Therapeutic plasmapheresis for autoimmune disease.
Therapeutic plasmapheresis is a process by which components in plasma, believed to cause or exacerbate disease, are selectively removed. The remaining blood components are then combined with replacement plasma or an inert substitute and returned to the patient. Removed components may include antibodies, immune complexes, mediators of inflammation or complement activation, toxins, lipids, and other potentially harmful molecules. The process is employed as a treatment strategy for many autoimmune diseases with varying levels of success. Typically, therapeutic plasmapheresis is used to rapidly decrease circulating antibodies or immune complexes during autoimmune episodes. It is often used in conjunction with other immunosuppressive therapies that help to prolong or enhance its beneficial effects.
Which autoimmune diseases?
Autoimmune diseases are frequently categorized by the tissues they affect. When organized this way, they form a continuum with systemic diseases on one end of the spectrum, such as systemic lupus erythematosus (SLE), which affects many organ systems, to specifically targeted diseases at the other end of the range, such as thyroid-specific Grave's disease. Plasmapheresis may be part of the treatment plan for autoimmune diseases falling anywhere along this continuum. Systemic autoimmune diseases for which therapeutic plasmapheresis is sometimes employed include SLE, rheumatoid arthritis (RA), and systemic vasculitis. Organ-specific autoimmune diseases for which the plasma exchange process has been part of the treatment plan include myasthenia gravis (which affects the acetylcholine receptors of neurons), Goodpasture's syndrome (which targets the kidney), Grave's disease, pemphigus disease (which affects the skin), and Guillain-Barre syndrome (which attacks nerve tissue). [1-3]
Though the causes of autoimmune disease remain unknown, a number of factors are associated with increased incidence. These factors include decreased numbers and function of T suppressor cells, the inheritance of certain histocompatibility haplotypes, excess estrogen, and infections, particularly viral ones.
The theoretical basis for most plasmapheresis procedures remains as it was when the procedure was first attempted 30 years ago: to remove pathogenic materials from the circulating blood by centrifugation or dialysis, thereby ameliorating tissue damage. The process, however, of performing plasmapheresis has changed dramatically since its inception. Highly automated mechanisms now replace what was once done manually.
In autoimmune diseases, the pathogenic materials targeted for removal are autoantibodies, immune complexes, complement components, and other mediators of the inflammatory response. The volume of removed plasma is replaced by saline and either albumin or plasma. If plasma is used as the replacement product, the procedure may also be called a plasma exchange.  Recent advances in technology have resulted in separation techniques so specific that they can remove individual blood components, such as antibodies, without requiring volume replacement. This procedure is more correctly called immunoadsorption. 
Plasmapheresis and immunoadsorption
Plasmapheresis and imunoadsorption usually begin with the separation of plasma from cellular blood components. This is usually accomplished with centrifugation. Available instruments can be calibrated to perform plasmapheresis, plateletpheresis (collection of donor platelets for patient use), erythrocytopheresis (used for treatment of sickle cell anemia), or leukopheresis (collection of donor stem cells for transplantation; removal of white blood cells for therapeutic purposes). Differential cell density gradients, with plasma's density of 1.027 G/mL, allow centrifugal separators to apherese by continuous or discontinuous methods. 
As an alternative to differential cell density gradient techniques, hollow fiber or rotating cylinder membranes may be used for separation. Membranes may be used together with a dialyzer or a centrifugation device and are available with different diameters, thicknesses, pore sizes, surface areas, and densities. Some membranes separate blood constituents by a filtration process, allowing smaller components to pass through the membrane while retaining larger ones; these are usually made of cellulose acetate. Others are made of a variety of materials designed to selectively retain specific plasma components by cryoprecipitation (removal of cryoglobulins) or affinity adsorption (such as removal of IgG-class antibodies by adsorption to Staphylococcus protein A). Membranes may be employed singularly or connected in tandem so that the first separates plasma from cellular components and the second selectively removes specific plasma components. 
