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ID PMID Title PublicationDate abstract
26931543 Evaluation of the Efficacy of Titanium Mesh Cages with Posterior C1 Lateral Mass and C2 Pe 2016 Jun BACKGROUND: Atlantoaxial fusion is a surgical technique that is performed for the treatment of atlantoaxial instability. The standard surgical procedure is fixation of the atlantoaxial complex via a C1 lateral mass and C2 pedicle screw with posterior wiring. Bone grafting material may still be biomechanically suboptimal, such as autologous bone obtained from osteoporotic patients, and may result in collapse and loosening of posterior wiring. METHODS: Fourteen patients with C1 lateral mass and C2 pedicle fixation as a result of atlantoaxial instability were included in this study. All patients were treated by a single surgeon using a titanium mesh cage with demineralized bone matrix packing. Patient clinical history, imaging data, and medical records were reviewed. To evaluate bony fusion, measurement of the atlantodental interval and computed tomography were performed in the preoperative period, immediate postoperative period, and at 1, 3, 6, and 12 months postoperatively. The Wilcoxon signed-rank test was used to compare differences in the radiologic evaluation at 1 and 12 months postoperatively. RESULTS: Bone fusion was achieved in all patients (100%). Of the 14 patients, 11 had rheumatoid arthritis and 3 had trauma. The mean atlantodental interval of patients with rheumatoid arthritis was 1.85 mm in the immediate postoperative period, 1.96 mm at 1 month postoperatively, 1.98 mm at 3 months postoperatively, 1.96 mm at 6 months, and 1.93 mm at 12 months. Hardware failure and other complications were not observed. CONCLUSIONS: The titanium mesh cage has several advantages compared with bone autografts, including reduced donor-site morbidity, immediate rigid fixation, and successful bone fusion.
26124700 Cost-utility analysis of certolizumab pegol versus alternative tumour necrosis factor inhi 2015 BACKGROUND: Certolizumab pegol, a PEGylated tumour necrosis factor (TNF)-inhibitor, improves the clinical signs and symptoms of rheumatoid arthritis (RA) when used in combination with methotrexate or as monotherapy. This study evaluatedthe cost-utility of certolizumab pegol versusTNF-inhibitors plus methotrexate in the treatment of moderate-to-severe RA in Spain. METHODS: A Markov cohort health state transition model was developed to evaluate the cost-utility (costs and quality-adjusted life years [QALYs]) of certolizumab pegol versus other TNF-inhibitors licensed in Spain in 2009. Efficacy was measured using the American College of Rheumatology (ACR) responses at 6 months, based on adjusted indirect comparisons from published clinical trials. Utilities were derived from EQ-5D data from certolizumab pegol RA clinical trials. Clinical history and resource use data came from published literature. Unit costs were taken from Spanish databases or published data (cost year 2009). Base case analyses were conducted from the payer perspective, with a lifetime horizon, 3.5 % annual discounting rates for costs and outcomes, and 3 % inflation rate for 2009 onwards. One-way sensitivity analyses were conducted. RESULTS: The average lifetime costs for certolizumab pegol, etanercept, adalimumab (every 2 weeks and weekly) and infliximab (3 mg/kg and 5 mg/kg) in combination with methotrexate were €140,971, €141,197, €139,148, €164,741, €136,961 and €152,561, respectively. The QALYs gained were 6.578, 6.462, 6.430 (for both adalimumab doses), 6.430, and 6.318 (for both infliximab doses), respectively. At a €30,000/QALY willingness-to-pay threshold, certolizumab pegol plus methotrexate dominated adalimumab weekly, etanercept, and infliximab 5 mg/kg, and was cost-effective versus adalimumab every 2 weeks and infliximab 3 mg/kg (all with methotrexate), with estimated ICERs of €12,346/QALY and €15,414/QALY, respectively. Certolizumab pegol monotherapy was more cost-effective versus adalimumab, and less expensive with similar health gains versus etanercept (6.416 QALYs vs 6.492). Univariate analysis showed ICERs to be sensitive to changes in time horizon, ACR response time point, baseline Heath Assessment Questionnaire (HAQ) score, and rate of HAQ-disability index deterioration after discontinuing treatment. CONCLUSIONS: This analysis shows that certolizumab pegol is cost-effective compared with other TNF-inhibitors recommended in Spain for the treatment of RA.
