Long-term immunoglobulin (Ig) therapy is one of the cornerstone modalities for a number of autoimmune neuromuscular disorders (NMDs) including chronic inflammatory demyelinating polyneuropathy (CIDP), multifocal motor neuropathy (MMN), inflammatory myopathies and myasthenia gravis (MG). By modulating the immune system through a number of mechanisms affecting both cellular and humoral autoimmune pathways, Ig therapies are highly effective both as an induction or maintenance therapy for diverse conditions. ^{Reference Perez1} These chronic NMDs often have a fluctuating course that requires long-term Ig infusions and necessitates a personalized treatment approach and ongoing monitoring.

In Canada, conventional intravenous immunoglobulin (IVIg) therapy has grown at a rate of 5%–10% annually since 2001, and NMDs are the second most common indication for IVIg, among which CIDP is the leading indication. ² Despite its efficacy, multiple factors pose challenges with chronic IVIg therapy, which include the need for long-term venous access, need for infusions to be monitored by healthcare professionals, administration in established healthcare settings with long wait times, a high incidence of systemic side effects and infusion site reactions. ^{Reference Tanvee, Brannagan and Lenihan3}

Subcutaneous immunoglobulin (SCIg) was first approved for CIDP in 2018 ^{Reference Goyal, Karam, Sheikh and Dimachkie4} but has increasingly been used as maintenance therapy for other NMDs as it offers a less invasive, more patient-centric alternative to IVIg with the distinct advantage of self-administered home administration. Studies have shown comparable efficacy of SCIg and steady absorption of immunoglobulins through subcutaneous (SC) route and may lead to a more consistent therapeutic effect with fewer peaks and troughs. ^{Reference Geng, Piracha, Rashid and Rigas5}

We conducted a prospective systematic study to assess the feasibility of the SCIg as a maintenance therapy for various autoimmune NMDs, with a focus on compliance, safety, convenience and dosing while maintaining efficacy. Specifically, this study aimed to assess whether SCIg can meet the needs of NMD patients by improving compliance and providing stable outcomes. Of the 58 patients with NMDs who were prescribed maintenance SCIg during the study period, 32 patients (male 50%, age range: 21–82; mean 56 years) initially consented to participate in the study. The study participants had diverse NMDs – CIDP: 15 (46.9%), MMN: 9 (28.1%), MG: 6 (18.8) and others (sensory neuropathy, immune myopathy): 2 (6.2%). Of the 32 participants, 2 withdrew from the program without initiating SCIg due to their limitation with self-administering the SCIg infusions, while 2 others switched back to IVIg due to reduced efficacy, which brings the overall dropout rate to 12.5% after having been prescribed SCIg.

For the SCIg dose stability analysis, only participants who completed at least three visits after starting SCIg were considered. A total of 28 met this criterion. The weekly SCIg dose ranged from 8.3 g to 50 g, with a mean of 24.9 g (Figure 1A), and all participants remained compliant with the prescribed dose. Most participants (18/28; 64%) remained on a stable SCIg dose throughout the study; in 5 of 28 (18%) participants, the SCIg dose needed to be increased from the first follow-up visit (SCIg-PE05, 08, 10, 18 and 26) (Figure 1B), whereas 5 of 28 (18%) participants were able to reduce the SCIg dose. For two participants, reduced dose was ineffective; one (SCIG-PE07) had to return to the initial SCIg dose, while the other participant (SCIG-PE10) required an increased dose beyond the starting dose (Figure 1D). Nonparametric analysis (Friedman test) showed that overall, the study population significantly maintained a stable dose of SCIg, as the p-value obtained was insignificant (p > 0.05), attributing to no evidence of significant dose variation among different follow-ups. Importantly, there were no events of SCIg wastage by study participants. The compliance was assured by the blood bank nurses through detailed accountability logging of product dispensing. Empty product vials were returned regularly before dispensing of future SCIg.

Figure 1. (A) Range of subcutaneous immunoglobulin (SCIg) doses reported by the participants. (B) Five participants reported increased SCIg dose compared to the starting dose. (C) The decreased SCIg dose was reported by five participants compared to the start dose. The participant, SCIG-PE01, started with an SCIg dose of 55 g and reported a gradual decrease in dose, with the last reported dose of 24 g per week. (D) Represents the dose pattern reported at different follow-ups compared to baseline (FU1).

