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. 2020 Sep;62(3):333-343.
doi: 10.1002/mus.26985. Epub 2020 Jun 10.

Clinical features of LRP4/agrin-antibody-positive myasthenia gravis: A multicenter study

Michael H Rivner  1 , Brandy M Quarles  1 , Jin-Xiu Pan  2 , Zheng Yu  2 , James F Howard Jr  3 , Andrea Corse  4 , Mazen M Dimachkie  5 , Carlayne Jackson  6 , Tuan Vu  7 , George Small  8 , Robert P Lisak  9 , Jerry Belsh  10 , Ikjae Lee  11 , Richard J Nowak  12 , Vanessa Baute  13 , Stephen Scelsa  14 , J Americo Fernandes  15 , Zachary Simmons  16 , Andrea Swenson  17 , Richard Barohn  5 , R Bhavaraju Sanka  6 , Clifton Gooch  7 , Eroboghene Ubogu  11 , James Caress  13 , Mamatha Pasnoor  5 , Hongyan Xu  18 , Lin Mei  2
Affiliations

Clinical features of LRP4/agrin-antibody-positive myasthenia gravis: A multicenter study

Michael H Rivner et al. Muscle Nerve. 2020 Sep.

Abstract

Introduction: Our aim in this study was to identify the prevalence and clinical characteristics of LRP4/agrin-antibody-positive double-seronegative myasthenia gravis (DNMG).

Methods: DNMG patients at 16 sites in the United States were tested for LRP4 and agrin antibodies, and the clinical data were collected.

Results: Of 181 DNMG patients, 27 (14.9%) were positive for either low-density lipoprotein receptor-related protein 4 (LRP4) or agrin antibodies. Twenty-three DNMG patients (12.7%) were positive for both antibodies. More antibody-positive patients presented with generalized symptoms (69%) compared with antibody-negative patients (43%) (P ≤ .02). Antibody-positive patients' maximum classification on the Myasthenia Gravis Foundation of America (MGFA) scale was significantly higher than that for antibody-negative patients (P ≤ .005). Seventy percent of antibody-positive patients were classified as MGFA class III, IV, or V compared with 39% of antibody-negative patients. Most LRP4- and agrin-antibody-positive patients (24 of 27, 89%) developed generalized myathenia gravis (MG), but with standard MG treatment 81.5% (22 of 27) improved to MGFA class I or II during a mean follow-up of 11 years.

Discussion: Antibody-positive patients had more severe clinical disease than antibody-negative patients. Most DNMG patients responded to standard therapy regardless of antibody status.

Keywords: LRP4; agrin; clinical features; myasthenia gravis; neuromuscular transmission disorders; seronegative myasthenia gravis.

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Conflict of interest statement