27747619 Comparison of Healthcare Costs Between Rheumatoid Arthritis Patients Treated with Infused 2015 Mar INTRODUCTION: While there is a substantial body of literature on the comparative healthcare costs of biologics used to treat rheumatoid arthritis (RA), nearly all of these investigations have been exclusively focused on anti-tumor necrosis factor-α (anti-TNF) agents in the setting of first-line biologic treatment. This study compared healthcare costs between RA patients treated with infused biologics after previously using at least one other biologic agent. METHODS: Using a large US administrative claims dataset, adult RA patients initiating an infused biologic (abatacept, infliximab, tocilizumab) between January 1, 2010 and January 1, 2012 (initiation = index) were identified. Rituximab was excluded because of unique dosing intervals, which make it difficult to determine treatment discontinuation using a claims database. Patients were required to have used one or more other biologic (infused or injected) at any time before index. Patients could contribute multiple observations to the dataset; one for each infused biologic they initiated between January 1, 2010 and January 1, 2012. A 6-month period before index was used to measure patient characteristics. A variable-length follow-up period after index was used to measure per-patient per-month (PPPM) healthcare costs, including biologic costs, RA-related healthcare costs, and all-cause healthcare costs. Generalized estimating equations models compared healthcare costs between the biologic agents, adjusting for patients' demographics and clinical characteristics. RESULTS: The sample comprised 3,771 infused biologic initiations (abatacept = 1,759; infliximab = 922; tocilizumab = 1,090); the mean age of participants was 55 years, 82 % were female, and the median follow-up ranged from 251 to 280 days. Compared with other patients, patients treated with tocilizumab had significantly lower (all P < 0.05) PPPM biologic costs (abatacept = $2,597, infliximab = $3,141, tocilizumab = $1,894), RA-related healthcare costs (abatacept = $2,929, infliximab = $3,598, tocilizumab = $2,236), and all-cause healthcare costs (abatacept = $3,735, infliximab = $4,600, tocilizumab = $3,042). CONCLUSIONS: Among RA patients treated with infused biologics after previously using at least one other biologic, patients treated with tocilizumab had the lowest real-world healthcare costs, largely driven by lower costs directly related to biologic treatment. Such biologic-related cost differences may be driven by variations in real-world treatment patterns (e.g., dose, escalation, treatment frequency).
27651928 One-year effects of glucocorticoids on bone density: a meta-analysis in cohorts on high an 2016 BACKGROUND: Bone loss during glucocorticoid (GC) therapy is poorly quantified. OBJECTIVE: Quantification of bone loss in GC-treated patients with chronic inflammatory diseases (CID; low dose) and transplants (high dose). METHODS: Meta-analysis of cohorts: PubMed, Cochrane, EMBASE and bibliographic searches (1995-2012). Eligible studies prospectively included GC-treated patients with two dual X-ray absorptiometry measurements of spine or hip over a period of at least 12 months. Only supplementation with calcium or vitamin D3 was allowed. 5602 titles yielded 285 articles: 51 study arms in CID (N=1565), 18 study arms in transplantation (N=571). Prednisone-equivalent GC doses and inverse variance weighted mean bone changes were used in a random effects model. RESULTS: In CID, the mean GC dose was 8.7 mg/day (range 1.2-16.4). The mean 1-year bone loss in the lumbar spine was -1.7% (95% CI -2.2% to -1.2%); in the femoral neck: -1.3 (-1.8 to -0.7). In transplantation, the mean GC dose was 18.9 mg/day (range 6.0-52.7). Bone loss in the lumbar spine was -3.6% (-5.2% to -2.0%); in the femoral neck: -3.1% (-5.1% to -1.1%). Within the two groups, bone loss was not related to GC dose. CONCLUSION: In CID, GC-related bone loss appears limited and manageable if current anti-osteoporotic strategies are fully implemented. In transplantation, and probably also other high-dose settings, bone loss is considerable and represents unmet need. The heterogeneity probably reflects the important influence of other factors, most notably the underlying disease and the efficacy of GC treatment.
