[Skip to Content]
[Skip to Content Landing]

Targeting B Cells and Microglia in Multiple Sclerosis With Bruton Tyrosine Kinase InhibitorsA Review

To identify the key insights or developments described in this article
1 Credit CME
Abstract

Importance  Currently, disease-modifying therapies for multiple sclerosis (MS) use 4 mechanisms of action: immune modulation, suppressing immune cell proliferation, inhibiting immune cell migration, or cellular depletion. Over the last decades, the repertoire substantially increased because of the conceptual progress that not only T cells but also B cells play an important pathogenic role in MS, fostered by the empirical success of B cell–depleting antibodies against the surface molecule CD20. Notwithstanding this advance, a continuous absence of B cells may harbor safety risks, such as a decline in the endogenous production of immunoglobulins. Accordingly, novel B cell–directed MS therapies are in development, such as inhibitors targeting Bruton tyrosine kinase (BTK).

Observations  BTK is centrally involved in the B cell receptor–mediated activation of B cells, one key requirement in the development of autoreactive B cells, but also in the activation of myeloid cells, such as macrophages and microglia. Various compounds in development differ in their binding mode, selectivity and specificity, relative inhibitory concentration, and potential to enter the central nervous system. The latter may be important in assessing whether BTK inhibition is a promising strategy to control inflammatory circuits within the brain, the key process that is assumed to drive MS progression. Accordingly, clinical trials using BTK inhibitors are currently conducted in patients with relapsing-remitting MS as well as progressive MS, so far generating encouraging data regarding efficacy and safety.

Conclusions and Relevance  While the novel approach of targeting BTK is highly promising, several questions remain unanswered, such as the long-term effects of using BTK inhibitors in the treatment of inflammatory CNS disease. Potential changes in circulating antibody levels should be evaluated and compared with B cell depletion. Also important is the potential of BTK inhibitors to enter the CNS, which depends on the given compound. Remaining questions involve where BTK inhibitors fit in the landscape of MS therapeutics. A comparative analysis of their distinct properties is necessary to identify which inhibitors may be used in relapsing vs progressive forms of MS as well as to clarify which agent may be most suitable for sequential use after anti-CD20 treatment.

Sign in to take quiz and track your certificates

Buy This Activity

JN Learning™ is the home for CME and MOC from the JAMA Network. Search by specialty or US state and earn AMA PRA Category 1 Credit(s)™ from articles, audio, Clinical Challenges and more. Learn more about CME/MOC

CME Disclosure Statement: Unless noted, all individuals in control of content reported no relevant financial relationships. If applicable, all relevant financial relationships have been mitigated.

Article Information

Accepted for Publication: December 9, 2022.

Published Online: February 13, 2023. doi:10.1001/jamaneurol.2022.5332

Corresponding Author: Martin S. Weber, MD, Department of Neuropathology, Department of Neurology, University Medical Center, Georg August University, Robert-Koch-Straße 40, 37099 Göttingen, Germany (martin.weber@med.uni-goettingen.de).

Conflict of Interest Disclosures: Dr Torke reported receiving travel support from EMD Serono and research support from the Universitätsmedizin Göttingen. Dr Weber reported receiving research support from the Deutsche Forschungsgemeinschaft (WE 3547/5-1, WE3547/7-1, in association with SFB TRR 274), Novartis, TEVA, Biogen-Idec, Roche, Merck, and the ProFutura Program of the Universitätsmedizin Göttingen; serving as an editor for PLOS One; receiving travel funding and/or speaker honoraria from Biogen-Idec, Merck Serono, Novartis, Roche, TEVA, Bayer, and Genzyme; and being an employee of the Universitätsmedizin Göttingen and Fraunhofer Gesellschaft, Germany. No other disclosures were reported.

