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ID PMID Title PublicationDate abstract
22906768 Emerging role of interleukin-22 in autoimmune diseases. 2013 Feb Interleukin-22 (IL-22) is an IL-10 family cytokine member that was recently discovered to be mainly produced by Th17 cells. Previous studies have indicated the importance of IL-22 in host defense against Gram-negative bacterial organisms (in gut and lung). Recently, there is emerging evidence that IL-22 is involved in the development and pathogenesis of several autoimmune diseases, such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), multiple sclerosis (MS), Sjögren's syndrome (SS) and psoriasis. Therapeutics targeting IL-22 therefore may have promise for treating various autoimmune diseases. In this review, we discuss the recent progression of the involvement of IL-22 in the development and pathogenesis of autoimmune diseases, as well as its clinical implications and therapeutic potential.
21752263 The Bruton tyrosine kinase inhibitor PCI-32765 ameliorates autoimmune arthritis by inhibit 2011 Jul 13 INTRODUCTION: The aim was to determine the effect of the Bruton tyrosine kinase (Btk)-selective inhibitor PCI-32765, currently in Phase I/II studies in lymphoma trials, in arthritis and immune-complex (IC) based animal models and describe the underlying cellular mechanisms. METHODS: PCI-32765 was administered in a series of murine IC disease models including collagen-induced arthritis (CIA), collagen antibody-induced arthritis (CAIA), reversed passive anaphylactic reaction (RPA), and passive cutaneous anaphylaxis (PCA). Clinical and pathologic features characteristic of each model were examined following treatment. PCI-32765 was then examined in assays using immune cells relevant to the pathogenesis of arthritis, and where Btk is thought to play a functional role. These included proliferation and calcium mobilization in B cells, cytokine and chemokine production in monocytes/macrophages, degranulation of mast cells and its subsequent cytokine/chemokine production. RESULTS: PCI-32765 dose-dependently and potently reversed arthritic inflammation in a therapeutic CIA model with an ED(50) of 2.6 mg/kg/day. PCI-32765 also prevented clinical arthritis in CAIA models. In both models, infiltration of monocytes and macrophages into the synovium was completely inhibited and importantly, the bone and cartilage integrity of the joints were preserved. PCI-32765 reduced inflammation in the Arthus and PCA assays. In vitro, PCI-32765 inhibited BCR-activated primary B cell proliferation (IC(50) = 8 nM). Following FcγR stimulation, PCI-32765 inhibited TNFα, IL-1β and IL-6 production in primary monocytes (IC(50) = 2.6, 0.5, 3.9 nM, respectively). Following FcεRI stimulation of cultured human mast cells, PCI-32765 inhibited release of histamine, PGD(2), TNF-α, IL-8 and MCP-1. CONCLUSIONS: PCI-32765 is efficacious in CIA, and in IC models that do not depend upon autoantibody production from B cells. Thus PCI-32765 targets not only B lymphocytes but also monocytes, macrophages and mast cells, which are important Btk-expressing effector cells in arthritis.
21536526 Store-and-feedforward adaptive gaming system for hand-finger motion tracking in telerehabi 2011 May This paper presents a telerehabilitation system that encompasses a webcam and store-and-feedforward adaptive gaming system for tracking finger-hand movement of patients during local and remote therapy sessions. Gaming-event signals and webcam images are recorded as part of a gaming session and then forwarded to an online healthcare content management system (CMS) that separates incoming information into individual patient records. The CMS makes it possible for clinicians to log in remotely and review gathered data using online reports that are provided to help with signal and image analysis using various numerical measures and plotting functions. Signals from a 6 degree-of-freedom magnetic motion tracking system provide a basis for video-game sprite control. The MMT provides a path for motion signals between common objects manipulated by a patient and a computer game. During a therapy session, a webcam that captures images of the hand together with a number of performance metrics provides insight into the quality, efficiency, and skill of a patient.
