Therapeutic plasma exchange and intravenous immunoglobulin immunomodulatory therapy

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Chapter 90 Therapeutic plasma exchange and intravenous immunoglobulin immunomodulatory therapy

James P. Isbister

Bloodletting to remove ‘evil humours’ has a long history of over 2000 years. Although not based on logic in the past, the removal of ‘noxious’ agents from the blood remains the rationale, but now there is scientific understanding of the pathophysiology of the diseases treated by plasma exchange.1 Exchange transfusions revolutionised the management of haemolytic disease in the newborn, and paved the way for therapeutic plasmapheresis and plasma exchange – the removal of plasma, with replacement by albumin-electrolyte solutions or fresh frozen plasma.

Plasma exchange was initially used in the management of hyperviscosity associated with malignant paraproteinaemia, but is now also used in the treatment of a wide range of autoimmune disorders (now > 100). Nevertheless, plasma exchange is expensive and not risk-free, and debate continues on its therapeutic role in many diseases.

For the past two decades, intravenous immunoglobulin (IVIG) has increasingly been used as an immunomodulatory agent beyond its original primary use as replacement therapy in patients with humoral immune deficiency. The use of this agent will also be referred to in this chapter as it is now being used in many disorders in which plasma exchange is effective, but the convenience and safety of IVIG therapy is preferred as an alternative. However, the underlying principles in managing autoimmune diseases in which IVIG is used are similar to those of therapeutic plasma exchange. The mechanism of action of IVIG as an immunomodulatory agent remains controversial and it is likely, as fine plasma exchange, that there is more than one mechanism in play. Therapeutic efficacy of IVIG has been established in controlled trials for a range of diseases including idiopathic thrombocytopenic purpura, Kawasaki disease, Guillain–Barré syndrome, dermatomyositis, and others. There is compelling evidence that IVIG can modulate immune reactions of T-cells, B-cells and macrophages, not only interfering with antibody production and degradation, but also modulating the complement cascade and cytokine networks.

RATIONALE FOR PLASMA EXCHANGE

Theoretically, plasma exchange should be effective to treat any disorder in which there is a pathogenic circulating factor responsible for the disease. However, this premise is probably too simplistic, and other mechanisms may contribute to its beneficial effects (Table 90.1). It is a non-specific procedure, which brings about numerous, potentially undesirable, alterations in the plasma’s milieu interieur.

Table 90.1 Rationale for plasma exchange

Removal of circulating toxic factor antibodies
Monoclonal antibodies
Autoantibodies
Alloantibodies, immune complexes, chemicals, drugs
Depletion of the mediators of inflammation
Replacement of deficient plasma factor(s)
Potentiation of drug action
Enhanced reticuloendothelial function
Altered immunoregulation
Potentiating effects of plasma exchange on other modes of therapy

PATHOPHYSIOLOGY OF AUTOIMMUNE DISEASE

Autoimmune disease originates from the breakdown of immunoregulation (i.e. immune tolerance), allowing the immune system to become autoaggressive. Autoimmune diseases having underlying humoral mechanisms result from either a circulating autoantibody against a self-antigen (alone or in combination with an environmental antigen) or circulating immune complexes (which may be deposited in the microcirculation of various organs, resulting in end-organ damage). Cellular and tissue damage is affected by the autoantibody or immune complexes activating the cellular and humoral components of the inflammatory response. The circulating proteolytic systems involved include the complement, coagulation, fibrinolytic and kinin systems. On the cellular side, neutrophils and macrophages are involved, with eosinophils and basophils also playing a part.

The varied clinical manifestations of autoimmune disorders relate more to the cell, tissue or organ involved, rather than the pathophysiological process. However, basic pathophysiological mechanisms by which autoimmune diseases occur need to be understood in order to standardise treatment. Although some cells of the host defence system, in particular the macrophages and lymphocytes, may have special differentiation appropriate to individual organs, their basic functional processes are not all that dissimilar between different organs.

In general, autoimmune disease can be an acute, self-limiting (‘one hit’) disorder, intermittent or a chronic perpetuating disorder. Acute autoimmune disease may have an identifiable trigger, such as an infection, followed by a 10-day to 3-week gap until the pathogenic humoral or cellular factors appear in the circulating blood. At this point, end-organ damage commences, and clinical features of the disease appear.

