Clinical Characteristics of EGPA Patients in Comparison to GPA Subgroup with Increased Blood Eosinophilia from POLVAS Registry.

Objective: To characterize the eosinophilic granulomatosis with polyangiitis (EGPA) population from the POLVAS registry depending on ANCA status and diagnosis onset, including their comparison with the granulomatosis with polyangiitis (GPA) subset with elevated blood eosinophilia (min. 400/µl) (GPA HE) to develop a differentiating strategy. Methods: A retrospective analysis of the POLVAS registry. Results: The EGPA group comprised 111 patients. The ANCA-positive subset (n = 45 [40.54%]) did not differ from the ANCA-negative one in clinics. Nevertheless, cardiovascular manifestations were more common in ANCA-negative patients than in those with anti-myeloperoxidase (MPO) antibodies (46.97% vs. 26.92%, p = 0.045). Patients diagnosed before 2012 (n = 70 [63.06%]) were younger (median 41 vs. 49 years, p < 0.01), had higher blood eosinophilia at diagnosis (median 4,946 vs. 3,200/µl, p < 0.01), and more often ear/nose/throat (ENT) and cardiovascular involvement. GPA HE comprised 42 (13.00%) out of 323 GPA cases with reported blood eosinophil count. Both GPA subsets had a lower prevalence of respiratory, cardiovascular, and neurologic manifestations but more often renal and ocular involvement than EGPA. EGPA also had cutaneous and gastrointestinal signs more often than GPA with normal blood eosinophilia (GPA NE) but not GPA HE. The model differentiating EGPA from GPA HE, using ANCA status and clinical manifestations, had an AUC of 0.92, sensitivity of 96%, and specificity of 95%. Conclusion: Cardiovascular symptoms were more prevalent in the ANCA-negative subset than in the MPO-ANCA-positive one. Since EGPA and GPE HE share similarities in clinics, diagnostic misleading may result in an inappropriate therapeutic approach. Further studies are needed to optimize their differentiation and tailored therapy, including biologics.

Cellular immune response to SARS-CoV-2 in patients with primary antibody deficiencies.

Introduction: Primary antibody deficiencies (PAD) are inborn defects of the immune system that result in increased susceptibility to infections. Despite the reduced response to vaccination, PAD patients still benefit from it by reducing the risk of severe infections and complications. SARS-CoV-2 vaccines are recommended in PAD patients, but their immune effects are poorly studied. Here, we analyze virus-specific T-cell responses in PAD patients after booster vaccination against SARS-CoV-2. Patients and methods: The study included 57 adult PAD patients on long-term immunoglobulin replacement therapy (IgRT) diagnosed with X-linked agammaglobulinemia (XLA; n = 4), common variable immunodeficiency (CVID; n = 33), isotype defects or IgG subclass deficiency (n = 6), and unclassified IgG deficiency (n = 14). Of those, 49 patients (86%) received vaccination against SARS-CoV-2 using mRNA vaccine (Pfizer-BioNTech). T-cell responses were assessed at a median of 21 (13 - 30) weeks after the booster dose (mainly the third dose) using commercially available interferon-gamma release assay (IGRA) with recombinant SARS-CoV-2 spike S1 protein. Results: Vaccinated PAD patients showed an increased (3.8-fold, p = 0.004) release of IFN-γ upon S1 stimulation. In this group, we also documented higher serum levels of anti-SARS-CoV-2 IgG (4.1-fold, p = 0.01), although they were not associated with IGRA results. Further subgroup analysis revealed very similar IGRA responses in CVID and unclassified IgG deficiencies that were 2.4-fold increased compared to XLA and 5.4-fold increased compared to patients with isotype defects or IgG subclass deficiencies (e.g., vs. CVID: p = 0.016). As expected, CVID and XLA patients showed decreased serum titers of anti-SARS-CoV-2 antibodies compared to other studied groups (e.g., CVID vs. unclassified IgG deficiency: 4.4-fold, p = 0.006). The results did not depend directly on IgRT mode or dose, number of vaccine doses and time from the last booster dose, and clinical manifestations of PAD. Interestingly, anti-SARS-CoV-2 titers were positively correlated with serum immunoglobulin levels before IgRT (e.g., for IgA: r = 0.45, p<0.001; for IgG: r = 0.34, p = 0.009) and the percentage of peripheral blood NK cells (r = 0.48, p<0.001). Conclusions: Our results documented satisfactory in vitro cellular immune response in PAD patients after booster SARS-CoV-2 vaccination. Therefore, even patients with agammaglobulinemia should benefit from vaccination due to the apparent induction of cell-mediated immunity, which, together with IgRT, grants comprehensive protection against the pathogen.

