Reshaping neuroimmunology: diagnosis and treatment in the era of precision medicine

Abstract

Precision medicine has revolutionized the field of neuroimmunology, with innovative approaches that characterize diseases based on their biology, deeper understanding of the factors leading to heterogeneity within the same disease, development of targeted therapies, and strategies to tailor therapies to each patient. This review explores the impact of precision medicine on various neuroimmunological conditions, including multiple sclerosis (MS), neuromyelitis optica spectrum disorder (NMOSD), myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD), optic neuritis, autoimmune encephalitis, and immune-mediated neuropathies. We discuss advances in disease subtyping, recognition of novel entities, promising biomarkers, and the development of more selective monoclonal antibodies and cutting-edge synthetic cell-based immunotherapies in neuroimmunological disorders. In addition, we analyze the challenges related to affordability and equity in the implementation of these emerging technologies, especially in situations with limited resources.

Resumo

A medicina de precisão está revolucionando o campo da neuroimunologia, com uma abordagem inovadora caracterizada pela classificação de doenças com base em sua biologia, compreensão mais profunda dos fatores que levam à heterogeneidade dentro da mesma doença, desenvolvimento de terapias com alvos específicos e estratégias para adaptar as terapias a cada paciente. Esta revisão explora o impacto da medicina de precisão em várias condições neuroimunológicas, incluindo esclerose múltipla (EM), distúrbio do espectro da neuromielite óptica (NMOSD), doença associada ao anticorpo anti-glicoproteína da mielina do oligodendrócito (MOGAD), neurites ópticas, encefalites autoimunes e neuropatias imunomediadas. Discutimos avanços na subclassificação de doenças, reconhecimento de novas entidades, biomarcadores promissores e desenvolvimento de anticorpos monoclonais mais seletivos e imunoterapias de ponta baseadas em células sintéticas para as condições acima. Além disso, analisamos os desafios relacionados com acessibilidade e equidade na implementação dessas tecnologias emergentes, especialmente em ambientes com recursos limitados.

Keywords

Precision Medicine - Autoimmune Diseases of the Nervous System - Multiple Sclerosis - Neuromyelitis Optica - Biomarkers - Immunomodulation - Pharmacogenetics

Palavras-chave

Medicina de Precisão - Doenças Autoimunes do Sistema Nervoso - Esclerose Múltipla - Neuromielite Óptica - Biomarcadores - Imunomodulação - Farmacogenética

Authors' Contributions

All authors provided intellectual contribution to content, helped draft and critically reviewed the manuscript.