Immunoadsorption is a modified plasmapheresis procedure with certain advantages. Plasmapheresis uses large amounts of valuable albumin or plasma products and exposes the recipient to the risk of hepatitis and other blood-borne, transmittable diseases. Because it requires substitution fluids, plasmapheresis also places patients at greater risk for allergic responses.  Furthermore, immunoadsorption, when coupled with a dialyzer, does not require the separation of plasma from blood in an extracorporeal system.
But immunoadsorption also has potential disadvantages. Immunoadsorbent membranes are not inert; they may generate free radical production and trigger the activation of cytokines, clotting and complement factors, and interleukin 1. Membranes may become clogged and may infrequently cause hemolysis.  The
reasons for the clinical effectiveness of plasmapheresis are not well understood, but they do not appear to be limited to the reduction of antibody and immune complex levels.  In addition to antibodies and immune complexes, the removal of proinflammatory agents and soluble adhesion molecules seems to enhance the beneficial effect. Therefore, immunoadsorption's more specific elimination of components may result in reduced efficacy when compared with plasmapheresis.
A wide range of immunoadsorbent materials is available for the removal of various plasma components. [5,7] Dextran sulfate columns, used primarily for patients with SLE, have been shown to significantly lower circulating levels of antiDNA and antiphospholipid antibodies and circulating immune complexes by crossreacting with negatively charged units. Columns with polyvinyl gels to which phenylalanine or tryptophan have been added are reported to eliminate antiDNA and antiphospholipid antibodies, immune complexes, and rheumatoid factor (Rf) by hydrophobic interactions. Attempts to develop adsorbers specific for antiDNA antibodies indicate that immune complex formation at the ligand may cause complement activation, and, thus, create a significant risk for the patient.
Staphylococcus protein A columns bind IgG subclasses 1, 2, and 4 by non-immunologic means, but are usually used before transplantation or for patients with hemophilia rather than those with autoimmune diseases. Antihuman IgG columns (with specificities for the heavy and light chains) remove virtually all IgG antibodies and substantially reduce IgM and IgA antibodies by immunologic means. These columns are primarily used with pretransplantation patients, but good responses have been reported in some patients with autoimmune type 1 diabetes mellitus. By coupling immunoadsorbent columns with monoclonal antibodies, an almost endless array of possibilities exists for the highly specific removal of plasma proteins.
Rationale and clinical outcomes
Regardless of whether therapeutic plasmapheresis or immunoadsorption is performed, virtually complete removal of an offending antibody from the circulation removes only a marginal amount of tissue-fixed antibodies. Histological staining techniques have revealed, for example, that immune complex deposits remain after plasmapheresis and immunoadsorption on the kidney tissue of patients with SLE.  In the absence of adjunct immunosuppressive agents, vigorous production of immunoglobulins may lead to "antibody rebound" whereby plasmapheresis stimulates antibody production and yields higher levels after treatment than were previously present.  At this time, plasmapheresis and immunoadsorption without the use of immunosuppressive agents is not a valid treatment option (see Table p. 38).
SLE. Therapeutic plasmapheresis for treatment of SLE crises has as its goal the reduction of circulating antibodies, immune complexes, and complement components. Removal of these components shifts the equilibrium between free and bound antigen-antibody complexes and improves the capability of phagocytic cells, which are blocked by high levels of circulating complexes, to further remove these complexes from the circulation. Circulating factors responsible for immunoregulatory T-cell dysfunction also appear to be removed resulting in improved T- and B-cell counts. The removal of immune complexes lessens the damage to blood vessels and organs triggered by immune complex deposition.[3,4]
Studies report mixed results for ther-apeutic plasmapheresis in SLE. One study involving 86 patients with severe SLE found that although levels of immune complexes decreased in patients treated with plasmapheresis and conventional therapy combined, no significant differences in clinical outcomes were observed between these patients and the control group who received only conventional therapy.  Other studies indicate that patients who have the highest levels of circulating immune complexes, and who, therefore, are the most ill, respond best to plasmapheresis.  Patients who do not receive immunosuppressive medications have poorer outcomes than those who do, regardless of other treatment protocols. Although evidence from randomized, controlled trials of the benefits of plasmapheresis is somewhat lacking, plasmapheresis in certain situations, such as during pregnancy when immunosuppressive therapy must be stopped, maybe warranted. 
