IVIG: At the Intersection of Immunology and Clinical Research

I t is an irony of nature that affects the lives of tens of millions of Americans. The ever-alert immune system that protects us against invading bacteria, viruses, foreign particles and cancerous cells can suddenly confuse “self” and “non-self” and turn its destructive forces on our own healthy body tissues.

This misdirected attack, known as autoimmune disease, can inflame or damage peripheral nerves, brain, muscle, skin, mucous membranes, blood vessels, joints, kidney, heart, gastrointestinal tract, cellular blood elements or multiple organs at the same time. Some autoimmune diseases more commonly affect one gender, race or age group. Sometimes they may be triggered by a recent acute viral infection. But more often, the underlying cause is unknown.

For many serious autoimmune disorders—such asrheumatoid and psoriatic arthritis, inflammatory bowel diseases and systemic lupus erythematosus — physicians prescribe corticosteroid therapy. Often, steroids will be combined with powerful smallmolecule drugs developed originally for cancer therapy (e.g., cyclophosphamide, methotrexate and azothioprine) or with synthetic protein immunomodulators.¹

But attempts to gain the upper hand through aggressive use of these immunosuppressive drugs usually come at a cost. Longterm corticosteroid therapy can result in such complications as diabetes, osteoporosis, formation of cataracts and aseptic necrosis of bone. Other immunosuppressive drugs may increase the risk of opportunistic infections, certain cancers or a host of other serious adverse events. And often, the disease simply fails to adequately respond.

All of these issues help to explain why, in the early 1980s, excellent clinical and safety findings using intravenous immunoglobulin (IVIG) in a difficult-to-treat autoimmune platelet disorder have been followed by literally hundreds of studies and case reports documenting its effects in a wide range of autoimmune diseases. The meandering path of IVIG clinical research recalls the insight of the great scientist Marie Curie a century ago: “The way of progress is neither swift nor easy.” Three decades after IVIG was first licensed for clinical use, studies are just now underway to answer whether this powerful natural mediator of immune function can reduce death or disability in several of the most lethal and problematic diseases to afflict mankind.

1980: A Serendipitous Discovery in ITP

Some of the most important discoveries in medicine occur by chance and close observation. In 1980, Swiss physicians who administered IVIGto a childwith congenital agammaglobulinemia who was also affected with immune thrombocytopenic purpura (ITP) were surprised to see his platelet counts increase sharply after administering IVIG. This team went on to successfully treat six children with acute ITP, with no untoward effects.² Shortly thereafter, U.S. and other investigators confirmed the plateletboosting effect of IVIG in children and adults with chronic ITP who were unresponsive to corticosteroids or required high maintenance doses, again with no significant side effects.³

While scientists speculated about the mechanisms by which IVIG protects platelets from self-attack and destruction, this fortuitous discovery spurred physicians throughout the world to evaluate its effects in dozens of other unrelated autoimmune diseases. The resulting profusion of uncontrolled patient series, individual case reports and a relative handful of welldesigned trials has been carefully sifted by clinical experts. Their meta-analyses, professional practice guidelines and insurance coverage policies collectively represent the current consensus that human autoimmune disorders clearly respond to IVIG therapy.

The Other Work of IgG Antibodies

On a separate track, immunologists set about trying to answer the larger question:When IVIG works, how exactly does it work? The answer begins by recognizing that only a small portion of the circulating and tissue-bound IgG antibodies in our bodies are directed against bacteria, viruses and other foreign agents to which we have been exposed in the past. The rest of our IgG has an immunomodulatory function. In a variety of ways, this IgG acts to regulate the potential for our immune system to mistake “us” for “them.” Generally speaking, autoimmune diseases that respond to IVIG are thought to be those whose native IgG is overwhelmed or otherwise unable to adequately perform its immunomodulatory function. IVIG supplies the missing antibodies that go to work restoring part or all of that function.

