Hiroshi Seshima

Removal Characteristics of Immunoglobulin G Subclasses by Conventional Plasma Exchange and Selective Plasma Exchange

Selective plasma exchange (SePE) using a selective membrane separator is a modified method of simple plasma exchange (PE). Immunoglobulin G (IgG) subclass distribution is one of the important immunological characteristics of IgG. However, there is little information regarding the removal characteristics of IgG subclasses by SePE and conventional PE. Here, we investigated the removal ratio of IgG subclasses by PE and SePE in seven patients with immunological disorders. When the mean processed volume was 0.88 plasma volume (PV) (corresponding to 2.12 L), the mean percent reductions by PE were as follows: IgG, 63.2%; IgG1, 64.5%; IgG2, 64.0%; IgG3, 61.4%; and IgG4, 69.5%. When the mean processed volume was 1.18 PV (corresponding to 2.98 L), the mean percent reductions by SePE were as follows: IgG, 51.6%; IgG1, 55.3%; IgG2, 52.0%; IgG3, 53.7%; and IgG4, 64.6%. In both PE and SePE, using albumin solution as the supplementary fluid, IgG was effectively eliminated regardless of IgG subclasses.

Removal Kinetics of Antibodies Against Glutamic Acid Decarboxylase by Various Plasmapheresis Modalities in the Treatment of Neurological Disorders

Plasmapheresis is one of the acute treatment modalities for neurological disorders associated with antibodies against glutamic acid decarboxylase (anti‐GAD). However, there is little information about the removal kinetics of anti‐GAD by various plasmapheresis modalities. Here, we investigated the removal rate of anti‐GAD and fibrinogen (Fib) by immunoadsorption (IA), plasma exchange using a conventional plasma separator (OP‐PE), and plasma exchange using a high cut‐off selective membrane plasma separator (EC‐PE) in two cases of anti‐GAD‐associated neurological diseases. In case 1, IA and OP‐PE were used, and the percent reductions were as follows: anti‐GAD: 38.2% and 69.1% and Fib: 67.7% and 68.2%, respectively. In case 2, OP‐PE and EC‐PE were used, and the percent reductions were as follows: anti‐GAD: 65.8% and 48.5% and Fib: 68.5% and 19.8%, respectively. OP‐PE could remove anti‐GAD more efficiently than IA. Further, EC‐PE could maintain coagulation factors such as Fib better than IA and OP‐PE. It is important to select the appropriate plasmapheresis modality on the basis of the removal kinetics.

Removal Characteristics of Immunoadsorption With the Immusorba TR-350 Column Using Conventional and Selective Plasma Separators.

In Japan, immunoadsorption (IA) is performed using a conventional plasma separator and Immusorba TR‐350 column (TR‐350) for the treatment of neurological immune diseases. By this method, TR‐350 has the limited maximal capacity of the immunoglobulin G (IgG) adsorption, and fibrinogen (Fbg) is reduced remarkably. Evacure EC‐4A10 (EC‐4A) is a selective plasma separator and the sieving coefficients of IgG and Fbg using EC‐4A were 0.5 and 0, respectively. Here, we investigated the removal characteristics of IgG and Fbg in IA by TR‐350 using two different plasma membrane separators: conventional plasma separator (PE‐IA) and EC‐4A (EC‐IA). In vitro filtration using plasma effluent was performed with a closed circuit. When the processed volume was 3 L, estimated removal amounts by PE‐IA were 3172 mg for IgG and 3329 mg for Fbg, respectively. When the processed volume was 3 L, estimated removal amounts by EC‐IA were 4946 mg and 1916 mg, respectively. EC‐IA can be considered useful for the removal of IgG, including auto‐antibodies, while retaining Fbg, thereby allowing even daily use.

Removal Dynamics of Immunoglobulin and Fibrinogen by Conventional Plasma Exchange, Selective Plasma Exchange, and a Combination of the Two.

