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ID PMID Title PublicationDate abstract
25827912 Comparative immunohistochemical evaluation of the zonal distribution of extracellular matr 2015 Apr The purpose of our study was to analyze the distribution of the major extracellular matrix glycosaminoglycan hyaluronan (HA), its receptor CD44 and cells which influence (re)modeling of the extracellular matrix (T- and B-cells, macrophages, endothelial cells) in menisci obtained from patients suffering from rheumatoid arthritis or osteoarthritis in order to analyze whether these markers could be useful to differentiate between both arthropathies. Human menisci were sampled from patients undergoing total knee arthroplasty. Histological staining (H&E, PAS/Alcian Blue for neutral and charged carbohydrate residues) and (immuno)histochemistry were performed for detection of HA, CD44, sphingosine-1-phosphate receptor 1 (EDG-1) as a marker for endothelial cells, CD3 as a marker for T-cells, CD20 as a marker for B-cells and CD68 as a marker for macrophages. The extracellular matrix in the vascularized zone showed higher amounts of HA as well as acid carbohydrate residues in comparison to the poorly vascularized zones of the meniscus in both disease entities. EDG-1 positive endothelial cells were present in all zones, with fewer cells being detected in the inner zones of the rheumatoid menisci than in the osteoarthritic ones. Macrophages, T- and B-cells as well as CD44-positive cells were more prominent in the vascularized zone of the meniscus than in the poorly vascularized central zone. The distribution patterns of the extracellular matrix components as well as the CD44-positive cells and the inflammation markers in the peripheral zone resembled the distribution in synovial tissue, indicating that both synovia and meniscus were involved in pathological changes in osteoarthritis and rheumatoid arthritis. IN CONCLUSION: the distribution of extracellular glycoconjugates and of cells modulating their synthesis showed similar results in both arthropathies, not enabling a differentiation between rheumatoid arthritis and osteoarthritis but underlining the role of these markers in inflammation and degradation in human meniscus.
25639738 Combination of IgG N-glycomics and corresponding transcriptomics data to identify anti-TNF 2015 Jun Prediction of responsiveness in biological therapies is an important and challenging issue in different diseases. Analyzing glycosylation pattern changes of key serum glycoproteins is one of the possible avenues to follow disease remission. The aim of this study was to investigate the changes of serum IgG glycoforms in Crohn's disease (CD) and rheumatoid arthritis patients in response to antitumor necrosis factor alpha (anti-TNF-α) treatment. IgG was isolated from patient serum samples using Protein A affinity pull-down, followed by the release of N-glycans with peptide-N-glycosidase F. The released glycans were fluorescently tagged with 8-aminopyrene-1,3,6-trisulfonate and analyzed by CGE with laser-induced fluorescent detection. Significant alterations were detected between responders and nonresponders in both disease groups. In CD patients, disease-specific alteration was found in response to anti-TNF-α therapy, which was also confirmed by transcriptomics data analysis of the corresponding glycosyltransferases and glycosidases.
27488122 The circadian clock regulates inflammatory arthritis. 2016 Nov There is strong diurnal variation in the symptoms and severity of chronic inflammatory diseases, such as rheumatoid arthritis. In addition, disruption of the circadian clock is an aggravating factor associated with a range of human inflammatory diseases. To investigate mechanistic links between the biological clock and pathways underlying inflammatory arthritis, mice were administered collagen (or saline as a control) to induce arthritis. The treatment provoked an inflammatory response within the limbs, which showed robust daily variation in paw swelling and inflammatory cytokine expression. Inflammatory markers were significantly repressed during the dark phase. Further work demonstrated an active molecular clock within the inflamed limbs and highlighted the resident inflammatory cells, fibroblast-like synoviocytes (FLSs), as a potential source of the rhythmic inflammatory signal. Exposure of mice to constant light disrupted the clock in peripheral tissues, causing loss of the nighttime repression of local inflammation. Finally, the results show that the core clock proteins cryptochrome (CRY) 1 and 2 repressed inflammation within the FLSs, and provide novel evidence that a CRY activator has anti-inflammatory properties in human cells. We conclude that under chronic inflammatory conditions, the clock actively represses inflammatory pathways during the dark phase. This interaction has exciting potential as a therapeutic avenue for treatment of inflammatory disease.-Hand, L. E., Hopwood, T. W., Dickson, S. H., Walker, A. L., Loudon, A. S. I., Ray, D. W., Bechtold, D. A., Gibbs, J. E. The circadian clock regulates inflammatory arthritis.
