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Immunoglobulin replacement therapy is the standard-of-care treatment for patients with primary immunodeficiency diseases who have impaired antibody production and function. Clinicians and patients may consider intravenous immunoglobulin (IVIG) or subcutaneous immunoglobulin (SCIG) options, and each route may offer different benefits for the individual. IVIG requires fewer infusion sites and less frequent infusions than some formulations of SCIG. However, SCIG does not require venous access, is associated with fewer systemic adverse infusion reactions than IVIG, and can independently be self-administered at home. Importantly, tailoring treatment experiences to the needs of the individual may improve treatment adherence and quality of life for patients with primary immunodeficiency diseases who often rely on long-term or lifelong treatment. This review aims to educate United States (US) healthcare providers on the administration process of SCIG, with a focus on more concentrated formulations of SCIG and facilitated SCIG. It provides practical guidance on initiating, optimizing, and monitoring SCIG therapy. The advantages and disadvantages of the different treatment options are also presented for discussion between the patient and clinician.

Immunoglobulin (Ig)-replacement therapy represents the mainstay of treatment for patients with primary antibody deficiency and is administered either intravenously (IVIg) or subcutaneously (SCIg). While hyaluronidase has been used in clinical practice for over 50 years, the development of a high-purity recombinant form of this enzyme (recombinant human hyaluronidase PH20) has recently enabled the study of repeated and more prolonged use of hyaluronidase in facilitating the delivery of SC medicines. It has been used in a wide range of clinical settings to give antibiotics, local anesthetics, insulin, morphine, fluid replacement, and larger molecules, such as antibodies. Hyaluronidase has been used to help overcome the limitations on the maximum volume that can be delivered into the SC space by enabling dispersion of SCIg and its absorption into lymphatics. The rate of facilitated SCIg (fSCIg) infusion is equivalent to that of IVIg, and the volume administered at a single site can be greater than 700 mL, a huge increase over conventional SCIg, at 20-40 mL. The use of fSCIg avoids the higher incidence of systemic side effects of IVIg, and it has higher bioavailability than SCIg. Data on the long-term safety of this approach are currently lacking, as fSCIg has only recently become available. fSCIg may help several areas of patient management in primary antibody deficiency, and the extent to which it may be used in future will depend on long-term safety data and cost-benefit analysis.

Hyaluronidase-facilitated subcutaneous immunoglobulin (fSCIg) is a new immunoglobulin product for replacement therapy in patients with primary antibody deficiencies (PAD). The pre-administration of recombinant human hyaluronidase associated with 10% immunoglobulin allowed the infusion of larger (up to 600 ml) amounts of immunoglobulin at a single infusion site, enabling patients to receive the necessary treatment in a single monthly dose. Here, we report the effectiveness and the tolerability of fSCIg in patients with severe PAD-related comorbidities: refractory autoimmune thrombocytopenia; systemic granulomatous disease; severe enteropathy, and Type I diabetes. We conclude that fSCIg could be a feasible option to improve the adherence to replacement therapy also by patients with severe PAD.

Subcutaneous immunoglobulin (SCIG) preparations are widely used in patients with inborn errors of immunity (IEI), with proven efficacy and good tolerance. We assessed treatment efficacy, safety, and quality of life in a large cohort of IEI patients who switched from intravenous immunoglobulin (IVIG) to SCIG. Our observational study included 200 patients aged 1–65 years with IEI. SCIG Cutaquig (16.5%) was administered every 7–10 days for at least 12 months via the rapid push method. We assessed the rate of infection, immunoglobulin G (IgG) concentration, adverse events, and quality of life. A total of 8,787 SCIG doses were administered during the study. The rate of infections (per person/month) during SCIG treatment was 0.05, which was significantly lower compared to 0.19 during the IVIG period (p<0.001). The median trough IgG was 6.9 g/L on IVIG, compared to 9.0 g/L during the first six months, and 9.2 g/L during the next six months on SCIG. Systemic reactions occurred in 12.4% of the IVIG infusions and 1.9% of the SCIG infusions. The total scores on quality of life summary assessments of physical and mental health were higher on SCIG therapy compared with IVIG (p<0.001). At the end of the study, 85.6% of the patients chose to remain on SCIG. Our data suggest that SCIG infusion via the rapid push method is effective, well tolerated, and feasible in large groups of IEI patients, including those in large countries such as Russia.

Purpose To investigate the efficacy, safety, tolerability, and serum IgG trough levels of hyaluronidase-facilitated subcutaneous immunoglobulin (fSCIG) 10% in US pediatric patients with primary immunodeficiency diseases (PIDDs). Methods This phase 3, open-label, prospective study (NCT03277313) was conducted at 17 US centers. Eligible patients aged 2 to < 16 years had PIDDs and had received immunoglobulin G (IgG) at a consistent dose for ≥ 3 months before screening. Participants received fSCIG 10% via dose ramp-up for up to 6 weeks (Epoch 1), then every 3–4 weeks for ≤ 3 years (Epoch 2). The primary endpoint was the rate of acute serious bacterial infections (ASBIs). Results Data were provided by 44 participants for Epoch 1 (mean ± SD age: 9.0 ± 3.6 years) and 43 (97.7%) for Epoch 2; 34 (77.3%) completed the study. Two ASBIs (both bacterial pneumonia) were reported in one participant with specific antibody deficiency. The mean rate of ASBIs was 0.04 events/participant-year (99% upper confidence interval limit: 0.20), significantly lower than the regulatory-defined threshold of 1.0 ( p  < 0.001). The mean rate of all infections was 3.12 events/participant-year. Stable mean serum IgG trough levels were maintained during Epoch 2 (10.4, 9.2, and 9.2 g/L at Months 0, 6, and 12, respectively). Most related treatment-emergent adverse events were mild or moderate in severity. No participant developed anti-recombinant human hyaluronidase neutralizing antibodies; 1/44 participants (2.3%) developed binding antibodies. Conclusion fSCIG 10% effectively prevented ASBIs in pediatric patients with PIDDs, with a favorable safety profile consistent with previous clinical studies.

