Browse

Search for: rheumatoid arthritis    methotrexate    autoimmune disease    biomarker    gene expression    GWAS    HLA genes    non-HLA genes   

ID PMID Title PublicationDate abstract
23689131 Phospholipase D1 has a pivotal role in interleukin-1β-driven chronic autoimmune arthritis 2013 Jul Interleukin-1β (IL-1β) is a potent proinflammatory and immunoregulatory cytokine playing an important role in the progression of rheumatoid arthritis (RA). However, the signaling network of IL-1β in synoviocytes from RA patients is still poorly understood. Here, we show for the first time that phospholipase D1 (PLD1), but not PLD2, is selectively upregulated in IL-1β-stimulated synoviocytes, as well as synovium, from RA patients. IL-1β enhanced the binding of NF-κB and ATF-2 to the PLD1 promoter, thereby enhancing PLD1 expression. PLD1 inhibition abolished the IL-1β-induced expression of proinflammatory mediators and angiogenic factors by suppressing the binding of NF-κB or hypoxia-inducible factor 1α to the promoter of its target genes, as well as IL-1β-induced proliferation or migration. However, suppression of PLD1 activity promoted cell cycle arrest via transactivation of FoxO3a. Furthermore, PLD1 inhibitor significantly suppressed joint inflammation and destruction in IL-1 receptor antagonist-deficient (IL-1Ra(-/-)) mice, a model of spontaneous arthritis. Taken together, these results suggest that the abnormal upregulation of PLD1 may contribute to the pathogenesis of IL-1β-induced chronic arthritis and that a selective PLD1 inhibitor might provide a potential therapeutic molecule for the treatment of chronic inflammatory autoimmune disorders.
24182325 Short-term treatment with a gonadotropin-releasing hormone antagonist, cetrorelix, in rheu 2014 OBJECTIVES: Gonadotropin-releasing hormone (GnRH) stimulates immune responses; therefore, antagonizing GnRH with cetrorelix may have anti-inflammatory effects. The aim of this study was to assess short-term cetrorelix therapy in rheumatoid arthritis (RA) patients. METHOD: In this proof-of-concept, randomized, double-blind study involving 99 patients with active, long-standing RA, 48 patients received subcutaneous cetrorelix (5 mg/day on days 1 and 2; 3 mg/day on days 3-5) and 51 received placebo. The primary end-point was the change in the 28-joint Disease Activity Score based on C-reactive protein (DAS28-CRP) by day 5, when the greatest GnRH suppression was anticipated. Secondary end-points included the change in tumour necrosis factor (TNF)-α, and achievement of American College of Rheumatology (ACR) responses and DAS28-CRP < 2.6 by day 5. Patients were followed up on days 10 and 15. RESULTS: By day 5, DAS28-CRP was non-significantly reduced by 0.82 in the cetrorelix group compared to a 0.57 reduction in the placebo group (p = 0.091), TNF-α (log pg/mL) was significantly reduced in the cetrorelix group compared with the placebo group [0.55, 95% confidence interval (CI) 0.08-1.01, p = 0.023], and more patients on cetrorelix achieved ACR20 responses (40% vs. 18%, p = 0.015) and DAS28-CRP < 2.6 (13% vs. 0%, p = 0.009). Inflammatory markers increased towards baseline levels after withdrawal of treatment. Rates of adverse events were similar in both groups. CONCLUSIONS: Although there was no significant difference in the primary end-point between groups, antagonizing GnRH led to significant improvements in key secondary end-points. Thus, GnRH antagonists may have rapid anti-inflammatory effects in RA, already occurring within 5 days. The data suggest a novel mode of action for TNF-α inhibition in RA, and potentially in other autoimmune diseases.