21330639 Impact of concomitant use of DMARDs on the persistence with anti-TNF therapies in patients 2011 Apr OBJECTIVE: To evaluate the effect of different concomitant disease modifying antirheumatic drugs (DMARDs) on the persistence with antitumour necrosis factor (anti-TNF) therapies in patients with rheumatoid arthritis (RA). METHOD: This analysis included 10 396 patients with RA registered with the British Society for Rheumatology Biologics Register, a prospective observational cohort study, who were starting their first anti-TNF therapy and were receiving one of the following DMARD treatments at baseline: no DMARD (n=3339), methotrexate (MTX) (n=4418), leflunomide (LEF) (n=610), sulfasalazine (SSZ) (n=308), MTX+SSZ (n=902), MTX+ hydroxychloroquine (HCQ) (n=401) or MTX+SSZ+HCQ (n=418). Kaplan-Meier survival analysis was used to study the persistence with anti-TNF therapy in each DMARD subgroup up to 5 years. Multivariate Cox proportional hazard models, stratified by anti-TNF used and start year and adjusted for a number of potential confounders, were used to compare treatment persistence overall and according to the reason for discontinuation between each of the DMARD subgroups, using MTX as reference. RESULTS: One-year drug survival (95% CI) for the first anti-TNF therapy was 71% (71% to 72%) but this dropped to 42% (41% to 43%) at 5 years. Compared with MTX, patients receiving no DMARD, LEF or SSZ were more likely to discontinue their first anti-TNF therapy while patients receiving MTX in combination with other DMARDs showed better treatment persistence. CONCLUSIONS: These results support the continued use of background DMARD combinations which include MTX. Consideration should be given to the discontinuation of LEF and SSZ monotherapy at the time anti-TNF therapies are started, with the possible exception of the SSZ+ETN combination.
22093933 [Autologous bone grafting plus screw fixation for medial tibial defects in total knee arth 2011 Aug 9 OBJECTIVE: To investigate the efficacy of autologous bone grafting plus screw fixation to reconstruct the medial tibial defects in total knee arthroplasty (TKA). METHODS: From November 2001 to November 2004, 46 patients (50 knees) with medial tibial bone defects underwent TKA at our hospital. There were 16 males (16 knees) and 30 females (34 knees). They included osteoarthritis (OA) (n = 35, 38 knees) and rheumatoid arthritis (RA) (n = 11, 12 knees). A total of 46 patients underwent three-dimensional CT (computed tomography) reconstruction to evaluate the tibial plateau defects after osteotomy. Single or double distal femoral osteotomic bone was used to reconstruct the bone defects with the hollow nail internal fixation. Another 80 TKA patients (86 knees) were randomly selected as the control group. The surgical outcome, lateral migration of tibial component and joint line elevation, etc. were analyzed and the follow-up knee society scores recorded. RESULTS: The patients were followed up for 6 to 9 years. Two patients were lost to follow-up and 1 died of myocardial infarction at 5 years post-TKA in the test group. In the last follow-up, 1 case suffered deep infections and all others had no prosthetic loosening. One case (1 knee) had resorption of wedge-shaped bone graft after 8 years. The remaining graft healed and there was no screw displacement. Medial platform split fracture occurred in 3 patients (3 knees) in the OA group. The quantity of distal femoral osteotomy, thickness of polyethylene insert, tibial implant size, joint line elevation and lateral migration of tibial base were greater than the other two groups (q test, P < 0.05). The pre- and post-operative KSS scores had significant differences in each group (F test, P < 0.05). But the same group showed no significant difference at 6, 9 years (q test, P > 0.05). CONCLUSION: As an easy and effective way of reconstructing the medial tibial bone defects, autologous bone grafting plus screw fixation can restore knee mechanical axis and stability. But in OA patients with tibial sclerosis, the complications of tibial component lateral migration, joint line elevation and splitting tibia fractures should be avoided during the reconstruction.
21719418 Does achieving clinical response prevent work stoppage or work absence among employed pati 2012 Feb OBJECTIVES: To evaluate the impact of clinical response on work stoppage or work absence among employed people with early RA. METHODS: First-year data from the combination of MTX and etanercept trial was used. The analyses were restricted to the 205 patients working full or part time at baseline who answered questions on whether they stopped working or missed days from work in one or more of the four follow-up visits. Work stoppage referred to the first occurrence of subjects reporting stopping work. Work absence was defined as whether patients reported missed days from work. Clinical response and activity state considered included the ACR and European League against Rheumatism response criteria, 28-joint DAS (DAS-28) remission and the minimum clinically important difference of the HAQ score. RESULTS: After adjustment for baseline characteristics, ACR70 responders were 72% less likely to stop working and 55% less likely to miss work than ACR20 non-responders (P < 0.05). Patients achieving DAS-28 remission were 54% less likely to stop work than those with DAS-28 > 3.2 (P < 0.05). Moderate improvements did not appear to effect work stoppage or missed days after adjustments. CONCLUSIONS: Results suggest that achieving clinical remission or major improvement might be necessary to significantly impact work outcomes.
