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ID PMID Title PublicationDate abstract
24953391 Statin treatment non-adherence and discontinuation: clinical implications and potential so 2014 Statins are the most powerful lipid lowering drugs in clinical practice. However, the efficacy of statin therapy, as seen in randomized control trials, is undermined by the documented non-adherence observed in clinical practice. Understanding the clinical consequences of statin non-adherence is an important step in implementing successful interventions aimed at improving adherence. Our previous systematic review included a literature search up to January 2010 on the effects of statin non-adherence or discontinuation on cardiovascular (CV) and cerebrovascular outcomes. We provide an update to this publication and a review of promising interventions that have reported a demonstrated improvement in statin adherence. Through a systematic literature search of PubMed, Ovid Medline, Ovid Embase, CINAHL, Cochrane Library and Web of Science, out of the 3440 initially identified, 13 studies were selected. Non-adherence in a primary prevention population was associated with a graded increase in CV risk. Individuals taking statins for secondary prevention were at particular risk when taking statin with highly variable adherence. Moreover, particular attention is warranted for non-adherence in diabetic and rheumatoid arthritis populations, as non-adherence is significantly associated with CV risk as early as 1 month following discontinuation. Statin adherence, therefore, represents an important modifiable risk factor. Numerous interventions to improve adherence have shown promise, including copayment reduction, automatic reminders, mail-order pharmacies, counseling with a health professional, and fixed-dose combination therapy. Given the complexity of causes underlying statin non-adherence, successful strategies will likely need to be tailored to each patient.
24934596 Myasthenia Gravis: paradox versus paradigm in autoimmunity. 2014 Aug Myasthenia Gravis (MG) is a paradigm of organ-specific autoimmune disease (AID). It is mediated by antibodies that target the neuromuscular junction. The purpose of this review is to place MG in the general context of autoimmunity, to summarize the common mechanisms between MG and other AIDs, and to describe the specific mechanisms of MG. We have chosen the most common organ-specific AIDs to compare with MG: type 1 diabetes mellitus (T1DM), autoimmune thyroid diseases (AITD), multiple sclerosis (MS), some systemic AIDs (systemic lupus erythematous (SLE), rheumatoid arthritis (RA), Sjogren's syndrome (SS)), as well as inflammatory diseases of the gut and liver (celiac disease (CeD), Crohn's disease (CD), and primary biliary cirrhosis (PBC)). Several features are similar between all AIDs, suggesting that common pathogenic mechanisms lead to their development. In this review, we address the predisposing factors (genetic, epigenetic, hormones, vitamin D, microbiota), the triggering components (infections, drugs) and their interactions with the immune system [1,2]. The dysregulation of the immune system is detailed and includes the role of B cells, Treg cells, Th17 and cytokines. We particularly focused on the role of TNF-α and interferon type I whose role in MG is very analogous to that in several other AIDS. The implication of AIRE, a key factor in central tolerance is also discussed. Finally, if MG is a prototype of AIDS, it has a clear specificity compared to the other AIDS, by the fact that the target organ, the muscle, is not the site of immune infiltration and B cell expansion, but exclusively that of antibody-mediated pathogenic mechanisms. By contrast, the thymus in the early onset subtype frequently undergoes tissue remodeling, resulting in the development of ectopic germinal centers surrounded by high endothelial venules (HEV), as observed in the target organs of many other AIDs.