25376957 Safety of rituximab in the routine treatment of rheumatoid arthritis in Italy in patients 2014 Nov 6 The paper reports the results from the observational retrospective-prospective RUBINO study conducted in Italy to assess the safety of rituximab in the treatment of rheumatoid arthritis (RA) in routine clinical practice. The percentage of patients who manifested at least one grade 3 or 4 adverse event (AE) assessed by the Common Terminology Criteria for Adverse Events version 3.0 (CTCAE v.3) during the observation period (primary objective) was evaluated. The percentage of patients manifesting a severe AE (SAE), clinical response to rituximab treatment, clinical remission according to disease activity score for 28 joints (DAS28) criteria, markers of disease and quality of life were also assessed. Fifty-three Italian rheumatology centers took part in the study. Patients with a diagnosis of RA and inadequate response to anti-tumor necrosis factor b (anti-TNFa) drugs were enrolled. Participating patients had previously received at least one cycle of rituximab, and treatment was still ongoing at the time of recruitment. Out of 205 patients enrolled, 60% manifested no form of AE, 14.2% had at least one grade 3 or 4 AE, and 11.2% patients reported an SAE. The overall percentage of patients manifesting AEs (40%) was lower compared to the DANCER (81% and 85%), REFLEX (85%) and RESET (85% and 69%) studies, but higher than that observed in the CERERRA registry (from 10.2% to 13.9%). This difference may be due to the shorter observation period applied in the CERERRA registry (only 12 months) compared to the RUBINO study (up to 3 years). All parameters of RA activity (erythrocyte sedimentation rate, C-reactive protein, health assessment questionnaire score, DAS28) improved significantly during the study.
25005029 Type II collagen antibody response is enriched in the synovial fluid of rheumatoid joints 2014 Jul 8 INTRODUCTION: Antibodies towards type II collagen (CII) are detected in patients with rheumatoid arthritis (RA) and in non-human primates and rodents with collagen induced arthritis (CIA). We have previously shown that antibodies specific for several CII-epitopes are pathogenic using monoclonal antibodies from arthritic mice, although the role of different anti-CII epitopes has not been investigated in detail in other species. We therefore performed an inter-species comparative study of the autoantibody response to CII in patients with RA versus monkeys and mice with CIA. METHODS: Analysis of the full epitope repertoire along the disease course of CIA was performed using a library of CII triple-helical peptides. The antibody responses to the major CII epitopes were analyzed in sera and synovial fluid from RA patients, and in sera from rhesus monkeys (Macaca mulatta), common marmosets (Callithrix jacchus) and mice. RESULTS: Many CII epitopes including the major C1, U1, and J1 were associated with established CIA and arginine residues played an important role in the anti-CII antibody interactions. The major epitopes were also recognized in RA patients, both in sera and even more pronounced in synovial fluid: 77% of the patients had antibodies to the U1 epitope. The anti-CII immune response was not restricted to the anti-citrulline protein antibodies (ACPA) positive RA group. CONCLUSION: CII conformational dependent antibody responses are common in RA and are likely to originate from rheumatoid joints but did not show a correlation with ACPA response. Importantly, the fine specificity of the anti-CII response is similar with CIA in monkeys and rodents where the recognized epitopes are conserved and have a major pathogenic role. Thus, anti-CII antibodies may both contribute to, as well as be the consequence of, local joint inflammation.
24255004 Intravenous tocilizumab: a review of its use in adults with rheumatoid arthritis. 2014 Feb Tocilizumab (Actemra®, RoActemra®) is a humanized monoclonal antibody that acts as an interleukin-6 receptor antagonist. Intravenous tocilizumab as monotherapy or in combination with disease-modifying anti-rheumatic drugs (DMARDs) is indicated for the treatment of adult patients with moderate to severe active rheumatoid arthritis (RA) who had an inadequate response to one or more DMARDs or tumor necrosis factor (TNF) α antagonists (the specific indication varies between countries); it may also be used as monotherapy in patients for whom continued methotrexate use is inappropriate. This article reviews the efficacy and tolerability of tocilizumab in these patients and briefly summarizes its pharmacology. Several large well-designed clinical trials and routine clinical practice studies showed that tocilizumab was an effective and generally well tolerated biologic for the treatment of adults with RA, including those with an inadequate response to DMARDs or TNFα antagonists. In these studies, tocilizumab as monotherapy or in combination with DMARDs (including methotrexate) had beneficial effects on the signs and symptoms of disease, health-related quality of life/physical function, and/or radiologic disease progression. In addition, tocilizumab monotherapy was more effective than adalimumab monotherapy in improving the signs and symptoms of disease in patients for whom continued methotrexate use was inappropriate. As with other biologic DMARDS, infections were the most common adverse event associated with tocilizumab therapy. Pooled and meta-analyses demonstrated that the efficacy and tolerability profile of tocilizumab was sustained during long-term (up to 9 years) therapy. Although additional comparative data are needed to position tocilizumab more definitively with respect to other biologic DMARDs, current evidence indicates that tocilizumab is effective as a first- or subsequent-line biologic in patients with moderate to severe RA.
