Agnieszka Padjas

Antibodies to N -homocysteinylated albumin as a marker for earlyonset coronary artery disease in men

N-homocysteinylated (Nepsilon-Hcy) proteins and corresponding antibodies have recently been discovered in humans and animals. Increased autoimmune response to Nepsilon-Hcy-proteins has been reported in stroke patients. The aim of the present study was to investigate whether antibodies against N-homocysteinylated albumin are associated with coronary artery disease (CAD). We studied 88 male patients aged 50 years or under with angiographically documented CAD and 100 age-matched apparently healthy men as controls. Serum levels of IgG antibodies against Nepsilon-Hcy-albumin were determined using an enzymelinked immunosorbent assay. Seropositivity to anti-Nepsilon-Hcy-albumin antibodies was 5-fold more frequent in CAD patients than in controls (52.3% vs 10.0%; p<0.0001). Plasma Hcy levels in CAD patients were also significantly higher in the former than in the latter group (medians, 13.0 microM vs 12.1 microM; p=0.026). Importantly, 41.2% of subjects with plasma total Hcy >14.5 mM were seropositive compared with 25.5% of normohomocysteinemic individuals (p=0.048). There was a weak correlation between anti-Nepsilon-Hcy-albumin antibodies and Hcy levels (r=0.16; p=0.03). By multivariate logistic regression analysis, seropositivity to anti-Nepsilon-Hcy-albumin antibodies was an independent predictor of early CAD (OR, 14.82; 95% CI, 4.47 to 49.19; p=0.00002). Interestingly, anti-Nepsilon-Hcy-albumin antibodies were associated with C-reactive protein levels (r=0.24; p=0.002). Seropositivity to anti-Nepsilon-Hcy-albumin antibodies showed no association with the MTHFR C677T polymorphism. Our results suggest that seropositivity to antibodies against Nepsilon-homocysteinylated albumin is associated with early-onset CAD. An autoimmune response to Nepsilon-Hcy-albumin may represent a novel mechanism involved in the early development of CAD.

Methodological rigor and reporting of clinical practice guidelines in patients with allergic rhinitis: QuGAR study

BACKGROUND There are several clinical practice guidelines about the management of allergic rhinitis (AR) being used by clinicians. OBJECTIVE We sought to assess the methodological rigor and transparency of reporting of clinical practice guidelines for the management of AR. METHODS We systematically searched MEDLINE, the TRIP database, and professional society Web sites for all guidelines about the management of AR published in English after the year 2000. Four reviewers independently assessed the rigor of development and reporting of included guidelines using the Appraisal of Guidelines for Research and Evaluation II instrument. RESULTS Our search revealed 432 records, of which 34 full-text articles were assessed for eligibility and 10 fulfilled inclusion criteria. Overall methodological rigor and reporting of guidelines varied from fulfilling most of the Appraisal of Guidelines for Research and Evaluation II criteria to almost none. Across all guidelines, the best reported domain was clarity of presentation, and the least rigorously addressed domain was applicability of guidelines. Agreement beyond chance among the 4 appraisers was fair. CONCLUSIONS Guideline users should be aware of the difference in the rigor of development and quality of reporting of guidelines about the management of AR. They should choose higher-quality guidelines to use in their practice and teaching. For most reviewed guidelines, there is room for improvement, particularly in the domains of applicability and implementation.

Skewing toward Treg and Th2 responses is a characteristic feature of sustained remission in ANCA-positive granulomatosis with polyangiitis