RA. The mechanism by which plasmapheresis helps patients with PA remains unclear, but the treatment removes elastase from activated neutrophils and proinflammatory cytokines such as interleukins 1, 6, and 8, and tumor necrosis factor. Support in the literature regarding the effectiveness of plasmapheresis for PA varies widely. One study involving 21 patients with PA found that joint function improved and intake of nonsteroidal antiinflammatory drugs was reduced after treatment with plasmapheresis.  Another study of 21 patients with PA, however, suggests that leukopheresis is more effective than plasmapheresis in producing beneficial clinical outcomes.
Multiple myeloma. Multiple myeloma, although not usually classified as an autoimmune disease, results in the overproduction of immunoglobulin peptides. Abundant immunoglobulin light chains obstruct the kidney tubules, resulting in significant toxicity with cast formation. Therapeutic plasmapheresis rapidly lowers circulating levels of these toxic light chains, allowing adjunct antineoplastic therapy to become effective. In a randomized controlled clinical trial of 29 patients with elevated creatinine levels, creatinine levels returned to normal within 2 months of treatment with plasmapheresis in 13 of 15 patients, compared with only 2 of 14 patients not treated with plasmapheresis.
Myasthenia gravis. Myasthenia gravis is caused by the production of IgG antibodies, which attack the acetylcholine receptors of skeletal muscles. Antiacetylcholine receptor antibodies block and destroy acetylcholine, resulting in muscular weakness and fatigue. In patients with severe symptoms, plasmapheresis in conjunction with other treatment protocols can rapidly decrease antireceptor antibodies. Literature on this topic is far from abundant, but removal of these antibodies is associated with clinical and electromyographic (a measure of the ability of the muscle fibers to contract) improvement. 
Guillain-Barre syndrome. Plasmapheresis is beneficial to patients with neurological disorders with putative autoimmune mechanisms, such as Guillain-Barre syndrome. The etiology of Guillain-Barre syndrome is unknown, but many cases appear shortly after an acute upper respiratory infection. The disease appears to be limited to the peripheral nervous system and is marked by inflammation and degeneration of nerve roots and ganglia. Experts theorize that tissue damage is caused by the binding of autoimmune antibodies to nervous tissue, followed by the activation or release of proinflammatory molecules, such as complement. Although the mortality rate is fairly high at about 20%, prognosis is good if patients survive the acute phase.'2 Cause of death is usually respiratory or vasomotor paralysis.
The theoretical basis for therapeutic plasmapheresis in Guillian-Barre syndrome is that removal of IgM antiperipheral nerve myelin antibodies and high titered IgG antiganglioside antibodies diminishes pathologic tissue changes mediated by these antibodies.  Data from several randomized controlled trials establish plasmapheresis as standard therapy in acute presentations of this disease. [12,13]
An alternative treatment for Guillain-Barre syndrome is intravenous IgG (IVIg). Experts have proposed several mechanisms for its efficacy. One is that IVIg, prepared from pools from many donors, contains antiidiotypic antibodies directed against autoantibodies, which may clear or neutralize autoantibodies by idiotypic/antiidiotypic interactions. Idiotypic/antiidiotypic interactions are suggested to suppress tissue damage caused by autoantibodies in a number of conditions including autoimmune thyroiditis, SLE, pernicious anemia, cold agglutinin disease, myasthenia gravis, and idiopathic thrombocytopenic purpura. Other hypothesized mechanisms for the effectiveness of IVIg are: (1) the prevention of immune and phagocytic cell attack of opsonized nerves by blockade of Fc receptors, and (2) the prevention of cytotoxic lymphocyte recruitment. 