25600626 Expression of citrulline and homocitrulline residues in the lungs of non-smokers and smoke 2015 Jan 20 INTRODUCTION: Smoking is a well-established risk factor for rheumatoid arthritis (RA), and it has been proposed that smoking-induced citrullination renders autoantigens immunogenic. To investigate this mechanism, we examined human lung tissue from 40 subjects with defined smoking status, with or without chronic obstructive pulmonary disease (COPD), and control tissues from other organs for citrullinated proteins and the deiminating enzymes peptidylarginine deiminase type-2 (PAD2) and -4 (PAD4). METHODS: Lung tissue samples, dissected from lobectomy specimens from 10 never smokers, 10 smokers without airflow limitation, 13 COPD smokers and eight COPD ex-smokers, and control tissue samples (spleen, skeletal muscle, liver, ovary, lymph node, kidney and heart), were analysed for citrullinated proteins, PAD2 and PAD4 by immunoblotting. Citrulline and homocitrulline residues in enolase and vimentin were analysed by partial purification by gel electrophoresis followed by mass spectrometry in 12 of the lung samples and one from each control tissues. Band intensities were scored semi-quantitatively and analysed by two-tailed Mann-Whitney T-test. RESULTS: Within the lung tissue samples, citrullinated proteins, PAD2 and PAD4 were found in all samples, with an increase in citrullination in COPD (P = 0.039), but minimal difference between smokers and non-smokers (P = 0.77). Citrullination was also detected at lower levels in the tissues from other organs, principally in lymph node, kidney and skeletal muscle. Mass spectrometry of the lung samples showed that vimentin was citrullinated at positions 71, 304, 346, 410 and 450 in non-smokers and smokers both with and without COPD. A homocitrulline at position 104 was found in four out of six COPD samples and one out of six non-COPD. Citrulline-450 was also found in three of the control tissues. There were no citrulline or homocitrulline residues demonstrated in α-enolase. CONCLUSIONS: We have shown evidence of citrullination of vimentin, a major autoantigen in RA, in both non-smokers and smokers. The increase in citrullinated proteins in COPD suggests that citrullination in the lungs of smokers is mainly due to inflammation. The ubiquity of citrullination of vimentin in the lungs and other tissues suggests that the relationship between smoking and autoimmunity in RA may be more complex than previously thought.
26155615 [Left and right ventricular diastolic dysfunction in patients with early rheumatoid arthri 2015 AIM: To estimate the rate of diastolic dysfunction (DD) of the left and right ventricles (LV and RV) in patients with early rheumatoid arthritis (RA) before using disease-modifying antirheumatic drugs (DMARDs) therapy and to investigate its association with traditional risk factors (TRFs) for cardiovascular diseases (CVD) and inflammatory markers. SUBJECTS AND METHODS: The investigation enrolled 74 patients with a valid diagnosis of RA, including 56 (74%) women (median age, 54 years; disease duration, 7 months); the patients who were seropositive for rheumatoid factor (RF) (87%) and/or anti-cyclic citrullinated peptide (anti-CCP) antibodies (100%) who had not been on DMARDs or glucocorticosteroids. TRFs for CVD and carotid artery atherosclerosis were assessed from duplex scanning data and echocardiography was performed in all the patients with early RA before starting the therapy. The ratio of the maximum blood flow velocity during early diastolic filling (E) to that during atrial systole (A) was used as a criterion for LVDD and RVDD. There were 3 types of impaired ventricular filling: 1) E/A <1; 2) E/A = 1-2; 3) E/A > 2. RESULTS: LVDD and RVDD were detected in 35 (48%) and 17 (23%) patients, respectively. RVDD was recorded only in conjunction with LVDD. Among LVDD and RVDD, the former was prevalent. All the patients with early RA were divided into 3 groups: 1) patients with LVDD and RVDD; 2) those with LVDD; 3) those without ventricular DD. All the three groups were matched for the level of DAS28, anti-CCP antibodies, and RF. The incidence of arterial hypertension, dyslipidemia, and abdominal obesity was higher in the patients of Groups 1 and 2 than in those of Group 3. There was a progressive decrease in high-density lipoprotein (HDL) cholesterol concentrations and increases in triglyceride (TG) levels and atherogenic index from Group 3 to Group 1, with the concentrations of total cholesterol and low-density lipoprotein cholesterol being similar in the 3 groups. Coronary heart disease was recorded more frequently in Group 2 than in Group 3. Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) proved to be also significantly higher in the patients with DD than in those without DD. Correlations were found between LV E/A and ESR, CRP, HDL cholesterol, TG, RV E/A and ESR, DAS28, TG. CONCLUSION: The patients with early-stage RA were found to have high incidence rates of LVDD and RVDD, which is related to the high prevalence of CVD, the high spread of TRF for CVD, and the high activity of an inflammatory process.
