Background: Intravenous immunoglobulin and subcutaneous immunoglobulin preparations are used to treat primary and secondary immunodeficiencies, as well as autoimmune and inflammatory conditions. Summary: For certain indications, only defined formulations or routes of administration are approved by health authorities. However, for other diseases, there are more options, and treatment decisions may be based on different aspects, such as patient conditions and preferences, pharmacokinetics, or pharmacoeconomic considerations. Key Messages: Understanding the two different treatment modalities may support the decision-making for the optimal therapeutic option for individual patients. This review summarizes the latest insights into the direct and indirect comparison between the two types of products.

For decades, polyclonal immunoglobulin (Ig) preparations have been used to treat a variety of different diseases [1]. Originally developed to substitute insufficient IgG levels in patients with primary or acquired antibody deficiencies, intravenous immunoglobulin (IVIG) preparations are increasingly used to treat inflammatory disorders such as Kawasaki disease [2], multifocal motor neuropathy [3], chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), and many more [4].

The modes of action of polyclonal Ig preparations are broad and heterogeneous, and diverse mechanisms are likely at play amid therapeutic use for substitution therapy or immunomodulation in different autoimmune and inflammatory settings [5]. Schneider et al. [6] investigated various immunoglobulin preparations and showed that these preparations include antibodies pooled from several thousand healthy donors and therefore reflect the antibody repertoires of the donor populations. In the substitution therapy, the modes of action comprise the recognition and subsequent elimination of pathogens and potentially the blockade of microbial attachments sites [6]. Ig preparations may compensate not only for quantitative but also specific qualitative deficiencies observed in primary antibody deficiencies [7] and thereby augment antimicrobial defense but eventually also restore tissue homeostasis and influence other immunodeficiency-related sequelae including autoimmunity or tumorigenesis. Notably, levels of naturally occurring tumor-specific antibodies were found to be reduced in the sera of subsets of immunodeficient patients at increased risk of malignancies [7]. The mechanisms of action of autoimmune diseases and inflammation remain only partially understood [8], eventually also due to certain limitations of animal models [9, 10]. The range of proposed mechanisms is broad, ranging from F(ab)’2-mediated effects involving the suppression or neutralization of inflammatory cytokines, autoantibodies, and regulation of leukocyte function and survival [11, 12], to Fc-mediated effects such as neonatal Fc receptor (FcRn) saturation [5]. A better understanding of these mechanisms might allow enhancing the therapeutic potential of immunoglobulins or their derivatives [1, 13, 14].

In the last years, subcutaneous immunoglobulins (SCIGs) have been increasingly used for the treatment of primary and secondary immunodeficiencies as well as selected autoimmune disorders [15‒18]. In this article, we highlighted recent aspects of pharmacokinetics, patient preference, and pharmacoeconomics, the consideration of which might facilitate informed decision-making on the therapeutic use of various IVIG or SCIG preparations.

Historical Milestones

The therapeutic use of polyclonal antibodies was first introduced in 1952 by the US physician Col. Ogden Bruton who treated a boy with agammaglobulinemia and severe recurrent infections [19]. Since the eighties, the intravenous application of polyclonal IgG as IVIG treatment has been the most common way of administration in many countries, both as replacement therapy or for the treatment of autoimmune and inflammatory conditions [1, 20]. For subcutaneous administration of IgG, portable syringe drivers were introduced in the USA in 1980 [21], followed by its use in other countries including New Zealand and parts of Europe, but due to the slow subcutaneous application of voluminous immunoglobulin preparation, SCIG did not become widely popular [22]. In 1991, however, rapid infusion methods were introduced (20 mL/h/pump) in Scandinavian countries and the use of SCIG has since become a common practice [23].