Therapeutic plasmapheresis is proposed to remove IgM and high-titered IgG antiganglioside antibodies, which, when bound to antigen, are capable of activating complement and triggering inflammatory responses. Intravenous IgG, on the other hand, introduces donor antibodies that suppress tissue damage through idiotypic/antiidiotypic networks or a blockade of immune receptors. Whether a combination of plasmapheresis and intravenous IgG improves patient outcome is currently under investigation. [12,13]
Systemic vasculitis. Systemic vasculitis, characterized by inflammatory changes in blood vessels, is a general term used for a group of diseases including Wegener's granulomatosis, microscopic polyarteritis, and crescentic glomerulonephritis. The pathologic mechanism in these diseases is thought to be the production of antineutrophil cytoplasmic autoantibody (ANCA), which, for unknown reasons, leads to the adherence of activated neutrophils to the endothelial cells of small blood vessels.  Most cases of systemic vasculitis are treated using antiinflammatory and immunosuppressive agents; however, several studies demonstrate the efficacy of removal of ANCA through therapeutic plasmapheresis in advanced cases. 
TTP. Thrombotic thrombocytopenic purpura (TTP) is characterized by 5 classic findings, all of which may or may not be present on initial evaluation: thrombocytopenia, microangiopathic hemolytic anemia, fever, renal failure, and neurologic impairment.  Although TTP sometimes precedes SLE, no convincing link between the 2 diseases has been established.  The pathogenesis of TTP remains unknown, but recent data implicate large polymers of von Willebrand's factor as a critical trigger. [1,3,15]
Because it is unclear whether the key pathogenic trigger is the presence of a procoagulant factor or the absence of an antithrombotic factor, controversy exists about whether the first line of treatment for TTP should be plasmapheresis (which may remove procoagulants such as von Willebrand's factor polymers) or plasma infusion (which may supply antithrombotic factors). Data from recent randomized controlled trials indicate that remission and survival are significantly higher in groups receiving plasmapheresis with fresh frozen plasma (FFP) or cryo-supematant (which lacks the von Willebrand's factor-rich cryo-precipitated fraction) as replacement fluids compared with those receiving plasma infusion alone.  Furthermore, the longer the delay in initiating plasmapheresis, the greater the likelihood that treatment will fail. 
Therapeutic plasmapheresis with FFP or cryosupematant replacement is now considered the treatment of choice for TTP. Approximately 80% of patients with TTP respond favorably to plasmapheresis.  Treatments continue until platelet counts normalize. Despite advances in treatment protocols, more than a third of all treated patients relapse, and the overall mortality rate of this disease is 10 to 20%. 
Therapeutic plasmapheresis and immunoadsorption techniques are employed as treatment strategies for a wide range of autoimmune diseases. When the replacement fluid for plasmapheresis is plasma, the procedure is also known as plasma exchange. The separation of plasma from cellular components of the blood may be achieved through centrifugation or by using filtration or affinity membranes in conjunction with dialysis or centrifugation. When using affinity membranes, the procedure is more correctly called immunoadsorption. Advances in membrane technology now allow highly specific removal of selected components from patient plasma.
For cases of SLE complicated by pregnancy, acute Guillain-Barre syndrome, and TTP, therapeutic plasmapheresis is an established treatment of choice. For other diseases, plasmapheresis appears beneficial in some circumstances, but reliable treatment protocols are not well established. This group includes SLE not complicated by pregnancy, RA, multiple myeloma, myasthenia gravis, systemic vasculitis, and others. In most cases for which benefits from therapeutic plasmapheresis are documented, adjunct immunosuppressive therapy is required.
Dianne M. Cearlock is professor and program director in the clinical laboratory sciences program at Northern Illinois University, DaKalb, IL. David C. Gerteisen is product manager at the DIGI-TRAX Corporation in Buffalo Grove, IL.
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|Author:||Cearlock, Dianne M.; Gerteisen, David C.|
|Publication:||Medical Laboratory Observer|
|Date:||Nov 1, 2000|
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