While plasma exchange (PE) can eliminate plasma proteins, including all immunoglobulin (Ig) and coagulation factors, selective plasma exchange (SePE) can retain fibrinogen (Fbg). Here, we investigated the removal dynamics of Ig and Fbg in 53 patients with immunological disorders by PE, SePE, and a combination of the two. When the mean processed plasma volume (PPV) was 0.9 plasma volume (PV), the mean percent reductions of Ig and Fbg by PE were both approximately 62%–65%. When the mean PPV was 1.1 PV, the mean percent reductions by SePE were 53.1% for IgG, 30.1% for IgA, 3.6% for IgM, and 19.0% for Fbg, respectively. In the three plasmapheresis sessions performed on alternate days, we classified treatments into three categories: PE group (PE–PE–PE, N = 2), SePE group (SePE–SePE–SePE, N = 14), and PE/SePE group (PE–SePE–SePE, N = 4). The mean percent reductions of IgG, IgA, IgM, and Fbg were 82.0%, 80.4%, 87.3%, and 80.9%, respectively, for the PE group; 76.4%, 57.7%, 43.3%, and 35.9%, respectively, for the PE/SePE group; and 75.4%, 50.6%, 3.2%, and 29.3%, respectively, for the SePE group. Plasmapheresis modalities can be combined according to clinical conditions, for instance, to achieve both the unspecific removal of pathogens by PE and retention of coagulation factors, such as Fbg, by SePE.

Selective Plasma Exchange for the Removal of Pemphigus Autoantibodies, Fibrinogen, and Factor XIII in Pemphigus Vulgaris

Pemphigus vulgaris is a serious autoimmune skin disorder associated with desmoglein 1 and 3. Selective plasma exchange (SePE) for pemphigus vulgaris remains unknown. We investigated the removal characteristics of pemphigus autoantibodies, immunoglobulins, and fibrinogen in three cases. When the mean processed volume for SePE was 1.2 plasma volumes, the mean percent reduction was 50.7% for desmoglein 1, 48.9% for desmoglein 3, 50.3% for IgG, 29.8% for IgA, 1.9% for IgM, and 17.6% for fibrinogen. In one case, the percent reduction after four sessions of SePE within eight days was 87.0% for desmoglein 1, 85.1% for desmoglein 3, 76.6% for IgG, 53.5% for IgA, 7.9% for IgM, 41.6% for fibrinogen, and 31.4% for factor XIII. SePE can effectively remove pemphigus autoantibodies and retain coagulation factors, e.g. factor XIII and fibrinogen. In severe cases, SePE can be useful and safe for induction therapy.

Removal Dynamics of Autoantibodies, Immunoglobulins, and Coagulation Factors by Selective Plasma Exchange on Three Consecutive Days: Removal Dynamics by Daily SePE

Selective plasma exchange has been shown to be effective in various diseases, but no studies have assessed the benefits of daily treatment. We aimed to investigate the removal dynamics of immunoglobulins, fibrinogen, and factor XIII on three consecutive days in three patients. For mean processed plasma volumes of 1.06 × plasma volume, reductions of 79.6%, 49.3%, and 8.6% were seen for immunoglobulins G, A, and M, respectively. The reductions for fibrinogen and factor XIII were 18.4% and 13.0%, respectively. Removal dynamics were similar for immunoglobulin G‐related autoantibodies and immunoglobulin G when using daily selective plasma exchange. Moreover, daily use effectively removed the immunoglobulin G while retaining the coagulation factors. When disease‐specific autoantibodies are limited to immunoglobulin G, daily selective plasma exchange may be a useful and safe method of intensive induction treatment for plasmapheresis. However, further study is required in larger cohorts to confirm these findings.

Fibrinogen Reduction During Selective Plasma Exchange due to Membrane Fouling

Fibrinogen is substantially reduced by most plasmapheresis modalities but retained in selective plasma exchange using Evacure EC‐4A10 (EC‐4A). Although EC‐4As fibrinogen sieving coefficient is 0, a session of selective plasma exchange reduced fibrinogen by approximately 19%. Here, we investigated sieving coefficient in five patients. When the mean processed plasma volume was 1.15 × plasma volume, the mean reduction of fibrinogen during selective plasma exchange was approximately 15%. Fibrinogen sieving coefficient was 0 when the processed plasma volume was 1.0 L, increasing to 0.07 when the processed plasma volume was 3.0 L, with a mean of 0.03 during selective plasma exchange. When fibrinogen sieving coefficient was 0, selective plasma exchange reduced fibrinogen by approximately 10%. Scanning electron microscopy images revealed internal fouling of EC‐4As hollow fiber membrane by substances such as fibrinogen fibrils. Thus, fibrinogen reduction by selective plasma exchange may be predominantly caused by membrane fouling rather than filtration.