Pharmacokinetic Aspects

In the sixties, Waldman et al. [24] showed that the catabolism of IgG differs compared to other isotypes as its turnover is slower and proportional to the serum concentration. In human plasma, IgG has an average half-life of 21 days [25], which depends on a pH-dependent recycling mechanism involving the FcRn [26]. Indeed, contrarily to many serum proteins that are internalized by endothelial cells and subsequently eliminated by lysosomal degradation, IgG upon binding to the FcRn is recycled and released into the circulation (Fig. 1). The FcRn protects IgG from degradation mainly at the vascular endothelium, but it is also expressed by several tissues and organs [27].

Fig. 1.

Recycle mechanism of IgG, mediated by the neonatal receptor FcRn.

Fig. 1.

Recycle mechanism of IgG, mediated by the neonatal receptor FcRn.

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The intravenous administration of high IgG quantities (up to 2 g/kg body weight) results in high peak levels in the plasma (30–50 g/L IgG) with a rapid decline within the first 48–72 h [4, 28] (Fig. 2), which might be explained by FcRn saturation effects [27]. Indeed, it has been shown that the half-life of IgG at serum concentrations of 30 g/L is reduced to 11 days [28]. Therapeutic benefits in inflammatory disorders are explained by high IgG peaks following infusion, which could contribute to the fast onset of action [4]. On the other hand, high IgG concentrations might be associated with adverse events (AEs) such as headache or fever [4, 29]. Toward the end of a treatment cycle, which usually takes 3–4 weeks, the plasma IgG concentration can drop significantly to similar levels to pre infusion, which is called trough level [4].

Fig. 2.

Serum IgG level after IVIG and SCIG administration. Serum IgG depicted as a result of the treatment of a PID patient with 30 g IVIG (every 3 weeks) or 36 g SCIG, distributed to three doses, once weekly. The red hatched area represents serum levels with potential wear-off effects.

Fig. 2.

Serum IgG level after IVIG and SCIG administration. Serum IgG depicted as a result of the treatment of a PID patient with 30 g IVIG (every 3 weeks) or 36 g SCIG, distributed to three doses, once weekly. The red hatched area represents serum levels with potential wear-off effects.

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Subcutaneously administered Ig first reach the lymphatic system before entering the blood circulation, resulting in decreased absorption rate and initial bioavailability compared to IVIG. Reduced bioavailability of SCIG has not been demonstrated to be dependent on production method or concentration [30, 31]. Peak serum levels are reached after 36–72 h in patients receiving SCIG at which IgG concentrations augment to approximately 60% compared to peaks achieved with IVIG [32]. The lower peak levels of SCIG might be attributed to the binding of IgG to constituents of the extracellular matrix or degradation by extracellular proteases [30]. The more frequent subcutaneous administration of smaller Ig doses results in higher trough levels compared to the intravenous application of larger volumes of IVIG [16, 33]. Indeed, trough levels of SCIG are up to 20% higher than the trough levels of IVIG, when considering dose-equivalent administration of once-weekly SCIG or IVIG administered every 21–28 days [34]. Furthermore, the differences between maximal and minimal serum IgG concentrations often do not exceed 10% for SCIG [34]. Even when it is not clear how important is the steady-state IgG serum levels reached with the subcutaneous route compared with the high peaks obtained with IVIG, there are some data suggesting that high IgG levels can help to a faster clinical stability, while the stable trough levels are important for the maintenance and the reduction of AEs [35]. More studies are required to confirm these results.

Efficacy and Safety of SCIG and IVIG Preparations

Clinical trials have shown efficacy and safety of antibody replacement therapy with IVIG in immunodeficient patients as well as of immunomodulatory therapy in autoimmune or inflammatory conditions [36‒41]. Most frequently observed AEs were headache, pyrexia, flu-like symptoms, and nausea/vomiting [36, 37, 42‒48]. Several of these AEs during IVIG therapy seem to be dependent on the infusion speed [48, 49] and can potentially be mitigated by ensuring adequate hydration of the patient [48].