References
1.
Gaitán  MI , de Alwis  MP , Sati  P , Nair  G , Reich  DS .  Multiple sclerosis shrinks intralesional, and enlarges extralesional, brain parenchymal veins.   Neurology. 2013;80(2):145-151. doi:10.1212/WNL.0b013e31827b916fPubMedGoogle Scholar
2.
Solomon  AJ , Schindler  MK , Howard  DB ,  et al.  “Central vessel sign” on 3T FLAIR* MRI for the differentiation of multiple sclerosis from migraine.   Ann Clin Transl Neurol. 2015;3(2):82-87. doi:10.1002/acn3.273PubMedGoogle Scholar
3.
Jarius  S , König  FB , Metz  I ,  et al.  Pattern II and pattern III MS are entities distinct from pattern I MS: evidence from cerebrospinal fluid analysis.   J Neuroinflammation. 2017;14(1):171. doi:10.1186/s12974-017-0929-zPubMedGoogle Scholar
4.
Lucchinetti  C , Brück  W , Parisi  J , Scheithauer  B , Rodriguez  M , Lassmann  H .  Heterogeneity of multiple sclerosis lesions: implications for the pathogenesis of demyelination.   Ann Neurol. 2000;47(6):707-717. doi:10.1002/1531-8249(200006)47:6<707::AID-ANA3>3.0.CO;2-QPubMedGoogle Scholar
5.
Faissner  S , Plemel  JR , Gold  R , Yong  VW .  Progressive multiple sclerosis: from pathophysiology to therapeutic strategies.   Nat Rev Drug Discov. 2019;18(12):905-922. doi:10.1038/s41573-019-0035-2PubMedGoogle Scholar
6.
Traub  J , Traffehn  S , Ochs  J ,  et al.  Dimethyl fumarate impairs differentiated B cells and fosters central nervous system integrity in treatment of multiple sclerosis.   Brain Pathol. 2019;29(5):640-657. doi:10.1111/bpa.12711PubMedGoogle Scholar
7.
Traub  JW , Pellkofer  HL , Grondey  K ,  et al.  Natalizumab promotes activation and pro-inflammatory differentiation of peripheral B cells in multiple sclerosis patients.   J Neuroinflammation. 2019;16(1):228. doi:10.1186/s12974-019-1593-2PubMedGoogle Scholar
8.
Lehmann-Horn  K , Kinzel  S , Feldmann  L ,  et al.  Intrathecal anti-CD20 efficiently depletes meningeal B cells in CNS autoimmunity.   Ann Clin Transl Neurol. 2014;1(7):490-496. doi:10.1002/acn3.71PubMedGoogle Scholar
9.
Boross  P , Leusen  JHW .  Mechanisms of action of CD20 antibodies.   Am J Cancer Res. 2012;2(6):676-690.PubMedGoogle Scholar
10.
Hauser  SL , Waubant  E , Arnold  DL ,  et al; HERMES Trial Group.  B-cell depletion with rituximab in relapsing-remitting multiple sclerosis.   N Engl J Med. 2008;358(7):676-688. doi:10.1056/NEJMoa0706383PubMedGoogle Scholar
11.
Palanichamy  A , Jahn  S , Nickles  D ,  et al.  Rituximab efficiently depletes increased CD20-expressing T cells in multiple sclerosis patients.   J Immunol. 2014;193(2):580-586. doi:10.4049/jimmunol.1400118PubMedGoogle Scholar
12.
Sabatino  JJ  Jr , Wilson  MR , Calabresi  PA , Hauser  SL , Schneck  JP , Zamvil  SS .  Anti-CD20 therapy depletes activated myelin-specific CD8+ T cells in multiple sclerosis.   Proc Natl Acad Sci U S A. 2019;116(51):25800-25807. doi:10.1073/pnas.1915309116PubMedGoogle Scholar
13.
Barmettler  S , Ong  MS , Farmer  JR , Choi  H , Walter  J .  Association of immunoglobulin levels, infectious risk, and mortality with rituximab and hypogammaglobulinemia.   JAMA Netw Open. 2018;1(7):e184169. doi:10.1001/jamanetworkopen.2018.4169PubMedGoogle Scholar
14.
Casulo  C , Maragulia  J , Zelenetz  AD .  Incidence of hypogammaglobulinemia in patients receiving rituximab and the use of intravenous immunoglobulin for recurrent infections.   Clin Lymphoma Myeloma Leuk. 2013;13(2):106-111. doi:10.1016/j.clml.2012.11.011PubMedGoogle Scholar