26554931 Role of extracellular vesicles in autoimmune diseases. 2016 Feb Extracellular vesicles (EVs) consist of exosomes released upon fusion of multivesicular bodies with the cell plasma membrane and microparticles shed directly from the cell membrane of many cell types. EVs can mediate cell-cell communication and are involved in many processes including inflammation, immune signaling, angiogenesis, stress response, senescence, proliferation, and cell differentiation. Accumulating evidence reveals that EVs act in the establishment, maintenance and modulation of autoimmune processes among several others involved in cancer and cardiovascular complications. EVs could also present biomedical applications, as disease biomarkers and therapeutic targets or agents for drug delivery.
26020239 Analysis of the prevalence and associated risk factors of tinnitus in adults. 2015 BACKGROUND: Tinnitus is a common condition in adults; however, the pathophysiology of tinnitus remains unclear, and no large population-based study has assessed the associated risk factors. The aim of this study was to analyze the prevalence and associated risk factors of tinnitus. METHODS: We conducted a cross-sectional study using data from the Korea National Health and Nutrition Examination Survey, with 19,290 participants ranging in age from 20 to 98 years old, between 2009 and 2012. We investigated the prevalence of tinnitus using a questionnaire and analyzed various possible factors associated with tinnitus using simple and multiple logistic regression analysis with complex sampling. RESULTS: The prevalence of tinnitus was 20.7%, and the rates of tinnitus associated with no discomfort, moderate annoyance, and severe annoyance were 69.2%, 27.9%, and 3.0%, respectively. The prevalence of tinnitus and the rates of annoying tinnitus increased with age. The adjusted odds ratio (AOR) of tinnitus was higher for females, those with a smoking history, those reporting less sleep (≤ 6 h), those with more stress, those in smaller households, those with a history of hyperlipidemia osteoarthritis, rheumatoid arthritis, asthma, depression, thyroid disease, an abnormal tympanic membrane, unilateral hearing loss, bilateral hearing loss, noise exposure from earphones, noise exposure at the workplace, noise exposure outside the workplace, and brief noise exposure. Additionally, unemployed individuals and soldiers had higher AORs for tinnitus. The AOR of annoying tinnitus increased with age, stress, history of hyperlipidemia, unilateral hearing loss, and bilateral hearing loss. CONCLUSIONS: Tinnitus is very common in the general population and is associated with gender, smoking, stress, sleep, hearing loss, hyperlipidemia, osteoarthritis, rheumatoid arthritis, asthma, depression, and thyroid disease history.
25168350 Risk factors for periprosthetic infection after reverse shoulder arthroplasty. 2015 Feb BACKGROUND: Management of periprosthetic infection after reverse shoulder arthroplasty (RSA) remains a challenge. Whereas the infection rate after RSA has improved, more information would be helpful to identify patient risk factors for infection after RSA. The purpose of this study was to evaluate risk factors for infection after RSA. METHODS: We identified 301 primary RSAs with a minimum of 1-year follow-up in a prospectively collected shoulder arthroplasty registry. We performed bivariate and multivariable logistic regression analyses to assess the association between patient demographic and clinical characteristics (age, sex, smoking, diabetes, rheumatoid arthritis, body mass index, and history of prior failed hemiarthroplasty or total shoulder arthroplasty) and periprosthetic infection after RSA. RESULTS: There were 15 periprosthetic infections after RSA (5.0%). Patients with a history of RSA for failed arthroplasty (odds ratio, 5.75; 95% confidence interval, 2.01-16.43; P = .001) and patients younger than 65 years had an increased risk for development of an infection (odds ratio, 4.0; 95% confidence interval, 1.21-15.35; P = .021). History of smoking, diabetes, rheumatoid arthritis, or obesity did not contribute to an increased risk of infection after RSA. CONCLUSIONS: This is the first study evaluating risk factors for infection after RSA while controlling for confounding variables with multivariable analysis. The greatest risk factors for infection after RSA were history of a prior failed arthroplasty and age younger than 65 years. Patients with these clinical characteristics should be counseled preoperatively about the increased risk for development of infection after RSA.
