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Jacques P.,Ghent University | McGonagle D.,Leeds Institute of Rheumatic and Musculoskeletal Medicine
Best Practice and Research: Clinical Rheumatology | Year: 2014

Given that entheses are sites of high mechanical stress that concentrate the forces of large contracting muscles down onto a small footprint of bone contact, it was recognized nearly 60 decades ago that stress and injury at such sites may play a role in the pathogenesis of mechanically related enthesopathy. In recent years, the role of mechanical stress and its related consequences on inflammatory enthesitis have also been recognized. Clinical imaging studies and experimental animal models of spondyloarthropathy including tumor necrosis factor (TNF) transgenic models and interleukin (IL)-23 overexpression systems are associated with a primary enthesitis with disease subsequently spreading to adjacent joint structures including the synovium and bone. Joint mechanical stress, without discernible microdamage or injury, leads to spondyloarthritis (SpA) in a TNF transgenic model. Normal-aged human entheses often demonstrate microdamage, but it is unclear whether an abnormal response to mechanical stress alone or the need for stress-induced microdamage is involved in human disease initiation. Clinically, the contribution of mechanical stress to SpA including psoriatic arthritis (PsA) helps conceptualize the disease in a new way and provides obvious mechanistic links to skin and nail Koebner responses. It also offers novel epidemiological explanations for why PsA develops in subjects with high body mass indices most typically in the fourth and fifth decades. Molecularly, the monogenic forms of SpA including caspase recruitment domain-containing protein 14 (CARD14) and IL36RN mutations have site-specific expression of mutated proteins in the skin, thus offering a direct molecular link between local inflammation-related pathway dysregulation and local stress or injury in disease causation. Given that many of the pathways that govern both immunity and mechanical stress including extracellular-signal-regulated kinase (ERK) and mitogen-activated protein kinase (MAPK) are shared, it may be difficult to develop strategies that selectively target mechanical stress-related pathways. However, occupational- and obesity-related factors may be potentially modifiable in susceptible individuals to prevent or ameliorate disease. © 2014 Elsevier Ltd. All rights reserved.

Tebby J.,University of Leeds | Lecky F.,A+ Network | Edwards A.,A+ Network | Jenks T.,A+ Network | And 5 more authors.
BMC Medicine | Year: 2014

Background: The impact of diabetes mellitus in patients with multiple system injuries remains obscure. This study was designed to increase knowledge of outcomes of polytrauma in patients who have diabetes mellitus. Methods: Data from the Trauma Audit and Research Network was used to identify patients who had suffered polytrauma during 2003 to 2011. These patients were filtered to those with known outcomes, then separated into those with diabetes, those known to have other co-morbidities but not diabetes and those known not to have any co-morbidities or diabetes. The data were analyzed to establish if patients with diabetes had differing outcomes associated with their diabetes versus the other groups. Results: In total, 222 patients had diabetes, 2,558 had no past medical co-morbidities (PMC), 2,709 had PMC but no diabetes. The diabetic group of patients was found to be older than the other groups (P <0.05). A higher mortality rate was found in the diabetic group compared to the non-PMC group (32.4% versus 12.9%), P <0.05). Rates of many complications including renal failure, myocardial infarction, acute respiratory distress syndrome, pulmonary embolism and deep vein thrombosis were all found to be higher in the diabetic group. Conclusions: Close monitoring of diabetic patients may result in improved outcomes. Tighter glycemic control and earlier intervention for complications may reduce mortality and morbidity. © 2014 Tebby et al.

Coates L.C.,Leeds Institute of Rheumatic and Musculoskeletal Medicine | Kavanaugh A.F.,University of California at San Diego | Mease P.J.,Swedish Medical Center | Ritchlin C.T.,University of Rochester
Journal of Rheumatology | Year: 2015

At the 2014 annual meeting of the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA), members discussed an update of their previous treatment recommendations published in 2009. Domain subcommittees representing the different aspects of psoriatic arthritis (PsA) had been reconvened in 2013 and a new group was formed that focused on PsA comorbidities and associated conditions. A combined literature review was completed in February 2013 followed by individual group literature reviews and analyses. Articles from each of these subcommittees were published in 2014, updating the evidence for individual therapies in PsA. At their 2014 annual meeting, GRAPPA members discussed their plans for a summary article on treatment recommendations, finalized the Grading of Recommendations Assessment, Development and Evaluation (GRADE)-formatted recommendations for individual drugs within the domain subcommittees, and presented these for debate. Modifications to the GRAPPA grid were also discussed in breakout groups and presented to the full membership. At the GRAPPA meeting adjacent to the 2014 American College of Rheumatology meeting, a new GRAPPA treatment schema was proposed to replace the original GRAPPA grid. Each domain subcommittee discussed treatment algorithms based on their GRADE recommendations for inclusion in the final treatment recommendations article, which will be submitted in 2015. Copyright © 2015. All rights reserved.

