Neonatal Fc receptor blockade as emerging therapy in diseases with plasma exchange indications.

Neonatal Fc receptor (FcRn) blockade may represent a mechanism similar to plasma exchange (PLEX) in reducing immunoglobulin levels and thus have a broad implication for apheresis practitioners. Although only efgartigimod received FDA approval for myasthenia gravis in December 2021, multiple trials are currently underway with different FcRn therapies in a varied group of IgG antibody-mediated neurological and hematological disorders which are outlined in this review. In this review we discuss FcRn's mechanism of action, and its potential use in various neurological and non-neurological diseases. In addition, we further compare the kinetics and adverse events of PLEX and FcRn blockade. We encourage apheresis practitioners to be familiar with this class of drugs in order to better understand how these two therapies can be used either standalone, or in combination with other therapies as both FcRn antagonism and PLEX improve clinical state by reducing IgG levels and pathogenic antibodies.

Therapeutic plasma exchange for neuromyelitis optica spectrum disorder: A multicenter retrospective study by the ASFA neurologic diseases subcommittee.

IMPORTANCE: Neuromyelitis optica/neuromyelitis optica spectrum disorder patients' response to therapeutic plasma exchange (TPE) is currently incompletely characterized. OBJECTIVE: Our study aims to understand the clinical status improvement of neuromyelitis optica/neuromyelitis optica spectrum disorder patients treated with TPE. DESIGN, SETTING, AND PARTICIPANTS: This is a multicenter retrospective study conducted between 1 January 2003 and 31 July 2017 at 13 US hospitals performing apheresis procedures. Subjects studied were diagnosed with neuromyelitis optica/neuromyelitis optica spectrum disorder who received TPE during presentation with acute disease. MAIN OUTCOMES AND MEASURES: The primary outcome was clinical status improvement in patients treated with TPE. Secondary measures were procedural and patient characteristics associated with response to treatment. RESULTS: We evaluated 114 patients from 13 institutions. There was a female predilection. The largest ethnic group affected was non-Hispanic Caucasian. The average age of diagnosis was 43.1 years. The average time to diagnosis was 3.1 years. On average, five procedures were performed during each treatment series. The most commonly performed plasma volume exchange was 1.0 to 1.25 using 5% albumin as replacement fluid. Most patients (52%) did not require an additional course of TPE and noted "mild" to "moderate" clinical status improvement. Maximal symptom improvement appeared by the fourth or fifth TPE treatment. CONCLUSION AND RELEVANCE: TPE improved the clinical status of patients. Adults responded more favorably than children. Procedural characteristics, including number of TPEs, plasma volume exchanged, and replacement fluid used, were similar between institutions. TPE was well-tolerated and had a low severe adverse event profile.

A centralized recipient database enhances the serologic safety of RBC transfusions for patients with sickle cell disease.

OBJECTIVES: To evaluate the utility of a centralized transfusion service model in preventing the transfusion of incompatible units in patients with sickle cell disease (SCD). METHODS: The serologic records of transfused patients with SCD were reviewed. The index hospital was where an alloantibody was initially detected. RESULTS: In total, 150 patients with SCD were evaluated; 66 (44.0%) of 150 were alloimmunized. In 42 (63.6%) of these patients, 1 or more antibodies evanesced. The median number of hospitals visited by patients with SCD for RBC transfusion with 1 or more evanesced antibodies was three (range, one to eight); the median number of nonindex hospitals was two (range, one to seven). Of the patients with evanesced antibodies, 28.6% received transfusions at various nonindex hospitals 20 or more times after the antibody evanesced. CONCLUSIONS: A centralized database can help identify patients with SCD who have evanesced alloantibodies and prevent issuing incompatible RBC units.

Lupus anticoagulant increases activated partial thromboplastin time (PTT) prolongation in incubated 1:1 mix.

UNLABELLED: Our study analyzes the effects of incubation time and strength of lupus anticoagulant (LAC) on clotting times and prolongation of activated partial thromboplastin time (PTT) 1:1 mix assays with incubation. The prolongation in seconds of PTT 1:1 mix after incubation in the confirmed presence or absence of LAC was correlated to strength of the LAC as well as length of incubation (1 vs. 2 hours). Our study suggests that when screening for possible Factor VIII (FVIII) inhibitors, a 2 hour incubation of a PTT 1:1 mix increases the frequency of false positives as compared to 1 hour incubation, and that most of these false positives are due to LACs. Prolongation of clotting times for PTT 1:1 mixes in patients with LAC is influenced by both length of incubation time and strength of the LAC. CONCLUSIONS: When using PTT 1:1 mixes to screen for FVIII inhibitors, the effect of a possible LAC on the interpretation of the PTT prolongation should be considered. This effect is influenced by both incubation time and LAC strength.

Role of endocytic inhibitory drugs on internalization of amyloidogenic light chains by cardiac fibroblasts.

Amyloidosis is a disease of protein misfolding that ultimately impairs organ function. Previously, we demonstrated that amyloidogenic light chains (kappa1, lambda6, and lambda3 subtypes), internalized by cardiac fibroblasts, enhanced sulfation of secreted glycosaminoglycans. In this study, we investigated the internalization and cellular trafficking of urinary immunoglobulin light chains into cardiac fibroblasts. We demonstrate that these light chains have the ability to form annular rings in solution. Internalization was assessed by incubating cells in the presence of light chain conjugated to Oregon Green 488 followed by monitoring with live cell confocal imaging. The rate of light chain internalization was reduced by treatment with methyl-beta-cyclodextrin but not filipin. Amyloid light chain did co-localize with dextran-Texas Red. Once internalized, the light chains were detected in lysosomes and then secreted into the extracellular medium. The light chain detected in the cell lysate and medium possessed a lower hydrophobic species. Nocodazole, a microtubule inhibitor, did not disperse aggregates. In addition, internalization and retention of the light chain proteins was altered in the presence of the proteasomal inhibitor MG132. These results indicate that the cell internalizes light chain by a fluid phase endocytosis, which is then modified and ultimately compromises the cell.

Cellular response of cardiac fibroblasts to amyloidogenic light chains.

Amyloidoses are a group of disorders characterized by abnormal folding of proteins that impair organ function. We investigated the cellular response of primary cardiac fibroblasts to amyloidogenic light chains and determined the corresponding change in proteoglycan expression and localization. The cellular response to 11 urinary immunoglobulin light chains of kappa1, lambda6, and lambda 3 subtypes was evaluated. The localization of the light chains was monitored by conjugating them to Oregon Green 488 and performing live cell confocal microscopy. Sulfation of the proteoglycans was determined after elution over Q1-columns with a single-step salt gradient (1.5 mol/L NaCl) via dimethylmethylene blue. Light chains were detected inside cells within 4 hours and demonstrated perinuclear localization. Over 80% of the cells showed intracellular localization of the amyloid light chains. The light chains induced sulfation of the secreted glycosaminoglycans, but the cell fraction possessed only minimal sulfation. Furthermore, the light chains caused a translocation of heparan sulfate proteoglycan to the nucleus. The conformation and thermal stability of light chains was altered when they were incubated in the presence of heparan sulfate and destabilization of the amyloid light chains was detected. These studies indicate that internalization of the light chains mediates the expression and localization of heparan sulfate proteoglycans.