CD20-mediated B cell depletion in acetylcholine receptor autoantibody-positive myasthenia gravis
DOI:
https://doi.org/10.17161/rrnmf.v4i2.19529Keywords:
acetylcholine receptor, myasthenia gravis, autoantibodies, CD20 B cell depletion, rituximabAbstract
Myasthenia gravis (MG) is an autoimmune disorder characterized by muscle weakness and fatigue, mediated in the majority of cases by IgG1 autoantibodies targeting the acetylcholine receptor (AChR). As AChR autoantibodies have been shown to be pathogenic, therapies targeting B cells have been applied in patients with AChR MG for more than a decade. Recently, a phase 2 trial of the CD20-targeting agent, rituximab, in AChR MG unfortunately failed to meet its primary endpoint. Converging data however from non-randomized clinical series, some of which with more participants than the phase 2 trial, support efficacy of rituximab in AChR MG, especially early onset disease. In this opinion article, we summarize both clinical data and mechanistic principles on the use of CD20 depletion therapy in AChR MG, which we believe lend support to the argument that CD20 depletion can still be a useful therapeutic strategy for patients with AChR MG.
Metrics
Downloads
References
N.E. Gilhus, Myasthenia Gravis, N. Engl. J. Med. 375 (2016) 2570–2581. https://doi.org/10.1056/NEJMra1602678.
A.-M. Bubuioc, A. Kudebayeva, S. Turuspekova, V. Lisnic, M.A. Leone, The epidemiol-ogy of myasthenia gravis., J. Med. Life. 14 (2021) 7–16. https://doi.org/10.25122/jml-2020-0145.
P. Stathopoulos, M.C. Dalakas, Evolution of Anti-B Cell Therapeutics in Autoimmune Neurological Diseases., Neurother. J. Am. Soc. Exp. Neurother. (2022). https://doi.org/10.1007/s13311-022-01196-w.
W. Hoch, J. McConville, S. Helms, J. Newsom-Davis, A. Melms, A. Vincent, Auto-antibodies to the receptor tyrosine kinase MuSK in patients with myasthenia gravis with-out acetylcholine receptor antibodies, Nat. Med. 7 (2001) 365–368. https://doi.org/10.1038/85520.
M.L. Fichtner, R. Jiang, A. Bourke, R.J. Nowak, K.C. O’Connor, Autoimmune Patholo-gy in Myasthenia Gravis Disease Subtypes Is Governed by Divergent Mechanisms of Immunopathology., Front. Immunol. 11 (2020) 776. https://doi.org/10.3389/fimmu.2020.00776.
K. Takata, P. Stathopoulos, M. Cao, M. Mané-Damas, M.L. Fichtner, E.S. Benotti, L. Jacobson, P. Waters, S.R. Irani, P. Martinez-Martinez, D. Beeson, M. Losen, A. Vincent, R.J. Nowak, K.C. O’Connor, Characterization of pathogenic monoclonal autoantibodies derived from muscle-specific kinase myasthenia gravis patients, JCI Insight. 4 (2019) e127167. https://doi.org/10.1172/jci.insight.127167.
M. van der Neut Kolfschoten, J. Schuurman, M. Losen, W.K. Bleeker, P. Martínez-Martínez, E. Vermeulen, T.H. den Bleker, L. Wiegman, T. Vink, L.A. Aarden, M.H. De Baets, J.G.J. van de Winkel, R.C. Aalberse, P.W.H.I. Parren, Anti-inflammatory activity of human IgG4 antibodies by dynamic Fab arm exchange, Science. 317 (2007) 1554–1557. https://doi.org/10.1126/science.1144603.
M.G. Huijbers, J.J. Plomp, S.M. van der Maarel, J.J. Verschuuren, IgG4-mediated auto-immune diseases: a niche of antibody-mediated disorders: IgG4-mediated autoimmune diseases, Ann. N. Y. Acad. Sci. 1413 (2018) 92–103. https://doi.org/10.1111/nyas.13561.
