) level (r = 0.80, P < 0.01) in the RA group. Higher levels of HO-1 were seen in the RA-L group (Larsen grade III-V) than in the RA-E (Larsen grade 0-II) group (P < 0.001). There was weak correlation between the levels of HO-1 protein and MMP-3 in synovial fluid in the RA group (r = 0.31, P < 0.01), while no positive correlation was observed in OA. Positive immunoreaction for HO-1 was observed in cells of synovial tissue including synovial fibroblasts and cells in synovial pannus. HO-1 protein levels in cultured media of RASFs were increased by stimulation by interleukin-1β at 6 h and tumor necrosis factor-alpha at 12 h, but suppressed by interferon-gamma at 12 and 24 h. These results indicated that HO-1 expression in synovial tissue might be stimulated by inflammatory cytokines. The correlation of HO-1 concentration in synovial fluid with serum CRP and MMP-3 in joint fluid indicated that HO-1 might be useful as a marker of joint inflammation in RA patients.
20724918 Development and characterization of a JAK-2-specific antibody suitable for immunohistochem 2011 Jan Janus kinases (JAKs) are tyrosine kinases called JAK-1, JAK-2, JAK-3, and Tyk-2, which have been shown to participate in the signaling pathways of several cytokines that are believed to play a key role in several autoimmune-mediated disorders including rheumatoid arthritis (RA). However, the availability of JAK-specific antibodies to be used in investigative efficacy studies in RA models is very limited. Therefore, in this study we developed and characterized a JAK-2-specific antibody that was used to evaluate its immunohistochemical expression in the joints of a rat adjuvant-induced arthritis (rAIA) RA preclinical model. An immunogen peptide sequence design was used to generate JAK-2-specific mouse, rat, and human polyclonal antibodies. JAK-2 plasmid cDNA was then generated and HEK293 transfected cell lines, gel electrophoresis, immunoblotting, and immunohistochemistry were used to further characterize the generated JAK-2 antibodies. We show that the generated JAK-2 antibody exhibits specificity and lacks cross-reactivity to JAK-1 and JAK-3. In addition, marked JAK-2 expression is shown in the rAIA in mixed inflammatory cells (macrophages and neutrophils), mast cells, and bone marrow elements. In conclusion, we show the development and characterization of a JAK-2-specific antibody that can be used in investigative and mechanistic studies such as preclinical efficacy models.
23054625 Cellular targeting in autoimmunity. 2012 Dec Many biologic agents that were first approved for the treatment of malignancies are now being actively investigated and used in a variety of autoimmune diseases such as rheumatoid arthritis (RA), antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, systemic lupus erythematosus (SLE), and Sjogren's syndrome. The relatively recent advance of selective immune targeting has significantly changed the management of autoimmune disorders and in part can be attributed to the progress made in understanding effector cell function and their signaling pathways. In this review, we will discuss the recent FDA-approved biologic therapies that directly target immune cells as well as the most promising investigational drugs affecting immune cell function and signaling for the treatment of autoimmune disease.
22704802 Vitamin D-binding protein (group-specific component) has decreased expression in rheumatoi 2012 Jul OBJECTIVES: This study used a proteomic approach to screen the proteins with decreased expression in the synovial tissues of rheumatoid arthritis (RA) patients by comparing their expression profiles to that of osteoarthritis (OA) and ankylosing spondylitis (AS) patients. The result was complemented by a SNP analysis. METHODS: Proteins extracted from the synovial membranes (n=10 for each disease) were separated by 2-D electrophoresis. The proteins with significantly decreased expression in the RA samples were subjected to MALDI-TOF/TOF MS. The result was verified using western blotting. Tag SNPs located in the targeted gene were assessed using the Taqman assay in a cohort of 267 Chinese patients with RA, 51 patients with AS and 160 healthy controls. The genotyping result was confirmed in a large cohort of 389 patients with RA, 200 patients with AS and 371 healthy controls. RESULTS: The proteomic approach detected significantly decreased expression of vitamin D-binding protein (VDBP) in the synovial membranes from patients with RA, which was confirmed with western blot analysis. rs2282679 was significantly associated with RA and AS (p=0.026794 and 0.007566, respectively). The result was confirmed in a large cohort of RA (OR=0.678639, 95%CI=[0.541113~0.851118], p=0.000776) and AS (OR=0.564053, 95%CI=[0.433716~0.733558], p=1.79e-005). CONCLUSIONS: 1,25-dihydroxyvitamin D3 inhibits cell proliferation, immunoglobulin production and the release of cytokines through binding to VDBP. VDBP also mediates bone resorption by activating osteoclasts. The decreased expression and the genetic effect of VDBP in RA suggest a novel pathogenic pathway that vitamin D contributes to the arthritic process of the disease.