25386842 New insights into ADAMs regulation of the GRO-α/CXCR2 system: focus on Sjögren's syndrom 2015 Chemokine-dependent signaling in immune cells is a very important mechanism leading to integrin activation and leukocyte recruitment. During the last years, several studies were performed investigating the role of the chemokine Growth-related oncogene-alpha (GRO-α) and its receptor CXC chemokine receptor 2 (CXCR2) in different diseases. Recently, many new functions and properties of GRO-α/CXCR2 system have been discovered and associated with atherosclerosis, angiogenesis, and many inflammatory conditions, such as autoimmune diseases. The purpose of this review is to discuss current advances in our understanding of the function of the GRO-α/CXCR2 system and related clinical implications associated with autoimmune diseases, such as primary Sjogren's syndrome (pSjS). Included is a discussion of the role of the ADAM17 metalloproteinase in modulating the GRO-α/CXCR2 axis in pSjS. Notably inhibitors of ADAM17 are being developed for the treatment of various autoimmune diseases. We hope to further evaluate this system in the pathogenesis of autoimmune diseases to promote a background for therapeutic interventions.
27346388 Calcium influx kinetics, and the features of potassium channels of peripheral lymphocytes 2016 Nov OBJECTIVE: The transient increase of the cytoplasmic free calcium level plays a key role in the process of lymphocyte activation. Kv1.3 and IKCa1 potassium channels are important regulators of the maintenance of calcium influx and present a possible target for selective immunomodulation. DESIGN: Case-control study. SUBJECTS AND METHODS: We took peripheral blood samples from 8 healthy individuals and 15 primary Sjögren's syndrome (pSS) patients. We evaluated calcium influx kinetics following activation in peripheral T lymphocytes. We also assessed the sensitivity of T lymphocytes to specific inhibition of the Kv1.3 and IKCa1 potassium channels, and the Kv1.3 channel expression. RESULTS: The basal cytoplasmatic calcium levels were lower in both Th1 and Th2 lymphocytes in pSS compared to controls. The peak of calcium influx in lymphocytes isolated from pSS patients is reached later, indicating that they respond more slowly to stimulation compared to controls. In healthy individuals, the inhibition of the IKCa1 channel decreased calcium influx in Th2 and CD4 cells to a lower extent than in Th1 and CD8 cells. On the contrary, the inhibition of Kv1.3 channels resulted in a larger decrease of calcium entry in Th2 and CD4 than in Th1 and CD8 cells. In the pSS group, neither of the inhibitors induced alteration in calcium influx. Expression of Kv1.3 channels on CD4, Th2 and CD8 lymphocytes in pSS was significantly higher compared to controls. CONCLUSION: The altered expression and specific inhibition of potassium channels seem to be related to altered calcium influx kinetics in pSS which distinguish pSS either from healthy controls or other systemic autoimmune diseases.
