Double seropositivity for AChR and MuSK autoantibodies in myasthenia gravis

Abstract

Autoimmune myasthenia gravis (MG) is an acquired, IgG-mediated disorder of neuromuscular transmission that targets the postsynaptic nicotinic acetylcholine receptor (AChR) ion channel in 90% of cases with generalized weakness. An alternative target, in 4 percent of cases, is the muscle-specific tyrosine kinase (MuSK) protein, a component of the functional postsynaptic AChR-complex. Rare double seropositive cases have been reported, both pediatric and adult [ 1 Li M. Ren L. Zhang Y. et al. Clinical characteristics of AChRAb and MuSKAb double seropositive myasthenia gravis patients. Clin Neurol Neurosurg. 2018; 172: 69-73 Crossref PubMed Scopus (12) Google Scholar , 2 Poulas K. Koutsouraki E. Kordas G. Kokla A. Tzartos S.J Anti-MuSK- and anti-AChR-positive myasthenia gravis induced by d-penicillamine. J Neuroimmunol. 2012; 250: 94-98 Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar , 3 Rostedt Punga A. Ahlqvist K. Bartoccioni E. et al. Neurophysiological and mitochondrial abnormalities in MuSK antibody seropositive myasthenia gravis compared to other immunological subtypes. Clin Neurophysiol. 2006; 117: 1434-1443 Crossref PubMed Scopus (36) Google Scholar , 4 Zouvelou V. Zisimopoulou P. Psimenou E. Matsigkou E. Stamboulis E. Tzartos S.J AChR-myasthenia gravis switching to double-seropositive several years after the onset. J Neuroimmunol. 2014; 267: 111-112 Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar , 5 Jordan B. Schilling S. Zierz S Switch to double positive late onset MuSK myasthenia gravis following thymomectomy in paraneoplastic AChR antibody positive myasthenia gravis. J Neurol. 2016; 263: 174-176 Crossref PubMed Scopus (11) Google Scholar ], and other synaptic proteins have been implicated, even more rarely. Reported clinical details for concurrent AChR-MuSK antibody seropositive cases have been limited. In this issue, Yaru Lu et al. describe two new pediatric cases and review 6 additional literature reports of the rare combination of dual positive (DP) MG. The symptoms and signs in these 8 patients were generally more severe than reported in adults: 6 had dyspnea (75%), and 4 (50%) experienced a myasthenic crisis. In contrast, among sixteen reported adult DP-MG patients, 38% had respiratory muscle involvement [ [6] Lu Y. Ran H. Yang W. Ma Q. Qiu L. Ou C. et al. AChR myasthenia gravis switching to MuSK or double antibody positive myasthenia gravis in two children and literature review. Neuromuscul Disord. 2020; 30: 534-538 Abstract Full Text Full Text PDF Scopus (5) Google Scholar ]. Detailed comparisons of symptoms between adult and pediatric DP-MG from larger cohorts of patients are lacking. Thymectomy was implicated as a predisposing factor for DP-MG in the present report (63% of cases), as has been reported for adult DP-MG [ [1] Li M. Ren L. Zhang Y. et al. Clinical characteristics of AChRAb and MuSKAb double seropositive myasthenia gravis patients. Clin Neurol Neurosurg. 2018; 172: 69-73 Crossref PubMed Scopus (12) Google Scholar , [5] Jordan B. Schilling S. Zierz S Switch to double positive late onset MuSK myasthenia gravis following thymomectomy in paraneoplastic AChR antibody positive myasthenia gravis. J Neurol. 2016; 263: 174-176 Crossref PubMed Scopus (11) Google Scholar ]. Thymectomy is considered non-beneficial for MuSK-MG and its value for treating pediatric MG in general is unclear, being reserved for children who respond poorly to pyridostigmine and immunosuppressants [ [7] Sanders D.B. Wolfe G.I. Benatar M. et al. International consensus guidance for management of myasthenia gravis: executive summary. Neurology. 2016; 87: 419-425 Crossref PubMed Scopus (506) Google Scholar ]. Two noteworthy points are: i) at least 7 of the 8 patients were solely AChR-IgG seropositive at initial MG diagnosis and, later, all were MuSK-IgG-positive (with or without AChR-IgG), and ii) symptoms were initially AChR-MG-characteristic (extraocular muscle weakness; responsive to cholinesterase inhibitor medication), but progressively worsened, became poorly responsive to cholinesterase inhibitor medication, and required corticosteroids; some cases required plasmapheresis or I.V. immune globulin for management. These observations raise interesting immunobiologic questions: i) What factors trigger the switch from AChR-MG to DP-MG? ii) Is the primary site of autoimmunization the postsynaptic membrane itself? iii) What drives the intermolecular antigenic spread, with MuSK-IgG production apparently following AChR-IgG production? One would anticipate, as observed, that MuSK-IgG coexisting with AChR-IgG would synergistically worsen MG in the DP phase. However, the non-membranolytic MuSK autoantibody (IgG4 does not activate complement) has potential to protect AChR in the postsynaptic membrane from lysis by AChR-IgG (IgG1 and IgG3). Perhaps the state of maturity of the neuromuscular synapse or the immune system itself is a determinant of the more severe symptoms of DP-MG in children than in adults?