Pharmacokinetic Profiles of Intravenous and Subcutaneous Immunoglobulin Produce Differential Immunomodulatory Effects on Serum Cytokines in CIDP

Martin Svačina, MD

In a recently published study, findings showed that the effects of intravenous (IVIg) and subcutaneous immunoglobulin (SCIg) on cellular immunomarkers of chronic demyelinating polyneuropathy (CIDP) were comparable, whereas serum cytokines were more diversely modulated by IVIg than SCIg. Overall, these suggest that differential pharmacokinetics of IVIg and SCIg can result in differential post-infusion cytokine profiles in this patient population.¹

Published in the European Journal of Neurology, the study comprised of serum and peripheral blood mononuclear cell samples from 30 patients with CIDP receiving IVIg, 10 patients with CIDP receiving SCIg, and 15 patients with common variable immunodeficiency (CVID) receiving IVIg. After 21 days post-administration, results showed that IVIg-treated patients with CIDP had increased interleukin (IL)-4 and IL-33 serum levels compared with those treated with SCIg. Multiple correlation cluster analyses revealed that IVIg-treated patients with CIDP had broader concordant cytokine modulation than SCIg recipients, which peaked 3 days after IVIg treatment.

"The observation that the kinetics of serum cytokines such as IL-4, IL-33 and MIP-1α were more stable after SCIg than after IVIg infusion might be a consequence of a more continuous alteration of cytokine release,” lead investigator Martin Svačina, a postdoctoral research fellow at the University Hospital of Cologne, and colleagues, wrote. "This could be derived from more stable serum IgG levels after SCIg treatment, and might reflect the lower rate of flu-like symptoms or headache after SCIg observed in the PATH study as these are associated with the release of pro-inflammatory cytokines."

Study authors noted the study was limited by the number of patients who were lost at follow-up, mainly because of the COVID-19 pandemic. Of 30 patients with CIDP receiving IVIg, 9 completed 3 days, 21 completed 7 days, and 11 completed 21 days of follow-up. All SICg recipients completed 3-day and 7-day follow-ups. Coming into the study, there were no between-group differences in mean age, gender ratios, or disability. Over the 21-day period, patients with CIDP who received IVIg had stable INCAT and MRC sum scores.

In a longitudinal analysis comparing the 2 treatments, no significant differences were observed at any time points in the frequencies of total, naïve and memory B cells, T cells, and classical monocytes, regardless of if patients had CIDP or CVID. Frequencies of intermediate and non-classical monocytes, their referring CD32a+ and/or CD32b/c+ subtypes (all P > 0.2), and whole NK cells (P = 0.8) were not different between the cohorts.

Investigators also observed that CD32B+ memory B cells decreased 7 days after IVIg or SCIg administration and then increased significantly compared with baseline after 21 days in IVIg-treated patients with CIDP. These observations were in line with previous studies, the authors noted. In addition, CD32B+ memory B-cell frequencies correlated with I-RODS score in IVIg-treated patients with CIDP, but not in SCIg recipients (r = .35; P = .007).

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In the study, after 7 days of either treatment, those with CIDP showed increases in myeloid dendritic cells whereas those with CVID on IVIg demonstrated the opposite. A stronger increase in CD32a+ naïve B cells in CVID compared with IVIg-treated patients with CIDP was also observed (CVID vs CIDP: 28% [±22] vs 10% [±6]; P = .008).

Investigators conducted a separate subgroup analysis of immune cell patterns, excluding those who only provided blood samples at baseline. Results showed no relevant differences relative to the initial analysis 21 days after IVIg treatment, with the exception of significantly reduced myeloid dendritic cell frequencies (0.006% [±0.003] vs 14% [±18]; P = .04).

"One limitation of our study is the fact that immune cells were not examined 21 days after SCIg administration, which could limit the comparability to IVIg,” the study authors wrote. “However, as all SCIg recipients had repeatedly administered SCIg weekly for at least 1 month at study inclusion, it appears very likely that immune cell compositions 21 days after SCIg administration and at baseline would be similar, as this time point reflects the baseline of a subsequent SCIg cycle."

In addition, "It should also be noted that immunoglobulin-derived IgG can bind to FcγRs on immune cells and thus interfere with anti-FcγR (CD32a or CD32b/c) flow cytometry antibody binding. Data on this are currently lacking, but all previous flow cytometry-based studies on FcγRs in CIDP were likely to have the same limitation, and since our results align with these studies, we are confident of their validity."

REFERENCE
1. Svacina MKR, Meibner A, Schweitzer F, et al. Immunomodulatory effects of intravenous and subcutaneous immunoglobulin in chronic inflammatory demyelinating polyneuropathy: an observational study. European Journal of Neurol. 2024;31(1):316079. doi:10.1111/ene.16079