15.
Roberts  DM , Jones  RB , Smith  RM ,  et al.  Rituximab-associated hypogammaglobulinemia: incidence, predictors and outcomes in patients with multi-system autoimmune disease.   J Autoimmun. 2015;57:60-65. doi:10.1016/j.jaut.2014.11.009PubMedGoogle Scholar
16.
Avouac  A , Maarouf  A , Stellmann  JP ,  et al.  Rituximab-induced hypogammaglobulinemia and infections in AQP4 and MOG antibody-associated diseases.   Neurol Neuroimmunol Neuroinflamm. 2021;8(3):e977. doi:10.1212/NXI.0000000000000977PubMedGoogle Scholar
17.
Calderón-Parra  J , Múñez-Rubio  E , Fernández-Cruz  A ,  et al.  Incidence, clinical presentation, relapses and outcome of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in patients treated with anti-CD20 monoclonal antibodies.   Clin Infect Dis. 2022;74(10):1786-1794. doi:10.1093/cid/ciab700PubMedGoogle Scholar
18.
Gaitzsch  E , Passerini  V , Khatamzas  E ,  et al.  COVID-19 in patients receiving CD20-depleting immunochemotherapy for B-cell lymphoma.   Hemasphere. 2021;5(7):e603. doi:10.1097/HS9.0000000000000603PubMedGoogle Scholar
19.
Luna  G , Alping  P , Burman  J ,  et al.  Infection risks among patients with multiple sclerosis treated with fingolimod, natalizumab, rituximab, and injectable therapies.   JAMA Neurol. 2020;77(2):184-191. doi:10.1001/jamaneurol.2019.3365PubMedGoogle Scholar
20.
Zecca  C , Gobbi  C .  Long-term treatment with anti-CD20 monoclonal antibodies is untenable because of risk: YES.   Mult Scler. 2022;28(8):1173-1175. doi:10.1177/13524585221088734PubMedGoogle Scholar
21.
Bar-Or  A , Calkwood  JC , Chognot  C ,  et al.  Effect of ocrelizumab on vaccine responses in patients with multiple sclerosis: the VELOCE study.   Neurology. 2020;95(14):e1999-e2008. doi:10.1212/WNL.0000000000010380PubMedGoogle Scholar
22.
Häusler  D , Häusser-Kinzel  S , Feldmann  L ,  et al.  Functional characterization of reappearing B cells after anti-CD20 treatment of CNS autoimmune disease.   Proc Natl Acad Sci U S A. 2018;115(39):9773-9778. doi:10.1073/pnas.1810470115PubMedGoogle Scholar
23.
Nissimov  N , Hajiyeva  Z , Torke  S ,  et al.  B cells reappear less mature and more activated after their anti-CD20-mediated depletion in multiple sclerosis.   Proc Natl Acad Sci U S A. 2020;117(41):25690-25699. doi:10.1073/pnas.2012249117PubMedGoogle Scholar
24.
Park  H , Wahl  MI , Afar  DE ,  et al.  Regulation of Btk function by a major autophosphorylation site within the SH3 domain.   Immunity. 1996;4(5):515-525. doi:10.1016/S1074-7613(00)80417-3PubMedGoogle Scholar
25.
Jefferies  CA , Doyle  S , Brunner  C ,  et al.  Bruton’s tyrosine kinase is a toll/interleukin-1 receptor domain-binding protein that participates in nuclear factor kappaB activation by toll-like receptor 4.   J Biol Chem. 2003;278(28):26258-26264. doi:10.1074/jbc.M301484200PubMedGoogle Scholar
26.
Gray  P , Dunne  A , Brikos  C , Jefferies  CA , Doyle  SL , O’Neill  LA .  MyD88 adapter-like (Mal) is phosphorylated by Bruton’s tyrosine kinase during TLR2 and TLR4 signal transduction.   J Biol Chem. 2006;281(15):10489-10495. doi:10.1074/jbc.M508892200PubMedGoogle Scholar
27.
Lee  KG , Xu  S , Kang  ZH ,  et al.  Bruton’s tyrosine kinase phosphorylates toll-like receptor 3 to initiate antiviral response.   Proc Natl Acad Sci U S A. 2012;109(15):5791-5796. doi:10.1073/pnas.1119238109PubMedGoogle Scholar
28.