25248927 Zonula occludens-1, occludin and E-cadherin expression and organization in salivary glands 2015 Jan Sjögren's syndrome (SS) is a chronic inflammatory autoimmune disorder that causes secretory dysfunction of the salivary glands leading to dry mouth. Previous studies reported that tight junction (TJ) proteins are down-regulated and lose polarity in human minor salivary glands with SS, suggesting that TJ structure is compromised in SS patients. In this paper, we utilized the NOD/ShiLtJ mouse with the main goal of evaluating this model for future TJ research. We found that the organization of apical proteins in areas proximal and distal to lymphocytic infiltration remained intact in mouse and human salivary glands with SS. These areas looked comparable to control glands (i.e., with no lymphocytic infiltration). TJ staining was absent in areas of lymphocytic infiltration coinciding with the loss of salivary epithelium. Gene expression studies show that most TJs are not significantly altered in 20-week-old NOD/ShiLtJ mice as compared with age-matched C57BL/6 controls. Protein expression studies revealed that the TJ proteins, zonula occludens-1 (ZO-1), occludin, claudin-12, as well as E-cadherin, do not significantly change in NOD/ShiLtJ mice. Our results suggest that ZO-1, occludin and E-cadherin are not altered in areas without lymphocytic infiltration. However, future studies will be necessary to test the functional aspect of these results.
25451629 Lyme disease: a rigorous review of diagnostic criteria and treatment. 2015 Feb Lyme disease was originally identified in Lyme, Connecticut, based upon an unusual cluster of what appeared to be patients with juvenile rheumatoid arthritis. It was subsequently identified as a new clinical entity originally called Lyme arthritis based on the observation that arthritis was a major clinical feature. However, Lyme arthritis is now called Lyme disease based upon the understanding that the clinical features include not only arthritis, but also potential cardiac, dermatologic and neurologic findings. Lyme disease typically begins with an erythematous rash called erythema migrans (EM). Approximately 4-8% of patients develop cardiac, 11% develop neurologic and 45-60% of patients manifest arthritis. The disease is transmitted following exposure to a tick bite containing a spirochete in a genetically susceptible host. There is considerable data on spirochetes, including Borrelia burgdorferi (Bb), the original bacteria identified in this disease. Lyme disease, if an organism had not been identified, would be considered as a classic autoimmune disease and indeed the effector mechanisms are similar to many human diseases manifest as loss of tolerance. The clinical diagnosis is highly likely based upon appropriate serology and clinical manifestations. However, the serologic features are often misinterpreted and may have false positives if confirmatory laboratory testing is not performed. Antibiotics are routinely and typically used to treat patients with Lyme disease, but there is no evidence that prolonged or recurrent treatment with antibiotics change the natural history of Lyme disease. Although there are animal models of Lyme disease, there is no system that faithfully recapitulates the human disease. Further research on the effector mechanisms that lead to pathology in some individuals should be further explored to develop more specific therapy.
25253569 Correcting the expression of miRNA-155 represses PP2Ac and enhances the release of IL-2 in 2015 Mar MicroRNA-155 is involved in immune cell, differentiation, maturation and function. MiR-155 showed variable dysregulated expression in autoimmune diseases such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) patients. MiR-155 was previously confirmed to directly target CAMP response element binding protein (CREB), which was previously identified as a positive regulator of protein phosphatase 2A (PP2A). PP2A is a key negative regulator of interleukin-2, which is an important immune modulator and was previously shown to be decreased in SLE. In this study we aimed at investigating the regulation of PP2A by miR-155 and hence its role in juvenile SLE disease pathogenesis. MiR-155 showed significant downregulation in PBMCs from juvenile SLE and juvenile familial Mediterranean fever (FMF) and significant upregulation in PBMCs from juvenile idiopathic arthritis (JIA) patients. In SLE, miR-155 expression was negatively correlated with Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) score and proteinuria and was positively correlated with white blood cell (WBC) count. The mRNA of the catalytic subunit of PP2A (PP2Ac) showed significant upregulation in PBMCs from SLE and FMF but not in JIA patients. Additionally, the relative expression of PP2Ac mRNA was positively correlated with SLEDAI score. Forced expression of miR-155 led to decreased relative expression of PP2Ac mRNA and increased IL-2 release in cultured-stimulated PBMCs. This study suggests for the first time the possible role of an miR-155-PP2Ac loop in regulating IL-2 release and identifies miR-155 as a potential therapeutic target in juvenile SLE disease through relieving IL-2 from the inhibitory role of PP2A.
