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Treating Pemphigus and Pemphigoid with IVIg

By Michelle Greer, RN, MBA
and
Michael T. Rigas, PharmD
Crescent Healthcare, Inc.

“The information provided in this article has been edited by Drs. Jean-Claude Bystryn and Sergei Grando of the IPPF Medical Advisory Baord. There are several companies that provided IVIG at home. The decision to utilize IVIG at home and what company to use, should be made between you and your treating physician.”

IVIG stands for intravenous immunoglobulin. Immunoglobulins are also known as antibodies, which are produced by the body to activate the immune system to attack virus and bacteria. IVIG is a medication that is a blood product. It is made from the plasma of thousands of carefully screened donors. 90 98% of IVIG is made up of Immunoglobulin G (IgG.) IgG is a Y-shaped protein that is the main antibody found in blood plasma.

Its role is to neutralize toxins and cause bacterial and viral inactivation. There are small amounts of other antibodies (IgA, IgE, IgM) found in IVIG products. There are many different brands of IVIG. The main differences are the IgA content, the type of sugar found in the solution and the methods use to protect the patient from viral transmission. The pH also varies depending on the brand.

There are several FDA-approved or labeled uses for IVIG. They include:

• Primary Immune Deficiencies
• Chronic Lymphocytic Leukemia
• Children with HIV
• Allogenic Bone Marrow Transplants
• Kawasaki Syndrome
• Idiopathic Thrombocytopenia Purpura

There are even more diseases and disorders that are considered standard treatment that aren’t FDA-approved, also called off label use. The majority of these are autoimmune diseases and disorders, including pemphigus and pemphigoid.
When IVIG is given for immune deficiencies, it is known as replacement therapy. This simply means the person lacks or doesn’t produce enough antibodies, and IVIG is given to make up for the deficiency.

Autoimmune diseases occur when the body fails to recognize itself and produces antibodies that activate immune response to attack one or more systems of the body. These antibodies are also called autoantibodies. Autoimmune diseases are also known as immune-mediated diseases or antibody-mediated autoimmune diseases.

Pemphigus is a rare autoimmune disorder in which antibodies are produced resulting in damage to cells in the upper part of the epidermis. This causes lesions or blisters to appear on the skin and/or mucous membranes of the mouth, nose, and eyes. Pemphigus refers to this group of blistering diseases known as Vulgaris, Foliaceus, and Paraneoplastic. Pemphigus Vulgaris (PV), is the most common and accounts for about 70% of all cases. It tends to be more common in people of Mediterranean descent. Pemphigus Foliaceus (PF) has six subtypes, and its incidence varies, but overall it is very rare and sporadic worldwide. Pemphigus, Paraneoplastic is found in patients with underlying neoplasms. Pemphigus can occur in any age group, but most commonly in ages 50 60.

Symptoms of pemphigus depend on the type and where the lesions are. In PV, mucous membranes are frequently affected first, and it may be months before skin blisters appear. A lot of people with PV might actually be seen and diagnosed by an oral surgeon. PV on the skin starts out as very fragile blisters that rupture quickly, causing painful, raw erosions on the skin. In PF, the mucous membranes are rarely involved, and the blisters usually appear on the trunk first. They are small and superficial and also rupture quickly causing skin erosions which become scaly and crusted. Pain is more localized.

Pemphigoid is another rare autoimmune disorder in which the body perceives skin proteins between the dermis and epidermis as foreign and attacks them. This also causes lesions or blisters to appear on the skin and/or mucous membranes of the mouth, nose, and eyes. There are two types of pemphigoid: Bullous and Cicatricial. In Bullous Pemphigoid (BP), it’s mainly the skin that’s affected. It occurs more in people age 50 70, although there have been cases in children and people of any age. Lesions tend to clear up with treatment without scarring. Sometimes lesions can clear up without any treatment. In Cicatricial pemphigoid (CP), the mucous membranes are frequently affected in addition to the skin, and scarring is more common. Because of this permanent damage to the eyes (visual problems) and throat (hoarseness, airway obstruction) can occur. CP occurs most frequently in the early to mid-60’s.