Roberts E.,South London and the Maudsley Mental Health Trust | Nunes V.D.,Guideline | Buckner S.,Guideline | Latchem S.,Guideline | And 11 more authors.
Annals of the Rheumatic Diseases | Year: 2016

Objectives: We conducted a systematic literature review to assess the adverse event (AE) profile of paracetamol. Methods: We searched Medline and Embase from database inception to 1 May 2013. We screened for observational studies in English, which reported mortality, cardiovascular, gastrointestinal (GI) or renal AEs in the general adult population at standard analgesic doses of paracetamol. Study quality was assessed using Grading of Recommendations Assessment, Development and Evaluation. Pooled or adjusted summary statistics were presented for each outcome. Results: Of 1888 studies retrieved, 8 met inclusion criteria, and all were cohort studies. Comparing paracetamol use versus no use, of two studies reporting mortality one showed a dose-response and reported an increased relative rate of mortality from 0.95 (0.92 to 0.98) to 1.63 (1.58 to 1.68). Of four studies reporting cardiovascular AEs, all showed a dose-response with one reporting an increased risk ratio of all cardiovascular AEs from 1.19 (0.81 to 1.75) to 1.68 (1.10 to 2.57). One study reporting GI AEs reported a dose-response with increased relative rate of GI AEs or bleeds from 1.11 (1.04 to 1.18) to 1.49 (1.34 to 1.66). Of four studies reporting renal AEs, three reported a dose-response with one reporting an increasing OR of ≥30% decrease in estimated glomerular filtration rate from 1.40 (0.79 to 2.48) to 2.19 (1.4 to 3.43). Discussion: Given the observational nature of the data, channelling bias may have had an important impact. However, the dose-response seen for most endpoints suggests a considerable degree of paracetamol toxicity especially at the upper end of standard analgesic doses.

Das S.,Leeds Institute of Rheumatic and Musculoskeletal Medicine | Das S.,NIHR Leeds Musculoskeletal Biomedical Research Unit | Vital E.M.,Leeds Institute of Rheumatic and Musculoskeletal Medicine | Vital E.M.,NIHR Leeds Musculoskeletal Biomedical Research Unit | And 13 more authors.
Annals of the Rheumatic Diseases | Year: 2014

Objectives: To evaluate the efficacy and safety of two different targeted approaches-abatacept or tocilizumab-after rituximab therapy in rheumatoid arthritis, and to explain observed difference in efficacy using blood and synovial studies of interleukin 6 (IL-6) and B cells in patients receiving rituximab therapy. Methods: Consecutive series of patients who had discontinued rituximab therapy owing to inefficacy or toxicity were treated with abatacept (n=16) or tocilizumab (n=35). Clinical response and reasons for discontinuation were evaluated. Serial blood and synovial samples were obtained from a group of 57 and 25 rituximab-treated patients, respectively, and were analysed for B cells and IL-6 using flow cytometry, immunohistochemistry and quantitative real-time PCR. Results: In the abatacept group, mean (SEM) Disease Activity Score in 28 joints calculated using the erythrocyte sedimentation rate (DAS28-ESR) reduced from 5.69 (0.42) at baseline to 4.94 (0.44) at 6 months ( p=0.12). In the tocilizumab group: mean (SEM) DAS28- ESR reduced from 5.75 (0.21) at baseline to 3.28 (0.26) at 6 months (p<0.001). This was paralleled by a significant swollen joint count reduction in the tocilizumab (5.47 (0.70) to 2.70 (0.61), p=0.033), but not abatacept (6.23 (1.3) to 4.15 (1.2), p=0.26), group. In the synovium, despite complete depletion of B cells in 19/22 patients, IL-6 mRNA expression was not significantly reduced after rituximab. Blood B cell numbers remained low 12 months after rituximab. Serum IL-6 was raised at baseline and significantly higher in rituximab clinical non-responders (p=0.035) than responders. A significant reduction in serum IL-6 was seen in rituximab clinical responders (p=0.005) but not in non-responders (p=0.237). Conclusion: In patients with rheumatoid arthritis for whom rituximab therapy failed despite adequate B cell depletion, IL-6-directed therapy might be a more logical and effective treatment choice than T cell costimulation blockade. Further controlled studies investigating other possible mechanisms are needed to validate these initial findings.

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