Hata  D , Kawakami  Y , Inagaki  N ,  et al.  Involvement of Bruton’s tyrosine kinase in FcepsilonRI-dependent mast cell degranulation and cytokine production.   J Exp Med. 1998;187(8):1235-1247. doi:10.1084/jem.187.8.1235PubMedGoogle Scholar
29.
Jongstra-Bilen  J , Puig Cano  A , Hasija  M , Xiao  H , Smith  CI , Cybulsky  MI .  Dual functions of Bruton’s tyrosine kinase and Tec kinase during Fcgamma receptor-induced signaling and phagocytosis.   J Immunol. 2008;181(1):288-298. doi:10.4049/jimmunol.181.1.288PubMedGoogle Scholar
30.
Ren  L , Campbell  A , Fang  H ,  et al.  Analysis of the effects of the Bruton’s tyrosine kinase (Btk) inhibitor ibrutinib on monocyte Fcγ receptor (FcγR) function.   J Biol Chem. 2016;291(6):3043-3052. doi:10.1074/jbc.M115.687251PubMedGoogle Scholar
31.
van der Bruggen  T , Nijenhuis  S , van Raaij  E , Verhoef  J , van Asbeck  BS .  Lipopolysaccharide-induced tumor necrosis factor alpha production by human monocytes involves the raf-1/MEK1-MEK2/ERK1-ERK2 pathway.   Infect Immun. 1999;67(8):3824-3829. doi:10.1128/IAI.67.8.3824-3829.1999PubMedGoogle Scholar
32.
Chen  SS , Chang  BY , Chang  S ,  et al.  BTK inhibition results in impaired CXCR4 chemokine receptor surface expression, signaling and function in chronic lymphocytic leukemia.   Leukemia. 2016;30(4):833-843. doi:10.1038/leu.2015.316PubMedGoogle Scholar
33.
Spaargaren  M , Beuling  EA , Rurup  ML ,  et al.  The B cell antigen receptor controls integrin activity through Btk and PLCgamma2.   J Exp Med. 2003;198(10):1539-1550. doi:10.1084/jem.20011866PubMedGoogle Scholar
34.
Glendenning  L , Gruber  R , Dufault  M ,  et al.  BTK inhibitors in cancer patients with COVID-19.   MS Virtual. 2020;26:270.Google Scholar
35.
Johnson  AJ , Harp  C , Yu  J , Goodyear  A , Crawford  JJ .  Fenebrutinib, a noncovalent, highly selective, long residence time investigational BTK inhibitor for the treatment of MS.   Mult Scler J. 2020;26:283-283.Google Scholar
36.
Crawford  JJ , Johnson  AR , Misner  DL ,  et al.  Discovery of GDC-0853: a potent, selective, and noncovalent Bruton’s tyrosine kinase inhibitor in early clinical development.   J Med Chem. 2018;61(6):2227-2245. doi:10.1021/acs.jmedchem.7b01712PubMedGoogle Scholar
37.
Goldmann  L , Duan  R , Kragh  T ,  et al.  Oral Bruton tyrosine kinase inhibitors block activation of the platelet Fc receptor CD32a (FcγRIIA): a new option in HIT?   Blood Adv. 2019;3(23):4021-4033. doi:10.1182/bloodadvances.2019000617PubMedGoogle Scholar
38.
von Hundelshausen  P , Siess  W .  Bleeding by Bruton tyrosine kinase-inhibitors: dependency on drug type and disease.   Cancers (Basel). 2021;13(5):1103. doi:10.3390/cancers13051103PubMedGoogle Scholar
39.
Liclican  A , Serafini  L , Xing  W ,  et al.  Biochemical characterization of tirabrutinib and other irreversible inhibitors of Bruton’s tyrosine kinase reveals differences in on- and off-target inhibition.   Biochim Biophys Acta Gen Subj. 2020;1864(4):129531. doi:10.1016/j.bbagen.2020.129531PubMedGoogle Scholar
40.
Chen  J , Kinoshita  T , Gururaja  T ,  et al.  The effect of Bruton’s tyrosine kinase (BTK) inhibitors on collagen-induced platelet aggregation, BTK, and tyrosine kinase expressed in hepatocellular carcinoma (TEC).   Eur J Haematol. 2018. doi:10.1111/ejh.13148PubMedGoogle Scholar
41.
Yu  H , Kong  H , Li  C ,  et al.  Bruton’s tyrosine kinase inhibitors in primary central nervous system lymphoma-evaluation of anti-tumor efficacy and brain distribution.   Transl Cancer Res. 2021;10(5):1975-1983. doi:10.21037/tcr-21-50PubMedGoogle Scholar