22505706 Peptidylarginine deiminase type 4 and methyl-CpG binding domain 4 polymorphisms in Chinese 2012 Jun OBJECTIVE: Peptidylarginine deiminase type 4 (PADI4) and methyl-CpG binding domain 4 (MBD4) are closely related with rheumatoid arthritis (RA). We hypothesized that PADI4 and MBD4 polymorphisms may contribute to RA susceptibility. METHODS: We studied PADI4 rs2240340 G/A, PADI4 rs874881 C/G, MBD4 rs140693 G/A, and MBD4 rs2005618 T/C gene polymorphisms in 329 patients with RA and 697 controls in a Chinese population. Genotyping was done using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS). RESULTS: When the PADI4 rs2240340 GG homozygote genotype was used as the reference group, the AA genotype was associated with a significantly increased risk of RA. In the recessive model, when PADI4 rs2240340 GG/GA genotypes were used as the reference group, the AA homozygote genotype was associated with a significant increased susceptibility to RA. PADI4 rs874881 C/G was in complete linkage disequilibrium with PADI4 rs2240340 G/A. MBD4 rs140693 G/A and MBD4 rs2005618 T/C polymorphisms were not associated with the risk of RA. In stratification analyses, a significantly increased risk for RA associated with the PADI4 rs2240340 AA genotype was evident among older patients and patients who were anticitrullinated protein antibody (ACPA)-positive compared with the PADI4 rs2240340 GG/GA genotype. CONCLUSION: These findings suggest that the functional single-nucleotide polymorphism PADI4 rs2240340 G/A variant allele is associated with RA development, especially among older patients and ACPA-positive patients. However, our results were obtained from a moderate-sized sample, and therefore this is a preliminary conclusion. Validation by a larger study from a more diverse ethnic population is needed to confirm these findings.
21247370 Reduction of interleukin-1β induced matrix metalloproteinase-3 release by extracts of six 2011 Sep Rheumatoid arthritis (RA) is a chronic inflammatory joint disease associated with matrix metalloproteinase (MMP)-3, leading to destruction of the cartilage. The objective of this study was to investigate and discuss the suitability of the 35 medicinal plants as therapeutic candidates to treat RA. Fibroblast-like synoviocytes (FLSs), derived from patients with RA, were adjusted to 2 × 10(6) cells/mL in a 24-well plate and pretreated with the distilled water extracts of the 35 plants (1, 10, and 100 µg/mL) for 1 h followed by interleukin-1β (IL-1β) (1 ng/mL) for 24 h. The concentration of MMP-3 was then determined using a Duoset ELISA Kit. The six plants (Artemisiae Capillaris Herba, AC; Bambusae Caulis In Taeniam, BC; Cassiae Semen, CS; Corni Fructus, CF; Leonuri Herba, LH; Schizonepetae Spica, SS) showed no toxicity, including MMP-3. The MMP-3 level was increased by 3.38-fold (212.23 μg/mL) in IL-1β-stimulated FLSs. The IL-1β-induced MMP-3 level was significantly and dose-dependently reduced by >50% by the six plants (P < 0.01: at 100  μg/ mL of CS and LH, P < 0.001: at 10 μg/mL of all plants, and at 100 μg/mL of AC, BC, CF, and SS). This is the first study on the MMP-3 inhibitory effect of the examined plants in FLSs isolated from RA patients. From our original research, the six candidate plants were identified.