24406543 Evolution of cost structures in rheumatoid arthritis over the past decade. 2015 Apr OBJECTIVE: To estimate the changes in direct and indirect costs induced by patients with rheumatoid arthritis (RA) in German rheumatology, between 2002 and 2011. To examine the impact of functional status on various cost domains. To compare the direct costs incurred by patients at working age (18-64 years) to patients at an age of retirement (≥65 years). METHODS: We analysed data from the National Database of the German Collaborative Arthritis Centres with about 3400 patients each year. Costs were calculated using fixed prices as well as annually updated cost factors. Indirect costs were calculated using the human capital as well as the friction cost approaches. RESULTS: There was a considerable increase in direct costs: from €4914 to €8206 in patients aged 18-64, and from €4100 to €6221 in those aged ≥65, attributable to increasing prescription of biologic agents (18-64 years from 5.6% to 31.2%, ≥65 years from 2.8% to 19.2%). This was accompanied by decreasing inpatient treatment expenses and indirect costs due to sick leave and work disability. The total growth of cost, on average, was €2437-2981 for patients at working age, and €2121 for patients at retirement age. CONCLUSIONS: The increase in treatment costs for RA over the last decade was associated with lower hospitalisation rates, better functional status and a lower incidence of work disability, offsetting a large proportion of risen drug costs. Since the rise in drug costs has manifested a plateau from 2009 onwards, no relevant further increase in total costs for patients with RA treated in German rheumatology is expected.
26776603 A longitudinal genome-wide association study of anti-tumor necrosis factor response among 2016 Jan 18 BACKGROUND: Studies of Caucasian patients with rheumatoid arthritis (RA) to identify genetic biomarkers of anti-tumor necrosis factor (TNF) response have used response at a single time point as the phenotype with which single nucleotide polymorphism (SNP) associations have been tested. The findings have been inconsistent across studies. Among Japanese patients, only a few SNPs have been investigated. We report here the first genome-wide association study (GWAS) to identify genetic biomarkers of anti-TNF response among Japanese RA patients, using response at 2 time-points for a more reliable clinical phenotype over time. METHODS: Disease Activity Scores based on 28 joint counts (DAS28) were assessed at baseline (before initial therapy), and after 3 and 6 months in 487 Japanese RA patients starting anti-TNF therapy for the first time or switching to a new anti-TNF agent. A genome-wide panel of SNPs was genotyped and additional SNPs were imputed. Using change in DAS28 scores from baseline at both 3 (ΔDAS-3) and 6 months (ΔDAS-6) as the response phenotype, a longitudinal genome-wide association analysis was conducted using generalized estimating equations (GEE) models, adjusting for baseline DAS28, treatment duration, type of anti-TNF agent and concomitant methotrexate. Cross-sectional analyses were performed using multivariate linear regression models, with response from a single time point (ΔDAS-3 or ΔDAS-6) as phenotype; all other variables were the same as in the GEE models. RESULTS: In the GEE models, borderline significant association was observed at 3 chromosomal regions (6q15: rs284515, p = 6.6x10(-7); 6q27: rs75908454, p = 6.3x10(-7) and 10q25.3: rs1679568, p = 8.1x10(-7)), extending to numerous SNPs in linkage disequilibrium (LD) across each region. Potential candidate genes in these regions include MAP3K7, BACH2 (6q15), GFRA1 (10q25.3), and WDR27 (6q27). The association at GFRA1 replicates a previous finding from a Caucasian dataset. In the cross-sectional analyses, ΔDAS-6 was significantly associated with the 6q15 locus (rs284511, p = 2.5x10(-8)). No other significant or borderline significant associations were identified. CONCLUSION: Three genomic regions demonstrated significant or borderline significant associations with anti-TNF response in our dataset of Japanese RA patients, including a locus previously associated among Caucasians. Using repeated measures of response as phenotype enhanced the power to detect these associations.