20872780 Elucidation of molecular mechanisms underlying the protective effects of thymoquinone agai 2011 Jan Thymoquinone (TQ) is the major active compound derived from the medicinal Nigella sativa. A few studies have shown that TQ exhibits anti-inflammatory activities in experimental models of rheumatoid arthritis (RA) through mechanisms that are not fully understood. The aim of this work was to evaluate the in vitro and in vivo effects of TQ and to investigate its influence on the major signalling pathways involved in pathophysiological RA changes. We used isolated human RA fibroblast-like synoviocytes (FLS) and a rat adjuvant-induced arthritis model of RA. In isolated RA FLS, TQ (0-10 µM) was not cytotoxic and inhibited slightly lipopolysaccharide (LPS)-induced FLS proliferation and strongly H(2)O(2)-induced 4-hydroxynonenal (HNE) generation. By studying different inflammatory and catabolic factors, we determined that TQ significantly abolished LPS-induced interleukin-1beta (IL-1β), tumour necrosis factor-alpha (TNFα), metalloproteinase-13, cyclooxygenase-2, and prostaglandin E(2). Furthermore, LPS-induced the phosphorylation of p38 mitogen-activated protein kinase, extracellular-regulated kinases ½, and nuclear factor-kappaB-p65 were also blocked by TQ in time-dependent manner. In our experimental RA model, the oral administration of TQ 5 mg/kg/day significantly reduced the serum levels of HNE, IL-1β and TNFα as well as bone turnover markers, such as alkaline phosphatase and tartrate-resistant acid phosphatase. The protective effects of TQ against RA were also evident from the decrease in arthritis scoring and bone resorption. In conclusion, the fact that TQ abolishes a number of factors known to be involved in RA pathogenesis renders it a clinically valuable agent in the prevention of articular diseases, including RA.
20952462 Tocilizumab for rheumatoid arthritis: a Cochrane systematic review. 2011 Jan OBJECTIVE: to compare the benefit and safety of tocilizumab to placebo in patients with rheumatoid arthritis (RA). METHODS: we searched multiple databases for published randomized or controlled clinical trials comparing benefit and safety of tocilizumab to placebo, disease-modifying antirheumatic drugs (DMARD), or other biologics. For dichotomous outcomes, we calculated the relative risk, and for continuous outcomes, the mean difference. RESULTS: eight randomized controlled trials were included in this systematic review, with 3334 participants, 2233 treated with tocilizumab and 1101 controls. The US and Canadian approved dose of tocilizumab, 8 mg/kg every 4 weeks, was given to 1561 participants. In patients taking concomitant methotrexate, compared to placebo, patients treated with approved dose of tocilizumab were substantially and statistically significantly more likely than placebo to achieve the American College of Rheumatology 50 (absolute percentage, 38.8% vs 9.6%, respectively; RR 3.2, 95% CI 2.7, 3.7); Disease Activity Score remission (30.5% vs 2.7%; RR 8.7, 95% CI 6.3, 11.8); and a clinically meaningful decrease in Health Assessment Questionnaire (HAQ)/Modified HAQ scores (60.5% vs 34%; RR 1.8, 95% CI 1.6, 1.9). There were no substantive statistically significant differences in serious adverse effects (0.8% vs 0.7%; RR 1.2, 95% CI 0.8, 1.6) or withdrawals due to adverse events (4.9% vs 3.7%; RR 1.4, 95% CI 0.9, 2.1); however, tocilizumab-treated patients were significantly more likely to have any adverse event (74% vs 65%; RR 1.05, 95% CI 1.03, 1.07); elevation in the ratio of low-density lipoprotein to high-density lipoprotein cholesterol (HDL; 20% vs 12%; RR 1.7, 95% CI 1.2, 2.2); and increase in the ratio of total to HDL cholesterol (12% vs 7%; RR 1.7, 95% CI 1.2, 2.6); and they were less likely to withdraw from treatment for any reason (8.1% vs 14.9%; RR 0.6, 95% CI 0.5, 0.8). CONCLUSION: at the approved dose of 8 mg/kg every 4 weeks, tocilizumab in combination with methotrexate/DMARD is beneficial in decreasing RA disease activity and improving function. Tocilizumab treatment was associated with a significant increase in cholesterol levels and occurrence of any adverse event, but not serious adverse events. Larger safety studies are needed to address these safety concerns.
