Chapter 90 Therapeutic plasma exchange and intravenous immunoglobulin immunomodulatory therapy

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.

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.

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