Immunoglobulin replacement therapy

Starting Ig replacement therapy

The goal of Ig replacement therapy for antibody disorders—no matter the setting, dosing, or route of administration—is to provide protection from infection. An individual’s adherence to therapy is very important for achieving this goal. Any barriers to therapy, real or potential, need to be addressed to ensure that the individual remains on schedule for their infusions. 

Ig replacement therapy is typically dosed based on the recipient’s weight. The prescriber, however, considers many factors when the medication is prescribed. Typically, a starting dose is between 400-600mg/kg/month. Doses are adjusted for clinical efficacy, with the expectation of minimizing the frequency and severity of infections while minimizing the side effects of the medication. IgG levels are usually monitored over time and correlated with the response to therapy. The goal is to keep the Ig in the bloodstream above a certain level even when the level is at its lowest point (the trough level) right before the next infusion is due.

It is also important to remember several things when considering Ig replacement therapy:

• Not all infections can be prevented. After starting Ig replacement therapy, individuals may still get infections. The hope, however, is that the frequency and severity of infections will significantly decrease so that permanent organ damage, like bronchiectasis, can be prevented.
• One size does not fit all. An individualized Ig replacement therapy regimen must be developed for each individual and modified as necessary to achieve treatment goals and the needs of each person.
• Once a diagnosis of PI involving antibody production and/or function has been made, Ig replacement therapy is likely needed for life. In some instances, reevaluation of the diagnosis may be undertaken. This must be done cautiously, as Ig replacement therapy must be stopped for four months to obtain accurate repeat lab tests.

Use this table to discuss the options with healthcare providers when immunoglobulin (Ig) replacement therapy is determined to be the treatment of choice and is deemed medically necessary. Decisions on which therapy is best should be made with some of these factors in mind. 

Tests to complete beforehand

Before starting Ig replacement therapy, it is important that a healthcare provider completes all immune studies needed to demonstrate that the individual’s Ig levels are not only low but also that the individual does not make specific antibodies. 

This is because people who do not have antibody disorders normally make antibodies during and after natural infections and in response to immunization with vaccines, so their Ig levels are not constant. To confirm that an individual cannot make functional antibodies to a specific antigen, immunologists generally use tetanus toxoid and pneumococcal vaccines. 

Blood drawn before giving the vaccine is used to measure the vaccine-specific antibody levels, which should be low. After vaccination, a second blood sample is drawn 4-6 weeks later to determine how well specific antibodies were made to these vaccines. It is important that the individual completes this second blood draw to determine the response to the vaccine within this 4-6-week timeframe. These results provide important information about the individual’s immune condition and insurance companies often review this information before approving Ig replacement therapy. Once Ig replacement therapy is started, it is not possible to get accurate results for these important tests without stopping Ig treatment for a few months.

Options for administration

Ig replacement therapy is generally administered as either IVIG or SCIG. SCIG can be given in two ways: conventional or facilitated. The facilitated method uses an additional enzyme medication to increase the amount of Ig that can be delivered during each subcutaneous infusion. 

Currently, among those receiving Ig replacement therapy in the U.S., approximately 50% use IVIG and 50% use SCIG. The individual with PI and their healthcare provider should have a discussion about which route of administration is most appropriate for the individual. There are advantages and disadvantages for each but all options are clinically effective. 

IVIG allows the infusion of higher doses over a short time, but it must be administered by a healthcare professional. SCIG does not require venous access and results in the slow release of Ig from the subcutaneous tissues into the blood, which enables IgG levels to remain more consistent between infusions. With SCIG, there is a steady level of IgG present in the bloodstream due to a more frequent dosing regimen and a slower rate of absorption. With IVIG, the dosing at longer intervals may cause peaks and valleys, called troughs. 

Many practical considerations need to be taken into account when deciding if IVIG or SCIG is the right choice. Because IVIG requires healthcare provider supervision, IVIG used to require travel to outpatient settings. However, more insurance companies, as well as Medicare, now cover the supplies and services needed for home IVIG.

SCIG provides the freedom to administer Ig at home or anywhere else at any time of day because medical supervision is not required. While this flexibility and control have been shown to enhance many individuals’ quality of life, the ability of the individual to adhere to the treatment regimen is an important consideration for SCIG since there are no fixed appointments.

In addition, fear of needles and poor manual dexterity, or an inability to make coordinated hand and finger movements to manipulate objects, can be limiting factors for SCIG. For fear of needles, strategies like using topical numbing creams can help. Manual dexterity is required for SCIG in order to draw up the Ig and manage the pump. IVIG requires less frequent infusions and only one infusion site, which is established by the administering healthcare provider.

SCIG is associated with a lower rate of systemic side effects, making this route of administration a good option for those experiencing unwanted adverse effects from IVIG. Also, administration of more frequent, smaller volumes provides a steady level of Ig, avoiding high peak levels that may be associated with side effects of IVIG, such as headaches, and symptoms of wear-off. College students and those whose jobs require frequent travel should seriously consider SCIG. 

The following are considerations for choosing SCIG over IVIG:

• Extreme prematurity (mainly infants born before 30 weeks).
• DiGeorge (22q11.2 deletion) syndrome.
• Jacobsen syndrome.

Insurance considerations

Use of immunoglobulin replacement therapy typically requires your healthcare provider to get prior authorization from your health insurance company. 

In addition, the Centers for Medicare and Medicaid Services (CMS) has indicated that only certain ICD-10 diagnostic codes for primary immunodeficiency (PI) warrant immunoglobulin replacement therapy under Medicare Part B. Other diagnostic codes may be covered under Medicare Part D. Adapted from CMS.