The objective of our study was to evaluate the T‐helper (Th) and regulatory T (Treg) cell profile in ANCA‐positive granulomatosis with polyangiitis (GPA) and its relation to disease activity. In a prospective study, we studied two groups of GPA patients: (i) disease flare (active‐GPA, BVAS>6, n = 19), (ii) sustained remission (≥ 1‐year prior enrollment, inactive‐GPA, BVAS = 0, n = 18). 24 age‐sex matched healthy subjects served as controls. Active‐GPA patients were followed for 6 months and reevaluated during remission (early remission; n = 13). We analyzed subsets of Th‐cells (flow cytometry), production of signature cytokines by in vitro stimulated lymphocytes, and broad spectrum of serum cytokines (Luminex). In all GPA patients we observed expansion of effector Th17 cells, and increased production of IL‐17A by in vitro stimulated T cells, as compared to controls. Disease flare was characterized by marked reduction in Treg cells, whereas in sustained remission we showed expansion of both Treg and Th2 subset. Finally, analyzing the cytokine profile, we identified CCL23 and LIGHT, as potential biomarkers of active disease. We conclude that in GPA, expansion of Treg and Th2 lymphocytes in parallel to increased Th17 response is a characteristic feature of sustained remission. In contrast, Treg cells are markedly decreased in disease flare.

Myocardial Ischaemia, Coronary Atherosclerosis and Pulmonary Pressure Elevation in Antiphospholipid Syndrome Patients

BACKGROUND Thrombotic events in antiphospholipid syndrome (APS) involve venous and arterial circulation with the possible involvement of coronary or pulmonary microcirculation. OBJECTIVES To evaluate the influence of antiphospholipid antibodies (aPL) and on myocardial ischaemia assessed by single-photon emission computerized tomography (SPECT), coronary atherosclerosis assessed by multidetector computerized tomography (MDCT) and pulmonary pressure assessed by transthoracic echocardiography (TTE) in patients with primary antiphospholipid syndrome (PAPS). MATERIAL AND METHODS TTE, SPECT (Tc 99m sestamibi) and MDCT-based coronary calcium scoring were performed in 26 consecutive PAPS patients (20 females, 6 males, aged 20-61, mean 39.7) without any signs of other autoimmunological disease and without clinical symptoms of heart disease. RESULTS Out of 26 patients, TEE showed normal left and right ventricle function in 25 (96.2%) and elevated (≥ 30 mm Hg) right ventricle systolic pressure in 7 (26.9%) patients. SPECT revealed myocardial perfusion defects in 15 (57.7%) patients: exercise-induced in 6 (23.1%) and persistent in 11 (42.3%). MDCT revealed coronary calcifications in 4 (15.4%) patients. The number of plaques ranged from 1 to 11 (median 2), volume 3-201.7 mm³ (median 7), calcium scores 1.3-202.6 (median 5.7). In the group with perfusion defects or coronary calcifications (n = 15), all the patients showed elevated aCL IgG. CONCLUSIONS In most of the relatively young APS patients, without any symptoms of ischemic heart disease, SPECT showed myocardial perfusion defects, and coronary calcifications in 1/6 of them. Right ventricle systolic pressure was elevated in 1/4 of APS patients. These pathologies, well known as cardiovascular risk markers, were associated with elevated levels of the IgG class of both anti-cardiolipin and antiB2 GPI antibodies. Thus, in a high percentage of APS patients, clinically silent myocardial ischaemia, pulmonary pressure elevation and coronary atherosclerosis are present and related to the presence of antiphospholipid antibodies.

Antiplatelet and Anticoagulant Agents for Secondary Prevention of Thromboembolic Events in People With Antiphospholipid Syndrome

Antiphospholipid syndrome (APS) is a systemic autoimmune disease characterized by the presence of antiphospholipid antibodies and subsequent arterial or venous thrombosis or pregnancy morbidity. Individuals with a definite APS diagnosis have an increased lifetime risk of recurrent thrombotic events. The aim of this systematic review was to assess the effects of antiplatelet or anticoagulant agents, or both, for the secondary prevention of recurrent thromboembolism, particularly ischemic stroke, in people diagnosed with APS. We searched several electronic databases up to February 2017 and supplemented them by searching several ongoing trials registers, checking the reference lists of included studies, systematic reviews, and practice guidelines, and contacting experts in the field. We included randomized controlled trials that evaluated any anticoagulant or antiplatelet agent, or both, in the secondary prevention of thromboembolism among patients with APS diagnosed according to the criteria valid when the …