23864141 Clarithromycin in rheumatoid arthritis: the addition to methotrexate and low-dose methylpr 2013 Nov To compare the efficacy of the addition of clarithromycin (CM) to methotrexate (MTX) and methylprednisolone (MP) in active rheumatoid arthritis (RA). 32 patients with RA consecutively randomized. CONTROL GROUP: sixteen patients treated for 24 months with MTX 10-15 mg i.m. weekly and MP 4-6 mg daily. CM group: sixteen patients treated with MTX 10-15 mg i.m. weekly and MP 4-6 mg daily for 24 months; CM therapy added in the first month (500 mg twice a day for the first 15 days followed by 500 mg a day for the remaining 15 days). Evaluation of the improvement following ACR criteria was performed at months 1 (primary endpoint), 3 and 6. Patients were furthermore observed after 12, 18 and 24 months from the study beginning. At month 1, following ACR70 improvement criteria, we found a significant additive value in CM group (10/16 = 63% vs 4/16 = 25%, p = 0.033--chi-square test). After discontinuation of CM, the difference between groups was anymore evident (month 3: CM group 10/16 = 63% vs control group 9/16 = 56%). At month 24, 7/16 (44%) in control group and 12/16 (75%) in CM group completed the follow-up. The addition of CM to MTX and MP can induce the remission ACR 70 in the majority of RA patients within 4 weeks, while MTX and MP alone need about 3 months to achieve the same result.
23974451 Serum 25-hydroxyvitamin D concentration in patients with psoriasis and rheumatoid arthriti 2013 Aug OBJECTIVE: To assess vitamin D status in psoriasis and rheumatoid arthritis (RA) patients and to study whether it was associated with disease activity, inflammatory markers, and serum tumor necrosis factor-alpha (TNF-α). METHODS: This cross-sectional study was conducted at Riyadh National Hospital, Riyadh, Saudi Arabia between March and September 2012. It included 43 patients with plaque psoriasis, 55 RA patients and 40 healthy controls matched for age. Blood samples were drawn from all participants for assessment of 25-hydroxyvitamin D [25(OH)D], TNF-α, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), parathyroid hormone (PTH), and serum corrected calcium. Disease activity of psoriasis and RA were assessed using Psoriasis Area and Severity Index (PASI) and Disease Activity Score Index of a 28 joint count (DAS28). RESULTS: We found a significant difference between psoriatic patients, RA patients, and healthy controls in the mean 25(OH)D (11.74±3.60, 15.45±6.42, and 24.55±11.21 ng/ml; p=0.000). We found that 25(OH)D was not correlated with PASI, DAS28, TNF-α, CRP, or ESR in psoriatic and RA patients. CONCLUSION: Serum 25-(OH)D levels are significantly lower in psoriatic and RA patients than in healthy control subjects. Low 25-OHD levels also may provide the rationale for vitamin D supplementation in the treatment of psoriasis and RA. More definitive evidence is also required to demonstrate the clinical benefit of vitamin D supplementation in the treatment of psoriasis and RA.
24528797 Oropharyngeal carcinoma arising after methotrexate and etanercept therapy for rheumatoid a 2014 Mar Etanercept is an anti-tumor necrosis factor α receptor agent used to treat inflammatory conditions. Previous reports described rapid development of skin squamous cell carcinoma (SCC) after etanercept use. This report describes a novel case of oropharyngeal SCC associated with the use of etanercept. A 45-year-old man with rheumatoid arthritis developed oropharyngeal pain within 2 months after the start of etanercept therapy and was diagnosed with tonsillar carcinoma. This patient had other exposures that increase the risk of oropharyngeal cancer, such as tobacco and alcohol use. However, owing to the timing of onset of his initial symptoms, etanercept should be considered as a possible factor in the etiology or progression of his tumor, especially in the context of reported skin SCC after etanercept therapy in patients at risk for SCC. Clinicians should be alert to signs of malignancy in patients on etanercept, particularly those at high risk for skin or head and neck cancers.