Increased oxidative stress response in circulating blood of systemic sclerosis patients - relation to disease characteristics and inflammatory blood biomarkers.

BACKGROUND: Systemic sclerosis (SSc) is a rare connective tissue disorder of unknown etiology characterized by organ fibrosis and microcirculation dysfunction. Emerging evidence suggests that SSc is related to increased oxidative stress, which contributes to further tissue and vascular damage. METHODS: Oxidative stress response in the peripheral blood was assessed in patients with SSc (n = 55) and well-matched controls (n = 44) using real-time monitoring of protein hydroperoxide (HP) formation by the coumarin boronic acid (CBA) assay. We also analyzed the relationship between HP generation and SSc clinics, systemic inflammation, and cellular fibronectin, an emerging biomarker of endothelial damage. RESULTS: SSc was characterized by a significantly faster (2-fold) fluorescent product generation in the CBA assay and higher cumulative HP formation (3-fold) compared to controls (p<0.001, both). The dynamics of HP generation were not associated with the form of the disease (diffuse vs. limited SSc), current immunosuppressive therapy use, presence of abnormal nailfold capillaries, and autoantibody profile. Still, it was enhanced in patients with more severe illness and certain clinical manifestations (i.e., pulmonary hypertension, digital ulcers, and cyclophosphamide treatment) and in smokers (current or past). Higher serum CRP, blood eosinophil count, and cellular fibronectin with lower hemoglobin levels were independent determinants of increased HP formation. CONCLUSIONS: Our data indicate a pro-oxidant imbalance in SSc, likely related to systemic inflammation and endothelial injury. However, extensive prospective studies are needed to verify whether it is also associated with clinical disease progression.

Genetic Association between TNFA Polymorphisms (rs1799964 and rs361525) and Susceptibility to Cancer in Systemic Sclerosis.

Tumor necrosis factor (TNF)-α is a proinflammatory cytokine that plays an important role in the pathogenesis of autoimmune diseases. The aim of the study was to establish an association between TNF-α promoter variability and systemic sclerosis (SSc). The study included 43 SSc patients and 74 controls. Four single nucleotide polymorphisms (rs361525, rs1800629, rs1799724, and rs1799964) located at the promoter of the TNFA gene were genotyped using commercially available TaqMan allelic discrimination assays with real-time PCR. The rs1799724 allele was associated with an increased SSc susceptibility (p = 0.028). In turn, none of the polymorphisms studied were related to the clinical and laboratory parameters of SSc patients, except for a higher prevalence of anti-Ro52 antibodies in the AG rs1800629 genotype in comparison to GG carriers (p = 0.04). Three of four cancer patients had both CT rs1799964 and AG rs361525 genotypes; thus, both of them were related to the increased risk of cancer, as compared to the TT (p = 0.03) and GG carriers (p = 0.0003), respectively. The TNFA C rs1799724 variant is associated with an increased risk of SSc, while the CT rs1799964 and AG rs361525 genotypes might enhance cancer susceptibility in SSc patients, although large observational and experimental studies are needed to verify the above hypothesis.

Central Retinal Artery Occlusion Is Related to Vascular Endothelial Injury and Left Ventricular Diastolic Dysfunction.