42.
Guo  Y , Liu  Y , Hu  N ,  et al.  Discovery of zanubrutinib (BGB-3111), a novel, potent, and selective covalent inhibitor of Bruton’s tyrosine kinase.   J Med Chem. 2019;62(17):7923-7940. doi:10.1021/acs.jmedchem.9b00687PubMedGoogle Scholar
43.
Zhang  Y , Li  Y , Zhuang  Z ,  et al.  Preliminary evaluation of zanubrutinib-containing regimens in DLBCL and the cerebrospinal fluid distribution of zanubrutinib: a 13-case series.   Front Oncol. 2021;11:760405. doi:10.3389/fonc.2021.760405PubMedGoogle Scholar
44.
Caldwell  RD , Qiu  H , Askew  BC ,  et al.  Discovery of evobrutinib: an oral, potent, and highly selective, covalent Bruton’s tyrosine kinase (BTK) inhibitor for the treatment of immunological diseases.   J Med Chem. 2019;62(17):7643-7655. doi:10.1021/acs.jmedchem.9b00794PubMedGoogle Scholar
45.
Haselmayer  P , Camps  M , Liu-Bujalski  L ,  et al.  Efficacy and pharmacodynamic modeling of the BTK inhibitor evobrutinib in autoimmune disease models.   J Immunol. 2019;202(10):2888-2906. doi:10.4049/jimmunol.1800583PubMedGoogle Scholar
46.
Piasecka-Stryczynska  K , Rejdak  K , Dyroff  M ,  et al.  Concentration of evobrutinib, a BTK inhibitor, in cerebrospinal fluid during treatment of patients with relapsing multiple sclerosis in a phase 2 study.   Mult Scler Relat Disord. 2021;51:103001. doi:10.1016/j.msard.2021.103001Google Scholar
47.
Turner  TJ , Brun  P , Ofengheim  D , Gruber  R . Comparative CNS pharmacology of tolebrutinib versus other BTK inhibitor candidates for treating MS. Presented at: ACTRIMS Forum 2022; February 24, 2022; West Palm Beach, FL.
48.
Owens  TD , Smith  PF , Redfern  A ,  et al.  Phase 1 clinical trial evaluating safety, exposure and pharmacodynamics of BTK inhibitor tolebrutinib (PRN2246, SAR442168).   Clin Transl Sci. 2022;15(2):442-450. doi:10.1111/cts.13162PubMedGoogle Scholar
49.
Zhang  B , Zhao  R , Liang  R ,  et al.  Orelabrutinib, a potent and selective Bruton’s tyrosine kinase inhibitor with superior safety profile and excellent PK/PD properties [abstract].   Cancer Res. 2020;80(16 Suppl):CT132. doi:10.1158/1538-7445.AM2020-CT132Google Scholar
50.
Song Yuqin  DL , Zhang  B , Luo  H , Zhao  R . Preliminary results of orelabrutinib concentrations in peripheral blood and cerebrospinal fluid in patients with relapsed/refractory primary or secondary CNS lymphoma. Presented at: Chinese Society of Clinical Oncology 24th Annual Meeting; 2021.
51.
Honigberg  LA , Smith  AM , Sirisawad  M ,  et al.  The Bruton tyrosine kinase inhibitor PCI-32765 blocks B-cell activation and is efficacious in models of autoimmune disease and B-cell malignancy.   Proc Natl Acad Sci U S A. 2010;107(29):13075-13080. doi:10.1073/pnas.1004594107PubMedGoogle Scholar
52.
Lipsky  A , Lamanna  N .  Managing toxicities of Bruton tyrosine kinase inhibitors.   Hematology Am Soc Hematol Educ Program. 2020;2020(1):336-345. doi:10.1182/hematology.2020000118PubMedGoogle Scholar
53.
Barf  T , Covey  T , Izumi  R ,  et al.  Acalabrutinib (ACP-196): a covalent Bruton tyrosine kinase inhibitor with a differentiated selectivity and in vivo potency profile.   J Pharmacol Exp Ther. 2017;363(2):240-252. doi:10.1124/jpet.117.242909PubMedGoogle Scholar
54.
Rogers  KA , Thompson  PA , Allan  JN ,  et al.  Phase II study of acalabrutinib in ibrutinib-intolerant patients with relapsed/refractory chronic lymphocytic leukemia.   Haematologica. 2021;106(9):2364-2373. doi:10.3324/haematol.2020.272500PubMedGoogle Scholar