SCIG has been evaluated in patients with primary immunodeficiency diseases (PID), CIDP [50‒56], myositis [57, 58], small fiber neuropathy related to Sjögren’s syndrome [59], MMN [60], and epidermolysis bullosa [61] as both induction and maintenance treatment. In all these studies, SCIG was safe and the main AEs were associated with mild and self-limiting local reactions at the site of administration such as pain, edema, swelling among others as a result of relatively high injection volumes [17, 41, 62]. The delayed increase of serum IgG concentration after SCIG infusion might explain the lower rate of systemic AEs observed with the subcutaneous treatment compared with the intravenous administration [62‒64] (Table 1 ).

Table 1.

Characteristics of IVIG and SCIG

 Characteristics of IVIG and SCIG
 Characteristics of IVIG and SCIG

However, in the absence of head-to-head comparison, it is not possible to directly compare intravenous or subcutaneous treatment strategies. In a systemic review and meta-analysis considering various IVIG and SCIG preparations from different manufacturers, no significant difference in overall infections or serious infections with IVIG versus SCIG was detected in patients with PID [65]. Furthermore, two studies comparing five different IVIGs and SCIGs evidenced comparable efficacy in patients with CIDP [66, 67]. The PATH-trial, the largest trial on SCIG treatment in CIDP, evaluated the safety and efficacy of SCIG in 172 patients [62]. Despite the lack of direct comparison to IVIG, the study protocol allowed an indirect comparison of the two treatments. Only patients who responded to IVIG treatment were included in the study and randomly allocated to different SCIG doses or to placebo for a treatment duration of 24 weeks. The clinical evaluation under this pretreatment was considered as baseline. The primary outcome reflected a worsening of the clinical assessment (INCAT-Score) versus baseline. As this assessment did not change between baseline and SCIG treatment, the authors of the study concluded that SCIG offers comparable efficacy to IVIG in the treatment of CIDP [62]. Furthermore, the European Academy of Neurology/Peripheral Nerve Society guideline strongly recommends both IVIG and SCIG as a maintenance treatment in CIDP with no preference but implies that dose adjustment should be done during the follow-up [68].

Wear-off effects, also referred to as end-of-cycle loss of efficacy [69], have been described for IVIG substitution as well as for immunomodulation therapies (Fig. 2). Trough levels of IVIG therapies at the end of a treatment cycle might potentially be too low to achieve optimal therapeutic effects, thereby leading to a loss of treatment efficacy [28, 70]. Due to the stable serum IgG levels during SCIG treatment, it can be speculated that the risk of such wear-off effects can be diminished when switching a patient from IVIG to SCIG [4, 28, 70].

Patient Preference and Quality of Life

Despite clinical benefits of IVIG or SCIG therapies, the need for repetitive infusion treatments, eventually in the setting of clinical visits can negatively impact the quality of life (QoL) of patients [71‒73]. For patients who successfully manage home-based administration of SCIG, the gain of flexibility and autonomy might add value and increase their QoL [71, 74‒76]. In a conjoint survey including 252 adult patients and 66 parents of children with PID, both groups preferred a home setting, monthly frequency, fewer needle sticks, and shorter treatment durations of IG treatment relative to alternative choices (p < 0.05) [77]. Despite the more frequent administration of SCIG, ranging from biweekly to daily depending on patient needs [78], reports assessing two different SCIG and two different IVIG products suggest that patients favor SCIG over IVIG treatment [62, 71], also in light of independence and less side effects [62].

Of note, the self-administration or administration of SCIG by a caregiver requires training by health care professionals, a high degree of independence, and high compliance to the treatment schedule [70, 72]. Poor parental supervision for younger patients, attention-deficit disorders, or low compliance in general might be exclusion criteria for the SCIG treatment option. The assessment of such exclusion criteria may be difficult, but in these cases, treatment with IVIG may be preferred [75]. Home IVIG administration has been also used by some patients as a maintenance treatment [79]. However, this modality cannot be self-administrated and has to be done by a trained person leading to less autonomy.

Various experts therefore suggest to proactively discuss the treatment options with the patients [70, 75]. The patient preference is often dependent on their priorities and doubts. Jolles et al. argue that patients who decide for home-based SCIG treatment are in general also willing to complete the adequate training and take the responsibility for the treatment [70]. In any case, it will be crucial to discuss the advantages and the disadvantages of both, SCIG and IVIG, with patients and caregivers. A patient-tailored approach to therapy with immunoglobulin preparations including the choice of the route of application is crucial to ensure patient adherence and maximizing treatment outcome.

