Effect of plasma exchange in accelerating natalizumab clearance and restoring leukocyte function.

BACKGROUND: Accelerating the clearance of therapeutic monoclonal antibodies (mAbs) from the body may be useful to address uncommon but serious complications from treatment, such as progressive multifocal leukoencephalopathy (PML). Treatment of PML requires immune reconstitution. Plasma exchange (PLEX) may accelerate mAb clearance, restoring the function of inhibited proteins and increasing the number or function of leukocytes entering the CNS. We evaluated the efficacy of PLEX in accelerating natalizumab (a therapy for multiple sclerosis [MS] and Crohn disease) clearance and alpha4-integrin desaturation. Restoration of leukocyte transmigratory capacity was evaluated using an in vitro blood-brain barrier (ivBBB). METHODS: Twelve patients with MS receiving natalizumab underwent three 1.5-volume PLEX sessions over 5 or 8 days. Natalizumab concentrations and alpha4-integrin saturation were assessed daily throughout PLEX and three times over the subsequent 2 weeks, comparing results with the same patients the previous month. Peripheral blood mononuclear cell (PBMC) migration (induced by the chemokine CCL2) across an ivBBB was assessed in a subset of six patients with and without PLEX. RESULTS: Serum natalizumab concentrations were reduced by a mean of 92% from baseline to 1 week after three PLEX sessions (p < 0.001). Although average alpha4-integrin saturation was not reduced after PLEX, it was reduced to less than 50% when natalizumab concentrations were below 1 mug/mL. PBMC transmigratory capacity increased 2.2-fold after PLEX (p < 0.006). CONCLUSIONS: Plasma exchange (PLEX) accelerated clearance of natalizumab, and at natalizumab concentrations below 1 mug/mL, desaturation of alpha4-integrin was observed. Also, CCL2-induced leukocyte transmigration across an in vitro blood-brain barrier was increased after PLEX. Therefore, PLEX may be effective in restoring immune effector function in natalizumab-treated patients.

Apheresis technologies and clinical applications: the 2000 International Apheresis Registry.

The developments in apheresis technologies and techniques and their clinical applications worldwide are technologically, sociologically, and economically driven. In the past, apheresis survey statistics have highlighted both the differences by geographical region in clinical practices and in the types of technologies utilized. While a national view of apheresis is critically important, an international view of apheresis may be more representative overall of this therapeutic modality than national results that are highly dependent on the local economics and the available technologies. These regional differences have provided a basis for the scientific and clinical assessments of these apheresis technologies and their clinical outcomes and have impacted the marketing and business developments of new technologies worldwide. The results of the International Apheresis Registry for 2000 reporting on 39 centers on 4 continents are presented. This survey collected data on 1,080 patients for a total of 15,257 treatments. Information gathered included patient demographics, medical history, treatment diagnoses, treatment specifics (type, methodology, access type, anticoagulants, drugs, equipment usage), side effects, clinical response, and payment provider. As in the prior International Apheresis Registry for 1983, the survey results highlighted the regional differences in apheresis usage and treatment specifics, indicating that an international overview of apheresis may be more representative of the impact of this therapeutic modality.

Overview of therapeutic apheresis in the U.S.A.

This article provides an overview of therapeutic plasma exchange in the United States. The original continuous flow blood cell separator was developed in the U.S.A. and remains the most popular type of equipment used. Treatments are expensive and limited by insurance reimbursement. Covered diseases are already established, with most of the treatments falling into those for hematologic and neurologic diseases. The majority of therapeutic plasma exchange is performed for a limited number of diagnoses. An estimated 110,000 treatments were provided in 1997, the majority in hospital-based units. It is unclear whether these numbers will increase or decline with the increasing limitations in reimbursement by insurance companies.

Clinical trials of a cryoglobulin filter.

The authors report the results of clinical trials of a high capacity cryoglobulin filter (Cryofilter) in seven patients with cryoglobulinemia unresponsive to high doses of prednisone or immunosuppressive drugs who required plasmapheresis. The objective of this study was to test the safety and efficacy of the cryofilter in a limited patient population according to the investigational Device Exemption guidelines of the FDA. The cryoglobulins were selectively filtered from plasma at 4 degrees C by a cryofilter characterized by a membrane surface area of 0.135 m2 and an average pore size of 4.3 microns. Safety was evaluated by patients vital signs, complement activation, and clinical score of symptoms in the course of 10 treatments. Efficacy of cryofiltration was evaluated by comparing sieving of the cryoglobulins to that of albumin; immunoglobulins G, A, and M; and fibrinogen. All seven patients completed the series of 10 treatments without notable complement activation or any signs of discomfort. The cryofilter was particularly selective in patients with high cryoglobulin concentrations. Improvement in clinical symptoms was observed in all patients.