55.
Fiorcari  S , Maffei  R , Vallerini  D ,  et al.  BTK inhibition impairs the innate response against fungal infection in patients with chronic lymphocytic leukemia.   Front Immunol. 2020;11:2158. doi:10.3389/fimmu.2020.02158PubMedGoogle Scholar
56.
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. doi:10.1056/NEJMoa1901981PubMedGoogle Scholar
57.
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(9):729-738. doi:10.1016/S1474-4422(21)00237-4PubMedGoogle Scholar
58.
Estupiñán  HY , Berglöf  A , Zain  R , Smith  CIE .  Comparative analysis of BTK inhibitors and mechanisms underlying adverse effects.   Front Cell Dev Biol. 2021;9:630942. doi:10.3389/fcell.2021.630942PubMedGoogle Scholar
59.
Dhillon  S .  Orelabrutinib: first approval.   Drugs. 2021;81(4):503-507. doi:10.1007/s40265-021-01482-5PubMedGoogle Scholar
60.
Sun  C , Tian  X , Lee  YS ,  et al.  Partial reconstitution of humoral immunity and fewer infections in patients with chronic lymphocytic leukemia treated with ibrutinib.   Blood. 2015;126(19):2213-2219. doi:10.1182/blood-2015-04-639203PubMedGoogle Scholar
61.
Chong  EA , Roeker  LE , Shadman  M , Davids  MS , Schuster  SJ , Mato  AR .  BTK inhibitors in cancer patients with COVID-19: “The winner will be the one who controls that chaos” (Napoleon Bonaparte).   Clin Cancer Res. 2020;26(14):3514-3516. doi:10.1158/1078-0432.CCR-20-1427PubMedGoogle Scholar
62.
Weber  MS , Nicholas  JA , Yeaman  MR .  Balancing potential benefits and risks of Bruton tyrosine kinase inhibitor therapies in multiple sclerosis during the COVID-19 pandemic.   Neurol Neuroimmunol Neuroinflamm. 2021;8(6):e1067. doi:10.1212/NXI.0000000000001067PubMedGoogle Scholar
63.
Torke  S , Pretzsch  R , Häusler  D ,  et al.  Inhibition of Bruton’s tyrosine kinase interferes with pathogenic B-cell development in inflammatory CNS demyelinating disease.   Acta Neuropathol. 2020;140(4):535-548. doi:10.1007/s00401-020-02204-zPubMedGoogle Scholar
64.
Li  R , Tang  H , Burns  JC ,  et al.  BTK inhibition limits B-cell-T-cell interaction through modulation of B-cell metabolism: implications for multiple sclerosis therapy.   Acta Neuropathol. 2022;143(4):505-521. doi:10.1007/s00401-022-02411-wPubMedGoogle Scholar
65.
Rijvers  L , van Langelaar  J , Bogers  L ,  et al.  Human T-bet+ B cell development is associated with BTK activity and suppressed by evobrutinib.   JCI Insight. 2022;7(16):e160909. doi:10.1172/jci.insight.160909PubMedGoogle Scholar
66.
Bhargava  P , Kim  S , Reyes  AA ,  et al.  Imaging meningeal inflammation in CNS autoimmunity identifies a therapeutic role for BTK inhibition.   Brain. 2021;144(5):1396-1408. doi:10.1093/brain/awab045PubMedGoogle Scholar
67.
Forsthuber  TG , Cimbora  DM , Ratchford  JN , Katz  E , Stüve  O .  B cell-based therapies in CNS autoimmunity: differentiating CD19 and CD20 as therapeutic targets.   Ther Adv Neurol Disord. 2018;11:1756286418761697. doi:10.1177/1756286418761697PubMedGoogle Scholar
68.
Maas  A , Hendriks  RW .  Role of Bruton’s tyrosine kinase in B cell development.   Dev Immunol. 2001;8(3-4):171-181. doi:10.1155/2001/28962PubMedGoogle Scholar
69.
Torke  S , Weber  MS .  Inhibition of Bruton’s tyrosine kinase as a novel therapeutic approach in multiple sclerosis.   Expert Opin Investig Drugs. 2020;29(10):1143-1150. doi:10.1080/13543784.2020.1807934PubMedGoogle Scholar