Pharmacoeconomic Aspects

Pharmacoeconomic analysis much depends on local price levels and idiosyncratic characteristics of health systems. However, costs beyond treatment expenses should be considered including indirect costs for nursing, travel, patient-training, or loss of productivity [80‒82]. In a recent 3-year cost-minimization analysis for PID patients performed by Perraudin et al. [81] in Switzerland, hospital-based IVIG treatment was compared to home-based SCIG treatment with a interprofessional team consisting of training sessions, feedback to physicians, and once yearly follow-ups (administration under supervision), comparing one IVIG product to one SCIG product from the same manufacturer. Assessed costs included direct costs such as for medication and ancillaries, hospital overheads or nursing, as well as indirect costs including transportation costs or loss of patient’s productivity due to the absence from work when receiving the Ig treatment. Due to the high training and nursing investments during the first year of SCIG treatment, the total costs of IVIG and SCIG therapies were comparable. As expenses related to training and supervision declined for SCIG patients during years 2 and 3, the total costs for the initial 3 years of SCIG treatment were about 10% lower as compared to IVIG. The cost-saving effects of SCIG as compared to IVIG treatment were also found in a model-based cost-minimization analysis for CIDP patients [83]. Using the same criteria as in the PID study, total costs over the first 48 weeks were more than 20% lower for home-based SCIG as compared to IVIG [82]. In this study, the costs of the immunoglobulin preparations were identified as the major cost-driver. Mainly due to the higher administration dose, SCIG was more expensive in the initial phase, but these additional costs declined during the maintenance phase (from week 28). As uncommon in Switzerland, the cost-effectiveness of home-based IVIG was not assessed. However, studies conducted in many other countries including Japan [84], Italy [83, 85], Germany [86], and Canada [87, 88] also point toward a cost-benefit of SCIG over IVIG, eventually when considering direct treatment costs and indirect costs together (Table 1). However, while these studies suggest a cost-minimization potential of SCIG versus IVIG treatment, they also highlight the need to consider divergent treatment schemes and the sensitivity of such analysis to patient- and country-specific factors.

Both IVIG and SCIG preparations offer adequate therapeutic options for various diseases. In most countries, IVIG shows a broader range of labeled indications as compared to SCIG. In the case that both therapeutic options are available, the treating physician needs to evaluate the patients’ preferences to tailor the treatment [70]. Compared to IVIG, systemic AEs and wear-off effects are less common during SCIG treatment, which might also offer higher flexibility and QoL to the patient [28, 29, 74]. However, the treatment success with SCIG relies on the adequate training and a good level of compliance and cognitive capabilities of the patient. The more structured treatment approach using IVIG with regular clinical visits may still be preferred for some patients, especially, if the circumstances for home-based SCIG treatment are suboptimal. Despite high investments of patient instructions and training, the total costs of SCIG appear to be lower than for IVIG, if the treatment is followed long term [82, 85, 88, 89].

Taken together, IVIG and SCIG have their own idiosyncratic characteristics. Treatment decisions should be based on the careful evaluation of multiple factors (clinical, pharmacoeconomic, and social) for a personalized treatment approach that leads to an increased QoL.

The authors thank Dr. Christoph Schneider (CSL Behring) for his inputs to the content of the manuscript.

Caroline von Achenbach is a full-time employee of CSL, Behring. Giselle Hevia Hernandez and Stephan von Gunten declare no conflict of interest.

The laboratory of S.V.G. is supported by grants from the Swiss National Science Foundation (310030_184757), the Swiss Cancer League/Swiss Cancer Research (KFS-4958-02-2020), and the Bern Center for Precision Medicine.

Caroline von Achenbach, Giselle Hevia Hernandez, and Stephan von Gunten wrote and approved the manuscript.

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