24927349 Safety evaluation of mercury based Ayurvedic formulation (Sidh Makardhwaj) on brain cerebr 2014 Apr BACKGROUND & OBJECTIVES: Sidh Makardhwaj (SM) is a mercury based Ayurvedic formulation used in rheumatoid arthritis and neurological disorders. However, toxicity concerns due to mercury content are often raised. Therefore, the present study was carried out to evaluate the effect of SM on brain cerebrum, liver and kidney in rats. METHODS: Graded doses of SM (10, 50, 100 mg/kg), mercuric chloride (1 mg/kg) and normal saline were administered orally to male Wistar rats for 28 days. Behavioural parameters were assessed on days 1, 7, 14 and 28 using Morris water maze, passive avoidance, elevated plus maze and rota rod. Liver and kidney function tests were done on day 28. Animals were sacrificed and brain cerebrum acetylcholinesterase activity, levels of malondialdehyde (MDA), reduced glutathione (GSH) in brain cerebrum, liver, kidney were estimated. The levels of mercury in brain cerebrum, liver and kidney were estimated and histopathology of these tissues was also performed. RESULTS: SM in the doses used did not cause significant change in neurobehavioural parameters, brain cerebrum AChE activity, liver (ALT, AST, ALP bilirubin) and kidney (serum urea and creatinine) function tests as compared to control. The levels of mercury in brain cerebrum, liver, and kidney were found to be raised in dose dependent manner. However, the levels of MDA and GSH in these tissues did not show significant changes at doses of 10 and 50 mg/kg. Also, there was no histopathological change in cytoarchitecture of brain cerebrum, liver, and kidney tissues at doses of 10 and 50 mg/kg. INTERPRETATION & CONCLUSIONS: The findings of the present study suggest that Sidh Makardhwaj upto five times the equivalent human dose administered for 28 days did not show any toxicological effects on rat brain cerebrum, liver and kidney.
24817495 The short-term effect after a single injection of high-molecular-weight hyaluronic acid in 2014 Jul BACKGROUND: Hyaluronic acid (HA) with a high molecular weight of 2700 kDa is approved in Japan to treat osteoarthritis of the knee, periarthritis scapulohumeralis, and knee pain associated with rheumatoid arthritis. The purpose of this preliminary study was to investigate the short-term efficacy, safety, and injectable volume of HA in the treatment of enthesopathies. METHODS: A total of 61 patients (16 with lateral epicondylitis, 14 with patellar tendinopathy, 15 with insertional Achilles tendinopathy, and 16 with plantar fasciitis) were each administered a single injection of HA (up to 2.5 ml). Efficacy and safety were assessed by comparing the visual analog scale (VAS) for pain and local symptoms before injection (baseline) and at 1 week after injection. We also investigated the injectable volume by means of the difference in syringe weight before and after injection and by the judgment of the administering investigator. RESULTS: The injection of HA resulted in a change in VAS (mean ± SD) of -2.20 ± 2.26 cm for the four sites overall and -2.55 ± 2.43 cm for lateral epicondylitis, -2.01 ± 2.16 cm for patellar tendinopathy, -1.80 ± 1.91 cm for insertional Achilles tendinopathy, and -2.38 ± 2.61 cm for plantar fasciitis. The injection of HA also improved local symptoms in each site. It was also determined that 2.5 ml of HA can be injected in each of the four sites. CONCLUSION: A single injection of HA resulted in similar improvements of pain in each of the four enthesopathies (lateral epicondylitis, patellar tendinopathy, insertional Achilles tendinopathy, and plantar fasciitis). These results suggest that HA could be clinically effective in the treatment of enthesopathies.