22833513 Sex differences in assessment of obesity in rheumatoid arthritis. 2013 Jan OBJECTIVE: To determine the prevalence of obesity and how accurately standard anthropometric measures identify obesity among men and women with rheumatoid arthritis (RA). METHODS: Dual x-ray absorptiometry (DXA) was performed for 141 persons with RA (56 men and 85 women). Two anthropometric proxies of obesity (body mass index [BMI] and waist circumference [WC]) were compared to a DXA-based obesity criterion. Receiver operating characteristic curves determined optimal cut points for each anthropometric measure, relative to DXA. The association of body fat and anthropometric obesity measures with disease status and cardiovascular risk was assessed in multiple regression analyses, controlling for age and glucocorticoid use. All analyses were performed separately for men and women. RESULTS: A total of 20%, 32%, and 44% of women and 41%, 36%, and 80% of men were classified as obese by BMI, WC, and DXA, respectively. Cut points were identified for anthropometric measures to better approximate DXA estimates of percent body fat (BMI ≥26.1 kg/m(2) for women and ≥24.7 kg/m(2) for men; WC ≥83 cm for women and ≥96 cm for men). For women and men, higher percent fat was associated with poorer RA status. Anthropometric measures were more closely linked to RA status for women, but identified cardiovascular risk for both women and men. CONCLUSION: A large percentage of this RA sample was overfat; DXA-defined obesity was twice as common in men as in women. Utility of revised BMI and WC cut points compared to traditional cut points remains to be examined in prospective studies, but results suggest that lower, sex-specific cut points may be warranted to better identify individuals at risk for poor RA and/or cardiovascular outcomes.
24591462 US trends in rates of arthroplasty for inflammatory arthritis including rheumatoid arthrit 2014 Jun OBJECTIVE: Although rates of arthroplasty have increased dramatically, rates among patients with rheumatoid arthritis (RA) are reported to be decreasing. It is not known if this is also the case among patients with other inflammatory arthritides. This study was undertaken to evaluate rates of arthroplasty due to RA, juvenile idiopathic arthritis (JIA), spondyloarthritis (SpA), and a composite group of patients with inflammatory arthritides (IA), compared to arthroplasty rates among patients without inflammatory or autoimmune conditions. METHODS: Administrative discharge databases (State Inpatient Databases of the Healthcare Cost and Utilization Project, New York Department of Health Statewide Planning and Research Cooperative System, California Statewide Health Planning and Development) were used to compare rates of knee, hip, and shoulder arthroplasty occurring from 1991 to 2005. RESULTS: Of 2,839,325 arthroplasties in 1991-2005, 2.7% were performed in patients with IA. The rate of arthroplasty for noninflammatory conditions doubled (124.5 per 100,000 persons in 1991 versus 247.5 per 100,000 persons in 2005), while the rate for IA remained stable at 5.1 per 100,000. Rates of arthroplasty for RA decreased slightly (4.6 per 100,000 versus 4.5 per 100,000) and those for JIA decreased by nearly 50% (0.22 per 100,000 versus 0.13 per 100,000), but the rate of arthroplasty for SpA increased by nearly 50% (0.22 per 100,000 versus 0.31 per 100,000). Age at the time of arthroplasty increased for patients with RA (mean ± SD 63.4 ± 12.7 years versus 64.9 ± 12.8 years), JIA (30.9 ± 12.2 years versus 36.7 ± 14.9 years), and SpA (54.3 ± 16.1 years versus 60.4 ± 13.9 years). However, the mean age at the time of arthroplasty among non-IA cases decreased (71.5 ± 11.8 years versus 69.0 ± 12.0 years). CONCLUSION: This population-based study is the first to show that arthroplasty rates have decreased significantly among patients with JIA and minimally among patients with RA, and have increased among patients with SpA. The increased age at the time of arthroplasty among patients with JIA and SpA suggests that these patients are increasingly able to defer surgical interventions. Further research is needed to assess the ongoing effect of biologic agents on the need for arthroplasties in patients with IA.