Subcutaneous immunoglobin (SCIG) replacement therapy

Subcutaneous immunoglobulin replacement therapy (SCIG) has gained popularity in the U.S. since the approval of the first SCIG Ig product in 2006. Currently, there are several products available that can be administered subcutaneously using a number of regimens. These products differ based on concentration, stabilizers, and infusion specifics.

In general, SCIG regimens require the individual with PI or a caregiver to learn how to administer infusions at home. Both forms of SCIG allow for self-administration at home, but facilitated SCIG may also be administered at home or in-office by a nurse, depending on insurance coverage and preference.

The following are currently available for subcutaneous use: 10%, 16.5%, and 20% IgG preparations for conventional SCIG, and a 10% IgG preparation plus an enzyme called hyaluronidase for facilitated SCIG. The Ig is infused under the skin, into the subcutaneous layer of the abdomen, thighs, or outer buttocks at one or multiple sites, depending on the volume being infused. The total monthly dose is calculated by the prescriber based on the individual’s weight, then divided according to the interval between infusions. The number of needle sticks (infusion sites) is also calculated for the individual depending on the volume and the concentration of Ig to be infused. Larger intervals between infusions require the infusion of larger volumes of product to achieve the same total dose per month. 

In general, SCIG is delivered using a small needle attached to tubing and a syringe, which is placed in a pump. The Ig products come in a variety of vial sizes depending on the manufacturer. Several needle and tubing sizes are available, and troubleshooting problems with SCIG often involves reviewing that the equipment being used, such as needle sets, tubing, and pump, are appropriate for the individual receiving the therapy.

Conventional SCIG can be given daily, weekly, every two weeks, or multiple times per week, as long as the total monthly dose is divided appropriately. Some individuals may prefer or better tolerate SCIG delivered by subcutaneous push instead of a pump, meaning that a small amount of SCIG is injected daily under the skin without the use of a pump. 

Facilitated SCIG is given every 3-4 weeks to deliver the total monthly dose at once into the subcutaneous space. This is facilitated by hyaluronidase, a naturally occurring enzyme in the subcutaneous tissues. Hyaluronidase is injected into the subcutaneous space before the Ig to expand the space and allow more medication to be infused into each site. The effects of the hyaluronidase enzyme are very short-lived, and the tissues revert back to normal in 24-48 hours. In facilitated SCIG, about 300-600ml can be delivered in one site or divided into two or more sites as tolerated.

The benefit of facilitated SCIG is a decrease in the frequency of infusions, as it allows for an entire 3-4 week dose to be administered at one time. The length of the infusion varies depending on the volume infused, but generally takes up to 1-2 hours.

As in IVIG, the typical starting dose for SCIG is between 400-600mg/kg/month. The prescriber adjusts the dose to clinical effect, with the expectation of minimizing the frequency and severity of recurrent infections. IgG levels are monitored over time, correlated with clinical outcomes, and the dose is adjusted as necessary. With conventional SCIG, there is a steady level of IgG present in the bloodstream (no peaks or troughs like IVIG) because of the more frequent infusions. With facilitated SCIG, there are peak and trough levels, but the peak levels are not as high and the trough levels are not as low as with IVIG.

Side effects of SCIG 

In general, SCIG is associated with fewer side effects than IVIG. SCIG is an option to consider when an individual does not tolerate IVIG well, when there is poor venous access, or when the individual’s lifestyle is more compatible with SCIG than IVIG. SCIG is an option for children, adults, pregnant women, the elderly, and for individuals with IgA deficiency secondary to having antibodies against IgA (very rare). 

Pre-medication is usually not required for SCIG and systemic side effects are typically mild. Severe reactions rarely occur, but individuals who have had severe reactions to IVIG may be at a higher risk of severe reactions to SCIG. 

The most common side effect of SCIG is local redness, swelling, and irritation at the injection site. Usually, these mild localized reactions improve with repeated infusions. In rare cases, the injection site reactions can be severe. To improve or avoid the infusion site reactions, and decrease the chance of other problems, individuals need thorough training to ensure they use proper technique to access the subcutaneous tissue. Local skin reactions may be due to inadequate needle length preventing the Ig from being infused into the subcutaneous tissue. For those with a fear of needles, a topical numbing medicine or ice can be applied to the skin prior to infusion.

The individual with PI or a caregiver should report all side effects and any discomfort experienced during or after an infusion of SCIG to the prescriber, the healthcare professional administering the therapy, the product's manufacturer, and MedWatch at the Food and Drug Administration (FDA). 

Optimizing the SCIG infusion experience 

Several SCIG variables allow individuals to optimize their infusion experience, including the number and location of infusion sites, the volume infused per site, needle length, and pump type. The number of needle sticks can be reduced by increasing the volume infused per site or using the more concentrated 16.5% or 20% IgG products. Conversely, more sites may be needed when using less concentrated 10% IgG products. With facilitated SCIG, the dose can be divided between 1-2 sites, depending on how the infusion is tolerated. 

If the individual is experiencing discomfort using abdominal infusion sites, other sites such as the thighs can be used. For those who have issues tolerating infusions, smaller volumes of SCIG daily may be needed. Several needle lengths are also available; the important thing is to use a needle long enough to ensure that the Ig is being administered into the subcutaneous tissues rather than the skin. A variety of infusion pumps are available ranging from simple, portable mechanical pumps to more complicated programmable pumps. Most importantly, SCIG can provide freedom of scheduling for those who self-infuse, resulting in fewer school and workday losses.