Central retinal artery occlusion (CRAO) is an emergency state characterized by sudden, painless vision impairment. Patients with CRAO have an increased risk of cardiovascular events, including stroke, likely related to vascular endothelial damage. Therefore, we investigated flow-mediated dilatation (FMD) of the brachial artery as a marker of endothelial dysfunction, intima-media complex thickness (IMT) of the common carotid artery, pointing to the arterial wall atherosclerotic alteration, and transthoracic echocardiographic parameters in 126 consecutive CRAO patients (66 men [52.4%], median age 55 years) and 107 control participants (56 men [52.3%], matched by age, sex, and body mass index). Most CRAO patients (n = 104, 82.5%) had at least one internal medicine comorbidity, mainly hypercholesterolemia and hypertension, which coexisted in one-fourth of them. Furthermore, they had a 38.2% lower relative increase of FMD (FMD%) and a 23.1% thicker IMT compared to the controls (p < 0.001, both, also after adjustment for potential confounders). On echocardiography, the CRAO group was characterized by increased dimensions of the left atrium and thicker left ventricular walls, together with impaired left ventricular diastolic function. CRAO is related to vascular endothelial damage, atherosclerosis, and left ventricular diastolic cardiac dysfunction. Thus, non-invasive ultrasound assessments, such as FMD%, IMT, and echocardiography, may be helpful in screening patients with increased CRAO risk, particularly those with other comorbidities.

Interactions via α2ß1 Cell Integrin May Protect against the Progression of Airway Structural Changes in Asthma.

Increased airway wall thickness and remodeling of bronchial mucosa are characteristic of asthma and may arise from altered integrin signaling on airway cells. Here, we analyzed the expression of ß1-subfamily integrins on blood and airway cells (flow cytometry), inflammatory biomarkers in serum and bronchoalveolar lavage, reticular basement membrane (RBM) thickness and collagen deposits in the mucosa (histology), and airway geometry (CT-imaging) in 92 asthma patients (persistent airflow limitation subtype: n = 47) and 36 controls. Persistent airflow limitation was associated with type-2 inflammation, elevated soluble α2 integrin chain, and changes in the bronchial wall geometry. Both subtypes of asthma showed thicker RBM than control, but collagen deposition and epithelial α1 and α2 integrins staining were similar. Type-I collagen accumulation and RBM thickness were inversely related to the epithelial expression of the α2 integrin chain. Expression of α2ß1 integrin on T-cells and eosinophils was not altered in asthma. Collagen I deposits were, however, more abundant in patients with lower α2ß1 integrin on blood and airway CD8+ T-cells. Thicker airway walls in CT were associated with lower α2 integrin chain on blood CD4+ T-cells and airway eosinophils. Our data suggest that α2ß1 integrin on inflammatory and epithelial cells may protect against airway remodeling advancement in asthma.

Reticular Basement Membrane Thickness Is Associated with Growth- and Fibrosis-Promoting Airway Transcriptome Profile-Study in Asthma Patients.

Airway remodeling in asthma is characterized by reticular basement membrane (RBM) thickening, likely related to epithelial structural and functional changes. Gene expression profiling of the airway epithelium might identify genes involved in bronchial structural alterations. We analyzed bronchial wall geometry (computed tomography (CT)), RBM thickness (histology), and the bronchial epithelium transcriptome profile (gene expression array) in moderate to severe persistent (n = 21) vs. no persistent (n = 19) airflow limitation asthmatics. RBM thickness was similar in the two studied subgroups. Among the genes associated with increased RBM thickness, the most essential were those engaged in cell activation, proliferation, and growth (e.g., CDK20, TACC2, ORC5, and NEK5) and inhibiting apoptosis (e.g., higher mRNA expression of RFN34, BIRC3, NAA16, and lower of RNF13, MRPL37, CACNA1G). Additionally, RBM thickness correlated with the expression of genes encoding extracellular matrix (ECM) components (LAMA3, USH2A), involved in ECM remodeling (LTBP1), neovascularization (FGD5, HPRT1), nerve functioning (TPH1, PCDHGC4), oxidative stress adaptation (RIT1, HSP90AB1), epigenetic modifications (OLMALINC, DNMT3A), and the innate immune response (STAP1, OAS2). Cluster analysis revealed that genes linked with RBM thickness were also related to thicker bronchial walls in CT. Our study suggests that the pro-fibrotic profile in the airway epithelial cell transcriptome is associated with a thicker RBM, and thus, may contribute to asthma airway remodeling.

Antiplatelet and anticoagulant agents for secondary prevention of stroke and other thromboembolic events in people with antiphospholipid syndrome.