24379260 [Adenosine, its analogues and conjugates]. 2013 Dec 3 Adenosine is an endogenous purine nucleoside that plays an important role in many biochemical processes. It acts through the four types of adenosine receptors: A1, A2A, A2B, A3 which are located i.a. in the immune, nervous, circulatory, respiratory or urinary system. Adenosine is used as an antiarrhythmic agent in the treatment of paroxysmal supraventricular tachycardia. However, due to a very short blood half-time other clinical applications are limited. In order to overcome this obstacle many analogues and conjugates of adenosine with better pharmacokinetic properties have been synthesized. Some of them have been successfully registered as drugs, but there is still a big number of adenosine analogues in clinical trials or preclinical studies. Synthesized compounds demonstrate not only antiarrhytmic, antinociceptive, antidibetic, antiphlogistic or antiviral actions but also influence the course of immune diseases, such as rheumatoid arthritis, nephritis, uveitis or endotoxin shock. This article is focused on novel adenosine analogues and conjugates with potential biological properties.
24731463 [Role and mechanism of NKp44+NK cells in the proliferation and inflammation of synovium of 2014 Jan 21 OBJECTIVE: To explore the effects of NKp44+NK cells from rheumatoid arthritis (RA) patients on the proliferation and monocyte chemotactic protein 1 production of fibroblast-like synoviocytes (FLS). METHODS: The proportions of natural killer (NK) p44 NK cells in peripheral blood (PB) of 50 RA patients and 50 healthy individuals were detected by flow cytometry. Synovial fluid (SF) samples from 30 RA patients were also detected. NKp44+NK cells in RA SF were sorted by flow cytometry for 5 times. The supernatant level of interleukin (IL)-22 was measured by enzyme-linked immunosorbent assay (ELISA). The proliferation of FLS after an addition of culture supernatant of NKp44+NK cells was detected by methyl thiazolyl tetrazolium (MTT) at 24, 48 and 72 h. Monocyte chemotactic protein (MCP)-1 production of RA FLS after an addition of rhIL-22 was detected by ELISA. RESULTS: The proportion of NKp44+NK cells in PB of RA patients was significantly higher than that of normal controls while the proportion of NKp44+NK cells in SF of RA patients was higher than that in PB of matched RA patients (1.270% vs 0, 15.190% vs 2.425%, P < 0.01). The supernatant level of IL-22 in NKp44+NK cell culture was (1 603 ± 332) ng/L. Rapid proliferation of RA FLS was observed at 24, 48, 72 h after an addition of culture supernatant (P < 0.01). IL-22 antibody obviously inhibited the proliferation of RA FLS induced by NKp44+NK cells. MCP-1 production of RA FLS was detected at 72 h after an addition of rhIL-22 (P < 0.01). CONCLUSION: NKp44+NK cells can promote the proliferation and MCP-1 production of RA FLS through the production of IL-22 so as to play an important role in the synovial proliferation and inflammation of RA.
23413059 Perioperative complications and learning curve of the Mobility Total Ankle System. 2013 Feb BACKGROUND: Only 2 articles related to the recently developed Mobility Total Ankle System (Johnson & Johnson Medical/DePuy International, Leeds, UK) have been published to date. The purpose of this study was to determine the perioperative complications associated with the Mobility Total Ankle System and whether a learning curve exists for this system. MATERIALS AND METHODS: We recruited 60 consecutive patients undergoing total ankle arthroplasty using the Mobility Total Ankle System for advanced osteoarthritis and rheumatoid arthritis between May 2008 and June 2010. Group A included the initial 30 patients who underwent surgery, and group B included the next 30 patients. Reporting of adverse perioperative events, including wound healing problems, fracture, aseptic loosening, tendinitis, component malposition, neuroma, and bony impingement, was limited to the first 3 months after the surgery. RESULTS: Eleven of the 30 patients in group A developed complications (36.7%), and 1 died of an unknown cause 6 months after leaving the hospital. The complications in this group included medial malleolar fracture in 6 patients, lateral malleolar fracture in 1, wound healing problems in 2, and varus deformity in 2. Five of the 30 patients in group B developed complications (16.7%). The complications in this group included medial malleolar fracture in 1 patient, medial impingement in 2, Achilles tendon rupture in 1, and wound problems in 1. There was no statistically significant difference (P = .08) between the 2 groups in the incidence of complications after total ankle replacement arthroplasty. There was also no significant difference between the 2 groups in the types of complications seen. CONCLUSIONS: Perioperative complications associated with total ankle replacement arthroplasty using the Mobility Total Ankle System were seen in 16 of 60 patients. Group A had a higher incidence of perioperative complications than did group B. However, the difference was not statistically significant. Either the expertise of the surgeon or the simplicity of the total ankle system can affect the learning curve, although these things were not specifically quantified in this study. LEVEL OF EVIDENCE: Level III, comparative case series.
