By Michael Rubin, MD
Professor of Clinical Neurology, Weill Cornell Medical College
In an uncontrolled, open-label series of patients with myasthenia gravis, double antibody-negative patients responded to immunosuppressive therapies in a similar manner as do those with antibodies to acetylcholine receptors (AChR) or muscle-specific tyrosine kinase. However, when treating myasthenia patients with a specific agent (efgartigimod) that blocks AChR antibodies at the level of endothelial cells, double antibody-negative patients do not respond as well.
Horiuchi K, Nakamura S, Yamada K, et al. Retrospective analysis of efgartigimod use in patients with double-seronegative generalized myasthenia gravis: A case series. Neuromuscul Disord 2024;39:37-41.
Myasthenia gravis (MG), the most common disorder of neuromuscular transmission, is an autoimmune disease caused by an antibody-mediated attack directed at neuromuscular junction nicotinic acetylcholine receptors or receptor-associated proteins. The disease is characterized by fluctuating skeletal motor weakness involving ocular, bulbar, limb, and respiratory muscles. Treatment modalities include anticholinesterase agents, immunosuppressive or immunomodulatory therapies, and thymectomy.
Most patients require chronic immunotherapy with corticosteroids, intravenous immunoglobulin, azathioprine, tacrolimus, cyclosporine, and/or mycophenolate. More recently, antibody-based biologic therapies, comprising efgartigimod, rozanolixizumab, or ravulizumab, are gaining acceptance. In clinical trials involving a majority of seropositive patients, each was found to be efficacious. Are they equally efficacious in seronegative patients?
To examine the efficacy of efgartigimod in seronegative MG, the researchers for this retrospective case series reviewed outcomes of 16 such patients, aged 18 years or older, treated with efgartigimod 10 mg/kg weekly for four weeks per cycle, between June 2022 and June 2023 at Hakodate Municipal Hospital, Hokkaido, Japan. Efgartigimod was initiated when patients’ MG worsened, with subsequent cycles determined by discussion with the patient. All patients were double-seronegative, defined as antibody-negative to both acetylcholine receptors (AChR) and muscle-specific tyrosine kinase (MuSK). Low-density lipoprotein receptor-related protein 4 (LRP4) antibodies were not measured. All patients demonstrated ptosis and ophthalmoplegia in addition to one of the following: fatiguability; diurnal variation; dysarthria; dysphagia; difficulty chewing; face, neck or limb weakness; or dyspnea. Edrophonium testing, repetitive nerve stimulation, or ice pack testing were consistent with MG, and all patients had previously improved with pyridostigmine, corticosteroids, intravenous immunoglobulin (IVIG), tacrolimus, or cyclosporine.
Outcome measures included Myasthenia Gravis Activities of Daily Living (MG-ADL) scores, duration of improved score, MG quality of life 15-item revised Japanese version score (MGQOL15r-J) at the start and finish of the observation period, the number of efgartigimod cycles required during the observation period, and the length of time between intervals. No statistical analysis was performed.
Among 16 patients (13 women and three men) with a mean age of 54 years, six worsened, requiring IVIG and intravenous methylprednisolone. MG-ADL worsened by two or more points in nine of 16 patients, with no MG crisis occurring during the study period. Adverse events were seen in five patients: one patient experienced headache after the initial injection, two patients developed upper respiratory infections that fully resolved, and two patients had COVID-19 infection. Over all cycles, MG-ADL and MGQOL15r-J scores showed slight improvement, and the oral corticosteroid dose was reduced. Although safe, and despite the absence of statistical analysis, it appears that no significant benefit accrued in double-seronegative patients treated with efgartigimod.
COMMENTARY
Among 80 double-seronegative MG patients, defined as having no antibodies to either AChR or MuSK, who attended the Pressman Family Neuromuscular Clinic at the University Health Network, Toronto General Hospital, from January 2015 to November 2022, retrospectively reviewed and compared to seropositive myasthenia patients, no significant differences in Myasthenia Gravis Impairment Index (MGII) and simple single question (SSQ) were found between the groups at baseline.
Scores improved significantly in the seronegative group at the final clinical evaluation, but the MGII was significantly better in the seropositive group. Medications were similar in both groups, and included combined steroidal and non-steroidal immunosuppressive agents, most commonly azathioprine, mycophenolate mofetil, and IVIG. Seronegative myasthenia likely is immune in origin, given that it responds to immunosuppressive medications, but the antibodies is these patients have yet to be identified.1
REFERENCE
- Martinez-Harms R, Barnett C, Alcantara M, Bril V. Clinical characteristics and treatment outcomes in patients with double-seronegative myasthenia gravis. Eur J Neurol 2024;31:e16022.