24738138 G protein-coupled receptor kinase 2 moderates recruitment of THP-1 cells to the endotheliu 2014 Feb BACKGROUND: G protein-coupled receptors (GP-CRs) are a major family of signaling molecules, central to the regulation of inflammatory responses. Their activation upon agonist binding is attenuated by GPCR kinases (GRKs), which desensitize the receptors through phosphorylation. G protein-coupled receptor kinase 2(GRK2) down-regulation in leukocytes has been closely linked to the progression of chronic inflammatory disorders such as rheumatoid arthritis and multiple sclerosis. Because leukocytes must interact with the endothelium to infiltrate inflamed tissues, we hypothesized that GRK2 down-regulation in endothelial cells would also be pro-inflammatory. OBJECTIVES: To determine whether GRK2 down-regulation in endothelial cells is pro-inflammatory. METHODS: siRNA-mediated ablation of GRK2 in human umbilical vein endothelial cells (HUVECs) was used in analyses of the role of this kinase. Microscopic and biochemical analyses of Weibel-Palade body (WPB) formation and functioning, live cell imaging of calcium concentrations and video analyses of adhesion of monocyte-like THP-1 cells provide clear evidence of GRK2 function in histamine activation of endothelial cells. RESULTS: G protein-coupled receptor kinase 2 depletion in HUVECs increases WPB exocytosis and P-selectin-dependent adhesion of THP-1 cells to the endothelial surface upon histamine stimulation, relative to controls. Further, live imaging of intracellular calcium concentrations reveals amplified histamine receptor signaling in GRK2-depleted cells, suggesting GRK2 moderates WPB exocytosis through receptor desensitization. CONCLUSIONS: G protein-coupled receptor kinase 2 deficiency in endothelial cells results in increased pro-inflammatory signaling and enhanced leukocyte recruitment to activated endothelial cells. The ability of GRK2 to modulate initiation of inflammatory responses in endothelial cells as well as leukocytes now places GRK2 at the apex of control of this finely balanced process.
24705406 Recognition of posttranslationally modified GAD65 epitopes in subjects with type 1 diabete 2014 Sep Posttranslational modification (PTM) of self-proteins has been shown to elicit clinically relevant immune responses in rheumatoid arthritis and celiac disease. Accumulating evidence suggests that recognition of modified self-proteins may also be important in type 1 diabetes. Our objective was to identify posttranslationally modified GAD65 peptides, which are recognized by subjects with type 1 diabetes, and to assess their disease relevance. We show that citrullination and transglutamination of peptides can enhance their binding to DRB1*04:01, a diabetes-susceptible HLA allele. These and corresponding modifications to amino acids at T-cell contact positions modulated the recognition of multiple GAD65 peptides by self-reactive T cells. Using class II tetramers, we verified that memory T cells specific for these modified epitopes were detectable directly ex vivo in the peripheral blood of subjects with type 1 diabetes at significantly higher frequencies than healthy controls. Furthermore, T cells that recognize these modified epitopes were either less responsive or nonresponsive to their unmodified counterparts. Our findings suggest that PTM contributes to the progression of autoimmune diabetes by eliciting T-cell responses to new epitope specificities that are present primarily in the periphery, thereby circumventing tolerance mechanisms.
24669546 The Strain Index and ACGIH TLV for HAL: risk of trigger digit in the WISTAH prospective co 2014 Feb OBJECTIVE: The objective of this study was to investigate the association between job physical exposure (JPE) and incidence of flexor tendon entrapment of the digits (FTED). BACKGROUND: FTED, commonly known as trigger digit, is associated with age, gender, and certain health disorders. Although JPE has been suggested as a risk factor for FTED, there are no prospective cohort studies. METHOD: A cohort of 516 workers was enrolled from 10 diverse manufacturing facilities and followed monthly for 6 years. Worker demographics, medical history, and symptoms of FTED were assessed. JPE was individually measured using the Strain Index (SI) and American Conference of Governmental Industrial Hygienists (ACGIH) threshold limit value for hand activity level (TLV for HAL). Changes in JPE (assessed quarterly) and symptoms (assessed monthly) were recorded during follow-up. FTED was defined as demonstrated triggering on examination. RESULTS: Point prevalence of FTED at baseline was 3.6%. During follow-up there were 23 incident FTED cases (left and/or right hands). The incident rate for first occurrence of FTED from enrollment was 1.38 per 100 person-years. Risk factors were JPE, age, gender, diabetes mellitus, carpometacarpal osteoarthrosis, and rheumatoid arthritis. In multivariate models, the SI showed strong association with risk of FTED when treated as a continuous variable and marginal association when dichotomized (SI > 6.1). TLV for HAL showed a statistical trend of increasing risk of FTED using the ACGIH limits, but no association as a continuous variable. CONCLUSIONS: Both JPE and personal risk factors are associated with FTED development. The SI and TLV for HAL are useful tools for estimating JPE.
