Exploring the Power of IVIG

Immune globulin (IG) products from human plasma were first used in 1952 to treat patients with immunoglobulin deficiencies. Initially, treatment was administered intramuscularly, until intravenous methods were shown to be effective in autoimmune idiopathic thrombocytopenic purpura (ITP) in 1981. Experts later convened to discuss the treatment possibilities for patients with primary immunodeficiency disease (PI), and fascination with the miraculous plasma derivative has only increased in ensuing decades. Intravenous IG (IVIG) therapy has been the featured topic in thousands of case reports and studies, and in 2014, it was the subject of dozens of clinical trials.

Currently, IG is approved by the U.S. Food and Drug Administration (FDA) to treat a wide variety of diseases, with more than 75 percent of the IG in the U.S. administered to patients with autoimmune or inflammatory conditions.¹ FDA-approved indications for IG therapy include PI, idiopathic thombocytopenic purpura, multifocal motor neuropathy, chronic lymphocytic leukemia, Kawasaki disease and chronic inflammatory demyelinating polyneuropathy. The use of IVIG is also now accepted for patients undergoing allogeneic bone marrow transplantation and kidney transplantation when the recipient has a high antibody titer or when the donor’s blood is ABO-incompatible. Additional approved indications with limitations include a variety of neuromuscular, hematologic and dermatologic conditions. But, there are a growing number of diseases and chronic conditions for which IVIG is showing promise when it comes to minimizing symptoms and improving the patient’s quality of life.¹

An Answer for Alzheimer’s?

Alzheimer’s disease (AD) is a neurodegenerative disease characterized by the death of neurons; currently there is no cure for this disease. AD has been dubbed a 21st century epidemic, and according to the Alzheimer’s Association, the disease affects one in nine people older than 65, and one in three people older than 85, although only between 2 percent and 7 percent of cases are diagnosed in the early stages. The World Health Organization estimates that 24.3 million people currently suffer from AD, with an increase of 4.6 million new cases each year.²

One area of growing interest is the potential use of IVIG to treat patients with AD. Pilot studies with the IVIG preparations Octagam (Octapharma) and Gammagard (Baxter Healthcare) in individuals with mild-to-moderate AD suggested stabilization of cognitive functioning in these patients, and a Phase II trial with Gammagard reported similar findings. However, subsequent reports from Octagam’s Phase II trial and Gammagard’s Phase III trial found no evidence for slowing AD progression. Although these secondary findings reduced enthusiasm for IVIG as a possible treatment for AD, additional trials are still underway.³

As the world’s third-largest manufacturer of plasma-derived medicines and a pioneer in the research and development of therapeutic alternatives, Grifols has been involved in ongoing research projects that explore the possibility of treating AD using plasma proteins. The company’s AD research efforts currently focus on early diagnosis, treatment with albumin, and prevention and protection by means of vaccination. Currently, the company is working on the validation of a diagnostic kit and on the development of a potential AD vaccine.⁴ (See “Saving the Aging Brain: Grifols Attacks Alzheimer’s Disease Head-On” on page 52.)

In 2012, Grifols launched a two-year study into methods of treatment for AD. Known as the AMBAR (Alzheimer Management by Amyloid Removal) study, it investigates combined treatment using albumin plasmapheresis and IVIG at different nominal doses. The researchers are attempting to find synergies between the two treatments in order to reduce the frequency and volume of plasmapheresis, ultimately making the treatment experience more pleasant for patients and easier for medical professionals to administer.

Directed by Dr. Merce Boada, clinical head of the neurology service at the Vall d’Hebron Hospital in Barcelona, Spain, the AMBAR study includes 350 patients at the mild to moderate stage of the disease, randomly grouped into three treatment groups and a fourth control group. The treatment groups consist of plasmapheresis with 20% albumin and IVIG high dose; plasmapheresis with infusion of 20% albumin; and IVIG low dose and plasmapheresis with infusion of 20% albumin low dose. Patients will be treated with a prototype of a plasma developed with Fenwal that was specially adapted for the study.

According to Dr. Boada, “The AMBAR study opens up new prospects and hopes in dealing with an illness where success involves maintaining the quality of life of these patients. Despite the complexity of the study, the principal investigators are really keen to take part because they are aware that there are no simple treatments for Alzheimer’s. They enjoy the challenge of offering new alternatives to patients and their families.”⁵

There is a growing interest in therapeutic strategies for the treatment of AD that focus on reducing the beta-amyloid peptide burden in the brain. In the last 10 years, Grifols has carried out two successful clinical trials that demonstrated the mobilization of beta-amyloid peptide in the blood of patients. The AMBAR study will allow researchers to confirm the tendency toward stabilization of the disease and to an improvement in the cognitive functions found in previous studies. Grifols plans to present the interim results of the AMBAR study by the end of 2015.⁶

Behavioral Improvements in Kids with Autism and PANDAS More than one million Americans suffer from autism spectrum disorders, including an estimated one-half million people, mainly children, who have a clinical diagnosis of autism. Autism is generally identified by behavioral manifestations, rather than a specific pathology, and it is now widely accepted that autism is linked to autoimmune disorders.⁷ As a result, researchers have been focusing on autoimmunity as a prime area for treatment breakthroughs.