26087385 Effects of Transplantation of CTLA4Ig-Overexpressing Adipose Tissue-Derived Mesenchymal St 2016 CTLA4Ig has therapeutic potential for rheumatoid arthritis patients unresponsive to methotrexate (MTX) or TNF-α blockers. However, recombinant CTLA4Ig proteins are short acting and expensive. Adipose tissue-derived mesenchymal stem cells (ASCs) present an ideal stem cell source for practical regenerative medicine due to their abundant availability and their beneficial properties including immunomodulation, homing activity, paracrine effects, and differentiation ability. Therefore, we aimed to determine whether CTLA4Ig and human ASCs show synergistic effects on immunomodulation and clinical improvement of sustained severe rheumatoid arthritis in a mouse model. hASCs overexpressing CTLA4Ig (CTLA4Ig-hASC) were serially transplanted into mice with collagen-induced arthritis. Arthritic mice were subjected to four treatments based on their arthritis score on day 62 postimmunization: control (C group), hASC (H group), CTLA4Ig-hASC (CT group), and MTX (MTX group). A group of healthy mice was used as a normal control (N). Mice in the N and C groups were infused with 150 µl saline, and 2 × 10(6) hASCs or CTLA4Ig-hASCs in 150 µl of saline were intravenously administered to those in the H and CT groups, respectively, on days 63, 70, 77, and 84 after CII immunization. About 1 mg/kg of methotrexate was intraperitoneally administered to the MTX group three times a week for 4 weeks. Serial hASC and CTLA4Ig-hASC transplantation modulated various cytokines and chemokines related to the development of rheumatoid arthritis. Both treatments protected against destruction of cartilage, with CTLA4Ig-hASCs being most effective. Serum levels of CII autoantibodies and C-telopeptide of type II collagen were significantly low in the group transplanted with CTLA4Ig-hASCs. In vitro, ASC and CTLA4Ig-hASC treatment significantly decreased T-bet and GATA-3 expression in splenocytes from arthritic mice, and CTLA4Ig-hASC treatment significantly increased the ratio of Treg/Th17 (CD4(+)CD25(+)FoxP3(+)/CD4(+)CD25(+)RORγt) cells. Serial hASC and CTLA4Ig-hASC transplantation offers promising treatment for rheumatoid arthritis, and CTLA4Ig-hASCs showed stronger therapeutic effects than nontransduced hASCs.
25966632 Association analysis of copy numbers of FC-gamma receptor genes for rheumatoid arthritis a 2016 Feb Segmental duplications (SDs) comprise about 5% of the human genome and are enriched for immune genes. SD loci often show copy numbers variations (CNV), which are difficult to tag with genotyping methods. CNV in the Fcγ receptor region (FCGR) has been suggested to be associated with rheumatic diseases. The objective of this study was to delineate association of FCGR-CNV with rheumatoid arthritis (RA), coeliac disease and Inflammatory bowel disease incidence. We developed a method to accurately quantify CNV in SD loci based on the intensity values from the Immunochip platform and applied it to the FCGR locus. We determined the method's validity using three independent assays: segregation analysis in families, arrayCGH, and whole genome sequencing. Our data showed the presence of two separate CNVs in the FCGR locus. The first region encodes FCGR2A, FCGR3A and part of FCGR2C gene, the second encodes another part of FCGR2C, FCGR3B and FCGR2B. Analysis of CNV status in 4578 individuals with RA and 5457 controls indicated association of duplications in the FCGR3B gene in antibody-negative RA (P=0.002, OR=1.43). Deletion in FCGR3B was associated with increased risk of antibody-positive RA, consistently with previous reports (P=0.023, OR=1.23). A clear genotype-phenotype relationship was observed: CNV polymorphisms of the FCGR3A gene correlated to CD16A expression (encoded by FCGR3A) on CD8 T-cells. In conclusion, our method allows determining the CNV status of the FCGR locus, we identified association of CNV in FCGR3B to RA and showed a functional relationship between CNV in the FCGR3A gene and CD16A expression.