24668534 Biomarkers in connective tissue disease-associated interstitial lung disease. 2014 Apr This article reviews major biomarkers in serum and bronchoalveolar lavage fluid (BALF) with respect to their diagnostic and prognostic value in connective tissue disease-associated interstitial lung disease (CTD-ILD). In some CTD such as systemic sclerosis (SSc), the incidence of ILD is up to two-third of patients, and currently ILD represents the leading cause of death in SSc. Because of the extremely variable incidence and outcome of ILD in CTD, progress in the discovery and validation of biomarkers for diagnosis, prognosis, patients' subtyping, response to treatment, or as surrogate endpoints in clinical trials is extremely important. In contrast to idiopathic interstitial pneumonias, autoantibodies play a crucial role as biomarkers in CTD-ILD because their presence is strictly linked to the pathogenesis and tissue damage. Patterns of autoantibodies, for instance, anticitrullinated peptide antibodies in rheumatoid arthritis or aminoacyl-tRNA synthetases (ARS) in polymyositis/dermatomyositis, have been found to correlate with the presence and occasionally with the course of ILD in CTD. Besides autoantibodies, an increase in serum or BALF of a biomarker of pulmonary origin may be able to predict or reflect the development of fibrosis, the impairment of lung function, and ideally also the prognosis. Promising biomarkers are lung epithelium-derived proteins such as KL-6 (Krebs von den Lungen-6), SP-D (surfactant protein-D), SP-A (surfactant protein-A), YKL-40 (chitinase-3-like protein 1 [CHI3L1] or cytokines such as CCL18 [chemokine (C-C) motif ligand 18]). In the future, genetic/epigenetic markers, such as human leukocyte antigen (HLA) haplotypes, single nucleotide polymorphisms, and micro-RNA, may help to identify subtypes of patients with different needs of management and treatment strategies.
24512328 Is murine gammaherpesvirus-68 (MHV-68) a suitable immunotoxicological model for examining 2015 Jan Immunosuppressive agents are used for treatment of a variety of autoimmune diseases including rheumatoid arthritis (RA), systemic lupus erythematosis (SLE), and psoriasis, as well as for prevention of tissue rejection after organ transplantation. Recrudescence of herpesvirus infections, and increased risk of carcinogenesis from herpesvirus-associated tumors are related with immunosuppressive therapy in humans. Post-transplant lymphoproliferative disorder (PTLD), a condition characterized by development of Epstein Barr Virus (EBV)-associated B-lymphocyte lymphoma, and Kaposi's Sarcoma (KS), a dermal tumor associated with Kaposi Sarcoma-associated virus (KSHV), may develop in solid organ transplant patients. KS also occurs in immunosuppressed Acquired Immunodeficiency (AIDS) patients. Kaposi Sarcoma-associated virus (KSHV) is a herpes virus genetically related to EBV. Murine gammaherpes-virus-68 (MHV-68) is proposed as a mouse model of gammaherpesvirus infection and recrudescence and may potentially have relevance for herpesvirus-associated neoplasia. The pathogenesis of MHV-68 infection in mice mimics EBV/KSHV infection in humans with acute lytic viral replication followed by dissemination and establishment of persistent latency. MHV-68-infected mice may develop lymphoproliferative disease that is accelerated by disruption of the immune system. This manuscript first presents an overview of gammaherpesvirus pathogenesis and immunology as well as factors involved in viral recrudescence. A description of different types of immunodeficiency then follows, with particular focus on viral association with lymphomagenesis after immunosuppression. Finally, this review discusses different gammaherpesvirus animal models and describes a proposed MHV-68 model to further examine the interplay of immunomodulatory agents and gammaherpesvirus-associated neoplasia.
