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textabstractIntroduction: Approximately 30 % of juvenile idiopathic arthritis (JIA) patients fail to respond to anti-TNF treatment. When clinical remission is induced, some patients relapse after treatment has been stopped.We tested the predictive value of MRP8/14 serum levels to identify responders to treatment and relapse after discontinuation of therapy.Methods: Samples from 88 non-systemic JIA patients who started and 26 patients who discontinued TNF-blockers were analyzed.MRP8/14 serum levels were measured by in-house MRP8/14 ELISA and by Bühlmann Calprotectin ELISA at start of anti-TNF treatment, within 6 months after start and at discontinuation of etanercept in clinical remission.Patients were categorized into responders (ACRpedi ≥ 50 and/or inactive disease) and non-responders (ACRpedi < 50) within six months after start, response was evaluated by change in JADAS-10.Disease activity was assessed within six months after discontinuation.Results: Baseline MRP8/14 levels were higher in responders (median MRP8/14 of 1466 ng/ml (IQR 1045-3170)) compared to non-responders (median MRP8/14 of 812 (IQR 570-1178), p < 0.001).Levels decreased after start of treatment only in responders (p < 0.001).Change in JADAS-10 was correlated with baseline MRP8/14 levels (Spearman's rho 0.361, p = 0.001).Patients who flared within 6 months after treatment discontinuation had higher MRP8/14 levels (p = 0.031, median 1025 ng/ml (IQR 588-1288)) compared to patients with stable remission (505 ng/ml (IQR 346-778)).Results were confirmed by Bühlmann ELISA with high reproducibility but different overall levels.Conclusion: High levels of baseline MRP8/14 are associated with good response to anti-TNF treatment, whereas elevated MRP8/14 levels at discontinuation of etanercept are associated with higher chance to flare

Self-care and adherence to medication: a survey in the hypertension outpatient clinic

<p>Abstract</p> <p>Background</p> <p>Self-care practices for patients with hypertension include adherence to medication, use of blood pressure self-monitoring and use of complementary and alternative therapies (CAM) The prevalence of CAM use and blood pressure self-monitoring have not been described in a UK secondary care population of patients with hypertension and their impact on adherence to medication has not been described. Adherence to medication is important for blood pressure control, but poor adherence is common. The study aimed to determine the prevalence of self-care behaviours in patients attending a secondary care hypertension clinic.</p> <p>Methods</p> <p>Cross-sectional questionnaire survey. 196 patients attending a secondary care hypertension clinic in a teaching hospital serving a multiethnic population, Birmingham, UK. Main outcome measures: Prevalence of use of CAM, home monitors, adherence to anti-hypertensive medication.</p> <p>Results</p> <p>CAM use in previous 12 months was reported by 66 (43.1%) respondents. CAM users did not differ statistically from non-CAM users by age, gender, marital status or education. Vitamins, prayer a dietary supplements were the most commonly used CAM. Nine (12.7%) women reported using herbal CAM compared to one man (1.2%), (p = 0.006). Ten (6.7%) respondents reported ever being asked by a doctor about CAM use. Perfect adherence to anti-hypertensive medication was reported by 26 (44.8%) CAM-users and 46 (60.5%) non-CAM users (p = 0.07). Being female and a CAM user was significantly associated with imperfect adherence to anti-hypertensive medication. Older and white British respondents were significantly more likely to report perfect adherence. Blood pressure monitors were used by 67 (43.8%) respondents, which was not associated with gender, CAM use or adherence to medication.</p> <p>Conclusion</p> <p>Hypertensive patients use a variety of self-care methods, including CAM, home blood pressure monitors, and adherence to prescribed medication. This study found the prevalence of CAM use in hypertensive patients was higher than in the UK population. It is important to acknowledge the self-care behaviour of hypertensive patients, in order to assess potential harm, and encourage effective methods of self-care.</p

Biomarker Need in Paediatric Rheumatology: from Discovery to Clinical Translation