22504561 Down-titration and discontinuation of infliximab in rheumatoid arthritis patients with sta 2012 Nov Down-titration, or discontinuing infliximab, has proven to be feasible in RA patients. Therefore, our local treatment protocol includes tapering infliximab dose. This observational study describes the prevalence of successful down-titration in daily clinical practice and its effect on costs and quality of life (QoL). METHODS: Infliximab was down-titrated with 25% of the original dose (3 mg/kg) every 8-12 weeks without interval change until discontinuation or flare in all RA patients with stable low 28-joint disease activity score (DAS28) and stable treatment for >6 months. During 1 year DAS28, RA medication, outpatient clinic visits, RA related absenteeism and EuroQoL5D (European QoL questionnaire, EQ5D) were documented. Prevalence of successful down-titration and changes in DAS28, QoL and costs were described. RESULTS: In 16% (95% CI 6 to 26) and 45% (95% CI 31 to 59), respectively, infliximab could be discontinued or down-titrated. Mean infliximab dose decreased significantly from 224 mg (95% CI 212 to 236 mg) at start, to 130 mg (95% CI 105 to 154 mg) after 1 year. Median DAS28 increased from 2.5 (p25-75=2.0-2.9) to 2.8 (2.2-3.6) (p=0.002). Extra corticosteroids were given in 8% of the visits. Disease modifying antirheumatic drugs were seldom changed. There was no statistical difference in QoL after down-titration. Mean reduction in the costs was €3474 (95% CI 2457 to 4492) per patient. CONCLUSION: In the majority of patients with stable low DAS28 and stable treatment, infliximab can be down-titrated or discontinued, which results in a considerable reduction in costs without influencing QoL.
23076921 Cemented, cementless or hybrid fixation options in total knee arthroplasty for osteoarthri 2012 Oct 17 BACKGROUND: It is not clear which fixation of total knee arthroplasty obtains the best clinical, functional and radiographic results in people with osteoarthritis and other non-traumatic diseases, such as rheumatoid arthritis. OBJECTIVES: To assess the benefits and harms of cemented, cementless and hybrid knee prostheses fixation techniques in participants with primary osteoarthritis (osteoarthritis following trauma was not included) and other non-traumatic diseases, such as rheumatoid arthritis. SEARCH METHODS: We searched CENTRAL (2011, issue 10), MEDLINE via PubMed, EMBASE, Current Controlled Trials, LILACS, The Cumulative Index to Nursing and Allied Health Literature, SPORTDiscus, Health Technology Assessment Database and the Database of Abstracts of Reviews of Effectiveness, all from implementation to October 2011, along with handsearches of high-yield journals and reference lists of articles. No language restrictions were applied. SELECTION CRITERIA: Randomized controlled trials (RCTs) evaluating cemented, cementless and hybrid fixation. Participants included patients that were 18 years or older with osteoarthritis and other non-traumatic diseases who were undergoing primary total knee arthroplasty. DATA COLLECTION AND ANALYSIS: Three authors independently selected the eligible trials, assessed the trial quality, risk of bias and extracted data. Researchers were contacted to obtain missing information. MAIN RESULTS: Five RCTs and 297 participants were included in this review. Using meta-analysis on roentgen stereophotogrammetric analysis (RSA) we observed that cemented fixation of the tibial components demonstrated smaller displacement in relation to cementless fixation (with and without hydroxyapatite) after a follow-up of two years (maximum total point-motion, N = 167, two RCTs, mean difference (MD) = 0.52 mm, 95% confidence interval (CI) 0.31 to 0.74). However, the risk of future aseptic loosening with uncemented fixation was approximately half that of cemented fixation according to the arthroplasty instability classification (moderate quality as assessed by GRADE) inferred from RSA (N = 216, three RCTs, risk ratio (RR) = 0.47, 95% CI 0.24 to 0.92) with a 16% absolute risk difference between groups. The number needed to treat for an additional beneficial outcome (NNTB) to prevent future aseptic loosening was 7 (95% CI 5 to 44). There was a low risk of bias for RSA among the studies included. It was not possible to perform meta-analysis on patient-important outcomes, such as the survival rate of the implant (any change of a component), patient global assessments, functional measures, pain, health-related quality of life measures and adverse events. Almost all included studies recorded functional measures of Knee Society and Hospital for Special Surgery knee scores, but the authors of each study found no significant difference between the groups. AUTHORS' CONCLUSIONS: There was a smaller displacement of the cemented tibial component in relation to the cementless fixation in studies with osteoarthritis and rheumatoid arthritis participants who underwent primary total knee prosthesis with a follow-up of two years; however, the cemented fixation presented a greater risk of future aseptic loosening than cementless fixation.