Publikationsverlauf

Eingereicht: 02. Oktober 2023

Angenommen: 17. November 2023

Artikel online veröffentlicht:
29. Dezember 2023

• References

• 1 Chitnis T, Prat A. A roadmap to precision medicine for multiple sclerosis. Mult Scler 2020; 26 (05) 522-532
• 2 Lublin FD, Reingold SC, Cohen JA. et al. Defining the clinical course of multiple sclerosis: the 2013 revisions. Neurology 2014; 83 (03) 278-286
• 3 Kuhlmann T, Moccia M, Coetzee T. et al; International Advisory Committee on Clinical Trials in Multiple Sclerosis. Multiple sclerosis progression: time for a new mechanism-driven framework. Lancet Neurol 2023; 22 (01) 78-88
• 4 Pitt D, Lo CH, Gauthier SA. et al. Toward Precision Phenotyping of Multiple Sclerosis. Neurol Neuroimmunol Neuroinflamm 2022; 9 (06) 1-8
• 5 Lennon VA, Wingerchuk DM, Kryzer TJ. et al. A serum autoantibody marker of neuromyelitis optica: distinction from multiple sclerosis. Lancet 2004; 364 (9451): 2106-2112
• 6 Sato DK, Callegaro D, Lana-Peixoto MA. et al. Distinction between MOG antibody-positive and AQP4 antibody-positive NMO spectrum disorders. Neurology 2014; 82 (06) 474-481
• 7 Kitley J, Waters P, Woodhall M. et al. Neuromyelitis optica spectrum disorders with aquaporin-4 and myelin-oligodendrocyte glycoprotein antibodies: a comparative study. JAMA Neurol 2014; 71 (03) 276-283
• 8 Banwell B, Bennett JL, Marignier R. et al. Diagnosis of myelin oligodendrocyte glycoprotein antibody-associated disease: International MOGAD Panel proposed criteria. Lancet Neurol 2023; 22 (03) 268-282
• 9 Takai Y, Misu T, Fujihara K, Aoki M. Pathology of myelin oligodendrocyte glycoprotein antibody-associated disease: a comparison with multiple sclerosis and aquaporin 4 antibody-positive neuromyelitis optica spectrum disorders. Front Neurol 2023; 14: 1209749
• 10 Barreras P, Vasileiou ES, Filippatou AG. et al. Long-term Effectiveness and Safety of Rituximab in Neuromyelitis Optica Spectrum Disorder and MOG Antibody Disease. Neurology 2022; 99 (22) e2504-e2516
• 11 Jarius S, Paul F, Aktas O. et al. MOG encephalomyelitis: international recommendations on diagnosis and antibody testing. J Neuroinflammation 2018; 15 (01) 134
• 12 Petzold A, Fraser CL, Abegg M. et al. Diagnosis and classification of optic neuritis. Lancet Neurol 2022; 21 (12) 1120-1134
• 13 Binks SNM, Klein CJ, Waters P, Pittock SJ, Irani SR. LGI1, CASPR2 and related antibodies: a molecular evolution of the phenotypes. J Neurol Neurosurg Psychiatry 2018; 89 (05) 526-534
• 14 Graus F, Titulaer MJ, Balu R. et al. A clinical approach to diagnosis of autoimmune encephalitis. Lancet Neurol 2016; 15 (04) 391-404
• 15 Dalmau J, Graus F. Diagnostic criteria for autoimmune encephalitis: utility and pitfalls for antibody-negative disease. Lancet Neurol 2023; 22 (06) 529-540
• 16 Fehmi J, Vale T, Keddie S, Rinaldi S. Nodal and paranodal antibody-associated neuropathies. Pract Neurol 2021; 21: 284-291
• 17 Uncini A, Mathis S, Vallat JM. New classification of autoimmune neuropathies based on target antigens and involved domains of myelinated fibres. J Neurol Neurosurg Psychiatry 2022; 93 (01) 57-67
• 18 Calvi A, Haider L, Prados F, Tur C, Chard D, Barkhof F. In vivo imaging of chronic active lesions in multiple sclerosis. Mult Scler 2022; 28 (05) 683-690
• 19 Bodini B, Tonietto M, Airas L, Stankoff B. Positron emission tomography in multiple sclerosis - straight to the target. Nat Rev Neurol 2021; 17 (11) 663-675