26635344 Monitoring Therapy Response of Experimental Arthritis with Radiolabeled Tracers Targeting 2016 Mar Rheumatoid arthritis is an autoimmune disease resulting in chronic synovial inflammation. Molecular imaging could be used to monitor therapy response, thus enabling tailored therapy regimens and enhancing therapeutic outcome. Here, we hypothesized that response to etanercept could be monitored by radionuclide imaging in arthritic mice. We tested 3 different targets, namely fibroblast activation protein (FAP), macrophages, and integrin αvβ3. METHODS: Male DBA/1J mice with collagen-induced arthritis were treated with etanercept. SPECT/CT scans were acquired at 1, 24, and 48 h after injection of (111)In-RGD2 (integrin αvβ3), (111)In-anti-F4/80-A3-1 (antimurine macrophage antibody), or (111)In-28H1 (anti-FAP antibody), respectively, with nonspecific controls included. Mice were dissected after the last scan, and scans were analyzed quantitatively and were correlated with macroscopic scoring. RESULTS: Experimental arthritis was imaged with (111)In-28H1 (anti-FAP), (111)In-anti-F4/80-A3-1, and (111)In-RGD2. Tracer uptake in joints correlated with arthritis score. Treatment decreased joint uptake of tracers from 23 ± 15, 8 ± 4, and 2 ± 1 percentage injected dose per gram (%ID/g) to 11 ± 11 (P < 0.001), 4 ± 4 (P < 0.001), and 1 ± 0.2 %ID/g (P < 0.01) for (111)In-28H1, (111)In-anti-F4/80-A3-1, and (111)In-RGD2, respectively. Arthritis-to-blood ratios (in mice with arthritis score 2 per joint) were higher for (111)In-28H1 (5.5 ± 1; excluding values > 25), (111)In-anti-F4/80-A3-1 (10.4 ± 4), and (111)In-RGD2 (7.2 ± 1) than for control (111)In-DP47GS (0.7 ± 0.5; P = 0.002), (111)In-rat IgG2b (0.5 ± 0.2; P = 0.002), or coinjection of excess RGD2 (3.5), indicating specific uptake of all tracers in arthritic joints. CONCLUSION: (111)In-28H1, (111)In-anti-F4/80-A3-1, and (111)In-RGD2 can be used to specifically monitor the response to therapy in experimental arthritis at the molecular level. Further studies, however, still need to be performed.
26561928 Anti-inflammatory effects of the extract of Gnaphalium affine D. Don in vivo and in vitro. 2015 Dec 24 ETHNOPHARMACOLOGICAL RELEVANCE: Gnaphalium affine D. Don (GA) has been traditionally used as a medicinal herb in China for the treatment of many ailments including rheumatoid arthritis. However, the anti-arthritic mechanism of GA has still not been demonstrated. This study aims to reveal the anti-inflammatory activity and anti-arthritic mechanism of ethanol extract of G. affine D. Don. MATERIALS AND METHODS: Anti-inflammatory potential of GA was analyzed in vivo in carrageenan induced mice paw edema (acute study). Also, in vivo study was applied in collagen-induced arthritis (CIA) rats. In vitro experiments for analyzing the anti-inflammatory potential of GA were performed on rat alveolar macrophages cell line (NR8383). Analysis of nitric oxide release in NR8383 cells was done by Griess reaction. RT-PCR and western blotting experiment was performed to analyze the expression of phosphorylated p65 and IκBα/β-actin in NF-κB pathway. The production of TNF-α, IL-1β, and COX-2 in NR8383 cells were measured by enzyme-linked immunosorbent assay. The chemical profile of GA was analyzed by HPLC-VWD. RESULTS: GA significantly reduced the paw volume in carrageenan induced rat paw edema rat at different doses (300 and 600 mg/kg), compared with the standard indomethacin treatment. In CIA, GA can obviously ameliorate the inflammatory symptom, including cytokine, histological symptom and paw swelling. In the vitro study, GA was able to reduce the nitric oxide (NO) levels in NR8383 cells that had been stimulated with lipopolysaccharide (LPS). The level of TNF-α, IL-1β, and COX-2 was also decreased with GA treatment in NR8383 cells that had been stimulated with lipopolysaccharide (LPS). Interestingly, GA was found to decrease the level of phosphorylated p65 and IκBα in NR8383 cells. Fifteen compounds were identified by HPLC-VWD with the reference substances and verified by LC-MS. CONCLUSIONS: The results of the experiment scientifically validated its traditional use in inflammatory conditions.