The course of the disease will be determined by several factors:

• biological function and importance of the system involved
• extent of damage
• replaceability or otherwise of the cells under attack
• time course of the damaging insult

The extent of damage is a product of the:

• characteristics of the antibodies or lymphocytes involved (e.g. antibody affinity, complement fixing capabilities and titre)
• function of other components of the host defence system (e.g. neutrophils, platelets, proteolytic systems and reticuloendothelial system)
• presence of other aggravating factors (e.g. infection, hormonal responses and circulatory responses)

The kinetics of the end-cell involved in the immunological damage is relevant in determining the final outcome of the disease. Ultimate recovery of organ function after ‘burn out’ of a self-limiting autoimmune disease, or control of a chronic autoimmune disease, is determined by the ability of the cell to replace and restore function to normal.

Cells are broadly divided into three kinetic characteristics:

• Continuous replicators: these cells are continuously replaced in the normal state. They are readily replaced when damaged, and if the immunological insult is removed or controlled, full replacement of the end-cells occurs. This is typically seen with the haemopoietic system, the cells lining the gut and skin cells.
• Discontinuous replicators: these are cells that are not being constantly replaced in the normal state, but when damaged, cell division is initiated and replacement occurs. This is seen with hepatocytes, renal tubular cells and the neuronal Schwann cells.
• Non-replicating cells: when damaged, these cells are irreplaceably destroyed with permanent loss of function. This is seen with neuronal cells, muscle cells and renal glomeruli.

The clinical features and final outcome of any autoimmune disease can thus be seen to be determined by many different factors, including the ability of the end-organ to repair following removal or control of the immunological insult. In many self-limiting autoimmune diseases, if the end-cell is a continuous or intermittent replicator, full recovery can be expected, as long as appropriate support to end-organ function and life support is given during the acute phase of the illness. Examples are acute tubular necrosis, acute demyelination, acute hepatic failure and some forms of marrow aplasia. However, in disorders with non-replicating cells such as acute glomerulonephritis, therapy must be aimed at removing the immunological insult or dampening its damaging affects as soon as possible, so as to minimise irreparable damage to the end-cells and thus long-term organ function. Immunological mediators may also produce disease without direct destruction of end-cells. This occurs when autoantibodies develop against cell receptors, with blocking or destruction of the receptor as is typically seen in myasthenia gravis and thyrotoxicosis.

Therapy in acute and chronic autoimmune disease aims to minimise irreparable end-organ damage and support patients during the acute illness. This therapy may include:

• non-specific therapy to suppress the effector mechanisms, e.g. corticosteroids, antiplatelet therapy, non-steroidal anti-inflammatory drugs, anticoagulation and depletion of humoral effector mechanisms by plasma exchange or defibrination
• therapy to reduce the circulating levels of a humoral factor is achieved with plasma exchange or immunoabsorption technique
• specific or broad-spectrum immunosuppressive agents to suppress or block the immune response, e.g. corticosteroids, cytotoxic agents, antilymphocyte globulin, high-dose intravenous gammaglobulin therapy
• therapy directed at altering reticuloendothelial function, which may then have effects on autoantibody and immune complex clearance, or clearance of circulating damaged cells
• intravenous immunoglobulin immunomodulatory therapy

As most disorders are multifactorial, it is unlikely that a single form of therapy will be successful. A multipronged approach to therapy needs to be planned following an analysis of the basic underlying pathophysiology. The stage of the disease is also important (Figure 90.1). Clearly, plasma exchange will have a different response when autoantibody production is rising rapidly, compared with a stage when autoantibody has ceased production. Also, immunoregulation is a complex process, and therapies may interfere at different points in the immune mechanisms.

image

Figure 90.1 The therapy of ‘one hit’ autoimmune disease.