Again, symptoms of pemphigoid depend on the type and location of the lesions. Patients with BP may present in several different ways, the most common being generalized, where the lesions can show up on any skin surface, with tendency toward the joint flexure areas. They can be painful and itchy. If mucous membrane involvement occurs in BP, it is less severe than in CP. Patients with CP experience painful erosions of mucous membranes. Depending on where these erosions are, symptoms include pain or a “gritty” sensation in the eyes due to decreased tear production, mouth blisters, hoarseness, difficulty swallowing, bleeding after blowing the nose, as well as skin lesions.

Besides assessing the skin and mucous membranes lesions, there are two tests that are done to diagnose pemphigus and pemphigoid. The first is a skin biopsy from the edge of a blister. The second test is called immunofluorescence studies, which can be direct and indirect. This involves shining a special light onto the microscopic samples of skin around blisters and the skin around them looking for telltale responses. Sometimes it is a dentist or oral surgeon that sees these symptoms first.

Once the diagnosis is made, pemphigus is treated with steroids and/or drugs that curb immune system response, or immunosuppressants. Because of the damage to the skin, there is a lot of inflammation. Steroids are very powerful anti-inflammatory agents. Immunosuppressants are prescribed to prevent or decrease the production of the autoantibodies. In many cases, this is all that is needed to remit and even resolve the condition. However, these drugs have side effects and with long term use, can create other problems.

Studies have shown that IVIG is effective in treating pemphigus. Several treatment courses are usually needed for the desired therapeutic effect. In fact, one study concluded that treating mucous membrane pemphigoid with IVIG can actually end up being less expensive than treating with steroids and immunosuppressants because there were fewer side effects with the patients receiving IVIG (1). The side effects associated with immunosuppressants created other issues that made the course of the disease more expensive in the long run. (1)
Why IVIG works in autoimmune diseases is much more complex than simply replacing a deficiency. When IVIG is administered in these instances, it is known as immune modulation. In other words, by administering IVIG, the goal is to stop the immune system from producing autoantibodies. There are several theories why IVIG is effective in doing this. IVIG is given in high doses in these instances. The theory is that if enough healthy IVIG is given the person’s autoantibodies will not have a chance to cause the response in the immune system that causes the autoimmune disease. (2)

IVIG is given intravenously, directly into the veins. The dose depends on what the IVIG is being given for and is also based on body weight. To treat pemphigus, the doses are as high as 2000mg/kg. Because the doses are higher, they are divided into infusions that are given over the course of up to five days, and they can be consecutive or nonconsecutive days.
IVIG has a half life that is on average 30 days, depending on the brand and the person. Half life means the point at which the IVIG concentration in the blood falls to half of its original value. That is why IVIG doses are repeated at regular intervals of monthly or every two to four weeks. Many times this regimen is indefinite or even life time. In other cases, the condition resolves and the IVIG can be discontinued.

If side effects are intolerable or severe, or if the veins are such that getting an IV in place is not possible, IVIG may be administered subcutaneously. In this case a needle is placed under the skin and the medication is given. These infusions are given more frequently and take longer because the skin cannot handle the volume of fluid that the veins can. This route is more common in children where the dose is low enough that the skin can absorb the volume successfully. However, for any patient, if the IVIG route is no longer viable, and the patient needs IVIG, the subcutaneous route may be a viable alternative.

In general, IVIG is considered to be safe, and the majority of people tolerate it without problems. The adverse reactions occur only in less than 1% of patients (3). Patients with pemphigus and pemphigoid who suffer from side effects of steroid therapy have a higher risk. Most of the side effects occur because it’s administered too quickly. Because of this, it is gradually infused, starting at a very low rate and increased at intervals until the maximum rate is reached. Many times, if side effects are experienced, simply reducing the infusion rate will eliminate them. Side effects can also be offset by taking premedications, such as diphenhydramine (Benadryl®), acetaminophen (Tylenol®), aspirin, and even IV hydration fluids. In addition, side effects usually subside as the body adjusts to the IVIG. Other more severe reactions can be minimized but not always prevented by careful prescreening and choosing the appropriate brand.