BACKGROUND: Antiphospholipid syndrome (APS) is a systemic autoimmune disease characterized by arterial or venous thrombosis (or both), and/or pregnancy morbidity in association with the presence of antiphospholipid antibodies. The prevalence of APS is estimated at 40 to 50 cases per 100,000 people. The most common sites of thrombosis are cerebral arteries and deep veins of the lower limbs. People with a definite APS diagnosis have an increased lifetime risk of recurrent thrombotic events. OBJECTIVES: To assess the effects of antiplatelet (AP) or anticoagulant agents, or both, for the secondary prevention of recurrent thrombosis, particularly ischemic stroke, in people with APS. SEARCH METHODS: We last searched the MEDLINE, Embase, CENTRAL, Cochrane Stroke Group Trials Register, and ongoing trials registers on 22 November 2019. We checked reference lists of included studies, systematic reviews, and practice guidelines. We also contacted experts in the field. SELECTION CRITERIA: We included randomized controlled trials (RCTs) that evaluated any anticoagulant or AP agent, or both, in the secondary prevention of thrombosis in people with APS, according to the criteria valid when the study took place. We did not include studies specifically addressing women with obstetrical APS. DATA COLLECTION AND ANALYSIS: Pairs of review authors independently worked on each step of the review, following Cochrane methods. We summarized the evidence using the GRADE approach. MAIN RESULTS: We identified eight studies including 811 participants that compared different AP or anticoagulant agents. NOAC (non-VKA oral anticoagulant: rivaroxaban 15 or 20 mg/d) versus standard-dose VKA (vitamin K antagonist: warfarin at moderate International Normalized Ratio [INR] - 2.5) or adjusted [INR 2.0-3.0] dose): In three studies there were no differences in any thromboembolic event (including death) and major bleeding (moderate-certainty evidence), but an increased risk of stroke (risk ratio [RR] 14.13, 95% confidence interval [CI] 1.87 to 106.8; moderate-certainty evidence). One of the studies reported a small benefit of rivaroxaban in terms of quality of life at 180 days measured as health state on Visual Analogue Scale (mean difference [MD] 7 mm, 95% CI 2.01 to 11.99; low-certainty evidence), but not measured as health utility on a scale from 0 to 1 (MD 0.04, 95% CI -0.02 to 0.10; low-certainty evidence). High-dose VKA (warfarin with a target INR of 3.1 to 4.0 [mean 3.3] or 3.5 [mean 3.2]) versus standard-dose VKA (warfarin with a target INR of 2.0 to 3.0 [mean 2.3] or 2.5 [mean 2.5]): In two studies there were no differences in the rates of thrombotic events and major bleeding (RR 2.22, 95% CI 0.79 to 6.23, low-certainty evidence), but an increased risk of minor bleeding in one study during a mean of 3.4 years (standard deviation [SD] 1.2) of follow-up (RR 2.55, 95% CI 1.07 to 6.07). In both trials there was evidence of a higher risk of any bleeding (hazard ratio [HR] 2.03 95% CI 1.12 to 3.68; low-certainty evidence) in the high-dose VKA group, and for this outcome (any bleeding) the incidence is not different, only the time to event is showing an effect. Standard-dose VKA plus a single AP agent (warfarin at a target INR of 2.0 to 3.0 plus aspirin 100 mg/d) versus standard-dose VKA (warfarin at a target INR of 2.0 to 3.0): One high-risk-of-bias study showed an increased risk of any thromboembolic event with combined treatment (RR 2.14, 95% CI 1.04 to 4.43; low-certainty evidence) and reported on major bleeding with five cases in the combined treatment group and one case in the standard-dose VKA treatment group, resulting in RR 7.42 (95% CI 0.91 to 60.7; low-certainty evidence) and no differences for secondary outcomes (very low- to low-certainty evidence). Single/dual AP agent and standard-dose VKA (pooled results): Two high-risk-of-bias studies compared a combination of AP and VKA (aspirin 100 mg/d plus warfarin or unspecified VKA at a target INR of 2.0 to 3.0 or 2.0 to 2.5) with a single AP agent (aspirin 100 mg/d), but did not provide any conclusive evidence regarding the effects of those drugs in people with APS (very low-certainty evidence). One of the above-mentioned studies was a three-armed study that compared a combination of AP and VKA (aspirin 100 mg/d plus warfarin at a target INR of 2.0 to 2.5) with dual AP therapy (aspirin 100 mg/d plus cilostazol 200 mg/d) and dual AP therapy (aspirin 100 mg/d plus cilostazol 200 mg/d) versus a single AP treatment (aspirin 100 mg/d). This study reported on stroke (very low-certainty evidence) but did not report on any thromboembolic events, major bleeding, or any secondary outcomes. We identified two ongoing studies and three studies are awaiting classification. AUTHORS' CONCLUSIONS: The evidence identified indicates that NOACs compared with standard-dose VKAs may increase the risk of stroke and do not appear to alter the risk of other outcomes (moderate-certainty evidence). Using high-dose VKA versus standard-dose VKA did not alter the risk of any thromboembolic event or major bleeding but may increase the risk of any form of bleeding (low-certainty evidence). Standard-dose VKA combined with an AP agent compared with standard-dose VKA alone may increase the risk of any thromboembolic event and does not appear to alter the risk of major bleeding or other outcomes (low-certainty evidence). The evidence is very uncertain about the benefit or harm of using standard-dose VKA plus AP agents versus single or dual AP therapy, or dual versus single AP therapy, for the secondary prevention of recurrent thrombosis in people with APS (very low-certainty evidence).