24730974 Hyaluronate-gold nanoparticle/tocilizumab complex for the treatment of rheumatoid arthriti 2014 May 27 Rheumatoid arthritis (RA) is a chronic inflammatory immune disease causing the inflammation of synovial membrane and the articular cartilage destruction. In this work, hyaluronate-gold nanoparticle/Tocilizumab (HA-AuNP/TCZ) complex was prepared for the treatment of RA. AuNP was used as a drug carrier with antiangiogenic effect. TCZ is a humanized monoclonal antibody against the interleukin-6 (IL-6) receptor and used as an immunosuppressive drug by interfering IL-6 in the pathogenesis of RA. HA is known to have cartilage-protective and lubricant effects. HA was modified with cystamine via reductive amination, which was reduced with dithiothreitol (DTT) to prepare end-group thiolated HA (HA-SH). AuNP was chemically modified with HA-SH and physically modified with TCZ. The formation of HA-AuNP/TCZ complex was corroborated by UV-vis spectroscopy, dynamic light scattering (DLS), and transmission electron microscopy (TEM). The therapeutic effect of HA-AuNP/TCZ complex on RA was confirmed in collagen-induced arthritis (CIA) model mice by ELISA, histological, and Western blot analyses.
23319024 Successful treatment of digital tip necrosis in rheumatoid vasculitis with anti-CD20 antib 2013 Jan We report a successful treatment with rituximab in the case of rheumatoid vasculitis causing digital tips necrosis in exacerbated rheumatoid arthritis. The vasculitis lesions did not respond completely to intravenous methylprednisolone and cyclophosphamide but responded on rituximab treatment. Deep necrosis of a digital tip resolved entirely after completing a course of rituximab.
25147926 Cellular adhesion gene SELP is associated with rheumatoid arthritis and displays different 2014 In rheumatoid arthritis (RA), a key event is infiltration of inflammatory immune cells into the synovial lining, possibly aggravated by dysregulation of cellular adhesion molecules. Therefore, single nucleotide polymorphisms of 14 genes involved in cellular adhesion processes (CAST, ITGA4, ITGB1, ITGB2, PECAM1, PTEN, PTPN11, PTPRC, PXN, SELE, SELP, SRC, TYK2, and VCAM1) were analyzed for association with RA. Association analysis was performed consecutively in three European RA family sample groups (Nfamilies = 407). Additionally, we investigated differential allelic expression, a possible functional consequence of genetic variants. SELP (selectin P, CD62P) SNP-allele rs6136-T was associated with risk for RA in two RA family sample groups as well as in global analysis of all three groups (ptotal = 0.003). This allele was also expressed preferentially (p<10-6) with a two- fold average increase in regulated samples. Differential expression is supported by data from Genevar MuTHER (p1 = 0.004; p2 = 0.0177). Evidence for influence of rs6136 on transcription factor binding was also found in silico and in public datasets reporting in vitro data. In summary, we found SELP rs6136-T to be associated with RA and with increased expression of SELP mRNA. SELP is located on the surface of endothelial cells and crucial for recruitment, adhesion, and migration of inflammatory cells into the joint. Genetically determined increased SELP expression levels might thus be a novel additional risk factor for RA.