21900785 Meta-analysis: cyclooxygenase-2 inhibitors are no better than nonselective nonsteroidal an 2011 Oct OBJECTIVE: To compare cyclooxygenase-2 (Cox-2) inhibitors alone with NSAIDs plus proton pump inhibitors (PPIs) in preventing gastrointestinal adverse events: upper gastrointestinal (UGI) adverse events and gastrointestinal symptoms in Osteoarthritis and Rheumatoid arthritis. METHODS: PubMed, the Cochrane Library, EMBASE, ISI Web of Knowledge, Chinese Biomedical Literature Database, and reference lists of relevant papers for articles published 1990-2010.12 were searched. The related data matching standards set for this study were extracted. Statistical analyses were carried out using RevMan (5.0) software. RESULTS: The meta-analysis of six randomized controlled trials with a total of 6219 patients revealed that there was no difference in the UGI adverse events between Cox-2 inhibitors and nonselective NSAIDs with concurrent use of PPIs [relative risk (RR) 0.61, 95% confidence interval (CI) 0.34-1.09]. There was no significant difference in gastrointestinal symptoms (RR 1.10, 95% CI: 0.88-1.39) and the cardiovascular adverse events (RR 1.67, 95% CI: 0.78-3.59) between the two groups. CONCLUSION: Cox-2 inhibitors are no better than nonselective NSAIDs with PPIs in regard to UGI adverse events, gastrointestinal symptoms and cardiovascular adverse events in Osteoarthritis and Rheumatoid arthritis. On the basis of the current evidence and the combined wishes of the patient, clinicians should carefully consider and weigh both gastrointestinal and cardiovascular risk before selecting NSAID plus PPIs or Cox-2 inhibitors.
21613310 Mavrilimumab, a human monoclonal antibody targeting GM-CSF receptor-α, in subjects with r 2011 Sep OBJECTIVE: To evaluate the safety, tolerability, pharmacokinetic and pharmacodynamic profiles of mavrilimumab, a human monoclonal antibody targeting the granulocyte-macrophage colony-stimulating factor receptor-α, in subjects with rheumatoid arthritis (RA). METHODS: A randomised, double-blind, placebo-controlled, dose-escalating phase I study in subjects with RA who received stable methotrexate treatment for ≥3 months before enrolment. SUBJECTS: received single intravenous escalating doses of mavrilimumab (0.01-10.0 mg/kg) or placebo. RESULTS: 32 subjects were enrolled in this study (1 unblinded subject at 0.01 mg/kg and another at 0.03 mg/kg were followed by five sequential double-blinded cohorts, n=6 each, treated with 0.1, 0.3, 1.0, 3.0 and 10.0 mg/kg, respectively). Adverse events were mild or moderate and were reported with similar frequency across all treatment cohorts. One subject (10.0 mg/kg) experienced moderate face and neck urticaria during infusion that resolved with symptomatic treatment. Systemic clearance of mavrilimumab approached that of endogenous IgG at doses >1.0 mg/kg; pharmacodynamic activity was confirmed in the 1.0 and 3.0 mg/kg cohorts by suppression of suppressor of cytokine signalling 3 mRNA transcripts. In exploratory analyses, reductions of acute phase reactants were observed in subjects with elevated C-reactive protein (>5 mg/l) and erythrocyte sedimentation rate (≥20.0 mm/h) at baseline. No significant change in Disease Activity Score 28-joint assessment (DAS28) was seen in any of the cohorts. In mavrilimumab-treated subjects (n=15) with baseline DAS28 >3.2, mean disease activity (DAS28) was significantly reduced at 4 weeks. CONCLUSION: In this first-in-human study, mavrilimumab showed preliminary evidence of pharmacodynamic activity. Importantly, the safety and pharmacokinetic profiles of mavrilimumab support further clinical studies in RA. TRIAL REGISTRATION NUMBER: NCT00771420.