S. Viegas, L. Jacobson, P. Waters, J. Cossins, S. Jacob, M.I. Leite, R. Webster, A. Vin-cent, Passive and active immunization models of MuSK-Ab positive myasthenia: Electro-physiological evidence for pre and postsynaptic defects, Exp. Neurol. 234 (2012) 506–512. https://doi.org/10.1016/j.expneurol.2012.01.025.
C. Zografou, A.G. Vakrakou, P. Stathopoulos, Short- and Long-Lived Autoantibody-Secreting Cells in Autoimmune Neurological Disorders, Front. Immunol. 12 (2021) 686466. https://doi.org/10.3389/fimmu.2021.686466.
J.S. Yi, J.T. Guptill, P. Stathopoulos, R.J. Nowak, K.C. O’Connor, B cells in the patho-physiology of myasthenia gravis, Muscle Nerve. 57 (2018) 172–184. https://doi.org/10.1002/mus.25973.
J. Diaz-Manera, E. Martinez-Hernandez, L. Querol, R. Klooster, R. Rojas-Garcia, X. Sua-rez-Calvet, J.L. Munoz-Blanco, C. Mazia, K.R. Straasheijm, E. Gallardo, C. Juarez, J.J. Verschuuren, I. Illa, Long-lasting treatment effect of rituximab in MuSK myasthenia, Neurology. 78 (2012) 189–193. https://doi.org/10.1212/WNL.0b013e3182407982.
P. Stathopoulos, A. Kumar, R.J. Nowak, K.C. O’Connor, Autoantibody-producing plas-mablasts after B cell depletion identified in muscle-specific kinase myasthenia gravis, JCI Insight. 2 (2017) e94263. https://doi.org/10.1172/jci.insight.94263.
P. Stathopoulos, A. Kumar, J.A.V. Heiden, E. Pascual-Goñi, R.J. Nowak, K.C. O’Connor, Mechanisms underlying B cell immune dysregulation and autoantibody pro-duction in MuSK myasthenia gravis: B cell abnormalities in MuSK myasthenia gravis, Ann. N. Y. Acad. Sci. 1412 (2018) 154–165. https://doi.org/10.1111/nyas.13535.
T.F. Tedder, A. Forsgren, A.W. Boyd, L.M. Nadler, S.F. Schlossman, Antibodies reac-tive with the B1 molecule inhibit cell cycle progression but not activation of human B lymphocytes, Eur. J. Immunol. 16 (1986) 881–887. https://doi.org/10.1002/eji.1830160802.
M. Bofill, G. Janossy, M. Janossa, G.D. Burford, G.J. Seymour, P. Wernet, E. Kelemen, Human B cell development. II. Subpopulations in the human fetus, J. Immunol. Baltim. Md 1950. 134 (1985) 1531–1538.
P. Kanatas, I. Stouras, L. Stefanis, P. Stathopoulos, B-Cell-Directed Therapies: A New Era in Multiple Sclerosis Treatment, Can. J. Neurol. Sci. J. Can. Sci. Neurol. (2022) 1–10. https://doi.org/10.1017/cjn.2022.60.
D.H. Whittam, E.C. Tallantyre, S. Jolles, S. Huda, R.J. Moots, H.J. Kim, N.P. Robertson, B.A.C. Cree, A. Jacob, Rituximab in neurological disease: principles, evidence and prac-tice, Pract. Neurol. 19 (2019) 5–20. https://doi.org/10.1136/practneurol-2018-001899.
Y. Du, C. Li, Y.-F. Hao, C. Zhao, Q. Yan, D. Yao, L. Li, W. Zhang, Individualized regi-men of low-dose rituximab monotherapy for new-onset AChR-positive generalized myas-thenia gravis., J. Neurol. (2022). https://doi.org/10.1007/s00415-022-11048-4.
R.J. Nowak, C.S. Coffey, J.M. Goldstein, M.M. Dimachkie, M. Benatar, J.T. Kissel, G.I. Wolfe, T.M. Burns, M.L. Freimer, S. Nations, V. Granit, A.G. Smith, D.P. Richman, E. Ciafaloni, M.T. Al-Lozi, L.A. Sams, D. Quan, E. Ubogu, B. Pearson, A. Sharma, J.W. Yankey, L. Uribe, M. Shy, A.A. Amato, R. Conwit, K.C. O’Connor, D.A. Hafler, M.E. Cudkowicz, R.J. Barohn, on behalf of the NeuroNEXT NN103 BeatMG Study Team, Phase 2 Trial of Rituximab in Acetylcholine Receptor Antibody-Positive Generalized My-asthenia Gravis: The BeatMG Study, Neurology. 98 (2022) e376–e389. https://doi.org/10.1212/WNL.0000000000013121.