• 20 Bittner S, Oh J, Havrdová EK, Tintoré M, Zipp F. The potential of serum neurofilament as biomarker for multiple sclerosis. Brain 2021; 144 (10) 2954-2963
• 21 Ning L, Wang B. Neurofilament light chain in blood as a diagnostic and predictive biomarker for multiple sclerosis: A systematic review and meta-analysis. PLoS One 2022; 17 (09) e0274565
• 22 Hauser SL, Bar-Or A, Cohen JA. et al; ASCLEPIOS I and ASCLEPIOS II Trial Groups. Ofatumumab versus Teriflunomide in Multiple Sclerosis. N Engl J Med 2020; 383 (06) 546-557
• 23 Waters P, Fadda G, Woodhall M. et al; Canadian Pediatric Demyelinating Disease Network. Serial Anti-Myelin Oligodendrocyte Glycoprotein Antibody Analyses and Outcomes in Children With Demyelinating Syndromes. JAMA Neurol 2020; 77 (01) 82-93
• 24 Huda S, Whittam D, Jackson R. et al. Predictors of relapse in MOG antibody associated disease: a cohort study. BMJ Open 2021; 11 (11) e055392
• 25 Wendel EM, Thonke HS, Bertolini A. et al; BIOMARKER Study Group. Temporal Dynamics of MOG Antibodies in Children With Acquired Demyelinating Syndrome. Neurol Neuroimmunol Neuroinflamm 2022; 9 (06) e200035
• 26 Jitprapaikulsan J, Fryer JP, Majed M. et al. Clinical utility of AQP4-IgG titers and measures of complement-mediated cell killing in NMOSD. Neurol Neuroimmunol Neuroinflamm 2020; 7 (04) e727
• 27 Yin HX, Wang YJ, Liu MG. et al. Aquaporin-4 Antibody Dynamics and Relapse Risk in Seropositive Neuromyelitis Optica Spectrum Disorder Treated with Immunosuppressants. Ann Neurol 2023; 93 (06) 1069-1081
• 28 Aktas O, Smith MA, Rees WA. et al; N-MOmentum scientific group and the N-MOmentum study investigators. Serum Glial Fibrillary Acidic Protein: A Neuromyelitis Optica Spectrum Disorder Biomarker. Ann Neurol 2021; 89 (05) 895-910
• 29 Kim H, Lee EJ, Kim S. et al. Longitudinal follow-up of serum biomarkers in patients with neuromyelitis optica spectrum disorder. Mult Scler 2022; 28 (04) 512-521
• 30 Dillenseger A, Weidemann ML, Trentzsch K. et al. Digital Biomarkers in Multiple Sclerosis. Brain Sci 2021; 11 (11) 1519
• 31 Kulakova OG, Tsareva EY, Lvovs D, Favorov AV, Boyko AN, Favorova OO. Comparative pharmacogenetics of multiple sclerosis: IFN-β versus glatiramer acetate. Pharmacogenomics 2014; 15 (05) 679-685
• 32 Zarzuelo Romero MJ, Pérez Ramírez C, Carrasco Campos MI. et al. Therapeutic Value of Single Nucleotide Polymorphisms on the Efficacy of New Therapies in Patients with Multiple Sclerosis. J Pers Med 2021; 11 (05) 335
• 33 Díaz-Villamarín X, Piñar-Morales R, Barrero-Hernández FJ, Antúnez-Rodríguez A, Cabeza-Barrera J, Morón-Romero R. Pharmacogenetics of siponimod: A systematic review. Biomed Pharmacother 2022; 153: 113536
• 34 Kim S-H, Jeong IH, Hyun JW. et al. Treatment Outcomes With Rituximab in 100 Patients With Neuromyelitis Optica: Influence of FCGR3A Polymorphisms on the Therapeutic Response to Rituximab. JAMA Neurol 2015; 72 (09) 989-995
• 35 Bennett JL, Aktas O, Rees WA. et al; N-MOmentum study investigators. Association between B-cell depletion and attack risk in neuromyelitis optica spectrum disorder: An exploratory analysis from N-MOmentum, a double-blind, randomised, placebo-controlled, multicentre phase 2/3 trial. EBioMedicine 2022; 86: 104321
• 36 Nishimura J, Yamamoto M, Hayashi S. et al. Genetic variants in C5 and poor response to eculizumab. N Engl J Med 2014; 370 (07) 632-639