Immunoglobulin replacement therapy (IgRT), either intravenous (IVIg) or subcutaneous (SCIg), is crucial for managing primary immune deficiencies (PIDs) with hypogammaglobulinemia by reducing infection rates and mortality. During the COVID-19 pandemic, a global shortage of SCIg prompted our unit to reduce SCIg doses or maintain the same dose intravenously. This study evaluates the impact of a standardized SCIg dose reduction on infection rates and clinical outcomes in patients with humoral PID and with a low burden of infections. Adult PID patients on SCIg for at least 6 months, with IgG trough levels ≥ 700 mg/dL (or ≥ 900 mg/dL under specific conditions), and no significant infections in the past 6 months were eligible. A dose reduction of 15 mg/kg/week (60 mg/kg/month) for every 150 mg/dL above 700 mg/dL (or 900 mg/dL) was proposed. Clinical and laboratory data, and infectious events at 6- and 12-month follow-ups, were analyzed. Thirty-one patients with PID were included: common variable immunodeficiency (54.83%), IgG subclass deficiency (9.67%), and other PIDs (35.48%). The average SCIg dose was initially reduced from 7.82 g/week to 5.72 g/week and adjusted to 6.94 g/week at 12 months. There was no significant change in severe or mild infections before and at 6- and 12-months post-dose adjustment. The dose reduction saved an average of 5,550 euros per patient annually, totaling 172,050 euros annually for our cohort. Optimizing SCIg doses in selected well-controlled humoral PIDs is feasible without increasing infection rates, conserving this plasma-derived product during shortages. Larger prospective studies are needed to confirm this strategy's utility and its application to other Ig formulations.

Intravenous immunoglobulin (IVIG) therapy is a well-documented and effective treatment for primary immunodeficiencies (PI). Subcutaneous immunoglobulins (SCIG) have emerged as an effective alternative for some patients that offers additional flexibility. Currently, caprylate/chromatography purified IGSC (human) 20% is approved to treat PI in North America and many countries worldwide. In this multi-center, open-label study, the pharmacokinetics (PK), efficacy, and safety of IGSC 20% were studied after biweekly (every two weeks) dosing for 16 weeks and compared to weekly IGSC 20% administration for 16 weeks in treatment-experienced PI patients. A loading/weekly maintenance SC regimen was also studied in PI patients naïve to IG treatment. In treatment-experienced patients, the least squares mean ratio of steady-state AUC 0−7 days for biweekly dosing showed non-inferiority to weekly dosing (90% confidence interval 1.0030–1.0685). Other PK parameters (C max , T max , steady state trough) were similar between treatments. Efficacy and safety measures were qualitatively similar to previously published results. No serious bacterial infections were reported. Annual rates for any type of infection were similar between the treatment groups. All severe treatment-related adverse events (AEs) were unrelated to treatment. Only mild to moderate suspected adverse drug reactions were observed. PK analyses showed that biweekly dosing of IGSC 20% was non-inferior to weekly dosing in treatment-experienced PI patients. Biweekly dosing had similar patterns to weekly in prevention of serious bacterial infections, rates of all infections and hospitalizations for infections. The IGSC loading/maintenance dosing regimen in naïve patients was safe and effective during the observation period.

Significant progress has been made in the elucidation of human antibody repertoires. Furthermore, non-canonical functions of antibodies have been identified that reach beyond classical functions linked to protection from pathogens. Polyclonal immunoglobulin preparations such as IVIG and SCIG represent the IgG repertoire of the donor population and will likely remain the cornerstone of antibody replacement therapy in immunodeficiencies. However, novel evidence suggests that pooled IgA might promote orthobiotic microbial colonization in gut dysbiosis linked to mucosal IgA immunodeficiency. Plasma-derived polyclonal IgG and IgA exhibit immunoregulatory effects by a diversity of different mechanisms, which have inspired the development of novel drugs. Here we highlight recent insights into IgG and IgA repertoires and discuss potential implications for polyclonal immunoglobulin therapy and inspired drugs.

Subcutaneous (SCIG) and intravenous immunoglobulin (IVIG) replacement are both used to prevent infections in patients with secondary immunodeficiency (SID). Compared with IVIG, SCIG has fewer systemic side effects and, additionally, facilitates home-based treatment. Shared decision-making practice should include discussion of aspects such as patient preference as well as the associated risks and benefits of treatment. We review the available evidence for the use of SCIG treatment in patients with SID, focusing on patient-reported outcomes (PROs). In most studies, there were improvements to health-related quality of life with SCIG treatment, compared with before initiating SCIG without prior IVIG treatment, or after switching to SCIG from IVIG treatment, or a no-SCIG/IVIG cohort. Treatment satisfaction with SCIG was similar between patients with SID and primary immunodeficiency disease. Patient preference and perception assessments highlighted the benefits of SCIG compared with IVIG, such as ease of use and administration, convenience, and time-effectiveness. In addition, many patients self-administered SCIG at home. Such aspects may be of specific benefit to patients with SID and hematological malignancy by reducing the risk of infection exposure in clinical settings. PRO data may be useful during shared decision-making discussions with patients with SID.