S. Brauner, A. Eriksson-Dufva, M.A. Hietala, T. Frisell, R. Press, F. Piehl, Comparison Between Rituximab Treatment for New-Onset Generalized Myasthenia Gravis and Re-fractory Generalized Myasthenia Gravis, JAMA Neurol. 77 (2020) 974–981. https://doi.org/10.1001/jamaneurol.2020.0851.
S.K. Sahai, A.H. Maghzi, R.A. Lewis, Rituximab in late-onset myasthenia gravis is safe and effective., Muscle Nerve. 62 (2020) 377–380. https://doi.org/10.1002/mus.26876.
T. Litchman, B. Roy, A. Kumar, A. Sharma, V. Njike, R.J. Nowak, Differential response to rituximab in anti-AChR and anti-MuSK positive myasthenia gravis patients: a single-center retrospective study., J. Neurol. Sci. 411 (2020) 116690. https://doi.org/10.1016/j.jns.2020.116690.
J. Lu, H. Zhong, S. Jing, L. Wang, J. Xi, J. Lu, L. Zhou, C. Zhao, Low-dose rituximab every 6 months for the treatment of acetylcholine receptor-positive refractory generalized myasthenia gravis., Muscle Nerve. 61 (2020) 311–315. https://doi.org/10.1002/mus.26790.
R.H. Roda, L. Doherty, A.M. Corse, Stopping oral steroid-sparing agents at initiation of rituximab in myasthenia gravis., Neuromuscul. Disord. NMD. 29 (2019) 554–561. https://doi.org/10.1016/j.nmd.2019.06.002.
K. Choi, Y.-H. Hong, S.-H. Ahn, S.-H. Baek, J.-S. Kim, J.-Y. Shin, J.-J. Sung, Repeated low-dose rituximab treatment based on the assessment of circulating B cells in patients with refractory myasthenia gravis, Ther. Adv. Neurol. Disord. 12 (2019) 1756286419871187–1756286419871187. https://doi.org/10.1177/1756286419871187.
R. Topakian, F. Zimprich, S. Iglseder, N. Embacher, M. Guger, K. Stieglbauer, D. Langenscheidt, J. Rath, S. Quasthoff, P. Simschitz, J. Wanschitz, D. Windisch, P. Müller, D. Oel, G. Schustereder, S. Einsiedler, C. Eggers, W. Löscher, High efficacy of rituximab for myasthenia gravis: a comprehensive nationwide study in Austria., J. Neurol. 266 (2019) 699–706. https://doi.org/10.1007/s00415-019-09191-6.
S. Jing, J. Lu, J. Song, S. Luo, L. Zhou, C. Quan, J. Xi, C. Zhao, Effect of low-dose rituximab treatment on T- and B-cell lymphocyte imbalance in refractory myasthenia gravis., J. Neuroimmunol. 332 (2019) 216–223. https://doi.org/10.1016/j.jneuroim.2019.05.004.
N. Singh, V. Goyal, Rituximab as induction therapy in refractory myasthenia gravis: 18 month follow-up study., J. Neurol. 266 (2019) 1596–1600. https://doi.org/10.1007/s00415-019-09296-y.
G. Beecher, D. Anderson, Z.A. Siddiqi, Rituximab in refractory myasthenia gravis: Ex-tended prospective study results, Muscle Nerve. 58 (2018) 452–455. https://doi.org/10.1002/mus.26156.
O. Landon-Cardinal, D. Friedman, M. Guiguet, P. Laforêt, N. Heming, E. Salort-Campana, F. Jouen, Y. Allenbach, O. Boyer, L. Chatenoud, B. Eymard, T. Sharshar, O. Benveniste, Efficacy of Rituximab in Refractory Generalized anti-AChR Myasthenia Gravis., J. Neuromuscul. Dis. 5 (2018) 241–249. https://doi.org/10.3233/JND-180300.
