No Place Like Home: The Growing Acceptance of Subcutaneous Immune Globulin

PRIOR TO THE approval of the first licensed intravenous immune globulin (IVIG) product in 1981, IgG replacement therapy for patients with primary humoral immunodeficiency disorders (PI) was a painful and wholly inadequate ordeal. Patients had to bear frequent small intramuscular injections of 16.5% immune serum globulin (IMIG), a product whose IgG clumps and fragments caused severe anaphylactic reactions if given by the intravenous route. Poor tolerability to these repeated injections typically limited IMIG dosage, which translated into subprotective steady-state serum IgG levels and often serious recurrent bacterial infections.

Shortly before IVIG was introduced, clinicians at the National Institutes of Health (NIH) reported on their experience with yet a third approach — subcutaneous infusion of IMIG — to treat a 24-year-old woman hospitalized with cellulitis, fever and a history of sinusitis, otitis media, sepsis and pneumonia. Multiple IMIG injections to the woman’s tolerable limit had brought her serum IgG level up to only 270 mg/dL, well below the protective range. The NIH team decided to train her to self-administer small volumes of IMIG subcutaneously on a daily basis, and her sepsis and sinopulmonary infection entirely resolved. She continued her daily self-infusions through a normal full-term pregnancy, even boosting her dose without incident to maintain a protective IgG level.¹ Other patients were started on subcutaneous replacement therapy with IMIG.

The new intravenous preparations enabled patients to receive their IG replacement therapy with a single clinic visit every three weeks to four weeks, ending interest in experimentation with subcutaneous IMIG delivery. But experience has revealed that IVIG treatment can come with its own downsides:

• Systemic adverse reactions.These most commonly include headache, chills, flulike symptoms, low-grade fever, urticaria, fatigue, nausea, lightheadedness, myalgia and arthralgia. Rarely, IVIG administration can result in serious adverse events that include thrombosis, renal dysfunction or failure, anaphylaxis, aseptic meningitis and hemolytic anemia.
• Low IgG trough levels. While a function of dose and serum half-life, IgG trough levels in the days leading up to the next scheduled IVIG infusion can potentially drop below the fully protective range.
• Vascular access challenges. In a small percentage of children and older adults in particular, reliably obtaining venous access for the infusion is problematic, necessitating placement of an infusion port. Unfortunately use of these devices is accompanied by risks of infection and thrombus formation.
• Lost school/work days. Depending on infusion time, each scheduled infusion visit requires the patient to be absent from school or work for a half day or longer.

In addition, many PI patients who will require IVIG replacement therapy over their lifetimes voice an entirely different kind of concern: the loss of autonomy or the “medicalization” of their disorder that arises from the need, every few weeks, to undergo an hours-long, nurse-supervised drug infusion procedure.

As early as the 1980s and 1990s, European investigators began to experiment with switching PI patients from IVIG to subcutaneous IG delivery.^2,3,4 Most documented strong patient preference for SCIG, with many citing flexibility of treatment timing and independence from the need to take time away for visits to the infusion clinic. Insulin-dependent diabetics safely self-administer their drug by subcutaneous injection or through an insulin pump. Could chronic IG therapy similarly be self-infused by patients or caregivers at home? For both adults and children with PI, the answer turned out to be “yes.”

In 2006, the first IG product specifically formulated for subcutaneous administration — CSL Behring’s 16% Vivaglobin — was approved in the U.S. A few years later, Vivaglobin was replaced by Hizentra, whose 20% concentration translated into a modestly lower infused volume requirement. Over the ensuing decade, a number of other subcutaneous immune globulin (SCIG) products have followed (Table).* Using a mechanical or electrically-powered syringe pump, patients can now skip the regular infusion clinic visits and instead self-infuse their product at home biweekly, weekly or multiple times per week, working together with their home infusion provider to customize their regimen to adapt to their individual needs and preferences.

Numerous IVIG-to-SCIG crossover studies have reported that the large majority of adult and pediatric PI patients elect to make a permanent switch to SCIG.^5,6 These are some of the most commonly cited reasons:

• “I can schedule my SCIG treatments at my own convenience.”
• “With SCIG, I don’t experience as many unpleasant reactions.”
• “I don’t have to miss work (or my child doesn’t have to miss school).”
• “I’m not reminded on a regular basis anymore that I have this genetic disease.”