26473409 Abatacept Inhibition of T Cell Priming in Mice by Induction of a Unique Transcriptional Pr 2016 Mar OBJECTIVE: To determine at the phenotypic, functional, and transcriptional levels whether abatacept, a CTLA-4Ig molecule that binds with high affinity to CD80/86 on antigen-presenting cells (APCs) and is used to treat rheumatoid arthritis, induces a state of immunologic tolerance in T cells and dendritic cells in mice. METHODS: We investigated the capacity of abatacept to regulate the development of antigen-specific immunologic tolerance in vivo using murine models of priming and tolerance to generate highly purified antigen-specific T cell populations and CD11c+ APCs. These were combined with detailed immunologic and full genome transcriptional analyses. RESULTS: We found that abatacept inhibited T cell activation, but did not render T cells anergic or lead to the generation of Treg cells. However, it induced a sustained inhibition of T cell activation due to the inability of these cells to progress through the cell cycle following T cell receptor stimulation. We also observed that this state was accompanied by an inhibition of dendritic cell activation due to their reduced licensing by T cells. CONCLUSION: This study provides detailed insight into the mode of action of abatacept, demonstrating that its effectiveness is not due to the induction of T cell tolerance, but rather to a sustained inhibition of T cell activation that results in reduced functionality of APCs, with significant implications for its clinical application.
25879437 Inhibition of inflammatory arthritis using fullerene nanomaterials. 2015 Inflammatory arthritis (e.g. rheumatoid arthritis; RA) is a complex disease driven by the interplay of multiple cellular lineages. Fullerene derivatives have previously been shown to have anti-inflammatory capabilities mediated, in part, by their ability to prevent inflammatory mediator release by mast cells (MC). Recognizing that MC can serve as a cellular link between autoantibodies, soluble mediators, and other effector populations in inflammatory arthritis, it was hypothesized that fullerene derivatives might be used to target this inflammatory disease. A panel of fullerene derivatives was tested for their ability to affect the function of human skin-derived MC as well as other lineages implicated in arthritis, synovial fibroblasts and osteoclasts. It is shown that certain fullerene derivatives blocked FcγR- and TNF-α-induced mediator release from MC; TNF-α-induced mediator release from RA synovial fibroblasts; and maturation of human osteoclasts. MC inhibition by fullerene derivatives was mediated through the reduction of mitochondrial membrane potential and FcγR-mediated increases in cellular reactive oxygen species and NF-κB activation. Based on these in vitro data, two fullerene derivatives (ALM and TGA) were selected for in vivo studies using K/BxN serum transfer arthritis in C57BL/6 mice and collagen-induced arthritis (CIA) in DBA/1 mice. Dye-conjugated fullerenes confirmed localization to affected joints in arthritic animals but not in healthy controls. In the K/BxN moldel, fullerenes attenuated arthritis, an effect accompanied by reduced histologic inflammation, cartilage/bone erosion, and serum levels of TNF-α. Fullerenes remained capable of attenuating K/BxN arthritis in mast cell-deficient mice Cre-Master mice, suggesting that lineages beyond the MC represent relevant targets in this system. These studies suggest that fullerene derivatives may hold promise both as an assessment tool and as anti-inflammatory therapy of arthritis.