K.R. Robeson, A. Kumar, B. Keung, D.B. DiCapua, E. Grodinsky, H.S. Patwa, P.A. Stathopoulos, J.M. Goldstein, K.C. O’Connor, R.J. Nowak, Durability of the Rituximab Response in Acetylcholine Receptor Autoantibody–Positive Myasthenia Gravis, JAMA Neurol. 74 (2017) 60–66. https://doi.org/10.1001/jamaneurol.2016.4190.
V. Afanasiev, S. Demeret, F. Bolgert, B. Eymard, P. Laforêt, O. Benveniste, Resistant myasthenia gravis and rituximab: A monocentric retrospective study of 28 patients, Neu-romuscul. Disord. 27 (2017) 251–258. https://doi.org/10.1016/j.nmd.2016.12.004.
J. Peres, R. Martins, J.D. Alves, A. Valverde, Rituximab in generalized myasthenia gravis: Clinical, quality of life and cost-utility analysis, Porto Biomed. J. 2 (2017) 81–85. https://doi.org/10.1016/j.pbj.2017.02.002.
N. Collongues, O. Casez, A. Lacour, C. Tranchant, P. Vermersch, J. de Seze, C. Lebrun, Rituximab in refractory and non-refractory myasthenia: a retrospective multicenter study., Muscle Nerve. 46 (2012) 687–691. https://doi.org/10.1002/mus.23412.
R.J. Nowak, D.B. Dicapua, N. Zebardast, J.M. Goldstein, Response of patients with re-fractory myasthenia gravis to rituximab: a retrospective study, Ther. Adv. Neurol. Disord. 4 (2011) 259–266. https://doi.org/10.1177/1756285611411503.
S. Blum, D. Gillis, H. Brown, R. Boyle, R. Henderson, D. Heyworth-Smith, P. Hogan, P. Kubler, C. Lander, N. Limberg, P. Pillans, K. Prain, C. Staples, M. Walsh, P. McCombe, R. Wong, Use and monitoring of low dose rituximab in myasthenia gravis., J. Neurol. Neurosurg. Psychiatry. 82 (2011) 659–663. https://doi.org/10.1136/jnnp.2010.220475.
P. Maddison, J. McConville, M.E. Farrugia, N. Davies, M. Rose, F. Norwood, H. Jungbluth, S. Robb, D. Hilton-Jones, The use of rituximab in myasthenia gravis and Lambert-Eaton myasthenic syndrome., J. Neurol. Neurosurg. Psychiatry. 82 (2011) 671–673. https://doi.org/10.1136/jnnp.2009.197632.
C. Lindberg, M. Bokarewa, Rituximab for severe myasthenia gravis--experience from five patients., Acta Neurol. Scand. 122 (2010) 225–228. https://doi.org/10.1111/j.1600-0404.2010.01345.x.
I. Illa, J. Diaz-Manera, R. Rojas-Garcia, J. Pradas, A. Rey, R. Blesa, C. Juarez, E. Gallar-do, Sustained response to Rituximab in anti-AChR and anti-MuSK positive Myasthenia Gravis patients., J. Neuroimmunol. 201–202 (2008) 90–94. https://doi.org/10.1016/j.jneuroim.2008.04.039.
C. Zhao, M. Pu, D. Chen, J. Shi, Z. Li, J. Guo, G. Zhang, Effectiveness and Safety of Rituximab for Refractory Myasthenia Gravis: A Systematic Review and Single-Arm Me-ta-Analysis., Front. Neurol. 12 (2021) 736190. https://doi.org/10.3389/fneur.2021.736190.
R. Tandan, M.K. 2nd Hehir, W. Waheed, D.B. Howard, Rituximab treatment of myasthe-nia gravis: A systematic review., Muscle Nerve. 56 (2017) 185–196. https://doi.org/10.1002/mus.25597.