24504769 Therapeutic potential of p38 MAP kinase inhibition in the management of cardiovascular dis 2014 Jun p38 mitogen-activated protein kinases (p38 MAPKs) are key signalling molecules that regulate cellular behavior in response to environmental stresses. They regulate pro-inflammatory cytokines and therefore p38 MAPKs are implicated in the pathogenesis of many inflammatory-driven conditions, including atherosclerosis. Therapeutic inhibition of p38 MAPKs to attenuate inflammation has been the focus of comprehensive research in the last 2 decades, following the discovery of p38α as the molecular target of pyrindinyl imidazole compounds, which suppress the cytokines tumor necrosis factor-α and interleukin-1. The potential of p38 MAPK inhibitors was initially explored within archetypal inflammatory conditions such as rheumatoid arthritis and Crohn's disease, but early studies demonstrated poor clinical efficacy and unacceptable side effects. Subsequent clinical trials evaluating different p38 MAPK inhibitor compounds in disease models such as chronic obstructive pulmonary disease (COPD) and atherosclerosis have shown potential clinical efficacy. This review aims to provide succinct background information regarding the p38 MAPK signaling pathway, a focus of p38 MAPKs in disease, and a brief summary of relevant pre-clinical studies. An update of human clinical trial experience encompassing a clinically orientated approach, dedicated to cardiovascular disease follows. It provides a current perspective of the therapeutic potential of p38 MAPK inhibitors in the cardiovascular domain, including safety, tolerability, and pharmacokinetics.
24500888 Membranoproliferative glomerulonephritis associated with autoimmune diseases. 2014 Apr Membranoproliferative glomerulonephritis (MPGN) has been classified based on its pathogenesis into immune complex-mediated and complement-mediated MPGN. The immune complex-mediated type is secondary to chronic infections, autoimmune diseases or monoclonal gammopathy. There is a paucity of data on MPGN associated with autoimmune diseases. We reviewed the Mayo Clinic database over a 10-year period and identified 12 patients with MPGN associated with autoimmune diseases, after exclusion of systemic lupus erythematosus. The autoimmune diseases included rheumatoid arthritis, primary Sjögren's syndrome, undifferentiated connective tissue disease, primary sclerosing cholangitis and Graves' disease. Nine of the 12 patients were female, and the mean age was 57.9 years. C4 levels were decreased in nine of 12 patients tested. The serum creatinine at time of renal biopsy was 2.2 ± 1.0 mg/dl and the urinary protein was 2,850 ± 3,543 mg/24 h. Three patients required dialysis at the time of renal biopsy. Renal biopsy showed an MPGN in all cases, with features of cryoglobulins in six cases; immunoglobulin (Ig)M was the dominant Ig, and both subendothelial and mesangial electron dense deposits were noted. Median follow-up was 10.9 months. Serum creatinine and proteinuria improved to 1.6 ± 0.8 mg/dl and 428 ± 677 mg/24 h, respectively, except in 3 patients with end-stage renal disease. In summary, this study describes the clinical features, renal biopsy findings, laboratory evaluation, treatment and prognosis of MPGN associated with autoimmune diseases.
24477725 Evaluation of sub-clinical atherosclerosis and plasma levels of minimally modified LDL in 2013 Nov INTRODUCTION: Accelerated atherosclerosis has been shown in some autoimmune diseases, mainly in Systemic Lupus Erythematosus and Rheumatoid Arthritis. Although high prevalence of corticosteroids use may be a confounding factor due to their detrimental effects on several risk factors, systemic inflammation per se is supposed to play an important role in atherogenesis in these patients. METHODS: We have evaluated sub-clinical atherosclerosis and plasma levels of circulating electronegative LDL, which represents the fraction of LDL that is minimally modified, in patients with ankylosing spondylitis (AS). Fourteen patients who fulfilled the modified New York criteria for AS were compared with 13 paired controls. Carotid intimal-media thickness (IMT) was assessed by ultrasonography bilaterally in common carotid artery, internal carotid artery and in the bifurcation. Groups were homogeneous regarding cardiovascular risk factors. Only a single patient in AS group was in use of corticosteroid. RESULTS: The presence of active inflammation was demonstrated by elevated BASDAI and higher CRP levels and in patients versus controls (12.36 vs. 3.45 mg/dl, P = 0.002). No difference was found in carotid IMT between both groups, in any site of artery. Averaged IMT (6 measurements, at 3 pre-specified sites bilaterally) was 0.72 ± 0.28 in AS group and 0.70 ± 0.45 mm in controls (P = 0.91). Minimally modified LDL did not differ significantly either between patients and controls (14.03 ± 17.40 vs. 13.21 ± 10.21; P = 0.88). CONCLUSIONS: Patients with AS did not show increased carotid IMT in comparison to controls. In the same way, circulating plasma levels of LDL (-), did not differ significantly in both groups.