In some circumstances, specific and directed therapy may attack the most relevant link in the pathophysiological chain, but overall multiple approaches to therapy may be required. In general, plasma exchange is a temporising procedure and concomitant immunosuppressive therapy is required to maintain control. Plasma exchange for autoimmune disease should generally be regarded as a first step in immunomodulatory therapy, and restricted to acute or fulminant situations in which autoantibodies or immune complexes are responsible for life-threatening or end-organ damaging complications. There are some situations in which the humoral factor may be only transient (‘one antigen hit’ disorders), and no follow-up immunosuppression is required (e.g. acute postinfectious polyneuritis). Increasing monoclonal antibody therapy with rituximab (an anti-CD20 antibody) is finding a role in the longer term management of autoimmune diseases.2,3

The availability and recognition of the immunomodulatory effects of intravenous immunoglobulin has resulted in an exponential increase in its use in immune and inflammatory disorders, with its availability being one of the main drivers of the supply of human-derived plasma products. In most of the immune and inflammatory disorders in which plasma exchange has been used, intravenous immunoglobulin has been used. The mechanisms of action of intravenous immunoglobulin remain controversial. Intravenous immunoglobulin, fractionated from normal human plasma, was introduced as a replacement therapy for humoral immunodeficiency disorders, but is now widely used for a range of autoimmune and inflammatory diseases. Progress is being made in understanding the complex mechanisms by which IVIG has immunomodulatory actions. The mechanisms of action of IVIG involve modulation of expression and function of immunoglobulin Fc receptors, interference with activation of the complement system and the cytokine and immunoglobulin idiotype networks, and regulation of cell growth. There is also evidence for effects on activation, differentiation and effector functions of dendritic cells and T and B lymphocytes.4

TECHNICAL CONSIDERATIONS

Cell separators available for plasma exchange therapy are broadly divided into two groups:5

• machines which use centrifugation for the separation and are also suitable for specific separation and removal of blood components (e.g. plasmapheresis, thrombopheresis and leukopheresis)
• machines which separate by membrane filtration and can only be used for separation of plasma components

Either of these techniques for plasma exchange can be combined with immunoabsorption techniques, in which immunoglobulins are specifically or non-specifically removed.6

As plasma is removed, it is replaced volume for volume with a solution of adequate colloid activity (e.g. 5% albumin) and appropriate electrolyte composition. Although the levels of other plasma proteins are reduced by plasma exchange, there are rarely clinically significant effects. However, if extremely large volumes are exchanged, or exchanges are done frequently, it may be necessary to replace some plasma proteins. In patients with coagulation factor deficiencies or immunodeficiency, fresh frozen plasma is usually required.

INDICATIONS (Table 90.2)

Plasma exchange is most beneficial for immunoproliferative and autoimmune diseases. In some conditions with unclear pathophysiology, beneficial effects of plasma exchange may be due to infusion of a deficient component in the replacement plasma, rather than removal of a circulating factor.

Table 90.2 Acute diseases in which plasma exchange may be beneficial*

Immunoproliferative diseases with monoclonal immunoglobulins

Hyperviscosity syndrome
Cryoglobulinaemia
Renal failure in multiple myeloma

Autoimmune diseases due to autoantibodies or immune complexes

Goodpasture’s syndrome
Myasthenia gravis
Guillain–Barré syndrome
Chronic inflammatory demyelinating polyneuropathy (CIDP)
Stiff-man syndrome
Systemic lupus erythematosus
Fulminant antiphospholipid syndrome
Thrombotic thrombocytopenic purpura
Haemolytic uraemic syndrome
Rapidly progressive glomerulonephritis
Coagulation inhibitors
Autoimmune haemolytic anaemia
Pemphigus
Paraneoplastic syndromes
Conditions in which replacement of plasma may be beneficial ± removal of toxins

Disseminated intravascular coagulation
Multiorgan dysfunction syndrome
Overwhelming sepsis syndromes (e.g. meningococcaemia)
Conditions in which the mechanisms are unknown

Reye’s syndrome
Removal of protein-bound or large molecular weight toxins

Paraquat poisoning
Envenomation?

* This is an incomplete list and only includes disorders that are relatively common or in which plasma exchange has a definitive role to play.

MONOCLONAL ANTIBODIES ASSOCIATED WITH IMMUNOPROLIFERATIVE DISEASES

Monoclonal immunoglobulins are a classic feature of multiple myeloma and Waldenström’s macroglobulinaemia, but may also be associated with other lymphoproliferative disorders. These monoclonal proteins may be associated with numerous clinical effects, many of which may be reversed by plasma exchange.