26663265 Using Dermal Temperature to Identify Rheumatoid Arthritis Patients With Radiologic Progres 2016 Aug OBJECTIVE: To explore development of a screening test for rheumatoid arthritis (RA) patients most likely to develop radiographic damage in the next year. The test is a simple, objective measurement of elevated dermal temperature over an inflamed joint in this observational, prospective cohort study. METHODS: Seropositive RA patients were sequentially enrolled into cohorts with hot or cool joints, as determined by a dermal thermometer. Patients naive to biologic therapy were maintained on a stable dosage of methotrexate (20-25 mg/week). The hot-joint cohort had a joint skin temperature greater than their body temperature on vital signs. Hand/wrist radiographs obtained at baseline and 1 year later were read and scored using modified Sharp/van der Heijde scores (SHS) by a single reader without sequence order or identifiers. RESULTS: Each cohort consisted of 104 patients enrolled into observation between 2009 and 2014. Patients in the cohort with hot joints had a mean ± SD joint temperature of 1.06 ± 0.69°F above central body temperature and a nearly 4-fold higher risk of new radiographic damage than those with cool joints (SHS score 8.7 ± 6.2 versus 2.5 ± 1.4; P < 0.001). Sensitivity and specificity for joint temperature to predict radiographic damage in the next year were 92% and 78%, respectively, in the hot-joint cohort. As expected, this cohort at baseline was younger, had more recent onset RA, and had higher Westergren erythrocyte sedimentation rate levels than the cool-joint cohort (P < 0.001 for each). CONCLUSION: Dermal joint temperature may become a screening test to quickly and accurately identify individual RA patients at high risk for radiographic damage and those who may benefit most from biologic therapy.
27126833 The role of specialty pharmacy drugs in the management of inflammatory diseases. 2016 Jun 1 PURPOSE: Specialty drugs used in patients with inflammatory disease states are reviewed, with a focus on the pharmacist's roles in facilitating medication procurement and in the clinical management of affected patients. SUMMARY: Pharmacists in the ambulatory care and community settings are strategically placed to be actively involved in specialty drug procurement and clinical management of patients with inflammatory diseases such as rheumatoid arthritis, plaque psoriasis, psoriatic arthritis, inflammatory bowel disease, and ankylosing spondylitis. Specialty medications used in the treatment of these diseases include anti-tumor necrosis factor (TNF) disease-modifying antirheumatic drugs (DMARDs), non-TNF DMARDs, and interleukin inhibitors. Pharmacist involvement in drug procurement in this area includes navigating insurance barriers and helping patients address high out-of-pocket costs; clinical management activities can include ensuring appropriate baseline screening and vaccine administration, providing drug-specific patient education, and performing routine follow-up and assessment. Patient education is the single biggest area where pharmacists can have a direct impact on overall clinical management of patients receiving specialty drugs for the treatment of inflammatory diseases. These patients need to be educated about dosing, administration, storage and disposal, common and rare adverse effects, adverse-effect management strategies, expectations of drug effect, and considerations for unique circumstances such as illness and planned surgery. CONCLUSION: Specialty drugs represent one of the fastest-growing sectors of pharmacy spending, with inflammatory disease therapies at the forefront. As pharmacists are accessible healthcare practitioners, their responsibilities should include financial and clinical management of patients with inflammatory diseases who are receiving specialty drugs.
27710596 The Effect of Quercetin on Inflammatory Factors and Clinical Symptoms in Women with Rheuma 2017 Jan OBJECTIVE: Previous studies have shown that the bioflavonoid quercetin has anti-inflammatory and anti-nociceptive effects. We investigated the effect of quercetin supplementation on inflammation, disease severity, and clinical symptoms in women with rheumatoid arthritis (RA). METHODS: The present study was a randomized, double-blind, placebo-controlled clinical trial in which 50 women with RA were allocated into a quercetin (500 mg/day) or placebo group for 8 weeks. Plasma levels of high-sensitivity tumor necrosis factor-α (hs-TNFα), erythrocyte sedimentation rate (ESR), clinical symptoms including early morning stiffness (EMS), morning and after-activity pain, and tender (TSC) and swollen joint counts (SJC) were determined. Disease activity and functional disability were assessed by Disease Activity Score 28 (DAS-28), physician global assessment (PGA), and a health assessment questionnaire (HAQ) at the beginning and end of the study. RESULTS: Quercetin supplementation for 8 weeks significantly reduced EMS, morning pain, and after-activity pain (p < 0.05). DAS-28 and HAQ scores decreased in the quercetin group compared to placebo and the number of patients with active disease significantly decreased in the quercetin group. Plasma hs-TNFα level was significantly reduced in the quercetin group compared to placebo (p < 0.05). There were no significant differences in TJC and SJC between groups but TJC significantly decreased in the quercetin group after the intervention. Supplementation had an effect on ESR but it was not significant (p > 0.05). CONCLUSIONS: Five hundred milligrams per day quercetin supplementation for 8 weeks resulted in significant improvements in clinical symptoms, disease activity, hs-TNFα, and HAQ in women with RA.