21078711 Disease phenotypes and gender association of FCRL3 single-nucleotide polymorphism -169T/C 2011 Feb OBJECTIVE: To investigate the association of the functional FCRL3 single-nucleotide polymorphism (SNP) -169T/C with disease phenotypes and susceptibility to systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) in Taiwanese. METHODS: FCRL3 SNP -169T/C was genotyped in 573 patients with SLE, 670 patients with RA, and 758 controls. Genotype distributions and allele frequencies were compared among the 3 groups as aggregates or as stratified by clinical characteristics, autoantibody profile, and sex within patient groups. RESULTS: Overall, FCRL3 SNP -169T/C was not associated with susceptibility to either SLE or RA. However, -169CC genotype was significantly reduced in leukopenia-positive SLE patients as compared to the leukopenia-negative SLE patients (CC vs CT+TT, p = 6 × 10(-4), OR 0.444, 95% CI 0.279-0.708) and controls (p = 6.1 × 10(-3), OR 0.583, 95% CI 0.396-0.857). On the other hand, -169TT genotypes were significantly more numerous in RA patients with non-destructive disease as compared with patients with destructive disease (CC+CT vs TT: p = 0.007, OR 1.672, 95% CI 1.149-2.432). The -169T allele frequency was also significantly increased in non-destructive RA compared with patients with destructive disease (C vs T: p = 0.010, OR 1.423, 95% CI 1.089-1.859). FCRL3 SNP -169TT homozygous donors were significantly more numerous among female cyclic citrullinated peptide (CCP)-negative RA patients versus female CCP-positive RA patients (CC+CT vs TT: p = 0.019, OR 1.64, 95% CI 1.085-2.479). CONCLUSION: The functional FCRL3 SNP -169T/C appears to play important roles in the development of certain phenotypes such as SLE leukopenia and RA disease severity in Taiwanese patients with SLE and RA.
22718925 Biologic monotherapy as initial treatment in patients with early rheumatoid arthritis. 2012 Jul Although biologic agents are most well established as part of combination regimens in patients with RA, biologic monotherapy is common in clinical practice. To date, few double-blind, randomized clinical trials have compared biologic monotherapy with MTX monotherapy. Five randomized double-blind trials evaluating the TNF antagonists etanercept (ERA and TEMPO), adalimumab (PREMIER) and golimumab (GO-BEFORE) and the IL-6 receptor antagonist tocilizumab (AMBITION) were identified. We noted considerable variation in patient characteristics (i.e. disease duration and disease severity) in the five trials. Studies involving monotherapy with TNF inhibitors found no clear clinical efficacy advantage over MTX monotherapy. In the two trials that included a TNF inhibitor/MTX combination arm, combination therapy was superior to monotherapy with either agent alone. In contrast, the AMBITION trial demonstrated that tocilizumab monotherapy was superior to MTX in terms of clinical response, disease activity, remission and functionality. Although results cannot be compared across clinical trials, tocilizumab was the only biologic agent to demonstrate superiority to MTX as monotherapy in patients with RA with limited/no exposure to MTX.
22064970 The vitamin D receptor regulates rheumatoid arthritis synovial fibroblast invasion and mor 2012 Mar 27 Serum levels of vitamin D levels are commonly reduced in patients with rheumatoid arthritis (RA) and have been implicated in disease pathogenesis. We recently identified a new vitamin D receptor transcriptional signature in synovial tissues from rats with mild and nonerosive arthritis, suggesting a vitamin D-mediated protective effect. In the present study, we address the hypothesis that part of the vitamin D protective effect is mediated via interference with fibroblast-like synoviocyte (FLS) invasive properties, an in vitro cellular phenotype that correlates with radiographic and histological damage in pristane-induced arthritis and RA. FLSs derived from DA rats with pristane-induced arthritis and RA patients were studied in an in vitro model of invasion through a collagen-rich barrier (Matrigel) over a 24-h period, in the presence or absence of calcitriol, an active form of vitamin D. Matrix metalloprotease (MMP) expression levels were analyzed with zymography and quantitative real-time polymerase chain reaction, and the cytoskeleton was studied with immunofluorescense microscopy. Calcitriol significantly inhibited DA and RA FLS invasion by 54% and 53%, respectively. Calcitriol also reduced interleukin (IL)-1β-induced expression of MMP-1 by 95% in DA FLSs and by 73.5% in RA FLS. Calcitriol treatment reduced actin cytoskeleton reorganization, reduced polarized formation of lamellipodia and reduced colocalization of phosphorylated focal adhesion kinase (p-FAK) with lamellipodia, all consistent with reduced cell ability to move and invade. In conclusion, we identified a new effect of calcitriol in FLS invasion. This discovery suggests that the reduced serum levels of vitamin D and its metabolites commonly seen in RA might increase risk for FLS-mediated cartilage and bone invasion and erosions. Treatment with vitamin D or its analogs has the potential to become a helpful adjuvant aimed at preventing or reducing joint destruction.