Thesis Outline Part I of this thesis focuses on the need for biomarkers for juvenile idiopathic arthritis (JIA) and existing and newly identified biomarkers are discussed. In Chapter 2, the management of JIA, including SJIA, is discussed in detail. Current treatment protocols and guidelines from around the world are summarised and concepts of management, such as the “window of opportunity” and treatment targets are also covered along with the role that biomarkers could and currently play in the diagnosis and management of JIA. In Chapter 3 an in-depth systematic literature review of biomarkers in SJIA is presented. Papers were evaluated for their identification of potential biomarkers pertaining to the diagnosis and management of SJIA. This paper highlighted the great lack of validation studies for SJIA biomarkers, but also more positively indicates the huge variety of potential biomarkers that are being explored by various research groups around the world in this field. Continuing to study such potential biomarkers could further our understanding of the different mechanisms at play in this systemic autoinflammatory disease. Part II focuses on two projects aimed at discovering new biomarkers for the AIDs Familial Mediterranean Fever (FMF) and Systemic onset JIA (SJIA). Chapter 4 outlines the search to identify if sub-phenotypes of SJIA can be identified from a biomarker profile and to identify a potential biomarker panel to discriminate SJIA from patients presenting with infection. Secondary objectives were to evaluate the use of multiple platforms to identify biomarkers of various molecular sizes and to use proteomic techniques which have been so far under-used in SJIA for both discovery and validation studies. The focus of Chapter 5 was to identify patterns of S100A12 of IL-18 neutrophil secretion of patients with FMF, which was measured in the serum of patients and in vitro secreted from patient and healthy control neutrophils. Results were correlated with genotype and disease activity. Part III changes tact by focusing on the translation of biomarkers into clinical practice. The most important aim of biomarker studies is the development of clinically relevant and applicable tests which will positively impact patient care and experience. A study of the biomarker S100A12 and response to therapy is included as well as two commentary papers which focus on the importance of innovation and the translational process of biomarker development. Chapter 6 investigated the association of S100A12 and treatment response in patients with JIA treated with methotrexate or anti-TNF biological therapy. Patients were categorised as treatment responders or non-responders based on various clinical evaluation parameters including ACRpedi50 score, JADAS-10 score and achievement of inactive disease and other risk factors including baseline and follow-up S100A12. Concluding Part III, the two commentaries are strongly influenced by personal experience in translational research settings (Chapter 7 and Chapter 8) and discuss the practical role of the clinical scientist in translational medicine and the directly related concept of interdisciplinarity as a way of driving innovation to reach the overriding goals as discussed above

Additional file 1: of Review of biomarkers in systemic juvenile idiopathic arthritis: helpful tools or just playing tricks?

Full summary of included studies. (DOCX 153 kb

Proinflammatory S100A12 Can Activate Human Monocytes via Toll-like Receptor 4

Rationale: S100A12 is overexpressed during inflammation and is a marker of inflammatory disease. Furthermore, it has been ascribed to the group of damage-associated molecular pattern molecules that promote inflammation. However, the exact role of human S100A12 during early steps of immune activation and sepsis is only partially described thus far. Objectives: We analyzed the activation of human monocytes by granulocyte-derived S100A12 as a key function of early inflammatory processes and the development of sepsis. Methods: Circulating S100A12 was determined in patients with sepsis and in healthy subjects with experimental endotoxemia. The release of human S100A12 from granulocytes as well as the promotion of inflammation by activation of human monocytes after specific receptor interaction was investigated by a series of in vitro experiments. Measurements and Main Results: S100A12 rises during sepsis, and its expression and release from granulocytes is rapidly induced in vitro and in vivo by inflammatory challenge. A global gene expression analysis of S100A12-activated monocytes revealed that human S100A12 induces inflammatory gene expression. These effects are triggered by an interaction of S100A12 with Toll-like receptor 4 (TLR4). Blocking S100A12 binding to TLR4 on monocytes or TLR4 expressing cell lines (HEK-TCM) abrogates the respective inflammatory signal. On the contrary, blocking S100A12 binding to its second proposed receptor (receptor for advanced glycation end products [RAGE]) has no significant effect on inflammatory signaling in monocytes and RAGE-expressing HEK293 cells. Conclusions: Human S100A12 is an endogenous TLR4 ligand that induces monocyte activation, thereby acting as an amplifier of innate immunity during early inflammation and the development of sepsi

Molecular signature characterisation of different inflammatory phenotypes of systemic juvenile idiopathic arthritis

Objectives The International League of Associations for Rheumatology classification criteria define systemic juvenile idiopathic arthritis (SJIA) by the presence of fever, rash and chronic arthritis. Recent initiatives to revise current criteria recognise that a lack of arthritis complicates making the diagnosis early, while later a subgroup of patients develops aggressive joint disease. The proposed biphasic model of SJIA also implies a 'window of opportunity' to abrogate the development of chronic arthritis. We aimed to identify novel SJIA biomarkers during different disease phases. Methods Children with active SJIA were subgrouped clinically as systemic autoinflammatory disease with fever (SJIA syst) or polyarticular disease (SJIA poly). A discovery cohort of n=10 patients per SJIA group, plus n=10 with infection, was subjected to unbiased label-free liquid chromatography mass spectrometry (LC-MS/MS) and immunoassay screens. In a separate verification cohort (SJIA syst, n=45; SJIA poly, n=29; infection, n=32), candidate biomarkers were measured by multiple reaction monitoring MS (MRM-MS) and targeted immunoassays. Results Signatures differentiating the two phenotypes of SJIA could be identified. LC-MS/MS in the discovery cohort differentiated SJIA syst from SJIA poly well, but less effectively from infection. Targeted MRM verified the discovery data and, combined with targeted immunoassays, correctly identified 91% (SJIA syst vs SJIA poly) and 77% (SJIA syst vs infection) of all cases. Conclusions Molecular signatures differentiating two phenotypes of SJIA were identified suggesting shifts in underlying immunological processes in this biphasic disease. Biomarker signatures separating SJIA in its initial autoinflammatory phase from the main differential diagnosis (ie, infection) could aid early-stage diagnostic decisions, while markers of a phenotype switch could inform treat-to-target strategies