22078698 [Efficacy and safety of abatacept in patients with rheumatoid arthritis and no prior treat 2011 Nov Abatacept (ABA) is a recombinant human fusion protein that blocks co-stimulation signals on T lymphocytes, impeding their activation. Randomized and controlled trials examining efficacy and safety have been performed with ABA combined with methotrexate (MTX), vs MTX monotherapy and vs infliximab (IFB) combined with MTX in patients with Rheumatoid Arthritis and who are naïve to biologic therapy. ABA has shown to be more effective than MTX and at least as effective as IFB+MTX, in terms of activity and clinical remission, physical function and reduction in radiological progression. Safety data at 7 years have shown that the drug is comparable to MTX in monotherapy and safer than the IFB+MTX combination, although infections still constitute the main risk when using ABA. This review summarizes the safety and efficacy data of the AIM, ATTEST, Phase IIb IM101-100 and AGREE trials.
22753654 Etanercept concentration in patients with rheumatoid arthritis and its potential influence 2012 Aug OBJECTIVE: For patients with rheumatoid arthritis (RA), recommendations are inconclusive about whether tumor necrosis factor-α (TNF-α)-blocker therapy should be evaluated at 3 or 6 months. Biomarkers are needed to predict at 3 months which patients would benefit from further treatment because of nonoptimal response. Our objective was to investigate whether serum etanercept (ETN) concentrations and anti-ETN antibodies at 3 months are predictors of clinical response to ETN at 6 months in patients with RA in terms of European League Against Rheumatism criteria and Disease Activity Score in 28 joints (DAS28). METHODS: Between 2009 and 2010, we included 19 women with active RA who were candidates for ETN therapy. Response criteria were evaluated at 3 and 6 months. Serum concentrations of ETN and anti-ETN antibodies were measured by ELISA at baseline and at 3 and 6 months. RESULTS: Eighteen patients completed followup. Three-month ETN concentrations were lower for 6-month nonresponders than responders (p = 0.03). Three-month ETN levels correlated significantly with change in DAS28 between baseline and 6 months (r = -0.62, p = 0.006). The best predictor of response at 6 months was observed with an ETN threshold of 3.1 μg/ml at 3 months. No anti-ETN antibodies were found. CONCLUSION: ETN concentrations at 3 months predict response to ETN therapy at 6 months. Low ETN concentrations could explain the absence of response to ETN, suggesting that patients with low ETN levels could benefit from increased ETN dose or earlier interruption of treatment.
21365318 Paracoccidioidomycosis induced by immunosuppressive drugs in a patient with rheumatoid art 2011 Jul Paracoccidioidomycosis (PCM) is a systemic mycosis caused by Paracoccidioides brasiliensis, which is endemic in many regions of Latin America. We describe the case of a 60-year-old man from a region endemic for PCM who presented with a long history of left hip pain. He had been treated over the past 3 years with immunosuppressive drugs (methotrexate, leflunomide, and adalimumab) for rheumatoid arthritis (RA). A hip radiograph showed lytic bone lesions, and a chest radiograph showed an expansive excavated lesion in the left lung, suggestive of a lung cancer with bone metastases. A left hip joint biopsy was inconclusive, but histological analysis of a surgical lung biopsy specimen was consistent with P. brasiliensis infection. Treatment with intravenous amphotericin B (50 mg/day) and hydrocortisone (25 mg/day) was initiated. However, increasing hip pain resulted in the amputation of the left lower limb, and the analysis of the surgical specimen revealed a diagnosis of bone sarcoma. Postoperatively, the patient developed sepsis and died approximately 1 month later. To our knowledge, this is the first report of PCM in a patient with RA who had been treated with immunosuppressive drugs, in particular TNF-α blocking agents. The atypical presentation (left hip pain alone) emphasizes the importance of considering PCM in the differential diagnosis of patients with pulmonary lesions and osteolytic lesions who live in a region endemic for PCM. This case report also demonstrates that health professionals in these regions must pay close attention to patients receiving immunosuppressive drugs because of the possibility of reactivating quiescent P. brasiliensis lesions.