By Michael Rubin, MD
Professor of Clinical Neurology, Weill Cornell Medical College
SYNOPSIS: A Phase II trial comparing subcutaneous (SC) administration of pooled immunoglobulin to intravenous (IV) administration of immunoglobulin in 23 patients with seropositive myasthenia gravis demonstrated a stable course after transition from IV to SC.
SOURCE: Pasnoor M, Bril V, Levine T, et al. Phase 2 trial in acetylcholine receptor antibody-positive myasthenia gravis of transition from intravenous to subcutaneous immunoglobulin: The MGSCIg study. Eur J Neurol 2023;30:1417-1424.
Clinically characterized by fluctuating muscle weakness, myasthenia gravis (MG) is an antibody-mediated autoimmune disorder that responds well to immunosuppressant and immunomodulatory treatment, including glucocorticoids, plasma exchange, and intravenous immunoglobulin (IVIG). Obtained from thousands of donors, IVIG is pooled immunoglobulin with an uncertain mechanism of action, working quickly (usually within a week) and benefiting up to six weeks. It can quickly reverse a myasthenic flare, is beneficial in myasthenic crisis, with fewer complications compared to plasma exchange, and is a useful alternative for refractory MG. Subcutaneous IVIG (SCIg) fosters patient autonomy, does not require venous access, and has no need for nursing care. Is it equally efficacious as IVIG?
Patients were recruited from five sites in North America and enrolled in a prospective, open-label, Phase II trial where MG patients already on IVIG as part of routine care were followed over a 10-week IVIG stabilization period (ISP) and then transitioned to SCIg to be followed in a 12-week experimental treatment period (ETP). Transition was from IVIG to SCIg IgPro20 (Hizentra, a 20% liquid formulation of human normal Ig), and occurred one week after the last IVIG infusion, as part of the 12-week SCIg ETP. Subjects received weekly to four times weekly SCIg using a 1:1.2 dosing ratio to IVIG.
Inclusion criteria comprised seropositive MG patients older than 18 years of age; Myasthenia Gravis Foundation of America (MGFA) clinical classification of II-IV; stable dose of prednisone or other immunosuppressive agent for 30 or 60 days, respectively, prior to the screening visit; and average IVIG maintenance of 0.2 g/kg to 2 g/kg every four weeks, with a stable IVIG dose for at least three cycles prior to entry. Patients who previously received rituximab or other biologic agents and those with a history of thrombotic events were excluded. SCIg efficacy in the 12-week ETP (week 0 to week 12) was the primary outcome measure, with secondary outcome measures comprising safety, tolerability, IgG levels, and change from week 0 to week 12 in the Myasthenia Gravis Composite (MGC) score, Myasthenia Gravis Quality of Life (MGQOL15), Myasthenia Gravis Activities of Daily Living (MG-ADL), and Treatment Satisfaction Questionnaire for Medication (TSQM). Statistical analysis included the two-sided Wilcoxon signed-rank test and the McNemar test of agreement, with P < 0.05 considered significant.
Among 23 MG patients enrolled, comprising 12 women and 11 men, with a mean age of 51.4 years, 22 completed the ISP (one withdrew because of a seizure during IVIG infusion) and were transitioned to SCIg. ETP patients were receiving stable doses of pyridostigmine bromide (90%), prednisone (50%), azathioprine (23%), mycophenolate mofetil (23%), cyclosporine (5%), and methotrexate (5%). Eight had a prior thymectomy. Most ETP patients received SCIg twice per week. At week 0, patients started SCIg infusions two to four times per week and, as more volume per infusion site was tolerated, the infusion frequency decreased to one or two times per week, with the range of SCIg dosage 16 g to 60 g per week.
Among the 22 ETP patients, three dropped out, two because of needle discomfort and one, considered a treatment failure, because of worsening MG requiring plasma exchange. All 19 remaining patients were treatment successes and achieved MG stability based on secondary outcome measures. SCIg was safe and well tolerated, and treatment satisfaction was comparable between ISP and ETP. During ETP, one patient deteriorated, requiring plasma exchange, one experienced vestibular neuritis, thought to be unrelated to SCIg, and two had transient decreases in hemoglobin at week 5 with spontaneous recovery. No thrombotic events were seen in this study. SCIg treatment of MG patients should be considered in lieu of IVIG and with an expectation that it will maintain similar disease stability.
COMMENTARY
Despite receiving standard immunosuppressive therapy, patients with anti-acetylcholine receptor positive myasthenia gravis demonstrate increased complement activation. Plasma levels of cleaved complement components, indicating activation of the classical and alternative, as well as the terminal, complement pathways, were significantly increased in both treatment-naïve seropositive patients as well as those under standard immunosuppressive therapy. Future treatment of seropositive myasthenia gravis may include agents that inhibit complement activation.