26914674 [Proximal carpal row carpectomy]. 2016 Jun OBJECTIVE: Resection of the proximal carpal row, termed proximal row carpectomy (PRC), is performed in order to treat pathologies of the proximal carpal row or radiocarpal joint between the scaphoid and scaphoid facet. It entails the articulation of the capitate and the lunate facet. INDICATIONS: Lunate necrosis, carpal collapse, joint infection with concomitant intercarpal ligament lesions. CONTRAINDICATIONS: Severe cartilage lesions of the lunate facet and the capitate, wrist capsule laxity, rheumatoid arthritis, neuromuscular dysbalance of the wrist-covering soft tissue structures. SURGICAL TECHNIQUE: Dorsal approach to the wrist, incision of the third and fourth extensor compartments, resection and coagulation of the dorsal interosseous nerve, usage of a ligament-sparing capsule incision, identification of the proximal carpal row and inspection of cartilage of the lunate facet and capitate, mobilization and excision of the lunate, scaphoid and triquetrum, articulation of lunate facet and capitate is controlled clinically and fluoroscopically, wound closure, application of plaster slabs. POSTOPERATIVE MANAGEMENT: Immobilization of the wrist on plaster slabs for 2 weeks, removal of sutures after 14 days. RESULTS: PRC is a surgical procedure with few complications. Satisfactory range of motion and grip strength could be preserved without limiting function of the upper extremity. Postoperative osteoarthritis of capitate and lunate facet did not correlate with the good clinical outcome.
26431358 Generation and preclinical characterization of an antibody specific for SEMA4D. 2016 Semaphorin 4D (SEMA4D or CD100) is a member of the semaphorin family of proteins and an important mediator of the movement and differentiation of multiple cell types, including those of the immune, vascular, and nervous systems. Blocking the binding of SEMA4D to its receptors can result in physiologic changes that may have implications in cancer, autoimmune, and neurological disease. To study the effects of blocking SEMA4D, we generated, in SEMA4D-deficient mice, a panel of SEMA4D-specific hybridomas that react with murine, primate, and human SEMA4D. Utilizing the complementarity-determining regions from one of these hybridomas (mAb 67-2), we generated VX15/2503, a humanized IgG4 monoclonal antibody that is currently in clinical development for the potential treatment of various malignancies and neurodegenerative disorders, including multiple sclerosis and Huntington's disease. This work describes the generation and characterization of VX15/2503, including in vitro functional testing, epitope mapping, and an in vivo demonstration of efficacy in an animal model of rheumatoid arthritis.
25645278 Pharmacological inhibition of Dock5 prevents osteolysis by affecting osteoclast podosome o 2015 Feb 3 Osteoporosis is caused by excessive activity of bone-degrading osteoclasts over bone-forming osteoblast. Standard antiosteolytic treatments inhibit bone resorption by inducing osteoclast loss, with the adverse effect of hindering also bone formation. Formation of the osteoclast sealing zone requires Dock5, a guanine nucleotide exchange factor for the small GTPase Rac, and C21, a chemical inhibitor of Dock5, decreases bone resorption by cultured osteoclasts. Here we show that C21 directly inhibits the exchange activity of Dock5 and disrupts osteoclast podosome organization. Remarkably, C21 administration protects mice against bone degradation in models recapitulating major osteolytic diseases: menopause, rheumatoid arthritis and bone metastasis. Furthermore, C21 administration does not affect bone formation and is not toxic. Our results validate the pharmacological inhibition of Dock5 as a novel therapeutic route for fighting osteolytic diseases while preserving bone formation.
27343722 Optimising B-cell depletion in autoimmune disease: is obinutuzumab the answer? 2016 Aug In Rheumatoid Arthritis (RA) and Systemic Lupus Erythematosus (SLE), B-cell depletion therapy using rituximab results in variable clinical responses between individuals, which likely relates to variable B-cell depletion in the presence of immune defects. Outcomes in clinical trials with other type I anti-CD20 mAbs, ocrelizumab and ofatumumab, are comparable to rituximab. A mechanistically different type II mAb, obinutuzumab (OBZ), with greater capacity for B-cell depletion, has recently entered clinical trials in SLE. Here we consider whether type II anti-CD20 mAbs will provide mechanistic advantages to overcome the disease-related immune defects in autoimmune diseases such as SLE.