Recombinant Human C1 Esterase Inhibitor for the Management of Adverse Events Related to Intravenous Immunoglobulin Infusion in Patients With Common Variable Immunodeficiency or Polyneuropathy: A Pilot Open-Label Study

Abstract

It has been hypothesized that low levels of C1 esterase inhibitor (C1-INH), a key inhibitor of the complement pathway, may play a role in the occurrence of adverse events (AEs) associated with intravenous immunoglobulin (IVIG) therapy. This open-label pilot study evaluated C1-INH replacement, with recombinant human C1-INH (rhC1-INH), as a potential therapy for adults requiring IVIG and experiencing AEs. Patients received two rounds of IVIG infusion [pre-treatment phase (no rhC1-INH), 4-8 weeks] and then three rounds of one dose of intravenous rhC1-INH 50 U/kg (maximum, 4,200 U) with subsequent IVIG infusion (treatment phase, 6-12 weeks). Nineteen adults completed the study; all had an autoimmune condition linked to common variable immunodeficiency (CVID) or polyneuropathy, and 57.9% had low baseline C1-INH levels. Mean ± SD total scores improved significantly with the Headache Impact Test (from 62.8 ± 6.2 at pre-treatment to 57.7 ± 9.1 after treatment; mean Δ, -5.0; p = 0.02) and Modified Fatigue Impact Scale (from 59.3 ± 13.1 to 51.2 ± 15.4; mean Δ, -8.1; p = 0.006). Significant improvements in the Migraine Disability Assessment were observed for three of five items (p ≤ 0.002). Mean ± SD C1-INH level increased from 26.8 ± 5.9 mg/dl after the second round of IVIG (pre-treatment) to 32.1 ± 7.8 mg/dl after the third rhC1-INH treatment; functional C1-INH levels increased from 115.8 ± 34.7% to 158.3 ± 46.8%. Future research is warranted to explore the benefit of C1-INH therapy for reduction of IVIG-related AEs, as well as the role of C1-INH in patients with CVID and autoimmune disease.

Clinical trial registration: ClinicalTrials.gov, identifier NCT03576469.

Keywords: Ruconest; angioedemas hereditary; complement C1 inhibitor protein; immunoglobulins intravenous; recombinant human C1 esterase inhibitor.

Conflict of interest statement

IRM reports serving as a speaker and an advisory board member for Pharming Group NV. JRH is an employee of Pharming Healthcare Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The authors declare that this study received funding from Pharming Healthcare Inc. The funder had the following involvement in the study: interpretation of data and medical accuracy review of the article content.

Copyright © 2021 Melamed, Miranda, Heffron and Harper.

Figures

Figure 1

Study design. *For recording AEs, concomitant medications, infections, hospitalizations, physician and/or emergency room visits, and school and/or work days missed because of infection or illness. AEs, adverse events; C1-INH, C1 esterase inhibitor; CBC, complete blood count; CMP, comprehensive metabolic panel; EOS, end of study; IVIG, intravenous immunoglobulin; rhC1-INH, recombinant human C1 esterase inhibitor.

Figure 2

Impact of rhC1-INH prior to IVIG administration on AE severity in IVIG-treated patients as assessed by the (A) Headache Impact Test, (B) Migraine Disability Assessment, and (C) Modified Fatigue Impact Scale. Potential score ranges for the Modified Fatigue Impact Scale are 0–84 for total score, 0–36 for physical subscale, 0–40 for cognitive subscale, and 0–8 for psychosocial subscale. AE, adverse event; IVIG, intravenous immunoglobulin; rhC1-INH, recombinant human C1 esterase inhibitor; SD, standard deviation.