24442438 Anti-CD79 antibody induces B cell anergy that protects against autoimmunity. 2014 Feb 15 B cells play a major role in the pathogenesis of many autoimmune disorders, including rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, and type I diabetes mellitus, as indicated by the efficacy of B cell-targeted therapies in these diseases. Therapeutic effects of the most commonly used B cell-targeted therapy, anti-CD20 mAb, are contingent upon long-term depletion of peripheral B cells. In this article, we describe an alternative approach involving the targeting of CD79, the transducer subunit of the B cell AgR. Unlike anti-CD20 mAbs, the protective effects of CD79-targeted mAbs do not require cell depletion; rather, they act by inducing an anergic-like state. Thus, we describe a novel B cell-targeted approach predicated on the induction of B cell anergy.
24140204 Evaluation of the antinociceptive and anti-inflammatory effect of Caralluma dalzielii. 2013 Dec 12 ETHNOPHARMACOLOGICAL RELEVANCE: Caralluma dalzielii has been used for treating several ailments including convulsion, leprosy, snake bites, otitis (ear pain), fungal diseases and rheumatoid arthritis in Northern Nigeria. However there is no scientific evidence to support its use in literature. To evaluate the antinociceptive and anti-inflammatory properties of the aqueous extract of Caralluma dalzielii in animal models. MATERIALS AND METHODS: The antinociceptive and anti-inflammatory properties were assessed using acetic acid induced writhing test in mice, sub plantar formalin induced nociception, the tail-flick test and formalin induced oedema in rats. Three doses of the extract (25, 50, 100 mg/kg) were used for the assessment. RESULTS: Caralluma dalzielii extract demonstrated strong dose-dependent antinociceptive and anti-inflammatory activities in all the models employed. All doses (25, 50, 100 mg/kg) produced a significant percentage inhibition (41.77, 77.11, and 90.76% in the early phase and 52.02, 85.35, 93.93% in the late phase) in the acetic acid writhing test and (42.85, 55.71, 86.43% in the early phase and 23.26, 37.98, 72.87 in the late phase) in the formalin induced nociception test, respectively. The tail-flick test showed a significant increase in the antinociceptive effect of the extract in both early and late phases when compared with the control. The inhibition of oedema in the formalin test was significant when compared to the control. CONCLUSION: The results indicated that Caralluma dalzielii showed excellent antinociceptive and anti-inflammatory properties suggesting that its traditional use in the treatment of pains and inflammatory diseases may be valid.
25532847 Design and optimisation of bioactive cyclic peptides: generation of a down-regulator of TN 2014 Dec 22 Although strong binding interactions between protein receptor and ligand do not require the participation of a large number of amino acids in either site, short peptide chains are generally poor at recreating the types of protein-protein interactions which take place during cell recognition and signalling process, probably because their flexible backbones prevent the side chains from forming sufficiently rigid and stable epitopes, which can take part in binding with the desired strength and specificity. In a recently-reported study, it was shown that a proto-epitope containing F, R and S amino acids has the ability to down-regulate TNF secretion by macrophages. This paper extends these findings, putting those amino acids into a short cyclic peptide scaffold, and determining the optimal configuration required to overcome the problems of conformational instability, and give rise to molecules which have potential as therapeutic agents in human disease, such as rheumatoid arthritis.