Non-classical and intermediate monocytes in 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.

Antiplatelet and anticoagulant agents for secondary prevention of stroke and other thromboembolic events in people with antiphospholipid syndrome.

BACKGROUND: Antiphospholipid syndrome (APS) is a systemic autoimmune disease characterized by arterial or venous thrombosis (or both) and/or pregnancy morbidity in association with the presence of antiphospholipid antibodies. The prevalence is estimated at 40 to 50 cases per 100,000 people. The most common sites of thrombosis are cerebral arteries and deep veins of the lower limbs. People with a definite APS diagnosis have an increased lifetime risk of recurrent thrombotic events. OBJECTIVES: To assess the effects of antiplatelet or anticoagulant agents, or both, for the secondary prevention of recurrent thrombosis, particularly ischemic stroke, in people with antiphospholipid syndrome. SEARCH METHODS: We searched the Cochrane Stroke Group Trials Register (February 2017), CENTRAL (last search February 2017), MEDLINE (from 1948 to February 2017), Embase (from 1980 to February 2017), and several ongoing trials registers. We also checked the reference lists of included studies, systematic reviews, and practice guidelines, and we contacted experts in the field. SELECTION CRITERIA: We included randomized controlled trials (RCTs) that evaluated any anticoagulant or antiplatelet agent, or both, in the secondary prevention of thrombosis in people diagnosed with APS according to the criteria valid when the study took place. We did not include studies specifically addressing women with obstetrical APS. DATA COLLECTION AND ANALYSIS: Pairs of review authors independently selected studies for inclusion, extracted data, and assessed the risk of bias for the included studies. We resolved any discrepancies through discussion or by consulting a third review author and, in addition, one review author checked all the extracted data. MAIN RESULTS: We included five studies involving 419 randomized participants with APS. Only one study was at low risk of bias in all domains. One study was at low risk of bias in all domains for objective outcomes but not for quality of life (measured using the EQ-5D-5L questionnaire). We judged the other three studies to be at unclear or high risk of bias in three or more domains.The duration of intervention ranged from 180 days to a mean of 3.9 years. One study compared rivaroxaban (a novel oral anticoagulant: NOAC) with standard warfarin treatment and reported no thrombotic or major bleeding events, but it was not powered to detect such differences (low-quality evidence). Investigators reported similar rates of clinically relevant non-major bleeding (risk ratio (RR) 1.45, 95% confidence interval (CI) 0.25 to 8.33; moderate-quality evidence) and minor bleeding (RR 1.21, 95% CI 0.51 to 2.83) for participants receiving rivaroxaban and the standard vitamin K antagonists (VKA). This study also reported some small benefit with rivaroxaban over the standard VKA treatment in terms of quality of life health state measured at 180 days with the EQ-5D-5L 100 mm visual analogue scale (mean difference (MD) 7 mm, 95% CI 2.01 to 11.99; low-quality evidence) but not measured as health utility (MD 0.04, 95% CI -0.02 to 0.10 [on a scale from 0 to 1]).Two studies compared high dose VKA (warfarin) with moderate/standard intensity VKA and found no differences in the rates of any thrombotic events (RR 2.22, 95% CI 0.79 to 6.23) or major bleeding (RR 0.74, 95% CI 0.24 to 2.25) between the groups (low-quality evidence). Minor bleeding analyzed using the RR and any bleeding using the hazard ratio (HR) were more frequent in participants receiving high-intensity warfarin treatment compared to the standard-intensity therapy (RR 2.55, 95% CI 1.07 to 6.07; and HR 2.03, 95% CI 1.12 to 3.68; low-quality evidence).In one study, it was not possible to estimate the RR for stroke with a combination of VKA plus antiplatelet agent compared to a single antiplatelet agent, while for major bleeding, a single event occurred in the single antiplatelet agent group. In one study, comparing combined VKA plus antiplatelet agent with dual antiplatelet therapy, the RR of the risk of stroke over three years of observation was 5.00 (95% CI 0.26 to 98.0). In a single small study, the RR for stroke during one year of observation with a dual antiplatelet therapy compared to single antiplatelet drug was 0.14 (95% CI 0.01 to 2.60). AUTHORS' CONCLUSIONS: There is not enough evidence for or against NOACs or for high-intensity VKA compared to the standard VKA therapy in the secondary prevention of thrombosis in people with APS. There is some evidence of harm for high-intensity VKA regarding minor and any bleeding. The evidence was also not sufficient to show benefit or harm for VKA plus antiplatelet agent or dual antiplatelet therapy compared to a single antiplatelet drug. Future studies should be adequately powered, with proper adherence to treatment, in order to evaluate the effects of anticoagulants, antiplatelets, or both, for secondary thrombosis prevention in APS. We have identified five ongoing trials mainly using NOACs in APS, so increasing experimental efforts are likely to yield additional evidence of clinical relevance in the near future.