V. Di Stefano, A. Lupica, M.G. Rispoli, A. Di Muzio, F. Brighina, C. Rodolico, Rituxi-mab in AChR subtype of myasthenia gravis: systematic review, J. Neurol. Neurosurg. Psychiatry. 91 (2020) 392–395. https://doi.org/10.1136/jnnp-2019-322606.
D. Maloney, T. Liles, D. Czerwinski, C. Waldichuk, J. Rosenberg, A. Grillo-Lopez, R. Levy, Phase I clinical trial using escalating single-dose infusion of chimeric anti-CD20 monoclonal antibody (IDEC-C2B8) in patients with recurrent B-cell lymphoma, Blood. 84 (1994) 2457–2466. https://doi.org/10.1182/blood.V84.8.2457.2457.
A.A. den Broeder, L.M. Verhoef, J. Fransen, R. Thurlings, B.J.F. van den Bemt, S. Teerenstra, N. Boers, N. den Broeder, F.H.J. van den Hoogen, Ultra-low dose of rituxi-mab in rheumatoid arthritis: study protocol for a randomised controlled trial, Trials. 18 (2017) 403. https://doi.org/10.1186/s13063-017-2134-x.
T. Li, G.-Q. Zhang, Y. Li, S.-A. Dong, N. Wang, M. Yi, Y. Qi, H. Zhai, L. Yang, F.-D. Shi, C.-S. Yang, Efficacy and safety of different dosages of rituximab for refractory gen-eralized AChR myasthenia gravis: A meta-analysis., J. Clin. Neurosci. Off. J. Neurosurg. Soc. Australas. 85 (2021) 6–12. https://doi.org/10.1016/j.jocn.2020.11.043.
S.-H. Kim, N.Y. Park, K.H. Kim, J.-W. Hyun, H.J. Kim, Rituximab-Induced Hypogam-maglobulinemia and Risk of Infection in Neuromyelitis Optica Spectrum Disorders: A 14-Year Real-Life Experience, Neurol. - Neuroimmunol. Neuroinflammation. 9 (2022) e1179. https://doi.org/10.1212/NXI.0000000000001179.
M.L. Vo, Rituximab Treatment for AChR Myasthenia Gravis: Results of the BeatMG Study, Neurol. Alert. (2022). https://www.reliasmedia.com/articles/149162-rituximab-treatment-for-achr-myasthenia-gravis-results-of-the-beatmg-study.
D. Menon, C. Barnett, V. Bril, Novel Treatments in Myasthenia Gravis, Front. Neurol. 11 (2020) 538. https://doi.org/10.3389/fneur.2020.00538.
D.B. Drachman, Another Failed Trial of Treatment for Myasthenia Gravis, NEJM J. Watch. (2021). https://www.jwatch.org/na54416/2021/12/21/another-failed-trial-treatment-myasthenia-gravis.
A. Behin, R. Le Panse, New Pathways and Therapeutic Targets in Autoimmune Myas-thenia Gravis, J. Neuromuscul. Dis. 5 (2018) 265–277. https://doi.org/10.3233/JND-170294.
V. Damato, J. Theorell, A. Al-Diwani, A.-K. Kienzler, M. Makuch, B. Sun, A. Handel, D. Akdeniz, A. Berretta, S. Ramanathan, A. Fower, D. Whittam, E. Gibbons, N. McGlashan, E. Green, S. Huda, M. Woodhall, J. Palace, F. Sheerin, P. Waters, M.I. Leite, A. Jacob, S.R. Irani, Rituximab abrogates aquaporin-4–specific germinal center ac-tivity in patients with neuromyelitis optica spectrum disorders, Proc. Natl. Acad. Sci. 119 (2022) e2121804119. https://doi.org/10.1073/pnas.2121804119.
E. Crickx, P. Chappert, A. Sokal, S. Weller, I. Azzaoui, A. Vandenberghe, G. Bonnard, G. Rossi, T. Fadeev, S. Storck, J. Fadlallah, V. Meignin, E. Rivière, S. Audia, B. Godeau, M. Michel, J.-C. Weill, C.-A. Reynaud, M. Mahévas, Rituximab-resistant splen-ic memory B cells and newly engaged naive B cells fuel relapses in patients with immune thrombocytopenia, Sci. Transl. Med. 13 (2021) eabc3961. https://doi.org/10.1126/scitranslmed.abc3961.