Some patients on IVIG replacement therapy report a sense of malaise over the days leading up to their next infusion as the serum IgG level approaches its deepest trough level. But because smaller doses of SCIG are infused more frequently, IgG serum levels remain more stable, and trough levels don’t drop nearly as low as occurs with IVIG. Patients who experience these “rebound” symptoms prior to receiving their next monthly IVIG dose report this problem usually disappears when they switch to SCIG therapy.

But PI patients who participated in crossover studies aren’t necessarily a representative sample of the entire population on IG therapy. After all, each agreed to switch their IG therapy to SCIG in the first place, and to respond multiple times to a battery of questions about their comparative treatment experience. Is SCIG really well accepted by most patients either previously treated with IVIG or just starting out on IG therapy?

I posed this question to Leslie Vaughan, RPh, chief operations officer at Nufactor, a Specialty Pharmacy. Vaughan brings a perspective shaped by her nearly 30 years of experience in IG home infusion therapy. “Many patients, or parents of young children, understandably have some trepidation at the beginning,” she said. “They wonder, ‘Am I going to be able to do this?’ But we’ve consistently found that with education, training and support, most do fine and quickly become very comfortable with self-infusion.”

“Most patients or caregivers can become independent with SCIG administration within three visits,” added Nufactor Clinical Nurse Educator Candy Finley, RN, IgCN. “On the first training visit, the nurse completes the infusion while explaining each step,” Finley explained. “The patient or caregiver completes each step on the second visit, with nurse assistance as necessary. Usually by the third visit, the nurse can observe and confirm that the patient is performing all steps correctly.”

Still, Vaughan pointed out that SCIG therapy is not for everyone: “Adults with very little body fat may not be good candidates. And for some patients with vision or dexterity issues, managing procedure set-up and needle insertion steps can be a problem.”

“For any patient starting or trialing SCIG therapy,” she added, “it’s important to individualize treatment. One patient may prefer to self-administer relatively large volumes of SCIG in each of a number of infusion sites in order to reduce the number of infusion sessions per week or month. Another patient may be more comfortable with placing a single needle and infusing less into that single site.” In other words, the flexibility of SCIG dosing strategy permits customization to accommodate each patient’s preferences and limitations, while still delivering the prescribed monthly gram dose of IgG.

The Benefits of Divided SCIG Dosing

For patients on maintenance IG therapy, IVIG administration every three weeks to four weeks results in immediate (within six hours) or delayed systemic adverse reactions in 5 percent to 15 percent of infusions, affecting as many as 20 percent to 40 percent of all patients.⁷ Prehydration, premedication, slowing the infusion rate and switching to a different IVIG brand are all employed to try to avoid or at least minimize the acuity of these unpleasant systemic reactions, but the very high IgG serum concentration peak within minutes of direct IV infusion of IgG makes them all but inevitable for some patients.

By contrast, regular subcutaneous administration of IG acts in not one but two ways to moderate the peak serum level and minimize risk of nonserious systemic reactions, as well as potentially serious systemic complications, including renal insufficiency, hemolysis and, in rare instances, thrombosis and anaphylactoid reactions:⁸

• SCIG therapy delivers a similar quantity of IgG as IVIG over a specified time period, but in smaller (or as desired much smaller) divided doses; for example, common once- or twice-weekly SCIG infusion schedules respectively split a monthly IVIG dose into three or six much smaller doses.
• Following infusion, large IgG proteins slowly transit through the lymphatic system, so the serum IgG level peaks (at a far lower concentration than with IV infusion) between two days and four days later.