26086678 Possible Role of Staphylococcal Enterotoxin B in the Pathogenesis of Autoimmune Diseases. 2015 Sep As a member of superantigens (SAgs) produced by Staphylococcus aureus, staphylococcal enterotoxin B (SEB) is a exotoxin superantigen that can regulate the activity of immunomodulatory and pro-inflammatory cell types. In addition, SEB plays a critical role in the pathogenesis of autoimmune disorders either by initiating the autoimmune process or by inducing a relapse in an individual in clinical remission from an autoimmune disorder. SEB can directly activate T lymphocytes, leading to the release of cytokines, superoxides, or other mediators of inflammation either directly or indirectly, because of its unique ability to cross-link human major histocompatibility complex (MHC) class II and T cell receptors (TCR), forming a trimolecular complex. This review discusses the potential effects of SEB in the pathogenesis of autoimmune diseases such as multiple sclerosis, systemic lupus erythematosus, and rheumatoid arthritis, and explores some updated therapeutic medications to neutralize SEB.
27567629 The evaluation of sleep quality and response to anti-tumor necrosis factor α therapy in r 2017 Jan Poor sleep quality (SQ) is increasingly recognized as giving rise to decreased quality of life, and raising pain perception. Our aim is to evaluate the SQ in rheumatoid arthritis (RA) patients treated with anti-tumor necrosis factor alpha (anti-TNF-α) therapy. This was a prospective observational and open-label study of RA patients. A total of 35 patients with RA were enrolled in this study. Of the 35 patients, 22 had high disease activity (DA), and 13 were in remission. High DA group was initiated an anti TNF-α therapy. Clinical and objective parameters of SQ were assessed by using the Pittsburgh Sleep Quality Index (PSQI) and polysomnography (PSG). The total PSQI score and the frequency of poor SQ were high in 60 % of the RA patients. The median PSQI score was significantly higher in the high DA group than in the remission group (P = 0.026). Following an anti-TNF-α therapy initiation, significant improvements were observed in the high DA group by PSQI test (P = 0.012). However, no statistically significant difference was found by PSG (P > 0.05). Although an improvement in DA with anti-TNF-alpha therapy did not provide an amelioration in laboratory parameters, we found a significant improvement in SQ by subjective PSQI test. These findings may support that sleep disorders in RA are likely to be associated with a complex pathophysiology.
26362745 Risk of infection with biologic antirheumatic therapies in patients with rheumatoid arthri 2015 Apr There are currently 10 licensed biologic therapies for the treatment of rheumatoid arthritis in 2014. In this article, we review the risk of serious infection (SI) for biologic therapies. This risk has been closely studied over the last 15 years within randomised controlled trials, long-term extension studies and observational drug registers, especially for the first three antitumour necrosis factor (TNF) drugs, namely infliximab, etanercept and adalimumab. The risk of SI with the newer biologics rituximab, tocilizumab, abatacept and tofacitinib is also reviewed, although further data from long-term observational studies are awaited. Beyond all-site SI, we review the risk of tuberculosis, other opportunistic infections and herpes zoster, and the effect of screening on TB rates. Lastly, we review emerging opportunities for stratifying the risk. Patients can be risk-stratified based on both modifiable and non-modifiable patient characteristics such as age, co-morbidity, glucocorticoid use, functional status and recent previous SI.