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.

Effectiveness of plasmapheresis in ANCA clearance in patients with ANCA-associated vasculitides.

Introduction: Plasmapheresis is a therapeutic method based on removal of high molecular weight particles from blood. It is used in a variety of clinical entities in which pathogenic role of such particles has been proven e.g. ANCA-associated vasculitides (granulomatosis with polyangiitis [GPA] and microscopic polyangiitis [MPA]). Efficacy of plasmapheresis in ANCA antibodies removal and its impact on disease activity has not been adequately investigated so far. Influence of antibodies levels on disease activity also remains unknown. Objectives: Analysis of plasmapheresis effect on serum ANCA levels in patients with ANCA-associated vasculitides. Patients and methods: Seven patients with diagnoses of ANCA-associated vasculitides were enrolled in the study between November 2015 and April 2016. All of them underwent plasmapheresis procedures. Serum ANCA levels were measured before and after plasmaphereses using fluoroimmunoenzymatic assay (FEIA). Disease activity was assessed using Birmingham Activity Vasculitis Score; BVAS ver. 3 before first plasma exchange procedure. Results: Patients in disease exacerbation (BVAS 5-10) with positive ANCA antibodies were enrolled in the study: 2 patients with GPA and 5 patients with MPA. Number of performed plasmapheresis procedures ranged from 5 to 7 (median=7). Decrease of serum antibodies concentration was observed in all patients (mean decrease of 88.3% (±10.1%)) with statistically significant difference in mean antibodies concentration before and after plasmapheresis procedures (113.0 vs 15.4; p=0.014). Conclusions: Plasmapheresis is an effective method of ANCA antibodies removal in patients in disease exacerbation.

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.

Antibodies against N-homocysteinylated proteins and their determinants in patients on long-term hemodialysis.