25501558 Thrombospondin-1 production is enhanced by Porphyromonas gingivalis lipopolysaccharide in 2014 Periodontitis is a chronic inflammatory disease caused by gram-negative anaerobic bacteria. Monocytes and macrophages stimulated by periodontopathic bacteria induce inflammatory mediators that cause tooth-supporting structure destruction and alveolar bone resorption. In this study, using a DNA microarray, we identified the enhanced gene expression of thrombospondin-1 (TSP-1) in human monocytic cells stimulated by Porphyromonas gingivalis lipopolysaccharide (LPS). TSP-1 is a multifunctional extracellular matrix protein that is upregulated during the inflammatory process. Recent studies have suggested that TSP-1 is associated with rheumatoid arthritis, diabetes mellitus, and osteoclastogenesis. TSP-1 is secreted from neutrophils, monocytes, and macrophages, which mediate immune responses at inflammatory regions. However, TSP-1 expression in periodontitis and the mechanisms underlying TSP-1 expression in human monocytic cells remain unknown. Here using real-time RT-PCR, we demonstrated that TSP-1 mRNA expression level was significantly upregulated in inflamed periodontitis gingival tissues and in P. gingivalis LPS-stimulated human monocytic cell line THP-1 cells. TSP-1 was expressed via Toll-like receptor (TLR) 2 and TLR4 pathways. In P. gingivalis LPS stimulation, TSP-1 expression was dependent upon TLR2 through the activation of NF-κB signaling. Furthermore, IL-17F synergistically enhanced P. gingivalis LPS-induced TSP-1 production. These results suggest that modulation of TSP-1 expression by P. gingivalis plays an important role in the progression and chronicity of periodontitis. It may also contribute a new target molecule for periodontal therapy.
25221848 Work disability among workers with osteoarthritis of the knee: risks factors, assessment s 2014 Dec The prevalence of knee osteoarthritis (OA) among individuals active in the workforce will increase considerably in the next generation and a significant percentage of these individuals are expected to experience work disability because of this disease. The aim of this review was to summarize the existing knowledge on the following: (a) work disability risk factors; (b) reliable and valid work disability assessment tools; and (c) efficient interventions to reduce work disability in individuals with knee OA. An electronic document search using key words and MeSH terms was performed with various databases. Two independent investigators were tasked with the screening of articles and quality assessment. A critical appraisal of what is known was performed and recommendations for clinical practice and future research were formulated. The database search yielded 61 references. One article on risk factors, three related to assessment tools, and two on interventions were retained. Age and previous work absence episodes were found to be risk factors of workplace disability. The Work Limitation Questionnaire, the Work Instability Scale for Rheumatoid Arthritis, and the Workplace Activity Limitations Scale were psychometrically sound for the population studied. Education-based interventions seem to be more effective than conventional interventions in helping individuals with knee OA return to work faster, reduce the number of days absent from work, and improve their overall well-being. This review is the first to summarize the evidence on work disability risk factors, assessment tools, and interventions for this growing population and to show a critical gap in the existing knowledge.
25162777 Healthcare costs for Crohn's disease patients treated with infliximab: a propensity weight 2014 Dec OBJECTIVE: The objective for the research was to evaluate the direct healthcare costs for Crohn's disease (CD) patients categorized by adherence status. METHODS: Adult patients with ≥1 claim for infliximab and ≥2 claims for CD who were continuously insured for 12 months before and after their first infliximab infusion (index date) were identified in a 2006-2009 US managed care database. Patients were excluded if they had rheumatoid arthritis claims, received infliximab billed as a pharmacy benefit, or received another biologic drug. Patients were categorized as being either adherent or intermittently adherent to infliximab using a pre-defined algorithm. Total and component direct costs, CD-related costs, rates of surgery, and days of hospitalization were estimated for the 360-day post-index period. Propensity weighted generalized linear models were used to adjust the cost estimates for potential confounding variables. RESULTS: The total propensity weighted cost for infliximab adherent patients was $40,425 (95% CI = [$38,686, $42,242]), compared to $41,082 (95% CI = [$38,163, $44,223]) for the intermittently adherent (p = 0.71). However, adherent patients had lower total direct medical costs, exclusive of infliximab, that were $13,097 (95% CI = [$12,141, $14,127]) compared with $20,068 (95% CI = [$17,676, $22,784]) for intermittently adherent patients as a result of substantially lower hospital and outpatient costs (p < 0.0001). CONCLUSIONS: Greater drug-related costs for infliximab adherent patients were offset by lower costs from hospitalization and outpatient visits. These findings indicate that adherent patients have improved clinical outcomes, at a similar aggregate cost, than patients who are only intermittently adherent to therapy.