25879879 Relative benefit-risk comparing diclofenac to other traditional non-steroidal anti-inflamm 2015 Mar 19 INTRODUCTION: There is argument over the benefits and risks of drugs for treating chronic musculoskeletal pain. This study compared the efficacy, safety, and tolerability of diclofenac, ibuprofen, naproxen, celecoxib, and etoricoxib for patients with pain caused by osteoarthritis (OA) or rheumatoid arthritis (RA). METHODS: A systematic literature review used Medline and EMBASE to identify randomised controlled trials. Efficacy outcomes assessed included: pain relief measured by visual analogue scale (VAS); Western Ontario McMaster Universities Arthritis Index (WOMAC) VAS or WOMAC Likert scale; physical functioning measured by WOMAC VAS or Likert scale; and patient global assessment (PGA) of disease severity measured on VAS or 5-point Likert scale. Safety outcomes included: Antiplatelet Trialists' Collaboration (APTC), major cardiovascular (CV) and major upper gastrointestinal (GI) events, and withdrawals. Data for each outcome were synthesized by a Bayesian network meta-analysis (NMA). For efficacy assessments, labelled doses for OA treatment were used for the base case while labelled doses for RA treatment were also included in the sensitivity analysis. Pooled data across dose ranges were used for safety. RESULTS: Efficacy, safety, and tolerability data were found for 146,524 patients in 176 studies included in the NMA. Diclofenac (150 mg/day) was likely to be more effective in alleviating pain than celecoxib (200 mg/day), naproxen (1000 mg/day), and ibuprofen (2400 mg/day), and similar to etoricoxib (60 mg/day); a lower dose of diclofenac (100 mg/day) was comparable to all other treatments in alleviating pain. Improved physical function with diclofenac (100 and 150 mg/day) was mostly comparable to all other treatments. PGA with diclofenac (100 and 150 mg/day) was likely to be more effective or comparable to all other treatments. All active treatments were similar for APTC and major CV events. Major upper GI events with diclofenac were lower compared to naproxen and ibuprofen, comparable to celecoxib, and higher than etoricoxib. Risk of withdrawal with diclofenac was lower compared to ibuprofen, similar to celecoxib and naproxen, and higher than etoricoxib. CONCLUSIONS: The benefit-risk profile of diclofenac was comparable to other treatments used for pain relief in OA and RA; benefits and risks vary in individuals and need consideration when making treatment decisions.
27903299 Arthroscopic arthrodesis for ankle arthritis without bone graft. 2016 Dec 1 BACKGROUND: Ankle arthrodesis is considered by many to be the standard operative treatment for end-stage ankle arthritis. The purpose of this study was to perform a new technique for ankle joint surface and determine the outcome for the union rates of ankle arthroscopic arthrodesis. METHODS: A total of 68 patients with posttraumatic arthritis, primary osteoarthritis, and rheumatoid arthritis were treated by ankle arthroscopic arthrodesis between May 2007 and December 2012. Our surgical indication was deformity less than 15° measured by weight-bearing radiographs. Firstly, the remaining articular cartilage was removed with different curettes and shavers. Then, the new technique (microfracture) was done at tibiotalar surfaces. Finally, the ankle was fixed with two cannulated percutaneous screws. The wound healing, complications, postoperative radiographs, and American Orthopaedic Foot and Ankle Society (AOFAS) score were evaluated. RESULTS: The average follow-up time was 32 months (range 25-58 months). There was no bone grafting, and a fusion rate of 100% was achieved. The average fusion time was 12.1 weeks. One patient developed superficial infection at 2 weeks postoperatively and was cured by nonsurgical treatment. No deep infections, deep venous thrombosis, or revision surgery were observed. Screws had been removed in four patients because of prominence. One patient had fusion in the subtalar joint because of arthritis at 5 years postoperatively. At the last follow-up, radiographic signs of developed or progressing arthritis were observed in nine patients at subtalar joint and in four patients at talonavicular joint. At 1-year follow-up, the mean AOFAS ankle/hindfoot score had increased to 84 from a mean preoperative value of 38 (P < 0.01). CONCLUSIONS: Arthroscopic arthrodesis provides surgeons with an alternative to traditional open techniques for the management of severe ankle arthritis. Our data show that preparation of the joint surface with microfracture is an effective technique to increase the union rate of arthroscopic ankle arthrodesis, while bone graft and other promoting substances are not necessary to be routinely used.
