More Than Medicine: The Hope, Hurdles, and Hidden Costs of IgG Therapy

Human immunoglobulin (Ig) G replacement therapy (IgG-RT), the product of pooled plasma from hundreds of healthy donors, reduces infection rates and associated mortality in patients with primary immunodeficiencies. Beyond primary immunodeficiencies, IgG possesses immunomodulatory abilities that have expanded its use to treat various hematologic and autoimmune diseases. First approved for inborn errors of immunity like X-linked agammaglobulinemia, then autoimmune and other inflammatory conditions like Kawasaki disease, Guillain–Barré syndrome, and in recent years, dermatomyositis, the indications for IgG therapy continue to expand. In the recent review published in the Journal of Immunotherapy and Precision Oncology, Jibran Ahmed and colleagues provide a concise update on the clinical indications for IgG therapy and summarizes the proposed mechanism of action, serving as a clinical reference for practicing physicians (1).

As a treatment for primary immunodeficiency, the utility of immunoglobulin in patients who lack humoral immunity is relatively straightforward; supply what the body does not make on its own. Pediatricians often make these diagnoses when their patients present with recurrent, severe infections. Treatment guidelines on initiating and dosing IgG-RT in this population are well established. Recently in the spotlight, secondary hypogammaglobulinemia has emerged as a complication of both established diseases and novel treatments.

Ahmed et al.’s [1] review aptly highlights this phenomenon, specifically with hematologic conditions and their associated therapeutics: multiple myeloma, chronic lymphocytic leukemia, and B-cell–targeted therapies such as rituximab-induced hypogammaglobulinemia.[2] Considering the patient population, multiple studies cited within the review showed benefit for IgG-RT in patients with severe infection and hypogammaglobulinemia. What is less clear is whether to prophylactically treat patients with very low levels of IgG who are not infected, because 3.5–40% of adult patients and up to 50% of pediatric patients developed rituximab-induced hypogammaglobulinemia, but not all suffered from serious infections. Less than half of these patients ultimately developed severe infections, and it is challenging to determine whether these infections are directly caused by rituximab-mediated processes or inherent immune dysregulation secondary to the underlying disease.[3] As with primary immunodeficiency, IgG-RT in secondary immunodeficiency decreases the risk of serious infection but appears to only minimally reduce the rate of non–life-threatening infections, such as recurrent upper respiratory infections.[4] Interestingly, patients with secondary immunodeficiency often become IgA deficient, suggesting further defects from B-cell depletion or with limited immunoglobulin class switching. It is unclear whether IgG-RT would lower the increased incidence of mild or moderate mucosal membrane infections in IgA deficiency.

The efficacy of IgG-RT for primary and secondary immunodeficiency relies on the collective immunologic experience of the plasma donor population, with preparations containing antibodies against many clinically relevant pathogens.[4] For autoimmune and other inflammatory conditions, the mechanism of action is more nuanced and appears to be independent of the donor’s exposure. Considering the multifaceted mechanism of IgG, donor immunoglobulin influences various immune cells and pathways, as nicely summarized by Ahmed et al,[2] specifically decreasing cytokine production, saturating Fc receptors, and inhibiting complement activation. Furthermore, immunoglobulins have been shown to decrease T-cell activation, reduce B-cell proliferation, and alter host antibody production. In the setting of using intravenous IgG (IVIG) as the steroid-sparing immunomodulatory therapy for autoimmune diseases, tachyphylaxis can occur, especially in the treatment of myositis.[5] Tachyphylaxis is a phenomenon in which the initial beneficial effects of IVIG diminish over time despite continued infusions. The mechanism of tachyphylaxis is not completely understood but is likely related to how the immune system responds to the therapy. Methods that ameliorate this phenomenon include adequate hydration and slower infusions but often require increased dosing to achieve the desired efficacy.

IgG therapy continues to expand with new indications for the treatment of serious immune checkpoint inhibitor–associated toxicities. With varying success, the use of IgG is often based on expert recommendations derived from similar presentations of classic autoimmune and inflammatory diseases. Evidence-based guidelines derived from placebo-controlled clinical trials on the initiation, dosing, duration, and efficacy for each specific indication are needed.

Although IgG therapy is effective and generally safe, its use can still be associated with adverse effects. Clinicians administering the therapy should keep in mind the patient’s underlying condition, mode of delivery, and preparation of IgG. In the setting of IgG-RT for immunodeficiency, its use is lifelong. Similarly, autoimmune diseases can be put into remission but are unlikely to be cured, and regular administration of IVIG is expected. The psychological effects of such dependency must be considered. Although some data suggest that depression, anxiety, and fatigue related to autoimmune neurologic diseases decreased with IVIG treatment, others continued to report mental health concerns.[6] For patients who require lifelong IVIG, we cannot ignore barriers to accessing care, including those who must travel far distances or are unable to travel, the frustration associated with the regular lifestyle demands of long infusions, and the profound sense of dependency on a medication. These obstacles directly influence patient compliance and subsequent clinical outcomes. In addition, with the uncertainty of the health care environment and possible disruptions of IgG supply or reimbursement, patients may face additional psychological distress. Addressing these issues during IVIG initiation and helping patients cope with the psychological challenges are crucial.

Because immunoglobulin must be produced from human donors, it cannot be synthetically mass produced and thus can become prohibitively costly. As IgG demand continues to grow globally, there are serious concerns about supply shortages and questions about how future demands will be met.[7,8] A recent study surveyed 14 institutions from five developed countries and reported that more than 60% experienced IgG supply shortages, and mitigation strategies were not well established.[9] As an example of a successful mitigation strategy, reduced dose subcutaneous IgG (SCIG) in select patients with well-controlled humoral primary immunodeficiency did not result in increased infection rates.[10] For other IVIG indications, we encourage a collaborative effort with national and international registries to gather data on patient-specific clinical features, use of IgG therapies, dosing, and route of administration, with documented clinical outcomes to provide guidelines that optimize the utility of a scarce resource. In addition, translational studies investigating predictive biomarkers would assist clinicians with patient selection. Ultimately, the goal is to build the fundamental research necessary to design large-scale prospective studies that could guide precision medicine for IVIG administration.

The cost disadvantage of IgG therapy compared to alternative therapies, including plasma exchange (PLEX) for neurological diseases, has been well documented.[11] IVIG has traditionally been the preferred treatment option owing to its ease of use. However, advancing technology now allows PLEX to be performed with a centrifugal system via peripheral access, as opposed to central access via a membrane filter, and has significantly reduced the treatment complexity and associated cost to nearly half that of IVIG.[11] Beyond economic incentive, the frequency and severity of adverse events are similar for both modalities, despite their different mechanisms. Further studies are needed to compare the efficacy and cost-effectiveness of PLEX versus IVIG versus SCIG for various diseases.

In conclusion, indications for IgG either as replacement or immune modulation continue to expand. Thus, it has become increasingly important for clinicians to recognize the utility of IgG therapy, its psychosocial burden to patients, and the global socioeconomic challenge to the health care system. Today, the concept of rational personalized clinical use of IVIG in the context of expanding clinical indications in high-income countries is juxtaposed against supply shortages due to increasing demands globally. Further clinical and translational research on biomarkers predicting clinical response, improving IgG production with possible chemical modifications for increased efficacy, and evidence-based national health policy are all needed. The hope is that this will then expand the accessibility, affordability, efficacy, and treatment of this exciting and evolving therapy.