Despite good correlation between randomized trials and nonrandomized studies-in particular, prospective studies-discrepancies beyond chance do occur and differences in estimated magnitude of treatment effect are very common.

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Objective-To study the prevalence of different causes of anaemia in patients with systemic lupus erythematosus (SLE) and their associations with immunological and clinical parameters and to evaluate the contribution of erythropoietin (Epo) and anti-erythropoietin (anti-Epo) autoantibodies to the development of SLE anaemia. Methods-132 SLE patients with anaemia (defined as haemoglobin of 12 g/dl or less for women and 13.5 g/dl or less for men) from among a total of 345 consecutive SLE patients were prospectively enrolled into the study. Standard haematological and immunological tests were performed and serum Epo and anti-Epo antibodies were assayed. Results-The identified causes were anaemia of chronic disease (ACD) n=49 (37.1%), iron deficiency anaemia (IDA) n=47 (35.6%), autoimmune haemolytic anaemia (AHA) n=19 (14.4%) and other causes n=17 (12.9%). There was significant heterogeneity in the severity of anaemia between the four groups (p<0.01) with AHA cases being on average more severe. The proportion of patients with anticardiolipin antibodies, low complement levels and anti-dsDNA diVered significantly among the four groups; these markers were particularly common in patients with AHA, and uncommon in patients with IDA. Twenty one of 100 tested patients had anti-Epo antibodies. Such antibodies were seen practically only in patients with ACD (odds ratio 3.1, p=0.041) and in patients with high lupus activity (ECLAM) scores (odds ratio 1.27 per point, p=0.055). Epo response was inadequate in 42.4% and 41.2% of patients with ACD and AHA, respectively. Conclusions-Anaemia in SLE usually takes the form of ACD and IDA, however autoimmune haemolysis is not uncommon. SLE patients with diVerent causes of anaemia diVer in regard to several immunological parameters. Epo response is blunted in anaemic SLE patients, particularly those with ACD and AHA.

Objective. To investigate the existence of circulating autoantibodies to erythropoietin (EPO) in sera from patients with systemic lupus erythematosus (SLE), and to correlate their presence with anemia and clinical activity. Methods. Ninety‐two consecutive patients with SLE, 80 patients with rheumatoid arthritis, and 42 normal individuals were studied. The patients with SLE were categorized into 3 groups according to hemoglobin (Hgb) level: group A (45 patients with Hgb >12 gm/dl), group B (26 patients with Hgb 10.1–12 gm/dl), and group C (21 patients with Hgb ⩽10 gm/dl). In all patients with SLE, the disease activity was evaluated using the European Consensus Lupus Activity Measurement scale. Antibodies to EPO were detected using an enzyme‐linked immunosorbent assay and purified recombinant human EPO as antigen. The specificity of the method was evaluated with homologous and crossreactive inhibition assays. Results. Antibodies to EPO were found in 15.2% of the SLE patient sera. The distribution of these antibodies among the 3 groups of SLE patients was as follows: 8.8% (4 of 45) from group A, 15.4% (4 of 26) from group B, and 28.6% (6 of 21) from group C. The prevalence of antibodies to EPO in patients with severe anemia (group C) was statistically significantly higher compared with patients without anemia (χ2 = 4.31, P < 0.05). Patients with antibodies to EPO had higher disease activity scores (P < 0.005) and lower levels of the C4 component of complement (P < 0.05) compared with patients without antibodies to EPO. Conclusion. In this study, the presence of antibodies to EPO in the sera of SLE patients is demonstrated for the first time. The presence of these antibodies is associated with severe anemia and active disease.