INTRODUCTION: The factors that determine the level of antibodies against N-homocysteinylated (N-Hcy) proteins have not been established so far. The clinical significance of these antibodies and their effect on cardiovascular (CV) risk in patients with end-stage renal disease (ESRD) are still unknown. OBJECTIVES: The aim of this study was to identify the factors that determine the level of antibodies against N-Hcyalbumin and N-Hcy hemoglobin in patients on long-term hemodialysis (HD). PATIENTS AND METHODS: The study involved 247 subjects on long-term HD (110 women, 137 men; age range, 23-89 years) and 60 controls matched for age, sex, and CV risk factors (serum creatinine level <140 micromol/l). Serum antibodies against N-Hcyalbumin and N-Hcyhemoglobin were determined using an in-house enzyme-linked immunosorbent assay. Total homocysteine (tHcy), folate, and 8-isoprostaglandin F2alpha (8-iso-PGF(2alpha)) were also measured. RESULTS: Patients on HD had higher serum levels of anti-N-Hcy-albumin (absorbancy at 490 nm: 0.56 [0.49-0.623] vs. 0.259 [0.198-0.338], P <0.0001) and anti-N-Hcy-hemoglobin antibodies (0.659 [0.597-0.723] vs. 0.379 [0.289-0.442], P <0.0001) as compared with controls. The level of both antibodies correlated with tHcy (r = 0.56, P <0.0001 and r = 0.67, P <0.0001, respectively), 8-iso-PGF(2alpha) (r = 0.48, P <0.0001 and r = 0.63, P <0.0001, respectively), and folate (r = -0.18, P = 0.0054 and r = -0.38, P <0.0001, respectively), but not with HD duration, the initial cause of ESRD, and CV comorbidity. CONCLUSIONS: In HD patients, tHcy is an independent predictor of antibodies against N-Hcy proteins. Folate and 8-iso-PGF(2alpha) concentrations were not independently associated with the levels of both antibodies.

[Antibodies to N-homocysteinylated albumin in patients with systemic lupus erythematosus]. / Przeciwciala przeciwko N-homocysteinylowanej albuminie u chorych na toczen rumieniowaty ukladowy.

INTRODUCTION: Hyperhomocysteinemia is known to predispose to atherosclerosis and occurs more commonly in patients with systemic lupus erythematosus (SLE) than in the general population. It has been shown that elevated plasma total homocysteine (tHcy) results in protein N-homocysteinylation and production o autoantibodies against N-homocysteinylated (N-Hcy) proteins. OBJECTIVES: The aim of the study was to investigate whether anti-N-Hcy-albumin antibodies occur in patients with SLE and identify factors that determine these antibodies in such population. Patients and methods. In 50 subjects with SLE and 50 age- and sex-matched healthy controls, we determined serum IgG antibodies to N-Hcy-albumin using an in-house enzyme linked immunosorbent assay. RESULTS: Patients had higher plasma tHcy and C-reactive protein (CRP) than controls, while serum folate and witamin B12 were lower in patients. Levels of anti-N-Hcy-albumin were higher in patients with SLE than in controls (medians: 0.31; vs. 0.19; p < 0.0001). In SLE patients, levels of anti- N-Hcy-albumin antibodies correlated with tHcy (r = 0.83; p <0.0001), CRP (r = 0.33; p = 0.02) and the duration of the disease (r = 0.3; p = 0.04). Seropositivity to anti-N-Hcy-albumin antibodies was more frequent in SLE patients than in controls (50% vs. 10%; p < 0.001). In SLE patients tHcy and CRP concentrations, along with the duration of the disease were independent predictors of anti-N-Hcy-albumin antibodies level. There were no associations between a type or levels of antinuclear antibodies patent's, or age with anti-N-Hcy-albumin antibodies. CONCLUSIONS: Compared with healthy controls, in SLE patients levels of anti-N-Hcy-albumin antibodies are significantly higher and are largely determined by tHcy, CRP and the disease duration. This novel autoimmune response might contribute to increased risk of vascular events in SLE patients.

Phlegmasia cerulea dolens as a complication of deep vein thrombosis in a man with primary antiphospholipid syndrome.

We report here the occurrence of phlegmasia cerulea dolens of both lower extremities as a complication of massive deep vein thrombosis in a 37-year-old man with primary antiphospholipid syndrome. The patient had no history of thromboembolic events or any comorbidities. Clinical and laboratory evaluation revealed a strong positive lupus anticoagulant as the unique thrombotic risk factor. In the literature, there is a single case of phlegmasia cerulea dolens as a complication of deep vein thrombosis in an obese woman with a history of thrombosis. We show that phlegmasia may occur in a previously healthy man with positive lupus anticoagulant.