Defective leukocyte function-related cryoprecipitable protein in cryoglobulinemia.

Cryoprecipitable proteins (CPP), purified from plasmas removed during plasmapheresis treatment of patients with type II and type III cryoglobulinemia (CG), were evaluated in vitro for their effect on normal leukocyte function. CPP reduced normal mononuclear cell blastogenesis and polymorphonuclear cell phagocytosis responses in a dose-dependent fashion. At the maximum concentration studied, 5,000 micrograms/ml, CPP were shown to suppress normal blastogenesis and phagocytosis 30-60% and 50-80% below the albumin control, respectively. A 50% suppression of normal blastogenesis and phagocytosis was observed at 500 micrograms/ml for type III CPP. Leukocyte functions in CG patients were evaluated and compared to those of healthy controls. Blastogenesis and phagocytosis were significantly inhibited in CG patients. These studies suggest that CG patients have defective leukocyte function and that CPP have suppressive effects on normal leukocyte function. Our studies suggest that removal of CPP in CG patients may prove beneficial not only in reducing typical symptoms of CG but also in reducing the potential inhibitory effects of CPP on leukocyte function.

Are selective macromolecule removal plasmapheresis systems useful for autoimmune diseases or hyperlipidemia?

Although technical limitations exist with existing selective removal systems, very few products are available and no major clinical trials have demonstrated the superiority or equivalence of selective removal systems over plasma exchange. It is generally recognized that selective removal systems are preferable, and that selective macromolecule removal plasmapheresis systems are useful for autoimmune diseases or hyperlipidemia. In the treatment of a disease with a selective removal device, the disease pathogen should be identified and the efficacy of removal demonstrated. In general, for plasmapheresis applications, there is a need to better understand the pathophysiology of the disease states and to identify the pathogenic molecules. With such information, development of the optimal selective removal method will be possible. There is the need for clinical studies to compare selective removal and plasma exchange for specific disease states. Incentives for the development of improved selective removal technologies where cost effectiveness could be demonstrated should be encouraged.

Myasthenia gravis therapy: immunoadsorbent may eliminate need for plasma products.

This in vitro study assessed the effectiveness of a new immunoadsorbent (Asahi IM-TR 350) in removing anti-acetylcholine receptor antibody from plasma with minimal loss of albumin. Plasma procured from a myasthenia gravis patient undergoing routine plasma exchange was perfused through the immunoadsorbent and recirculated in vitro to simulate a clinical treatment. To assess the temperature dependency of sorption, perfusion was performed at various temperatures. Plasma solute concentrations were taken before and after perfusion to calculate solute rejection coefficients. The immunoadsorbent has a high sorption capacity for anti-acetylcholine receptor antibody, while allowing a minimum loss of albumin. For patients with myasthenia gravis, this immunoadsorbent can provide an alternative to plasma exchange that does not require the use of plasma products.

Selective removal of anti-acetylcholine receptor antibody in the low temperature operation of membrane plasma fractionation.

The removal of anti-acetylcholine receptor antibody (anti-AChR Ab) by the plasma fractionator, Kuraray EVAL 2A, was measured as a function of the filtration temperature (4 and 37 degrees C). Plasmas procured from eight myasthenia gravis (MG) patients undergoing routine plasma exchanges (PE: membrane plasma filtration: n = 4, and centrifugation: n = 4) were used in the studies. Plasma flow rate was 20 ml/min, and plasma perfusion in single pass was terminated when the transmembrane pressure of the filter reached 300 mm Hg. Solute concentration data from before and after perfusion were used to assess the sieving coefficient (SC) of each solute. Results show that the SCs for anti-AChR Ab and albumin were significantly (P < .0002) lower at 4 degrees C (0.15 and 0.52, respectively) as compared to 37 degrees C (0.44 and 0.72, respectively). The SC of anti-AChR Ab (0.15) was significantly lower than the SC of IgG (0.42; P < .006) at 4 degrees C, even though it also belongs to the IgG class. The ratio of the SC of anti-AChR Ab to albumin at 4 degrees C (0.29) was significantly lower than that at 37 degrees C (0.57; P < .003). These data indicate that the selectivity of removal of anti-AChR Ab from albumin is higher at 4 degrees C than that at 37 degrees C. The volume treated at 4 degrees C was significantly lower than that treated at 37 degrees C, and it was less than that required for a clinical treatment; however, it was shown that filter backwashing is possible without loss of solute removal selectivity.(ABSTRACT TRUNCATED AT 250 WORDS)

Backwashing procedure for on-line reuse of a plasma fractionator in cryofiltration.

