BACKGROUND The anti‐CD20 monoclonal antibody rituximab has immune‐modulatory effects similar to intravenous immunoglobulin (IVIG). We performed a systematic review and meta‐analysis to determine the efficacy and safety of rituximab in autoimmune diseases that are also treated with IVIG. STUDY DESIGN AND METHODS The most common indications for immune modulation with IVIG, as identified from a 2012 regional audit in Canada, were chronic inflammatory demyelinating polyneuropathy (CIDP), immune thrombocytopenia (ITP), myasthenia gravis, multifocal motor neuropathy, Guillain‐Barré syndrome, systemic lupus erythematosus (SLE), Sjogren's syndrome, and pemphigus vulgaris. We searched MEDLINE, EMBASE, and the Cochrane Library until July 2016 for studies evaluating rituximab in each of these conditions. The primary outcome in our meta‐analysis was clinical response at 6 months as defined by disease‐specific criteria in randomized trials. We also calculated pooled proportions of responders within disease types from observational studies. RESULTS Ninety‐five rituximab studies were identified: 86 were observational studies in patients with ITP (n = 1746), SLE (n = 1047), pemphigus vulgaris (n = 564), Sjogren's syndrome (n = 138), myasthenia gravis (n = 66), and CIDP (n = 31) and nine were randomized controlled trials (n = 992) in patients with ITP, SLE, and Sjogren's syndrome that compared rituximab with placebo plus standard of care. Among randomized trials, response rates were higher with rituximab (relative risk, 1.38; 95% confidence interval [CI], 1.05‐1.83). The pooled proportion of rituximab responses ranged from 94% (95% CI, 88%‐98%) for pemphigus vulgaris to 48% (95% CI, 30%‐66%) for CIDP. Rituximab was generally well tolerated in observational studies although in the randomized trials, adverse events were more common in the rituximab group. CONCLUSION Rituximab is an immune‐modulating agent with biologic activity across many autoimmune conditions. Our data support the use of comparative trials with broad eligibility criteria to evaluate rituximab as an alternative to IVIG in autoimmune diseases.

BackgroundAlloimmunisation and haemolytic transfusion reactions (HTRs) can occur in patients with sickle cell disease (SCD) despite providing phenotype‐matched red blood cell (RBC) transfusions. Variant RBC antigen gene alleles/polymorphisms can lead to discrepancies in serological phenotyping. We evaluated differences between RBC antigen genotyping and phenotyping methods and retrospectively assessed if partial antigen expression may lead to increased risk of alloimmunisation and HTRs in SCD patients at a tertiary centre in Canada.MethodsRBC antigen phenotyping and genotyping were performed by a reference laboratory on consenting SCD patients. Patient demographic, clinical and transfusion‐related data were obtained from a local transfusion registry and chart review after research ethics board approval.ResultsA total of 106 SCD patients were enrolled, and 91% (n = 96) showed additional clinically relevant genotyping information when compared to serological phenotyping alone. FY*02N.01 (FY*B GATA‐1) (n = 95; 90%) and RH variant alleles (n = 52, 49%; majority accompanied by FY*02N.01) were common, the latter with putative partial antigen expression in 25 patients. Variability in genotype‐phenotype antigen prediction occurred mostly in the Rh system, notably with the e antigen (kappa: 0.17). Fifteen (14.2%) patients had a history of alloimmunisation, with five having HTR documented; no differences in clinical outcomes were found in patients with partial antigen expression. Genotype/extended‐phenotype matching strategies may have prevented alloimmunisation events.ConclusionWe show a high frequency of variant alleles/polymorphisms in the SCD population, where genotyping may complement serological phenotyping. Genotyping SCD patients before transfusion may prevent alloimmunisation and HTRs, and knowledge of the FY*02N.01 variant allele increases feasibility of finding compatible blood.