In the instance of ITP, that natural regulatory function has gone awry. ITP patients produce antiplatelet antibodies that attach themselves to glycoproteins on the surface of their platelets. Coated with these abnormal antibodies, the platelets are quickly engulfed by macrophages and other phagocytes (literally “cells that eat”) whose normal job is to clear bacteria and other invading pathogens. Included in IVIG prepared from large pools of donor plasma are specialized antibodies, called anti-idiotypic antibodies, that bind to and neutralize those antiplatelet antibodies. Other antibodies in IVIG appear to competitively block antibody receptors on macrophages, thus preventing them from engulfing healthy antiplatelet antibody-coated platelets.

Other autoimmune disorders for which IVIG is now often prescribed include autoimmune neuropathies, neuromuscular junction defects, inflammatory myopathies, mucocutaneous blistering disorders, a potentially life-threatening vasculitis and at least one central nervous system disorder (see Table 1).

Inflammatory Injury: The New Frontier for IVIG Research

It is now well appreciated, particularly in certain peripheral neuropathies (Guillain-Barré syndrome and chronic inflammatory demyelinating polyneuropathy) and inflammatory myopathies (dermatomyositis and polymyositis), that IVIG acts to rein in harmful inflammatory activity. Perhaps the most dramatic demonstration of this powerful IVIG anti-inflammatory effect is seen in Kawasaki disease. Symptoms of this acute childhood vasculitis include fever, rash, erythema of the lips and oral mucosa, and often development of potentially deadly coronary artery aneurysms. A single dose of IVIG in combination with high-dose aspirin promptly reduces fever and cuts the frequency of giant coronary artery aneurysms from 15 percent to 25 percent to around 1 percent.⁴

While IVIG is known to tamp down inappropriate inflammation in several ways, two in particular are now believed to have an outsized role:^5,6

1. Cytokine regulation. IVIG modulates production of proinflammatory cytokines that attract and stimulate cytotoxic T cells, macrophages and other toxic inflammatory mediators, while up regulating anti-inflammatory cytokines.

2. Inhibition of the complement cascade. By interfering with inappropriate complement activation and scavenging active complement components,IVIG acts to prevent formation of the membrane attack complex (MAC) that directly causes tissue damage.

Just as the discovery of IVIG’s effectiveness in ITP prompted researchers to test it in a wide array of autoimmune disorders, mounting evidence of its powerful anti-inflammatory function has spurred interest in evaluating how IVIG might affect the course of diseases where inflammation accounts for much, if not most, of the injury.

Now, after nearly three decades of clinical research that has established its therapeutic role in rare or little-known autoimmune diseases, ambitious new clinical studies are trying to answer whether IVIG can improve outcomes in other more common disorders that include a critical inflammatory component. Two of them — myocardial infarction (MI) and acute ischemic stroke — are all too familiar for the hundreds of thousands of people they continue to disable or kill every year.

IVIG for Acute Myocardial Infarction

The goal of the various coronary artery revascularization approaches in patients who survive a myocardial infarction is to preserve as much remaining healthy muscle in their ventricles as possible. Yet not everyone who suffers an MI is a candidate for revascularization. For those who are candidates, reperfusion may not only come too late but it can perversely contribute to a secondary inflammatory “reperfusion injury” to healthy heart muscle.

In an entirely new approach, Norwegian investigators are evaluating IVIG (Octagam, manufactured by Octapharma) in a double-blind placebo-controlled Phase III trial in patients who have experienced a myocardial infarction with resulting poor ventricular function. Pointing out that levels of certain pro-inflammatory cytokines are elevated during the first days following an MI, these researchers postulate that by broadly attenuating their expression, IVIG can reduce inflammation and resulting permanent damage to the left ventricle of the heart. 7 An earlier trial, by this same Oslo-based group, in patients with chronic heart failure showed that IVIG therapy induced a marked rise in plasma levels of certain anti-inflammatory cytokines, with a modest but statistically significant increase in left ventricular function.⁸