22089463 Maintenance of efficacy and safety with subcutaneous golimumab among patients with active 2011 Dec OBJECTIVE: To evaluate the efficacy/safety of subcutaneous (SC) golimumab in patients with rheumatoid arthritis (RA) who previously received intravenous (IV) golimumab with or without methotrexate (MTX). METHODS: Adult patients with RA (n = 643) with persistent disease despite MTX (≥ 15 mg/wk for ≥ 3 months) were randomized to IV placebo + MTX (n = 129) or IV golimumab 2-4 mg/kg (± MTX) every 12 weeks (n = 514). Patients who completed the study through Week 48 could participate in the longterm extension (LTE), comprising open-label golimumab 50 mg SC every 4 weeks (± MTX) for 24 weeks (LTE-0 to LTE-24) followed by 16 weeks of safety followup (LTE-24 to LTE-40; MTX could be adjusted). RESULTS: At Week 48, 28% (nominal p < 0.001 vs placebo), 11%, and 8% of patients who received IV golimumab + MTX, golimumab alone, and placebo + MTX, respectively, achieved ≥ 50% improvement in the American College of Rheumatology response criteria (ACR50). Among the 505 patients who entered the LTE and were still participating, the proportion of patients treated with golimumab 50 mg SC (± MTX) achieving an ACR50 response increased to 44% at both LTE-14 and LTE-24. ACR20, ACR70, and 28-joint Disease Activity Score using C-reactive protein exhibited similar response patterns as ACR50. Infections were the most commonly reported adverse events through the end of IV golimumab dosing (37% placebo + MTX, 45% golimumab, 51% golimumab + MTX) and with SC golimumab from LTE-0 through LTE-40 (35% golimumab, 36% golimumab + MTX). Concomitant MTX use yielded lower incidences of antibodies to SC golimumab and injection-related reactions. CONCLUSION: Clinical improvements observed in golimumab-treated patients were sustained or improved in patients switched from IV (2-4 mg/kg ± MTX) to open-label SC (50 mg ± MTX) golimumab. Both IV and SC golimumab demonstrated acceptable safety profiles (Clinicaltrials.gov NCT00361335).
22197557 FAS/FAS-L dependent killing of activated human monocytes and macrophages by CD4+CD25- resp 2012 Feb Conclusive resolution of an immune response is critical for the prevention of autoimmunity and chronic inflammation. We report that following co-culture with autologous CD4+CD25- responder T cells, human CD14+ monocytes and monocyte-derived macrophages become activated but also significantly more prone to apoptosis than monocytes/macrophages cultured alone. In contrast, in the presence of CD4+CD25+ regulatory T cells (Tregs), monocytes and macrophages survive whilst adopting an anti-inflammatory phenotype. The induction of monocyte death requires responder T cell activation and cell-contact between responder T cells and monocytes. We demonstrate a critical role for FAS/FAS-L ligation in responder T cell-induced monocyte killing since responder T cells, but not Tregs, upregulate FAS-ligand (FAS-L) mRNA, and induce FAS expression on monocytes. Furthermore, responder T cell-induced monocyte apoptosis is blocked by neutralising FAS/FAS-L interaction, and is not observed when monocytes from an autoimmune lymphoproliferative syndrome (ALPS) patient with complete FAS-deficiency are used as target cells. Finally, we show that responder T cell-induced killing of monocytes is impaired in patients with active rheumatoid arthritis (RA). Our data suggest that resolution of inflammation in the course of a healthy immune response is aided by the unperturbed killing of monocytes with inflammatory potential by responder T cells and the induction of longer-lived, Treg-induced, anti-inflammatory monocytes.