Non-classical and intermediate monocytesin patients following venous thromboembolism:Links with inflammation

BACKGROUND Monocyte subsets are involved in atherosclerotic vascular disease and its thromboembolic complications. Moreover, the role of monocytes has been suggested in the pathogenesis of venous thromboembolism (VTE). OBJECTIVES We hypothesized that pro-inflammatory non-classical and intermediate monocytes are increased in the first months following VTE. MATERIAL AND METHODS We enrolled 70 patients aged 18-65 years (mean age 41.6 ±11.6) with the firstever provoked (n = 32; 45.7%) or unprovoked (n = 38; 54.28%) VTE episode, and 46 healthy controls. The exclusion criteria were: acute infection, cancer, autoimmune disorders, previous myocardial infarction (MI), or stroke. Monocyte subsets were assessed 12 (8.5-21.5) months after VTE using flow cytometry and were defined as classical (CD14++CD16-), intermediate (CD14++CD16+) and non-classical (CD14+CD16++). RESULTS Patients with VTE had higher intermediate and non-classical monocyte counts compared to the control group (16.8 ±9.3 vs 10.4 ±4.0 cells/μL, and 64.1 ±25.2 vs 44.1 ±19.2 cells/μL, respectively, both p < 0.001). Increased non-classical monocyte counts were observed in patients who experienced a VTE incident within 12 months prior to enrollment (71.5 ±27.4 vs 56.03 ±20.6 cells/μL; p = 0.01) and those with unprovoked VTE (70.2 ±4.1 vs 58.8 ±4.3 cells/μL; p = 0.06). There were no differences in monocyte subsets related to the current anticoagulation. CONCLUSIONS Our data has shown for the first time that VTE is associated with an increased number of nonclassical and intermediate monocytes, which may indicate the involvement of monocyte-related mechanisms in the pathophysiology of this disease.

246 Assessment of the Quality of Methodological Rigour and Reporting of Clinical Practice Guidelines for the Management of Allergic Rhinitis—Qugar Study.

Background To assess the methodological rigour and transparency of reporting in clinical practice guidelines for the management of allergic rhinitis (AR). Methods We systematically searched MEDLINE, TRIP database (including the National Guidelines Clearinghouse) and professional society websites for guidelines about the management of AR published after the year 2000. We assumed that older guidelines would no longer influence current clinical practice. If the guideline was updated after 2000 we assessed the most recent version. We included all guidelines published in English and endorsed by an international or national government agency or professional group, irrespective of country of origin or publication status. Two reviewers independently screened search results using predefined eligibility criteria and assessed the rigour of development and reporting of included guidelines using the AGREE II instrument (www.agreetrust.org). Results Our search revealed 432 records of which 34 full text articles were assessed for eligibility. Nine documents fulfilled our criteria–3 international and 6 national guidelines from Japan, Singapore, South Africa, UK and the USA. Overall methodological rigour and reporting of guidelines about the management of AR was variable—from fulfilling most AGREE II criteria to almost none. There was no association between the methodological rigour and time of publication or the target scope of the guideline (national versus international). Across all guidelines the most rigorously reported domain was “clarity of presentation” (median score 53%), mainly due to fair presentation of different management options (item 16), followed by “scope and purpose” (median score 42%). The least rigorously addressed was “applicability” domain with median score of 2% across all guidelines. Median scores for domains “stakeholder involvement”, “rigour of development” and editorial independence” were 17%, 15% and 25%, respectively. The ARIA guidelines (2010 update) achieved the highest scores in 5 out of 6 domains and the lowest score on any domain was 60%. Conclusions Guideline users should be aware of the variability in quality of development and reporting of guidelines for the management of AR. They should choose higher quality guidelines to inform their practice. For many guidelines there is much room for improvement, in particular in the domains of applicability and implementation.