SCIG administration, with its slow delivery of IgG into the circulation in small divided doses, predictably results in very low systemic reaction rates. Across five published case series evaluating SCIG therapy in PI patients, reported rates of systemic adverse reactions ranged between zero and less than one percent.⁹ In the largest of these studies, which monitored more than 33,000 SCIG infusions in 158 patients, the systemic adverse reaction rate was just 0.3 percent, including 100 mild and six moderate adverse events in 28 patients, with no anaphylactoid or other severe systemic reactions.¹⁰

Unsurprisingly, most patients who self-infuse SCIG don’t require premedication to limit systemic side effects. But there is a trade-off: more local injection site reactions, which tend to moderate or largely resolve over time.

SCIG Usage for Autoimmune Neuromuscular Disorders Skyrockets

Over the last several years, Nufactor’s home infusion therapy program has seen well over 15 percent annual growth in numbers of PI patients self-administering SCIG. But the story of successful patient adoption of SCIG doesn’t stop there. Beginning in the 1990s, numerous patient case series, as well as placebo-controlled trials, have established the efficacy and safety of IVIG for several autoimmune neuromuscular disorders, in particular chronic inflammatory demyelinating polyneuropathy (CIDP), multifocal motor neuropathy (MMN) and myasthenia gravis (MG).^11,12,13 Collectively, these three conditions now account for well over one-third of U.S. demand for polyclonal IG products. This is partly because many CIDP, MMN and MG patients who respond to IG require ongoing maintenance IG therapy, and partly because that maintenance dose (typically 1 g/kg every three weeks to four weeks) exceeds the average PI dose by more than two-fold.

But while newly diagnosed hypogammaglobulinemic PI patients and their physicians can elect to start right away with SCIG replacement therapy in lieu of IVIG, this is not the case for patients prescribed IG therapy for their autoimmune neuropathy. CIDP is a good example. Because only roughly one-half of patients adequately respond to IG therapy,¹⁴ clinicians start with a trial of IVIG to determine whether it results in improvement in their disability score. If it does, and ongoing maintenance treatment is required to sustain the therapeutic benefit, SCIG may be considered as an option for patients who qualify.

Similar to the experience with PI, small divided SCIG doses and slow lymphatic transit also appears to sharply reduce both the number and severity of the systemic reactions in patients with inflammatory neuropathies on high-dose IG therapy. Two of its most common side effects — headache and nausea — were examined by Danish investigators in 59 patients with CIDP, MMN or post-polio syndrome treated with IVIG, and 27 CIDP and MMN patients treated with SCIG. In the SCIG group, headache reached a median peak value of just 1 (range 0 to 13 on a 0-to-100 visual analog scale) on day six, versus a median peak value of 11 (range 0 to 96) in the IVIG group on day four. A similar dichotomy was seen with reported nausea, again favoring SCIG. Just as importantly, the peak severity experienced by any patient was also far lower in the SCIG group.¹⁵

The same advantages that have made SCIG so popular within the PI patient community equally apply for patients prescribed maintenance IG therapy for their neurological disorder. Between 2015 and 2019, Nufactor’s neurological disease patient population on maintenance SCIG therapy has climbed 70 percent annually. The company appears to be on track for similar growth in 2020.

An Option to Consider Amid the COVID-19 Pandemic

As the COVID-19 pandemic continues, patients with risk factors for severe COVID-19 disease are, in particular, being encouraged to minimize their exposure to others in the community. PI patients obviously qualify, as do many autoimmune neurological patients on IG therapy because of age, comorbid conditions or concomitant immune suppressive medications such as rituximab, azathioprine or methotrexate.

Home SCIG therapy thus others yet one more very real advantage over regular clinic visits for an IVIG infusion: a means to minimize risk of COVID-19 exposure risk. As some infectious disease epidemiologists are now suggesting that it may be years before the COVID-19 outbreak is completely behind us, there may be no better time for clinicians who prescribe maintenance IG to take a fresh look at which of their patients might be appropriate for SCIG therapy.

* Among these is Takeda’s HyQvia, an innovative “facilitated” SCIG (fSCIG) product that incorporates pre-administered recombinant hyaluronidase to increase tissue permeability, permit very large volumes to be infused into just one or two sites, and reduce dosing to once every three or four weeks. In addition, two 10% IVIG products, Gamunex-C (Grifols) and Gammagard Liquid (Takeda), are also approved for subcutaneous administration to treat PI.