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Background: Cardiorespiratory transfusion reactions drive most transfusion-related morbidity and mortality. Transfusion-associated circulatory overload and transfusion-related acute lung injury have established causes, important impacts, mitigation options, and revised definitions, while non-conforming CRTRs fall into a category known as transfusion-associated dyspnea. Though procedures to investigate high-risk febrile transfusion reactions are typically rooted in detecting incompatibility or bacterial contamination, a common standard for examining CRTRs is lacking. CRTRs are further challenged by charting limitations, confounding (or enhanced susceptibility) by comorbidities, and/or overlapping insults. Deeper profiling of CRTRs could improve categorizations, reveal best-value diagnostics, and decipher the nature of (and/or minimize) reactions coded as TAD. Methods: The primary objective of this multi-center study is to reduce uncertainty in final conclusions drawn on CRTRs (cases), defined by dyspnea with objective disturbances and/or significant hemodynamic insults, with/without fever (±F). HRFTRs (controls) represent higher-grade F (T≥39°C or chills/rigors or lower-grade F (≥38°C by +Δ1°C) with non-respiratory effects). Patients (goal: 200) consent to additional sampling (≤24h post-TR) to identify contributing factors in case/control presentations, and in diagnostic groups (TRALI, TACO±F, TAD). Mechanistic axes of interest are cardiorenal, hemolytic, leukoagglutinating, biolipid, vasoactive, and inflammatory. Secondary goals include elucidation of real-life “insult-multiplicity” in CRTRs, tests of greatest yield, and distinguishing features in TRALI/TACO/TAD. Conclusions: A deep systematic CRTR probe may not only reduce diagnostic uncertainty but frame biomarker performance and pathologic signatures in definition-specific CRTRs. The re-classifiability or biology of TAD may be better understood. High-quality, mechanistic, true-to-quantity hemovigilance better exposes burdens and management options. Trial Registration: The trial is registered with ClinicalTrials.gov. with registry number NCT04267029.

Direct oral anticoagulants (DOACs) are used for the prevention and treatment of thromboembolism in a variety of clinical settings. Although rates of DOAC-associated major bleeding are similar to, or lower than that of warfarin, there are currently no antidotes available to reverse DOAC anticoagulant effect. In the absence of specific reversal agents a variety of strategies have evolved to overcome DOAC-induced coagulation inhibition. Widely used agents to treat bleeding in DOAC treated patients include prothrombin complex concentrate (PCC), activated PCC (aPCC, FEIBA) or recombinant activated factor VII (rVIIa); these agents are used despite a known risk of thrombosis and a lack of evidence of efficacy. We present preliminary results of a retrospective review of patients treated with PCC, aPCC and/or rVIIa for DOAC-associated major bleeding at Hamilton Health Sciences, Hamilton, Ontario, Canada to (i) characterize utilization of these agents and (ii) describe the clinical course and complications after administration in this setting. Eligible patients were adults (≥ 18 yrs) treated with PCC, aPCC and/or rVIIa for major DOAC-associated bleeding between 2010 and 2013. After screening 503 patients with anticoagulant associated major bleeding (661 cases), 11 patients (12 cases) were eligible for inclusion with the remainder excluded as they were treated with warfarin. Median age was 81 years (interquartile range [IQR] 74-86) with 64% male. Patients were treated with dabigatran (73%) or rivaroxaban (27%). The majority of patients were treated for atrial fibrillation (91%) with a median CHADS2 score of 3 (IQR 2-3). Bleeding events occurred within 12 hours of DOAC administration in 9 patients (82%) or 13-24 hours in 2 patients (18%). Intracranial hemorrhage was the most common site of bleeding (54%) followed by gastrointestinal (27%), ocular (9%) and body cavity (9%). APCC and PCC were administered to 6 patients (54%) and 5 patients (46%), respectively. Six patients (54%) were admitted to the intensive care unit with median length of stay 2.5 days (IQR 2-4). Three patients (27%) underwent surgical procedures. Median length of hospital admission for the cohort was 10 days (IQR 4-29). There were no thromboembolic complications. In-hospital mortality was 18%. This case series demonstrates that PCC and aPCC are used "off-label" for reversal of DOAC anticoagulant effect in the setting of major bleeding. Our observed mortality rate was generally higher than that reported in the clinical trials leading to DOAC approval; this is likely explained by the severity of bleeding complications of which the majority were intracranial hemorrhage. Our failure to observe thromboembolic complications is reassuring; however, the small sample size does not allow us to confidently rule out even high frequency toxic events. Our results confirm the need for rigorous studies comparing strategies for DOAC reversal in patients with major or life-threatening bleeding. Disclosures Siegal: Daiichi Sankyo: Other: participated in an advisory board; Boerhinger Ingelheim: Other: participated in an advisory board; Portola Pharmaceuticals: Other: participated in an advisory board; Interactive Forums Inc.: Other: created educational slides. Off Label Use: We conducted a chart review of the off-label use of prothrombin complex concentrate, activated prothrombin complex concentrate and recombinant factor VIIa for direct oral anticoagulant reversal..