A comparative Ig dose analysis for the intravenous and SC routes was conducted to determine if the total Ig dose needed to be increased when smaller weekly doses are administered (Figure 2A). Of the 28 study participants, 4 were directly started on maintenance SCIg therapy (1 gm/kg) without previous IVIg administration. The recommended dose adjustment for 20% SCIg preparations is 1.37–1.53 times the IVIg maintenance dose to prevent non-inferiority in terms of bioavailability. ^{Reference Berger, Rojavin, Kiessling and Zenker6} Our study participants were switched with an equivalent dose conversion of 1:1 from IVIg monthly to 20% SCIg weekly regimen – a Canadian Blood Service recommendation as well as European practice. ^{Reference Fadeyi and Tran7,Reference Krishnarajah, Lehmann and Ellman8} In this cohort, 19 of 24 (79%) maintained the same Ig dose or were able to reduce the SCIg dose from their baseline IVIg dose during the study (Figure 2A). Notably, five (20.8%) patients on SCIg required a lower Ig dose compared to the baseline IVIg dose (Figure 2B). Five (20.8%) participants required a higher Ig dose after switching to SCIg to maintain stable disease (Figure 2B). Of the four patients who started directly on SCIg, three remained on a stable dose throughout the study, while one participant needed a slightly increased weekly dose, that is, from 12 g to 16 g per week.

Figure 2. (A) The reported dose of subcutaneous immunoglobulin (SCIg) at different follow-ups compared to the intravenous immunoglobulin (IVIg) dose before transitioning. (B) Last reported SCIg dose compared to the IVIg dose reported by the same participant.

The incidence of adverse events (AEs) with IVIg in previous studies has been reported to range from 87.5% to 93.9%. ^{Reference Seidling, Hoffmann, Enk and Hadaschik9,Reference Kuwabara, Mori and Misawa10} In our cohort, 16 of 24 (66.7%) participants who were previously treated with IVIg reported having AEs. The most common AEs included headache, nausea, fever and abdominal pain. After transitioning to SCIg, the incidence and severity of side effects were significantly lower, that is, 7 of 24 (29.2%), with 3 of 7 participants reporting resolution of side effects during the study (Figure 3A). Importantly, those who reported side effects with SCIg also had 16 of 24 AEs (66.7%) with IVIg (Figure 3B), and no participant reported any new AEs after switching to SCIg.

Figure 3. (A) The number of participants who reported side effects and resolution of side effects over the study period. (B) Impact of the side effects reported by the participants. (C) Represents the participants’ reported convenience and global satisfaction while transitioning to the subcutaneous immunoglobulin (SCIg) from intravenous immunoglobulin (IVIg) (TSQM v 1.4 was adopted for the analysis).

To assess the overall impact of AEs, we used the side effect domain of Treatment Satisfaction Questionnaire for Medication (TSQM v 1.4). The impact of the reported AEs was significantly higher with IVIg as compared to SCIg (p = 0.0004) (Figure 3B). In terms of convenience, participants on SCIg reported a significantly higher degree of convenience compared to the IVIg (p = 0.00004). This degree of significance indicates that SCIg treatment was consistently more convenient for the participating population. Additionally, a clear improvement in the ease of treatment planning was observed (Figure 3C). The global satisfaction domain also reported significant stability, where it stayed very consistent (p = 0.00001), reflecting participants’ high confidence with SCIg therapy.

In summary, this prospective comparative study shows that SCIg is a promising maintenance therapy option in patients with autoimmune NMDs who require chronic Ig therapy. Although some studies have used higher doses when transitioning to SCIg, our study shows that most patients with NMD can be maintained on an equivalent or reduced dose of Ig as compared to their baseline monthly IVIg dose. Moreover, SCIg is associated with excellent patient compliance, reduced incidence of AEs and better patient satisfaction. The abolition of reliance on healthcare facilities and the elimination of waiting times, with the flexibility of dosing regimen through self-infusions, likely contribute to high patient satisfaction. Further data analysis will be conducted to assess the comparative efficacy and economic impact when patients are transitioned to the SC route of Ig delivery.