23925361 [The efficacy and safety of tocilizumab combined with disease-modifying anti-rheumatoid dr 2013 Apr OBJECTIVE: To evaluate the efficacy and safety of human anti-interleukin-6 (IL-6) receptor antibody (tocilizumab) in combination with disease-modifying anti-rheumatoid drugs (DMARDs) for the treatment of rheumatoid arthritis (RA) patients with moderate to severe activity and inadequate response to DMARDs. METHODS: The present study was a multi-center, randomized, double-blinded, placebo controlled trial. Eligible patients were randomized (tocilizumab:Placebo = 2:1) to one of two groups: tocilizumab 8 mg/kg group or placebo group. The drug was administered every 4 weeks by infusion along with stable dose of DMARDs. The primary analysis evaluated at week 24 included: the proportion of patients with American College of Rheumatology (ACR)20, ACR50 and ACR70 response; the average changes of ACR core components from baseline; the proportion of patients with disease activity score (DAS28) ≤ 3.2 and DAS28 < 2.6. Patients who completed double-blinded phase could choose to enter 24-week open-label therapy with tocilizumab 8 mg/kg infusion every 4 weeks. RESULTS: Totally 139 patients from tocilizumab group and 69 patients from placebo group completed the 24-week double-blinded period respectively with comparable baseline characteristics. The proportion of patients with ACR20, ACR50 and ACR70 in tocilizumab group was significantly higher than that in placebo group: 69.8% vs 24.6% (P < 0.05), 38.8% vs 10.1% (P < 0.05) and 12.9% vs 2.9% (P < 0.05) respectively. ACR core components change, proportion of patients with DAS28 ≤ 3.2 and DAS28 < 2.6 were all better in tocilizumab group than those in the placebo group. Decreased level of biomarkers C-terminal crosslinking telopeptide of type I collagen generated by matrix metalloproteinases (ICTP), matrix metalloproteinase 3 (MMP-3) and N-terminal propeptide of type IIA collagen (PIIANP) were observed in patients with tocilizumab treatment, indicating its positive effects on bone metabolism. A total of 202 patients received tocilizumab treatment in the study with the longest duration as 48 weeks, and all the indexes were improved further with the elongation of the treatment time. During the doubled blind phase, 42.4% of patients in the tocilizumab group had ≥ 1 adverse event (AE), compared with 27.9% of patients in the control group. The most common AE was infection, and most of the AEs were mild to moderate. Serious AEs occurred in 0.7% and 5.9% of patients in the tocilizumab and control groups, respectively. More patients in the tocilizumab group had higher percentage of increased alanine transaminase and aspartate transaminase (12.9% and 9.4%) compared to the placebo group (4.4% and 4.4%). Increase of total cholesterol, high density lipoprotein, low density lipoprotein, and triacylglycerol were observed in the tocilizumab group, but no increase of occurrence of cardiac events. No additional safety signals were found during the extension phase. CONCLUSION: The study showed that tocilizumab combined with DMARDs was safe and effective in reducing articular and systemic symptoms in patients with an inadequate response to DMARDs.
24432685 [Effect of sanshui baihu decoction on the proliferation of fibroblast-like synoviocytes an 2013 Oct OBJECTIVE: To observe the effect of Sanshui Baihu Decoction (SBD) containing serum on the proliferation of in vitro cultured fibroblast-like synoviocytes (FLS) derived from rheumatoid arthritis (RA) and osteoarthritis (OA) and its secretion of interleukin-6 (IL-6) and IL-17, and to explore the pharmacological mechanism of SBD. METHODS: The FLS obtained from cultured RA and OA patients' synovial tissue were cultured and passaged in vitro in a routine way. The cultured medium was changed to DMEM with 20% SBD containing serum and cultured for 72 h after cultured for 3 to 6 generations. The proliferation rate of FLS was detected by MTT assay. Levels of IL-6 and IL-17 in the supernatant were detected by ELISA. Leflunomide and saline containing serum were used as positive and negative control respectively. RESULTS: SBD containing serum significantly inhibited the proliferation of RA-FLS and OA-FLS, and decreased the secretion of IL-17 in RA-FLS. Its inhibition efficiency of SBD was equivalent to that of Leflunomide. No obvious inhibition on the secretion of IL-6 in RA-FLS was observed. It had no significant effect on the secretion of IL-17 and IL-6 in OA-FLS. CONCLUSION: SBD could inhibit the proliferation of FLS and the secretion of IL-17 in RA-FLS, which might be one of its pharmacological mechanisms for treating RA.