In a cohort of 204 unselected consecutive human immunodeficiency virus type 1 (HIV-1)-infected patients, the association of circulating autoantibodies to endogenous erythropoietin (EPO) with HIV-1-related anemia was studied. Circulating autoantibodies to EPO were present in 48 (23.5%) of the 204 patients studied. Circulating autoantibodies were an independent predictor of anemia (odds ratio [OR]=5.0; 95% confidence interval [CI], 2.5-9.9), as strong as other known causes of anemia. The association of anti-EPO antibodies with anemia became stronger when the analysis was limited to the group of patients without any medical condition causing anemia (OR=10.4; 95% CI, 3.2-33.9). Moreover, the effect on hemoglobin levels remained significant even after adjusting for other anemia parameters. Anti-EPO autoantibodies were associated with higher EPO levels (r=.25, P=.012) and with a more prominent EPO response to anemia. Our findings suggest that autoimmunity, among other factors, may contribute to the pathogenesis of HIV-1-related anemia.

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Pulmonary endothelium dysfunction is a key characteristic of ARDS. The aim of this study was to investigate endothelium-derived markers, such as angiopoietin-2 (Ang-2) and endothelial cell-specific molecule-1 (endocan), at the vascular and alveolar compartments as outcome predictors in ARDS. Fifty-three consecutive ARDS patients were studied. The primary outcome was 28-day mortality. Secondary endpoints were days of unassisted ventilation and days with organ failure other than ARDS, during the 28-day study period. Nonsurvivors presented higher lung injury scores and epithelial lining fluid (ELF) Ang-2 levels compared to survivors, with no significant differences in plasma Ang-2, endocan, and protein C concentrations between the two groups. In logistic regression analysis, ELF Ang-2 levels > 705 pg/ml were the only independent variable for 28-day mortality among the previous four. Plasma endocan values > 13 ng/pg were the only parameter predictive against days of unassisted ventilation during the 28-day study period. Finally, lung injury score > 2.25 and ELF Ang-2 levels > 705 pg/ml were associated with increased number of days with organ failure, other than ARDS. Our findings suggest that Ang-2 levels are increased in the alveolar compartment of ARDS patients, and this may be associated both with increased mortality and organ failure besides lung.

Clinical Development Phases I‐III Regulatory, Quality, Manufacturing Heparin‐induced thrombocytopenia (HIT) without or with thrombosis (HIT‐T) constitutes an acquired immune prothrombotic state, occurring in patients under unfractionated heparin or rarely low molecular weight heparin treatment. Heparin binding to secreted platelet factor‐4 (PF4) generates PF4 neo‐epitopes, against which polyclonal IgG‐antibodies are produced. IgG‐Hep/PF4 complexes bind on specific platelet, monocyte and endothelial cell Fcγ surface receptors, causing platelet consumption (thrombocytopenia), cell activation, release of prothrombotic tissue factor‐bearing microparticles and thrombin generation. Mild to moderate thrombocytopenia and venous or arterial thrombosis are the two hallmarks of HIT. “4T” scoring‐system predicts HIT‐probability, while diagnosis is further confirmed via specific laboratory assays, which reveal either the presence of IgG antibodies against Hep/PF4 complex (immunological assays), or whether patient's serum can activate donor platelets in the presence of heparin (functional assays). HIT‐treatment imposes immediate heparin cessation and initial parenteral anticoagulation with alternative anticoagulants, such as direct thrombin inhibitors (DTIs: lepirudin, argatroban, bivalirudin, desirudin) or indirect FXa inhibitors (IXaIs: danaparoid, fondaparinux). Monitoring of DTIs and IXaIs (via activated partial thromboplastin time or modern assays such as hemoclot thrombin inhibitor and anti‐Xa activity, respectively) is essential especially in patients with renal or hepatic failure or in patients with HIT‐related consumptive coagulopathy, in order to avoid serious bleeding events or anticoagulant underdosing. Vitamin K antagonists, which are contraindicated during acute phase, are permitted only after platelet count has substantially recovered and must be continued for at least 30 days and 3 months in isolated HIT and HIT‐T, respectively, with target international normalized ratio (INR) between 2.0 and 3.0.