HYPERVISCOSITY SYNDROME

Characteristic clinical features of hyperviscosity in association with monoclonal proteins include visual disturbance, neurological dysfunction and hypervolaemia, all of which can be rapidly relieved by plasma exchange.7

HAEMOSTATIC DISTURBANCES

Monoclonal proteins may impair haemostasis by adversely affecting platelet function or by inhibitory effects on coagulation factors. Plasma exchange is usually effective in controlling haemorrhage and may also be helpful in preparing patients for surgery.

RENAL FAILURE

The development of renal failure in the course of multiple myeloma is generally regarded as a sign of poor prognosis. In most cases, the renal failure is multifactorial in origin, but some of these factors may be reversible by plasma exchange. Patients presenting acutely with hyperviscosity, dehydration and hypercalcaemia may show recovery of renal function following adequate hydration, alkaline diuresis and plasma exchange.

IMMUNOLOGICAL DISEASES

DISEASES MEDIATED BY SPECIFIC AUTOANTIBODIES

Goodpasture’s syndrome

Circulating antiglomerular basement membrane antibodies can be demonstrated in most cases of Goodpasture’s syndrome. The disease classically has a fulminant presentation with rapidly progressive renal failure and life-threatening pulmonary haemorrhage. Early diagnosis and intensive plasma exchange may be necessary to preserve renal function and control pulmonary haemorrhage. Patients who are already in anuric renal failure rarely show improvement in renal function.8

Myasthenia gravis

Removal of the acetylcholine receptor autoantibody is associated with clinical improvement in the majority of patients with this disorder. The beneficial effects of plasma exchange are usually transient, and the procedure should normally be used in conjunction with other forms of therapy (see Chapter 49). The major role for plasma exchange is usually in myasthenic crisis, in patients whose condition is resistant to other forms of therapy, and prior to surgery. Therapy can be monitored by acetylcholine receptor autoantibody assays and respiratory function tests. Patients undergoing plasma exchange may transiently deteriorate during the procedure, due to a combination of the physical exertion and removal of medication from the circulation, and adequate ventilatory support should be available. IVIG may also be use in myasthenia gravis.9–11

Stiff-man syndrome

Stiff-man syndrome (STS) is a rare neurological disorder characterised by involuntary axial and proximal limb rigidity and continuous motor unit activity on electromyography. Autoantibodies to glutamic acid decarboxylase are usually demonstrable. Although plasma exchange is successful in STS, those who are autoantibody negative are less likely to respond.12,13

Autoimmune haematological disorders

Haemostatic failure due to autoantibodies directed against coagulation factors may present a major management problem. Antibodies directed against factor VIII are the commonest, occurring spontaneously or in association with replacement therapy in haemophiliacs. First-line therapy in patients with coagulation factor inhibitors usually requires activated factor VII therapy with recombinant FVIIa or appropriate prothrombin concentrates.14

IMMUNE COMPLEX DISEASE

Rapidly progressive glomerulonephritis

Immune complex-induced rapidly progressive glomerulonephritis may occur by itself or be associated with several systemic disorders (e.g. systemic lupus erythematosus, polyarteritis nodosa and Wagener’s granulomatosis).15–17 Plasma exchange may result in improvement in renal function even in patients who present with anuria. The decomplementing and defibrinating effects of plasma exchange may be partly responsible for clinical improvement. The therapeutic role of plasma exchange in rapidly progressive glomerulonephritis is difficult to assess, but most experienced physicians feel that the procedure leads to a more rapid and complete recovery of renal function in fulminant, rapidly deteriorating cases. However, the ultimate prognosis of the disease depends on adequate immunosuppression to inhibit immune complex formation, or spontaneous disappearance of the inciting antigen.

Systemic lupus erythematosus (SLE)

Plasma exchange has a role in acute life-threatening or organ-damaging relapses of SLE. Rapid deterioration in renal function, cerebritis and acute fulminant lupus pneumonitis are clinical situations in which plasma exchange should be considered.18

Cryoglobulinaemia

The various forms of cryoglobulinaemia may be associated with vasculitis or hyperviscosity. In some cases, there may be an acute fulminant presentation with cutaneous vasculitis, renal failure and neurological impairment. In this situation, plasma exchange should be considered an urgent definitive form of therapy.