More recently, U.S. collaborators described a dramatic improvement in left ventricular ejection fraction (LVEF) in six patients with acute-onset inflammatory cardiomyopathy following treatment with high-dose IVIG (2 grams/kg). All had failed to respond to conventional therapy, and were referred for heart transplantation with a mean LVEF of less than 22 percent. At discharge, the mean LVEF had improved to just over 50 percent, with four of the six patients experiencing complete recovery. It remains to be seen whether these encouraging results in this rare non-ischemic myocarditis population bears any relevance to the potential for IVIG in MI patients, whose inflammatory response is the result of acute left ventricular ischemia.

IVIG for Neuropathic Pain

Neuropathic pain is very common, and all too commonly, this vexing problem is extremely difficult to manage. Such conditions as diabetic neuropathy, post-herpetic neuralgia and post-stroke pain affect as many as 3 percent of adults, many of whom cannot get adequate relief with their prescribed treatment.

Betting on its multiple anti-inflammatory effects, Canadian investigators are conducting a Phase II double-blind, salinecontrolled cross-overtrial to assess whetherIVIG can subdue the neuroinflammation thought to be responsible for neuropathic pain.Adozen patientswith moderate to severe treatment-resistant neuropathic pain will receive a divided dose of 2 grams/kg of IVIG (Gamunex, manufactured by Talecris Biotherapeutics) or a saline placebo infusion. Complete responders with prolonged relief will cross over to the alternative treatment when their pain returns, if this occurs within six months of treatment.

Separately, a German research team has just initiated a double-blind cross-over trial that will enroll 36 patients with complex regional pain syndrome, a frequent complication after limb trauma. They will receive three doses of IVIG (Gamunex) or a saline placebo every four weeks, followed by a washout period of three months, then the alternative treatment.

IVIG for Acute Ischemic Stroke

Stroke is among the three leading causes of death and the most important cause of permanent disability. In roughly 75 percent of cases, an acute ischemic event caused by blockage of a brain blood vessel is the immediate cause. But what immediately follows literally adds insult to injury: An inappropriate inflammatory response initiated by complement activation causes a second wave of structural damage and necrosis in surrounding ischemic brain tissues.

Hypothesizing that it might help mitigate stroke injury mediated by complement and other misguided immune functions, 9 a team led by National Institutes of Health investigators recently tested IVIG in an experimental mouse model of ischemic stroke. 10 Of 65 animals treated with a single infusion of IVIG 30 minutes before or three hours after stroke was induced, just one died. This contrasted with 13 deaths in the 66 animals that were infused with control reagents used to stabilize or suspend the IgG antibodies in IVIG.

Histological analyses matched well with these results. Ischemic brain sections of IVIG-treated mice revealed intact tissue architecture with only occasional neuronal loss, in contrast with edema, loss of architecture and extensive necrosis in the control groups. Surprisingly, a low dose of IVIG (0.5 grams/kg) was found to work about as well as a dose four times higher. There may be a neat explanation for this: Much of the systemically infused human IgG crossed the blood-brain barrier and accumulated at the site of the infarction, possibly attracted by harmful complement activation going on there.

Encouraging results like these must be tempered with an awareness that nearly every would-be therapy that reduced mortality and limited injury in small animal stroke models later failed to pan out in human studies. But unlike IVIG, none could lay claim to an established track record of effectiveness with excellent safety in human neurological and other inflammatory disorders. NIH investigators are currently in the early planning stages of a human stroke trial.

Looking Ahead

Clinical use of IVIG has evolved dramatically since immunologists 30 years ago confirmed its ability to provide protective antibody levels in primary immunodeficiency patients. 11 Today, thanks to hundreds of studies and case reports that followed, IVIG is routinely ordered by neurologists, rheumatologists, dermatologists, oncologists and transplant specialists.

But if past serves as prelude for this extraordinarily dynamic element of innate human immunity, the most exciting clinical discoveries with IVIG therapy may yet lie ahead.