• 37 Cree BAC, Bennett JL, Kim HJ. et al; N-MOmentum study investigators. Inebilizumab for the treatment of neuromyelitis optica spectrum disorder (N-MOmentum): a double-blind, randomised placebo-controlled phase 2/3 trial. Lancet 2019; 394 (10206): 1352-1363
• 38 Yamamura T, Kleiter I, Fujihara K. et al. Trial of Satralizumab in Neuromyelitis Optica Spectrum Disorder. N Engl J Med 2019; 381 (22) 2114-2124
• 39 Traboulsee A, Greenberg BM, Bennett JL. et al. Safety and efficacy of satralizumab monotherapy in neuromyelitis optica spectrum disorder: a randomised, double-blind, multicentre, placebo-controlled phase 3 trial. Lancet Neurol 2020; 19 (05) 402-412
• 40 Pittock SJ, Berthele A, Fujihara K. et al. Eculizumab in Aquaporin-4-Positive Neuromyelitis Optica Spectrum Disorder. N Engl J Med 2019; 381 (07) 614-625
• 41 Pittock SJ, Barnett M, Bennett JL. et al. Ravulizumab in Aquaporin-4-Positive Neuromyelitis Optica Spectrum Disorder. Ann Neurol 2023; 93 (06) 1053-1068
• 42 Pittock SJ, Zekeridou A, Weinshenker BG. Hope for patients with neuromyelitis optica spectrum disorders - from mechanisms to trials. Nat Rev Neurol 2021; 17 (12) 759-773
• 43 Krämer J, Bar-Or A, Turner TJ, Wiendl H. Bruton tyrosine kinase inhibitors for multiple sclerosis. Nat Rev Neurol 2023; 19 (05) 289-304
• 44 Martin E, Aigrot MS, Grenningloh R. et al. Bruton's Tyrosine Kinase Inhibition Promotes Myelin Repair. Brain Plast 2020; 5 (02) 123-133
• 45 Dybowski S, Torke S, Weber MS, Targeting B. Targeting B Cells and Microglia in Multiple Sclerosis With Bruton Tyrosine Kinase Inhibitors: A Review. JAMA Neurol 2023; 80 (04) 404-414
• 46 Montalban X, Arnold DL, Weber MS. et al; Evobrutinib Phase 2 Study Group. Placebo-Controlled Trial of an Oral BTK Inhibitor in Multiple Sclerosis. N Engl J Med 2019; 380 (25) 2406-2417
• 47 Reich DS, Arnold DL, Vermersch P. et al; Tolebrutinib Phase 2b Study Group. Safety and efficacy of tolebrutinib, an oral brain-penetrant BTK inhibitor, in relapsing multiple sclerosis: a phase 2b, randomised, double-blind, placebo-controlled trial. Lancet Neurol 2021; 20 (09) 729-738
• 48 von Baumgarten L, Stauss HJ, Lünemann JD. Synthetic Cell-Based Immunotherapies for Neurologic Diseases. Neurol Neuroimmunol Neuroinflamm 2023; 10 (05) e200139
• 49 Granit V, Benatar M, Kurtoglu M. et al; MG-001 Study Team. Safety and clinical activity of autologous RNA chimeric antigen receptor T-cell therapy in myasthenia gravis (MG-001): a prospective, multicentre, open-label, non-randomised phase 1b/2a study. Lancet Neurol 2023; 22 (07) 578-590
• 50 Qin C, Tian DS, Zhou LQ. et al. Anti-BCMA CAR T-cell therapy CT103A in relapsed or refractory AQP4-IgG seropositive neuromyelitis optica spectrum disorders: phase 1 trial interim results. Signal Transduct Target Ther 2023; 8 (01) 5
• 51 Gupta S, Simic M, Sagan SA. et al. CAR-T Cell-Mediated B-Cell Depletion in Central Nervous System Autoimmunity. Neurol Neuroimmunol Neuroinflamm 2023; 10 (02) e200080
• 52 Lu CY, Terry V, Thomas DM. Precision medicine: affording the successes of science. NPJ Precis Oncol 2023; 7 (01) 3
• 53 Khoury MJ, Bowen S, Dotson WD. et al. Health equity in the implementation of genomics and precision medicine: A public health imperative. Genet Med 2022; 24 (08) 1630-1639
• 54 Rocha CS, Secolin R, Rodrigues MR, Carvalho BS, Lopes-Cendes I. The Brazilian Initiative on Precision Medicine (BIPMed): fostering genomic data-sharing of underrepresented populations. NPJ Genom Med 2020; 5: 42