OTHER IMMUNE-MEDIATED DISEASES

Renal transplant rejection

Humoral mechanisms appear to play a part in hyperacute renal allograft rejection. Plasma exchange ± IVIG may be useful in tiding patients over episodes of acute graft rejection, but results of clinical trials have been conflicting.19,20 General opinion is that plasma exchange helps in a limited number of patients who cannot be currently preselected by any clinical or laboratory criteria.

Thrombotic thrombocytopenic purpura

Thrombotic thrombocytopenic purpura (TTP) is a potentially fulminant and life-threatening disorder characterised by platelet microthrombi in small vessels, resulting in microangiopathy. The clinical syndrome is manifest by the pentad of thrombocytopenia, microangiopathic haemolytic anaemia, fever, renal dysfunction and neurological abnormalities. Abdominal symptoms, hepatic dysfunction and pulmonary abnormalities may also occur. With the appropriate clinical features, thrombocytopenia and a microangiopathic blood film, diagnosis is established.

TTP has been linked to a severe deficiency in ADAMTS13 with metalloprotease activity, with its target cleavage sequence in von Willebrand factor (vWF). The presence of an autoantibody inhibitor to this vWF reducing metalloproteinase has been documented in patients with both acute TTP and those with chronic relapsing forms. In normal plasma, vWF undergoes proteolysis by a specific protease, and deficiency of this cleaving protease reduces or abolishes the plasma clearance of ultralarge vWF multimers, resulting in intravascular aggregation of platelets, particularly at sites of intravascular shear stress. The inhibitor to the metalloproteinase has been demonstrated to be an IgG autoantibody.

There is a primary idiopathic form of the disease that usually has an acute presentation and probably has an underlying autoimmune mechanism. This form may be associated with a variety of prodromal infections (viral or bacterial). Bacterial cytotoxins, produced by Shigella dysenteriae type 1 and certain Escherichia coli serotypes, have been related to TTP and haemolytic uraemic syndrome (HUS), probably by initiating damage to vascular endothelial cells, possibly via cytokine mechanisms. TTP may be associated with various drugs (cytotoxic agents), toxins and bites. Cytomegalovirus (CMV), human immunodeficiency virus (HIV) and herpes viruses have also been implicated. Chemotherapy-associated TTP/HUS is being increasingly recognised and may be associated with a range of cytotoxic medications. Severe microangiopathy resembling TTP has also been reported as a complication of acute graft-versus-host disease in patients receiving ciclosporin prophylaxis following allogeneic bone marrow transplant.

TTP used to be a fatal disease in 90% of patients, but dramatic improvement in its outcome has occurred over the past two decades with the development of effective therapy. Plasma exchange has become the cornerstone of the treatment with fresh frozen plasma replacement.21,22 Cryoprecipitate-poor plasma (depleted in vWF) may offer advantages over whole fresh frozen plasma. It is now possible to achieve remissions in the majority of patients and cures are now common, though unfortunately relapse may occur. The clinical course at relapse is usually milder than the disease at presentation and less aggressive therapy may be needed.

Haemolytic uraemic syndrome (HUS)

This syndrome has many similarities to TTP, but renal involvement in contrast to cerebral in TTP is the hallmark in association with microangiopathy and thrombocytopenia.23 The prognosis and approach to management of HUS is similar to TTP. It usually occurs in children (related to bacterial or viral infections), but may rarely be seen in adults, in whom the disease may take a more chronic and sinister course. In adult cases medications are commonly implicated.