Side effects are manageable and may include:

  • Headache
  • Fever
  • Fatigue
  • Chills
  • Flushing
  • Dizziness
  • Urticaria
  • Chest Tightness
  • Nausea and Vomiting
  • Muscle cramping
  • Blood Pressure changes

There are other reactions that more severe but rare. These include:

  • Anaphylaxis – a severe allergic reaction. People at higher risk for this type of reaction would be premedicated. At least one dose would need to be given in a medically supervised setting, such as a doctor’s office or a hospital infusion center. The level of IgA should be checked to avoid anaphylactic reaction to IgA present in the IVIG preparation.
  • Aseptic Meningitis Syndrome – severe headache that resolves when IVIG is stopped.
  • Thrombotic Event – a blood clot forms because the IVIG is slightly thicker than blood. Certain conditions or something in the medical history may make a person susceptible to clot formation. People at higher risk would be premedicated with aspirin, or a stronger prescription blood thinner. Some people may benefit from hydration before IVIG administration.
  • Renal Failure – potential problem for people with underlying kidney disease or diabetes. An IVIG brand without sucrose can minimize this complication. The IVIG would also be given at a slower rate.

IVIG can be administered safely in the home, as long as medical support is available. In fact, if IVIG is well tolerated for the first few infusions, people can actually be instructed to monitor their own infusions. Some home infusion companies have access to all brands, which give people receiving IVIG the option of getting the best brand for their clinical status, or switching if they react to one. Another benefit of receiving IVIG at home for treatment of pemphigus and pemphigoid is less risk of being exposed to infection that may occur in a hospital or clinic setting. Wound care management in people with blistering diseases must be impeccable, and whenever possible exposure to potential infections must be avoided.

Insurance coverage for pemphigus and pemphigoid can be somewhat difficult, and in some cases, there is no guarantee of coverage. However, these days, more off label uses of IVIG are being accepted as standard when conventional treatments have failed. Therefore, many insurance companies and medical groups are covering IVIG at home for pemphigus and pemphigoid. In fact, until 2006, Medicare only covered IVIG at home for people with immune deficiencies. With the Part D changes, there is now home IVIG coverage for autoimmune disorders, including blistering diseases. Copays and deductibles can exist depending on the health plan, including the Medicare Part D plans. In some instances, the setting for IVIG administration may be influenced by amount of the patient’s copays and deductibles which may be less in one setting compared to the other.

In conclusion, IVIG is a relatively safe and effective steroid-sparing therapy that appears successful in treating pemphigus and pemphigoid in many, but not all cases, where steroids and immunosuppressants given alone have failed. IVIG can be safely administered at home, and many insurance companies have recognized that IVIG is a standard (although not proven) therapy in treating these conditions. All of this gives people with autoimmune blistering disorders hope and additional treatment options.

References

(1) Daoud Y, Amin KG, Mohan K, Ahmed AR Cost of Intravenous Immunoglobulin Therapy Versus Conventional Immunosuppressive Therapy in Patients with Mucous Membrane Pemphigoid: A Preliminary Study (December). Ann Pharmacother. 2005 Nov.

(2) Yu Z, Lennon VA. Mechanism of intravenous immune globulin therapy in antibody-mediated autoimmune diseases. N Engl J Med. 1999; 340:227-228.

(3) Struff WG, Klasser M, Eckert V, Dietrich RL Safety monitoring of a polyvalent immunoglobulin preparation: documentation of 15,548 administrations. Int J Clin Pharmacol Ther 2005; 43: 420-428.

文章分类 Medical

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