22691662 Early morbidity and mortality associated with elderly odontoid fractures. 2012 Jun Odontoid fracture treatment is well documented, but challenges remain in treating these fractures in elderly patients. Issues include identifying the optimal treatment for bony union, determining the stability of a nonunion, and understanding the long-term consequences of nonunion. In elderly patients, the focus tends to shift to morbidity and mortality.This retrospective review describes the early morbidity and mortality in the authors' elderly odontoid fracture population. The authors reviewed the medical records, radiographs, and death certificates of 37 patients aged 65 years or older who were diagnosed with type 2 odontoid fractures between 1994 and 2004. Average follow-up was 28.7 ± 32.5 weeks (range, 0-133 weeks). More than three-fourths of the patients were injured in a fall. All of the odontoid fractures were type 2. The 3 most common co-morbidities were hypertension, heart disease, and rheumatoid arthritis. The majority of patients were treated nonoperatively with a collar or halo. Six patients experienced 1 procedure-related complication. Overall, 18 (48.6%) of 37 patients experienced complications, including 3 (8.15%) deaths.In elderly patients with odontoid fractures, one should be prepared for a hospital course complicated by medical issues; early mortality rates are significant. These issues appear to exist regardless of the fracture treatment chosen; one must anticipate respiratory, swallowing, balance, and cardiac problems. Management strategies should be individualized to the patients; operative and nonoperative treatments remain viable options.
23011084 Soluble CD163 serum levels are elevated and correlated with IL-12 and CXCL10 in patients w 2013 Apr CD163, a membrane glycoprotein restricted to monocyte-macrophage cell lineage, is released in the terminal phase of acute inflammation and during chronic inflammation, with anti-inflammatory and antiangiogenic role. The proteolytically detached ectodomain of CD163 is the soluble component sCD163. A few studies were performed regarding circulating sCD163 in human diseases. Only two were accomplished in patients with rheumatoid arthritis (RA). Our concern was (1) to evaluate sCD163 serum concentrations in active RA patients with long-standing evolution, (2) to correlate them with clinical parameters, laboratory markers, disease activity, and (3) to search possible relationships with some cytokines (IL-12, IL-17) and chemokine (CXCL10), involved in RA pathogenesis. First and third topics were not achieved until now, and the second one points out discordant findings and unspecified aspects. It was achieved immunoassay of serum sCD163, IL-12, IL-17, CXCL10 and traditional methods for RA laboratory markers. The mean sCD163 level of 33 patients was significantly higher than in 20 normal controls (p = 0.0001), 59.3 % of them with concentrations above normal cut-off value. sCD163 levels were weakly correlated with CRP and RF but not with ERS and disease activity. IL-12 and CXCL10 serum levels strongly correlated with sCD163 concentrations, while IL-17 positively but insignificantly correlated. In conclusion, serum sCD163 levels are significantly elevated in long-standing RA patients, but sCD163 has no role as a biomarker of disease activity. High correlation of sCD163 with IL-12 and CXCL10 suggests the association of their well-known anti-inflammatory function in long-standing RA patients.
21524309 Oral bisphosphonate-related osteonecrosis of the jaws in rheumatoid arthritis patients: a 2011 Apr 27 BACKGROUND: Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a clinical condition characterized by the presence of exposed bone in the maxillofacial region. Its pathogenesis is still undetermined, but may be associated with risk factors such as rheumatoid arthritis (RA). The aim of this paper is to report two unpublished cases of BRONJ in patients with RA and to conduct a literature review of similar clinical cases with a view to describe the main issues concerning these patients, including demographic characteristics and therapeutic approaches applied. METHODS: Two case reports of BRONJ involving RA patients were discussed RESULTS: Both patients were aging female taking alendronate for more than 3 years. Lesions were detected in stage II in posterior mandible with no clear trigger agent. The treatment applied consisted of antibiotics, oral rinses with chlorhexidine, drug discontinuation and surgical procedures. Complete healing of the lesions was achieved. CONCLUSIONS: This paper brings to light the necessity for rheumatologists to be aware of the potential risk to their patients of developing BRONJ and to work together with dentists for the prevention and early detection of the lesions. Although some features seem to link RA with oral BRONJ and act as synergistic effects, more studies should be developed to support the scientific bases for this hypothesis.