M.H.R.: consultant and research support from Alexion and Allergan; research support from UCB, Mallinckrodt, Cytokinetics, Momenta, Shire Takeda, Orion, Biohaven, Catalyst, Grifols, Seikagaku, and Ra Pharmaceuticals. B.M.Q.: research support from Alexion, UCB, Mallinckrodt, Cytokinetics, Momenta, Shire Takeda, Orion, Biohaven, Catalyst, Grifols, Seikagaku, and Ra Pharmaceuticals. J.F.H.: research support from Alexion, Argenx BVBA, Centers for Disease Control and Prevention, Muscular Dystrophy Association (MDA), National Institutes of Health (NIH, including National Institute of Neurological Disorders and Stroke and National Institute of Arthritis and Musculoskeletal and Skin Diseases), and Ra Pharmaceuticals; honoraria from Alexion; and nonfinancial support from Alexion, Argenx BVBA, Ra Pharmaceuticals, and Toleranzia. M.M.D.: consultant for ArgenX, CSL‐Behring, Kezar, Momenta, NuFactor, RMS Medical, Sanofi Genzyme, Shire Takeda, and Spark; grants from Alexion, Alnylam, Amicus, Biomarin, Bristol‐Myers Squibb, Catalyst, CSL‐Behring, US Food and Drug Administration/Office of Orphan Products Development, GlaxoSmithKline, Genentech, Grifols, Mitsubishi Tanabe Pharma, MDA, NIH, Novartis, Sanofi Genzyme, Octapharma, Orphazyme, Sarepta, Shire Takeda, Spark, UCB Biopharma, Viromed, and TMA. C.J.: speaker's bureau for Mitsubishi Tanabe Pharma America, Avanir, CSL Behring, and Strongbridge; research support and consultant fees from Cytokinetics and Mitsubishi Tanabe Pharma America; consultant fees from Argenx, Alexion, and ITF; data safety monitoring board for Mallinckrodt, Brainstorm, and Anelixis. T.V.: speaker and/or consultant for Alexion, ARGX, and UCB; participated in clinical trials sponsored by Alexion, ARGX, Ra Pharmaceuticals, UCB, and Grifols. G.S.: consultant for Alexion. R.P.L.: over past 2 years has been funded for research support from the NIH, National Multiple Sclerosis Society (USA), Genentech, Teva, Novartis, Medimmune, Ra Pharmaceuticals, Argenx, Alexion, Catalyst, and Chugai; served as a consultant to Argenx, Novartis, Mallinckrodt, Catalyst, GLG, Alpha Sites, Insights Consulting, Informa Pharma Consulting, Slingshot Consulting, Schlessinger Group Consulting, Health Choices, Adivo Associates, Haven Consulting, kc2 Medical Communications, and Cello Health Bioconsulting. I.L.: funding support from the Myasthenia Gravis Foundation of America (MGFA) for the MG Registry project. R.J.N.: research support from the NIH, Genentech, Alexion, Ra Pharmaceuticals, MGFA, Momenta, Argenx, Annexon Biosciences, and Grifols; consultant/advisor for Alexion Pharmaceuticals, Argenx, CSL Behring, Grifols, Ra Pharmaceuticals, Roivant, Viela Bio, and Momenta (no conflicts directly related to this study). J.A.F.: funding from Mallinckrodt Pharmaceuticalsand consultant fees from Biogen. Z.S.: research support from Cytokinetics, Mallinckrodt, and Biohaven; consulting fees from Biohaven; payment from Wiley for his position as editor‐in‐chief for Muscle & Nerve. A.S.: research support from Amylyx. R.B.: consultant for NuFactor and Momenta and receives research support from PTC, Ra Pharmaceuticals, Orphazyme, Sanofi Genzyme, FDA/OOPD, NIH, and the Patient‐Centered Outcomes Research Institute. R.B.S.: advisory board for Argenyx. C.G.: editorial board of the journal Neurology. E.U.: research support from NIH/NINDS and Genzyme Sanofi; clinical program support from the MDA; book royalties from Springer Science + Business Media; and has a nonexclusive commercial license (held by Baylor Licensing Group) for immortalized human blood‐nerve barrier endothelial cells. J.C.: research grant funding from Orion and Cytokinetics. M.P.: consultant and on advisory board for TerumoBCT, Alexion, CSL Behring, Momenta, Argenx, and Calalyst. L.M.: recipient of the NIH grant supporting this research project and author of a patent on LRP4 antibodies. The remaining authors declare no potential conflicts of interest.

Figures

FIGURE 1
FIGURE 1
Sequence of study visits and details on which procedures are performed at each visit. Abbreviations: ACHR, acetylcholine receptor; IVIG, intravenous immunoglobulin; LRP4, low‐density lipoprotein receptor–related protein 4; PLEX, plasma exchange; MG, myathenia gravis; MuSK, muscle‐specific kinase; QMG, quantitative myasthenia gravis score
FIGURE 2
FIGURE 2
Symptoms of both antibody‐positive and ‐negative patients at two time periods. A, Disease onset. B, Time of study visit (study entry exam). Abbreviations: DNMG, double‐seronegative myasthenia gravis (negative for AChR and MuSK); LAPMG, double‐seronegative myasthenia gravis with positivity for LRP4 and/or agrin antibodies [Color figure can be viewed at wileyonlinelibrary.com]
FIGURE 3
FIGURE 3
Percentage of patients in each MGFA class for three time periods. A, Study entry MGFA class for antibody‐negative patients. B, Study entry MGFA class for antibody‐positive patients. C, Maximal MGFA class for antibody‐negative patients. D, Maximal MGFA class for antibody‐positive patients. E, MGFA class at disease onset for antibody‐positive patients. Abbreviations: LAPMG, double‐seronegative myasthenia gravis with positivity for LRP4 and/or agrin antibodies; MGFA, Myasthenia Gravis Foundation of America; QNMG, quadruple seronegative myasthenia gravis (negative for acetylcholine receptor, muscle‐specific kinase, low‐density lipoprotein receptor–related protein 4, and agrin) [Color figure can be viewed at wileyonlinelibrary.com]
FIGURE 4
FIGURE 4
Percentage of patients with MGFA class III or higher at time of maximum disease severity and during the study entry exam. Abbreviations: MGFA, Myasthenia Gravis Foundation of America; QNMG, quadruple seronegative myasthenia gravis (negative for acetylcholine receptor, muscle‐specific kinase, low‐density lipoprotein receptor–related protein 4, and agrin) [Color figure can be viewed at wileyonlinelibrary.com]
FIGURE 5
FIGURE 5
Clinical symptoms of LRP4/agrin‐positive patients at three discrete time‐points. Rear bars: maximal symptoms; middle bars: initial symptoms; front bars: return exam symptoms. Abbreviations: Dist, distal; LAPMG, double‐seronegative myasthenia gravis with positivity for LRP4 and/or agrin antibodies; LRP4, low‐density lipoprotein receptor–related protein 4; LE, lower extremity; Prox, proximal; Resp, respiratory; UE, upper extremity [Color figure can be viewed at wileyonlinelibrary.com]
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