R. Huda, New Approaches to Targeting B Cells for Myasthenia Gravis Therapy, Front. Immunol. 11 (2020) 240. https://doi.org/10.3389/fimmu.2020.00240.
B.A.C. Cree, J.L. Bennett, H.J. Kim, B.G. Weinshenker, S.J. Pittock, D.M. Wingerchuk, K. Fujihara, F. Paul, G.R. Cutter, R. Marignier, A.J. Green, O. Aktas, H.-P. Hartung, F.D. Lublin, J. Drappa, G. Barron, S. Madani, J.N. Ratchford, D. She, D. Cimbora, E. Katz, Inebilizumab for the treatment of neuromyelitis optica spectrum disorder (N-MOmentum): a double-blind, randomised placebo-controlled phase 2/3 trial, The Lancet. 394 (2019) 1352–1363. https://doi.org/10.1016/S0140-6736(19)31817-3.
B. Keung, K.R. Robeson, D.B. DiCapua, J.B. Rosen, K.C. O’Connor, J.M. Goldstein, R.J. Nowak, Long-term benefit of rituximab in MuSK autoantibody myasthenia gravis pa-tients., J. Neurol. Neurosurg. Psychiatry. 84 (2013) 1407–1409. https://doi.org/10.1136/jnnp-2012-303664.
E. Cortés-Vicente, R. Rojas-Garcia, J. Díaz-Manera, L. Querol, C. Casasnovas, A. Guer-rero-Sola, J.L. Muñoz-Blanco, J.E. Bárcena-Llona, C. Márquez-Infante, J. Pardo, E.M. Martínez-Fernández, M. Usón, P. Oliva-Nacarino, T. Sevilla, I. Illa, The impact of rituxi-mab infusion protocol on the long-term outcome in anti-MuSK myasthenia gravis, Ann. Clin. Transl. Neurol. 5 (2018) 710–716. https://doi.org/10.1002/acn3.564.
R. Jiang, M.L. Fichtner, K.B. Hoehn, P. Stathopoulos, R.J. Nowak, S.H. Kleinstein, K.C. O’Connor, Single-cell repertoire tracing identifies rituximab refractory B cells during my-asthenia gravis relapses, Immunology, 2019. https://doi.org/10.1101/840389.
M.L. Fichtner, K.B. Hoehn, E.E. Ford, M. Mane-Damas, S. Oh, P. Waters, A.S. Payne, M.L. Smith, C.T. Watson, M. Losen, P. Martinez-Martinez, R.J. Nowak, S.H. Kleinstein, K.C. O’Connor, Reemergence of pathogenic, autoantibody-producing B cell clones in myasthenia gravis following B cell depletion therapy, MedRxiv. (2022) 2022.07.21.22277677. https://doi.org/10.1101/2022.07.21.22277677.
R. Koul, A. Al Futaisi, R. Abdwani, Rituximab in Severe Seronegative Juvenile Myas-thenia Gravis: Review of the Literature, Pediatr. Neurol. 47 (2012) 209–212. https://doi.org/10.1016/j.pediatrneurol.2012.05.017.
G. Masi, Y. Li, T. Karatz, M.C. Pham, S.R. Oxendine, R.J. Nowak, J.T. Guptill, K.C. O’Connor, The clinical need for clustered AChR cell-based assay testing of seronegative MG, J. Neuroimmunol. 367 (2022) 577850. https://doi.org/10.1016/j.jneuroim.2022.577850.
I. Schiavetti, M. Ponzano, A. Signori, F. Bovis, L. Carmisciano, M.P. Sormani, Severe outcomes of COVID-19 among patients with multiple sclerosis under anti-CD-20 thera-pies: A systematic review and meta-analysis., Mult. Scler. Relat. Disord. 57 (2022) 103358. https://doi.org/10.1016/j.msard.2021.103358.
Downloads
Published
Issue
Section
License
Copyright (c) 2023 Panagiotis Kanatas, Kevin C. O'Connor, Panos Stathopoulos
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.
