IVIG: Panacea or pricey placebo?

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By Dr. Janice Mann

When most of us think of donating blood or receiving a transfusion, we tend to think of the transfer of red blood cells that carry oxygen in our blood. If we lose too much blood during surgery or injury, or can’t make enough blood due to illness, the red blood cells are replaced by a transfusion. While this type of transfusion is the most common, there are other parts of the blood that can be transfused as well — including the white blood cells (that fight infections), platelets (which help your blood to clot), and serum (the liquid part of your blood).

Found within the blood serum are different proteins, including antibodies. Our bodies make antibodies to fight infections — different antibodies recognize different infections, and we make thousands of them throughout our lives. Sometimes it’s these antibodies that are needed and are transfused. But unlike red blood cell transfusions, thousands of donors are needed to create the blood product known as immune globulin (IG). Since it is usually given by intravenous, or IV, infusion (that is, through a vein) the product is often called IVIG.

In Canada, Canadian Blood Services and Héma-Québec are able, through voluntary blood donors, to supply the individual blood components (such as red blood cells) needed for transfusions. But because blood plasma products like IVIG require thousands of donors, Canada must purchase IVIG and other blood plasma products from commercial manufacturers in the US, where blood donors are paid for giving blood. Canadian Blood Services supplies IVIG to hospitals at no charge, and each dose of IVIG can cost between $550 and $2,200 per child and between $2,000 and $8,000 per adult. The global demand for products like IVIG is high, and since Canada is unable to produce enough of its own products, we are potentially at risk for shortages and disruptions in supply in the future.

To add to the uncertainty of our continued supply of IVIG, our demand for blood plasma products also continues to increase. In fact, Canada is one of the highest consumers per capita of IVIG in the world, and between 1998 and 2006, Canada’s use of IVIG more than doubled at a cost of $196.1 million.

But what are we using all of this IVIG to treat? IVIG can be used if your body, for whatever reason, isn’t producing enough of its own antibodies, and you need antibodies from others to be able to fight infections and stay healthy. IVIG may also be used to treat inflammation or to manage conditions that can cause your immune system to go awry and attack parts of your own body like your platelets or your nerves. In Canada, IVIG is approved to treat six conditions that fall into these categories. They include primary immune deficiency, immune thrombocytopenic purpura, secondary immune deficiency states, chronic inflammatory demyelinating polyneuropathy, Guillain-Barré Syndrome, and multifocal motor neuropathy.

Although IVIG is used to treat these approved conditions, their treatment may not be why our use of IVIG is so high. It may actually be the “off-label” use of IVIG —using IVIG to treat other conditions that it isn’t officially approved by Health Canada to treat — that is contributing to our high and increasing use of the product. IVIG has been used to treat a wide variety of other illnesses, including neurological conditions, blood conditions, autoimmune or inflammatory conditions, skin conditions, and recurrent miscarriage.

But does IVIG actually work to treat or improve all of these different conditions?

When the need arises for answers to an important question such as this, the health care community turns to CADTH — an independent agency that finds, assesses, and summarizes the research on drugs and medical devices. CADTH searched for medical studies that would help to answer questions about the role of IVIG in the treatment of off-label conditions, then appraised and summarized the evidence so that it could be used by clinicians and other decision-makers in the health care system.

When CADTH looked at all of the evidence for a variety of different neurological conditions, the studies in general claim that IVIG treatment for neurological conditions is promising, but compelling evidence that IVIG works to improve most of these conditions is lacking at this time. For example, the results for epilepsy were mixed — meaning some studies find a benefit with IVIG treatment while others do not. But IVIG is no better than placebo (no active treatment) for Alzheimer’s or post-polio syndrome. However, evidence suggests that IVIG may be better than plasma exchange for the treatment of pediatric Guillain-Barré Syndrome, and IVIG is shown to be more effective than placebo for the treatment of multiple sclerosis in adults.

Looking at the evidence for using IVIG to treat different conditions of the blood, CADTH found that there wasn’t a lot of evidence. For example there was no evidence on off-label hematological conditions such as aplastic anemia, autoimmune neutropenia, hyperhemolysis after transfusion, and acquired hemophilia. That means we don’t know whether IVIG is effective to treat these conditions. A limited amount of evidence was found for blood conditions affecting a fetus or newborn. Overall, the evidence on the effectiveness of off-label use of IVIG for these specific conditions compared with other treatment options was mixed.

When CADTH looked at the evidence for using IVIG to treat autoimmune diseases, the evidence indicated that off-label use of IVIG may be effective in some autoimmune disease but not in others. For example, IVIG improves outcomes for patients with systemic lupus erythematosus, and it improves cardiac outcomes in infants of mothers with antiphospholipid syndrome during pregnancy. However limited evidence does not show a benefit with IVIG for dermatomyositis, myasthenia gravis, polymyositis, Kawasaki disease, Sydenham’s chorea, or cardiac complications of acute rheumatic fever. Overall, there is limited evidence to suggest that off-label IVIG is clinically effective for the treatment of autoimmune diseases and more evidence is needed.

CADTH also looked for evidence on whether IVIG is effective to treat dermatological conditions such as Stevens-Johnson Syndrome, toxic epidermal necrolysis, polymyositis, dermatomyositis, bullous pemphigoid, and systemic sclerosis. In general, evidence on IVIG use for dermatological conditions is scarce and the studies are small. Some studies suggest a possible benefit of IVIG treatment for some skin conditions, but more evidence is needed to understand whether IVIG is helpful for these patients.

When CADTH looked at the evidence to see if IVIG can improve the chances of a live birth in women who have experienced repeated miscarriage, the results were unclear. Some studies find no difference in live birth rates with IVIG treatment compared with placebo or other treatments. But other studies do find a difference, with significant improvements in rates of live birth with IVIG. This suggests that larger, well-conducted studies are needed to better understand the effectiveness of IVIG treatment in women who have had repeated miscarriages.

The range of conditions that can be treated with IVIG — both those that are approved and those considered off-label — is vast. Our increasing use of this blood plasma product coupled with our dependency on out-of-country suppliers is concerning. By better understanding whether IVIG is effective in the treatment of these conditions, we can make decisions that help to ensure this valuable resource is being used in the best possible way. Evidence from CADTH helps to do just that.

If you’d like more information on IVIG from CADTH, you can find it at: www.cadth.ca/IVIG. You can also follow CADTH on Twitter @CADTH_ACMTS or speak to CADTH Implementation Support Team member in your region.

Dr. Janice Mann MD is a Knowledge Mobilization Officer at CADTH.