Inflammatory demyelinating neuropathies and the Guillain–Barré syndrome (GBS)

This acute self-limiting disease in which an acute demyelinating neuropathy occurs (usually following a viral infection) commonly results in admission to the intensive care unit (ICU) (see Chapter 49). There is demyelination due to postinfectious autoimmunity, with both cellular and humoral arms of the immune system attacking myelin. There is now wide experience in the use of plasma exchange and IVIG therapy in GBS, with controlled trials substantiating its benefits of shortening of the illness and complications. Therapy should be instituted early.11,24 As GBS also responds to high-dose IVIG there is debate as to which should be the first line of therapy. Decisions are usually made on the basis of local logistics and economics as the therapies are comparable in relationship to efficacy and safety.25 In some cases the onset of recovery after therapy may be delayed, probably due to time for remyelination to occur. Some patients show rapid improvement after plasma exchange, suggesting the presence of neuronal blocking factors. Chronic inflammatory demyelinating peripheral neuropathy (CIPD) is related to GBS, and plasma exchange and/or IVIG have important roles in treatment, in many cases requiring long-term therapy.

COMPLICATIONS

Plasma exchange is a relatively safe procedure, but close supervision by experienced physicians and apheresis operators is essential. A sound understanding of the haemodynamic, biochemical, haematological and immunological effects of plasma exchange is of paramount importance. Potential complications of plasma exchange include fluid imbalance, reactions to replacement fluids, vasovagal reactions, pyrogenic reactions, hypothermia, embolism (air or microaggregates), hypocalcaemia, anaemia, thrombocytopenia, haemostatic disturbances, hepatitis, hypogammaglobulinaemia, and altered pharmacokinetics of drugs. Prevention and treatment of most of these complications are usually obvious, but specific mention should be made of the following.

CIRCULATORY EFFECTS

Any extracorporeal procedure is likely to lead to problems of circulatory instability. Intravascular volume changes, vasovagal reactions, medications and infusion fluids may all alone, or in combination, be responsible for circulatory problems. If there are no associated oxygen transport defects, the patient will usually be able to compensate. However, if there are pre-existing defects (e.g. altered blood volume, vascular disease or renal failure), close monitoring is essential. A strict fluid and electrolyte balance should be kept at all times, both during the plasma exchange and as a daily tally.

PLASMA ONCOTIC PRESSURE

Most patients compensate for minor fluctuations in plasma oncotic pressure (COP). Patients who have oedema or local factors predisposing to interstitial fluid accumulation (e.g. raised intracranial pressure, interstitial pulmonary oedema, deep-venous thrombosis and renal impairment) need close attention.

INFECTION

Many patients who are undergoing plasma exchange are already immunosuppressed, either due to their disease or secondary to drug therapy. In patients requiring recurrent and frequent plasma exchange, attempts should be made to maintain serum immunoglobulin levels. When fresh frozen plasma is not used as replacement fluid, the bactericidal and opsonic activities of blood are probably impaired, and it is probably advantageous to infuse at least 2 units of fresh frozen plasma at the conclusion of the procedure. At the completion of a course of plasma exchange consideration may need to be given to a dose of intravenous gammaglobulin.

HAEMOSTASIS

Plasma exchange causes perturbations in the haemostatic system which may result in either bleeding or thrombosis. The significance of these alterations will depend largely on the volume and frequency of exchange, pre-existing defects in the system, anticoagulation, other risk factors for thrombosis, replacement fluids and invasive procedures.

REACTIONS TO REPLACEMENT FLUIDS

The rapid infusion of any blood component may be associated with allergic or vasomotor reactions. Plasma exchange is a rather unique situation in which blood or blood products and plasma substitutes are being infused at resuscitation rates into normovolaemic, normotensive patients.

EFFECTS OF INTRAVASCULAR PROTEINS

If plasma protein fractions or albumin are being used for replacement fluids, not only will coagulation and complement components be depleted, but various transport and binding proteins in the circulation will be significantly reduced. These may have significant effects on drug activity and elimination (e.g. antithrombin III levels may have effects on heparin activity). The effects of corticosteroids may be potentiated after plasma exchange owing to a reduction in binding proteins.

REFERENCES

1 Isbister JP. Plasma exchange: a selective form of blood-letting. Med J Aust. 1979;2:167-173.

2 Scheinberg M, Hamerschlak N, Kutner JM, et al. Rituximab in refractory autoimmune diseases: Brazilian experience with 29 patients (2002–2004). Clin Exp Rheumatol. 2006;24:65-69.