23864158 Long-term survival of GSB III elbow prostheses and risk factors for revisions. 2013 Oct INTRODUCTION: Although replacement of the elbow joint is a complex procedure there is not much clinical evidence that contributes to surgical decision-making, mainly due to small clinical samples and short follow-up. Therefore, we performed a long-term analysis up to 30 years after implantation of a GSB III total elbow prosthesis to quantify long-term outcome and to identify possible risk factors for implant revision. MATERIALS AND METHODS: All patients who received a primary GSB III total elbow prosthesis between 1978 and 1998 were included. Information about patient characteristics, the latest known implant status and possible risk factors were collected, Kaplan-Meier survival curves plotted, and 10- and 20-year survival calculated. The cohort was stratified for known risk factors such as diagnosis, age, or gender and included in a Cox regression analysis. RESULTS: A total of 253 patients [mean age at operation 56.9 years (range from 17.5 to 84 years)] with 293 GSB III prostheses were included. The median follow-up was 9.1 years (0 months to 29.3 years). Whereas 81 prostheses did not need revision during the observation period, 76 had been implanted in patients who died before any revision was required, and 75 had not been revised by the last known follow-up. 61 prostheses were revised. This corresponds to a 10-year survival rate of 0.8 (95 % CI 0.74-0.85) and a 20-year rate of 0.67 (95 % CI 0.57-0.76). Prostheses in patients with post-traumatic conditions survived significantly shorter than those in patients with rheumatoid arthritis; previous operations lead to a 2.8 times greater risk of revision (p = 0.004). Neither age at implantation nor gender had a significant influence on prosthesis survival. CONCLUSIONS: The results indicate a good long-term prognosis for this design. The prognosis has to be adjusted for the underlying disease. Previous operations such as joint reconstruction significantly increase the risk of revision.
24612981 Chronic oral or intraarticular administration of docosahexaenoic acid reduces nociception 2014 Mar 10 INTRODUCTION: Clinical and preclinical studies have shown that supplementation with ω-3 polyunsaturated fatty acids (ω-3 PUFAs) reduce joint destruction and inflammation present in rheumatoid arthritis (RA). However, the effects of individual ω-3 PUFAs on chronic arthritic pain have not been evaluated to date. Thus, our aim in this study was to examine whether purified docosahexaenoic acid (DHA, an ω-3 PUFA) reduces spontaneous pain-related behavior and knee edema and improves functional outcomes in a mouse model of knee arthritis. METHODS: Unilateral arthritis was induced by multiple injections of Complete Freund's Adjuvant (CFA) into the right knee joints of male ICR adult mice. Mice that received CFA injections were then chronically treated from day 15 until day 25 post-initial CFA injection with oral DHA (10, 30 and 100 mg/kg daily) or intraarticular DHA (25 and 50 μg/joint twice weekly). Spontaneous flinching of the injected extremity (considered as spontaneous pain-related behavior), vertical rearing and horizontal exploratory activity (considered as functional outcomes) and knee edema were assessed. To determine whether an endogenous opioid mechanism was involved in the therapeutic effect of DHA, naloxone (NLX, an opioid receptor antagonist, 3 mg/kg subcutaneously) was administered in arthritic mice chronically treated with DHA (30 mg/kg by mouth) at day 25 post-CFA injection. RESULTS: The intraarticular CFA injections resulted in increasing spontaneous flinching and knee edema of the ipsilateral extremity as well as worsening functional outcomes as time progressed. Chronic administration of DHA, given either orally or intraarticularly, significantly improved horizontal exploratory activity and reduced flinching behavior and knee edema in a dose-dependent manner. Administration of NLX did not reverse the antinociceptive effect of DHA. CONCLUSIONS: To the best of our knowledge, this report is the first to demonstrate DHA's antinociceptive and anti-inflammatory effects as individual ω-3 PUFAs following sustained systemic and intraarticular administration in a mouse model of CFA-induced knee arthritis. The results suggest that DHA treatment may offer a new therapeutic approach to alleviate inflammation as well as a beneficial effect on pain-related functional disabilities in RA patients.