IVIG was first used to treat autistic children in the mid-1990s by Dr. Sudhir Gupta at the University of California, Irvine. The study involved 10 children who each received IVIG therapy every four weeks for at least six months. Dr. Gupta stated: “A consistent (although variable) change was observed in calmer and improved social behavior, better eye contact, loss of echolalia and response to commands. The speech improved in terms of better articulation and improved vocabulary; however, little effect was observed on spontaneous meaningful speech in most patients. One of the patients almost completely recovered speech and another had marked improvement in speech. These two patients are attending regular school.”⁸

Of note, for those children who did improve, the IVIG therapy not only improved the behavior of the children, but it also produced change in their antibody levels. Researchers also found that after the IVIG therapy, the antibody titers to myelin basic protein and neurofilament protein actually went down below the detection limit. This finding documented the therapeutic result of IVIG and encouraged further study.⁹

In March 2012, a National Institutes of Health (NIH) scientist and her colleagues launched a multi-site placebo-controlled study testing the effectiveness of IVIG for reducing obsessive compulsive disorder (OCD) symptoms in children with pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection (PANDAS). IVIG is used to treat other autoimmune illnesses and showed promise in a pilot study with PANDAS patients.10 OCD is a common behavioral symptom in children diagnosed with PANDAS; previous human and animal research identified mechanisms by which strep-triggered antibodies mistakenly attack specific brain circuitry, resulting in obsessional thoughts and compulsive behaviors.

“Strep bacteria has evolved a kind of camouflage to evade detection by the immune system,” said Susan Swedo, MD, of the NIH’s National Institute of Mental Health (NIMH), who first characterized PANDAS two decades ago. “It does this by displaying molecules on its cell wall that look nearly identical to molecules found in different tissues of the body, including the brain. Eventually, the immune system gets wise to this ‘molecular mimicry,’ recognizes strep as foreign and produces antibodies against it; but because of the similarities, the antibodies sometimes react not only with the strep, but also with the mimicked molecules in the human host. Such cross-reactive ‘anti-brain’ antibodies can cause OCD, tics and the other neuropsychiatric symptoms of PANDAS. We predict that IVIG will have striking benefits for OCD and other psychiatric symptoms, and will prove most effective for children who show high levels of anti-brain antibodies when they enter the study.”¹⁰

In another study, researchers investigated whether plasma exchange or IVIG would be better than a placebo in reducing the severity of neuropsychiatric symptoms in PANDAS patients. Of the 29 children in the study, 10 received plasma exchange (five single-volume exchanges over two weeks), nine received IVIG (1 g/kg daily on two consecutive days) and 10 received a placebo (saline solution given in the same manner as IVIG). Symptom severity was rated at baseline and at one month and 12 months after treatment. At one month, the IVIG and plasma-exchange groups showed striking improvements in OCD symptoms, and tic symptoms also were significantly improved with plasma exchange. Treatment gains were maintained at one year, with 14 (82 percent) of 17 children much or very much improved over baseline (seven of eight for plasma exchange, and seven of nine for IVIG).¹¹

A Deterrent for Diabetic-Related Neuropathy

Diabetes mellitus (DM) is a chronic, lifelong condition that affects the body’s ability to use the energy found in food. There are three major types of diabetes: type 1, type 2 and gestational. Diabetic neuropathy is a type of nerve damage that can occur in diabetic patients when high blood sugar injures nerve fibers, typically in the legs and feet. According to The Neuropathy Association, there are now between 15 million and 18 million Americans suffering from diabetic peripheral neuropathy (DPN) due to the increasing prevalence of diabetes. Sixty percent to 70 percent of the 25.8 million adults and children in the U.S. with diabetes have DPN.¹²

Depending on the affected nerves, symptoms of diabetic neuropathy can range from pain and numbness in the extremities to problems with the digestive system, urinary tract, blood vessels and heart. For some people, these symptoms are mild; for others, diabetic neuropathy can be painful and disabling.

While not a treatment for diabetes itself, IVIG has proven effective in treating some forms of diabetic-related neuropathy, according to results of a study published in the Archives of Neurology. A separate study by the same group shows that chronic inflammatory demyelinating polyneuropathy (CIDP) is equally common in type 1 and type 2 diabetes patients, and much more common than in the general population.“We have the impression that clinically significant CIDP is a sufficiently common occurrence in patients with diabetes mellitus (DM) that it should be considered in the differential diagnosis of any diabetic patient with a worsening, relatively severe neuropathy, particularly where there is major motor involvement,” writes Khema R. Sharma, MD, and colleagues from the University of Miami School of Medicine in Florida. “There is growing evidence that idiopathic CIDP and polyneuropathy in patients with DM that meets the electrophysiological criteria for CIDP (DM-CIDP) have many similarities.”¹³

Previous studies have confirmed that DM patients presenting with CIDP respond favorably to IVIG treatment, but until recently, there were few defined recommendations on how best to taper treatment regimen once patients begin to improve. A study published in February 2013 in the Journal of the American Academy of Neuropathy reviewed the effects of treating CIDP and dermatomyositis with low-dose IVIG as a monotherapy. The study followed seven CIDP patients and three dermatomyositis patients who were treated using weekly low doses of IVIG as a monotherapy (0.4 g/kg) started without loading doses and gradually tapered off treatment. The study concluded that 100 percent of patients showed significant improvement in all categories from baseline to endpoint; all patients showed improvement within the first 24 weeks of treatment, and 80 percent successfully reached a state of remission and were no longer receiving IVIG. The average length of treatment was 3.4 years for CIDP and 5.0 years for dermatomyositis.¹⁴

Promising Plasma Therapies Yet to Be Seen

Significant progress has been made in understanding the anti-inflammatory effects of IVIG in the treatment of autoimmune and chronic inflammatory disorders. It has been 30-plus years since it was first proven to provide protective antibody levels in PI patients, and since then, hundreds of studies and case reports have led to additional medical breakthroughs and potential uses for this miraculous plasma derivative. Currently, clinical trials are studying the possible benefits of IVIG therapy for diagnoses as diverse as fibromyalgia, narcolepsy and stroke.15 While much has been accomplished, those on the frontlines of clinical research expect the most exciting clinical breakthroughs using IVIG and other plasma-based therapies to improve quality of life for patients are yet to be seen.