During membrane plasma fractionation therapy there are reported incidences of membrane plugging requiring the corrective actions of either filter replacement or backwashing (BW) in order to continue the treatment. In this preliminary study, a simple BW procedure to allow for on-line reuse of the filter (Asahi AP06M) during the treatment was evaluated to assess its efficacy and safety in cryofiltration (CF). Evaluations were carried out on two patients treated for rheumatoid arthritis. Seven tests, each using 1 L or 2 L warmed saline as a BW solution were performed to evaluate the decrease of the transmembrane pressure (TMP) between just before and after backwashing and TMP change during cryofiltration procedures between before and after backwashing. Sieving coefficients of total protein, albumin, immunoglobulins (G, M, A), fibrinogen, and rheumatoid factor were also calculated at 1,000 ml plasma volume processed. Results showed statistically significant decreases of TMP from 300 mm Hg to 70 mm Hg between just before and after both backwashing procedures, and that there were no significant changes in the TMP increase during the cryofiltration procedure between pre- and post-BW. The protein sievings were not significantly affected by BW. The use of a second liter for rinsing did not reduce the inlet pressure further suggesting that 1 L BW was adequate. The accumulated solutes did not affect significantly the effective mean pore size. The BW procedure did not affect the overall patient safety during therapy.(ABSTRACT TRUNCATED AT 250 WORDS)

Do humoral factors removed by plasmapheresis suppress the cellular immune system in cryoglobulinemia?

The efficacy of plasmapheresis (PP) is believed to be primarily related to the removal of plasma humoral factors. Little is known, however, about the effect of solute removal on cellular systems. The effect of the presence of cryoprecipitable proteins (CPPT) on mononuclear blastogenesis (MNB) and polymorphonuclear cell phagocytosis (PMN-P) was studied. MNB stimulated by concanavalin A (Con A), phytohemagglutinin (PHA), and pokeweed mitogen (PWM) was significantly inhibited in cryoglobulinemic (CG) patients to 70, 75, and 60% that of normal controls, respectively. PMN-P were significantly suppressed to 30% that of normals. CPPT purified from cryoglobulinemic plasmas, type I and type III CG, exhibited higher suppressive effects (and in a concentration dependent manner) on normal MNB and PMN-P than albumin used as a control. The studies indicate that patients with CG have defective leukocyte function and that CPPT have suppressive effects on normal leukocyte function in vitro. Removal of plasma CPPT may improve the immunologic status of CG patients.

Membrane pore size and filtration selectivity in cryoglobulinemic plasma fractionation.

Efficiency of albumin (Alb) and immunoglobulin G (IgG) separation from cryoprecipitable proteins (CPP) and IgM was compared between a membrane plasma fractionator with a mean pore diameter (MPD) of 0.1 micron, surface area of 0.65 m2, and a new large pore diameter filter with a MPD of 4.3 microns, and surface area of 0.14 m2. In five in vitro tests at 4 degrees C using polyclonal cryoglobulinemic (CG) plasma from a patient treated by plasma exchange (PE), the large pore filter retained only 22% of the mass of Alb, and a comparable amount of CPP and IgM, as compared to the plasma fractionator, at a fraction of its total retention capacity. The new filter can replace PE in treatment of polyclonal CG.

Rapid improvement in a patient with leukocytoclastic vasculitis with secondary mixed cryoglobulinemia treated with cryofiltration.

A patient with leukocytoclastic vasculitis (LCV) with secondary mixed cryoglobulinemia was treated by cryofiltration in an effort to stop the progression of the disease despite the use of high dose prednisone. Three cryofiltration procedures within one week were performed on this patient. Clinical assessments made through the course of this therapy and the followup period showed excellent response. Peripheral blood mononuclear cell transformation functions (MNC-TF) were evaluated at the pre-1st and post-2nd cryofiltration treatment. MNC-TF pretreatment were significantly suppressed. Post-2nd cryofiltration, MNC-TF were improved. Our study demonstrates that cryofiltration is a safe and effective treatment of a patient with LCV with secondary mixed cryoglobulinemia, without requiring plasma replacement products.