3 Virgolini L, Marzocchi V. Rituximab in autoimmune diseases. Biomed Pharmacother. 2004;58:299-309.

4 Negi VS, Elluru S, Siberil S, et al. Intravenous immunoglobulin: an update on the clinical use and mechanisms of action. J Clin Immunol. 2007;27:233-245.

5 Stegmayr BG. A survey of blood purification techniques. Transfus Apher Sci. 2005;32:209-220.

6 Ullrich H, Kuehnl P. New trends in specific immunoadsorption. Transfus Apher Sci. 2004;30:223-231.

7 Mehta J, Singhal S. Hyperviscosity syndrome in plasma cell dyscrasias. Semin Thromb Hemost. 2003;29:467-471.

8 Shah MK, Hugghins SY. Characteristics and outcomes of patients with Goodpasture’s syndrome. Southern Med J. 2002;95:1411-1418.

9 Zhu KY, Feferman T, Maiti PK, et al. Intravenous immunoglobulin suppresses experimental myasthenia gravis: immunological mechanisms. J Immunol. 2006;176:187-197.

10 Gajdos P, Chevret S, Toyka K. Intravenous immunoglobulin for myasthenia gravis. Cochrane Database Syst Rev. 2006;2:CD002277.

11 Green DM. Weakness in the ICU: Guillain–Barré syndrome, myasthenia gravis, and critical illness polyneuropathy/myopathy. Neurologist. 2005;11:338-347.

12 Shariatmadar S, Noto TA. Plasma exchange in stiff-man syndrome. Ther Apher. 2001;5:64-67.

13 Cantiniaux S, Azulay JP, Boucraut J, et al. [Stiff man syndrome: clinical forms, treatment and clinical course]. Rev Neurol (Paris). 2006;162:832-839.

14 Abshire T, Kenet G. Recombinant factor VIIa: review of efficacy, dosing regimens and safety in patients with congenital and acquired factor VIII or IX inhibitors. J Thromb Haemost. 2004;2:899-909.

15 Stegmayr BG, Almroth G, Berlin G, et al. Plasma exchange or immunoadsorption in patients with rapidly progressive crescentic glomerulonephritis. A Swedish multi-center study. Int J Artif Organs. 1999;22:81-87.

16 Rahman T, Harper L. Plasmapheresis in nephrology: an update. Curr Opin Nephrol Hypertens. 2006;15:603-609.

17 Jayne DR, Gaskin G, Rasmussen N, et al. Randomized trial of plasma exchange or high-dosage methylprednisolone as adjunctive therapy for severe renal vasculitis. J Am Soc Nephrol. 2007;18:2180-2188.

18 Pagnoux C, Korach JM, Guillevin L. Indications for plasma exchange in systemic lupus erythematosus in 2005. Lupus. 2005;14:871-877.

19 Lehrich RW, Rocha PN, Reinsmoen N, et al. Intravenous immunoglobulin and plasmapheresis in acute humoral rejection: experience in renal allograft transplantation. Hum Immunol. 2005;66:350-358.

20 Rocha PN, Butterly DW, Greenberg A, et al. Beneficial effect of plasmapheresis and intravenous immunoglobulin on renal allograft survival of patients with acute humoral rejection. Transplantation. 2003;75:1490-1495.

21 Brunskill SJ, Tusold A, Benjamin S, et al. A systematic review of randomized controlled trials for plasma exchange in the treatment of thrombotic thrombocytopenic purpura. Transfus Med. 2007;17:17-35.

22 Ozkalemkas F, Ali R, Ozkocaman V, et al. Therapeutic plasma exchange plus corticosteroid for the treatment of the thrombotic thrombocytopenic purpura: a single institutional experience in the southern Marmara region of Turkey. Transfus Apher Sci. 2007;36:109-115.

23 Amirlak I, Amirlak B. Haemolytic uraemic syndrome: an overview. Nephrology. 2006;11:213-218.

24 Raphael JC, Chevret S, Hughes RA, et al. Plasma exchange for Guillain–Barré syndrome. Cochrane Database Syst Rev. 2002;2:CD001798.

25 Tsai CP, Wang KC, Liu CY, et al. Pharmacoeconomics of therapy for Guillain–Barré syndrome: plasma exchange and intravenous immunoglobulin. J Clin Neurosci. 2007;14:625-629.

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