27586803 From TGN1412 to TAB08: the return of CD28 superagonist therapy to clinical development for 2016 Jul CD28 superagonists (CD28SA) are CD28-specific monoclonal antibodies which are able to activate T-cells without overt TCR engagement. In rodents, CD28SA efficiently activate regulatory T-cells and are therapeutically effective in multiple models of autoimmunity, inflammation and transplantation. However, a phase I study of the human CD28SA TGN1412 in 2006 resulted in a life-threatening cytokine storm. This brief review summarises preclinical work before and since the failed phase I trial with an emphasis on understanding the reasons why there had been no warning of toxicity, and how a novel assay paved the way for a new phase I, phase Ib (both completed), and an ongoing phase II study.
27663233 Macrophages mediated diagnosis of rheumatoid arthritis using fibrin based magnetic nanopar 2017 Jan BACKGROUND: A variety of bioimaging tools assists in the diagnosis and evaluation of rheumatoid arthritis (RA) and other osteoarthritis. However, detection of RA in the early stages by targeting its macrophages with suitable contrast agents will help in arresting the progression of the disease. METHODS: In the present study, we investigated the effectiveness of using magnetic fibrin nanoparticles (MFNPs) conjugated with folic acid (FA-MFNPs) as a specific contrast agent to target the activated macrophages, which overexpress the folate receptors (FR) in the knee joints of rats with antigen-induced arthritis (AIA). RESULTS: FA-MFNPs were spherical with an average size of 18.3±1.6nm. In vitro studies have shown effective internalization of FA-MFNPs into the Raw264.7 macrophage cells. In vivo studies were carried out by injecting FA-MFNPs intravenously into the arthritic rats. The results showed enhanced MR imaging in the synovium of arthritic joints. Prussian blue histological staining confirmed uptake of FA-MFNPs by macrophages in the synovial tissue. CONCLUSION: The animal experiment results indicate that FA-MFNPs can be used as a specific MRI contrast agent in identifying phagocytic active macrophages in the synovial joints. GENERAL SIGNIFICANCE: Blood is the precursor source for synthesising the fibrin-based iron oxide (magnetic) nanoparticles (MFNPs) with diameters between 12 and 15nm. It has excellent superparamagnetic behaviour, biocompatibility, osteogenic potency, hemocompatibility, and biodegradable properties. MFNPs-based nanocomposites might be a promising contrast agent for bioimaging.
26111961 Diagnostic accuracy of anti-MCV and anti-CCP antibodies in rheumatoid arthritis: A meta-an 2015 Dec OBJECTIVE: The purpose of this study was to compare the diagnostic performance of anti-mutated citrullinated vimentin (anti-MCV) and anti-cyclic citrullinated peptide (anti-CCP) antibodies in rheumatoid arthritis (RA). METHODS: We searched the Medline, Embase, and Cochrane library databases and performed two meta-analyses on the diagnostic accuracy of anti-MCV and anti-CCP in patients with RA compared to healthy controls. RESULTS: We identified 12 studies that included a total of 2003 RA patients and 831 healthy controls for the meta-analysis. The pooled sensitivity and specificity of anti-MCV were 68.6% [95% confidence interval (CI) 66.6-79.7] and 94.2% (95% CI 92.4-96.7) and those of anti-CCP were 61.7% (95% CI 59.5-63.8) and 97.1% (95% CI 96.7-98.1), respectively. Anti-MCV PLR, NLR, and DOR were 12.99 (95% CI 8.013-21.27), 0.297 (95% CI 0.238-0.369), and 47.78 (95% CI 28.59-79.84), and those for anti-CCP were 16.71 (95% CI 11.42-24.47), 0.378 (95% CI 0.325-0.439), and 54.20 (95% CI 31.65-92.82), respectively. The AUC of anti-MCV was 0.886, and its Q* index was 0.817, indicating modest accuracy, while the AUC of anti-CCP was 0.946, and its Q* index was 0.885. The sensitivity of anti-MCV was significantly higher than that of anti-CCP in the diagnosis of RA (difference 0.069, 95% CI 0.039-0.098, p < 0.0001), but the specificity of anti-MCV was lower than that of anti-CCP (difference -0.029, 95% CI -0.051 to -0.006, p = 0.012). The Q* index of anti-MCV was significantly lower than that of anti-CCP (difference -0.068, 95% CI -0.070 to -0.065, p < 0.0001). CONCLUSION: Our meta-analysis demonstrates that anti-MCV is more sensitive but less specific, and has lower diagnostic accuracy than anti-CCP in RA, although anti-MCV and anti-CCP showed comparable high PLRs.