24781620 Patellar clunk syndrome in fixed-bearing posterior-stabilised versus cruciate-substituting 2014 Apr PURPOSE: To compare the outcome of fixed-bearing posterior-stabilised versus cruciate-substituting prostheses in 46 patients who underwent primary bilateral total knee replacement (TKR). METHODS: Records of 35 women and 11 men aged 54 to 78 (mean, 67) years who underwent primary bilateral TKR for osteoarthritis (n=44) and rheumatoid arthritis (n=2) were retrospectively reviewed. A fixed-bearing posterior-stabilised prosthesis (Zimmer NexGen Legacy flex [LPS-Flex]) was used in one knee, and a fixed-bearing cruciate-substituting prosthesis (Depuy Press Fit Condylar Sigma CS [PFC CS]) was used in the contralateral knee. The mean time interval between the 2 operations was 34 (range, 4-60) months. All operations were performed by the same group of surgeons using standardised techniques. The medial parapatellar approach was used, and the patella was resurfaced. Rehabilitation was also standardised. Outcome measures included the pre- and post-operative active range of movement and the American Knee Society Score. Postoperative complications were documented. RESULTS: At one year, the mean fixed flexion contracture, maximum flexion, and American Knee Society scores in knees with PFC CS and LPS-Flex prostheses were comparable. Three knees with the PFC CS prosthesis developed the patellar clunk syndrome, compared to none with the LPS-Flex prosthesis (p=0.24). The onset of the patellar clunk syndrome was around one year after surgery. Despite this, the axial alignment and rotation of the femoral and tibial components were good. CONCLUSION: Both prostheses produce good clinical outcome. The PFC CS prosthesis is more likely to be associated with the patellar clunk syndrome.
24671707 Deimination of linker histones links neutrophil extracellular trap release with autoantibo 2014 Jul Autoantibodies to nuclear antigens arise in human autoimmune diseases, but a unifying pathogenetic mechanism remains elusive. Recently we reported that exposure of neutrophils to inflammatory conditions induces the citrullination of core histones by peptidylarginine deiminase 4 (PAD4) and that patients with autoimmune disorders produce autoantibodies that recognize such citrullinated histones. Here we identify histone H1 as an additional substrate of PAD4, localize H1 within neutrophil extracellular traps, and detect autoantibodies to citrullinated H1 in 6% of sera from patients with systemic lupus erythematosus and Sjögren's syndrome. No preference for deiminated H1 was observed in healthy control sera and sera from patients with scleroderma or rheumatoid arthritis. We map binding to the winged helix of H1 and determine that citrulline 53 represents a key determinant of the autoantibody epitope. In addition, we quantitate RNA for H1 histone subtypes in mature human neutrophils and identify citrulline residues by liquid chromatography and tandem mass spectrometry. Our results indicate that deimination of linker histones generates new autoantibody epitopes with enhanced potential for stimulating autoreactive human B cells.-Dwivedi, N., Neeli, I., Schall, N., Wan, H., Desiderio, D. M., Csernok, E., Thompson, P. R., Dali, H., Briand, J.-P., Muller, S., Radic, M. Deimination of linker histones links neutrophil extracellular trap release with autoantibodies in systemic autoimmunity.