70.
Ochs  J , Nissimov  N , Torke  S ,  et al.  Proinflammatory CD20+ T cells contribute to CNS-directed autoimmunity.   Sci Transl Med. 2022;14(638):eabi4632. doi:10.1126/scitranslmed.abi4632PubMedGoogle Scholar
71.
Bhullar  KS , Lagarón  NO , McGowan  EM ,  et al.  Kinase-targeted cancer therapies: progress, challenges and future directions.   Mol Cancer. 2018;17(1):48. doi:10.1186/s12943-018-0804-2PubMedGoogle Scholar
72.
Huang  D , Zhou  T , Lafleur  K , Nevado  C , Caflisch  A .  Kinase selectivity potential for inhibitors targeting the ATP binding site: a network analysis.   Bioinformatics. 2010;26(2):198-204. doi:10.1093/bioinformatics/btp650PubMedGoogle Scholar
73.
Berglöf  A , Hamasy  A , Meinke  S ,  et al.  Targets for ibrutinib beyond B cell malignancies.   Scand J Immunol. 2015;82(3):208-217. doi:10.1111/sji.12333PubMedGoogle Scholar
74.
Dejaco  C , Duftner  C , Grubeck-Loebenstein  B , Schirmer  M .  Imbalance of regulatory T cells in human autoimmune diseases.   Immunology. 2006;117(3):289-300. doi:10.1111/j.1365-2567.2005.02317.xPubMedGoogle Scholar
75.
Lehmann-Horn  K , Schleich  E , Hertzenberg  D ,  et al.  Anti-CD20 B-cell depletion enhances monocyte reactivity in neuroimmunological disorders.   J Neuroinflammation. 2011;8:146. doi:10.1186/1742-2094-8-146PubMedGoogle Scholar
76.
Kappos  L , Hartung  HP , Freedman  MS ,  et al; ATAMS Study Group.  Atacicept in multiple sclerosis (ATAMS): a randomised, placebo-controlled, double-blind, phase 2 trial.   Lancet Neurol. 2014;13(4):353-363. doi:10.1016/S1474-4422(14)70028-6PubMedGoogle Scholar
77.
Douglas  AP , Trubiano  JA , Barr  I , Leung  V , Slavin  MA , Tam  CS .  Ibrutinib may impair serological responses to influenza vaccination.   Haematologica. 2017;102(10):e397-e399. doi:10.3324/haematol.2017.164285PubMedGoogle Scholar
78.
Pleyer  C , Ali  MA , Cohen  JI ,  et al.  Effect of Bruton tyrosine kinase inhibitor on efficacy of adjuvanted recombinant hepatitis B and zoster vaccines.   Blood. 2021;137(2):185-189. doi:10.1182/blood.2020008758PubMedGoogle Scholar
79.
Sun  C , Gao  J , Couzens  L ,  et al.  Seasonal influenza vaccination in patients with chronic lymphocytic leukemia treated with ibrutinib.   JAMA Oncol. 2016;2(12):1656-1657. doi:10.1001/jamaoncol.2016.2437PubMedGoogle Scholar
80.
Bryer  E , Paul  S , Chen  J , Pleyer  C , Wiestner  A , Sun  C .  CLL-140 booster and BTKi interruption improve response to SARS-CoV-2 vaccine in patients with CLL.   Clin Lymphoma Myeloma Leuk. 2022;22:S270–S271. doi:10.1016/S2152-2650(22)01330-1Google Scholar
81.
Ellwardt  E , Ellwardt  L , Bittner  S , Zipp  F .  Monitoring B-cell repopulation after depletion therapy in neurologic patients.   Neurol Neuroimmunol Neuroinflamm. 2018;5(4):e463. doi:10.1212/NXI.0000000000000463PubMedGoogle Scholar
82.
Becker  A , Martin  EC , Mitchell  DY ,  et al.  Safety, tolerability, pharmacokinetics, target occupancy, and concentration-QT analysis of the novel BTK inhibitor evobrutinib in healthy volunteers.   Clin Transl Sci. 2020;13(2):325-336. doi:10.1111/cts.12713PubMedGoogle Scholar
83.
Montalban  X , Shaw  J , Syed  S ,  et al. Effect of evobrutinib, a Bruton’s tyrosine kinase inhibitor, on immune cell and immunoglobulin levels over 48 weeks in a phase 2 study in relapsing multiple sclerosis. Presented at: 27th Annual Meeting of the European Charcot Foundation; November 21, 2019; Baveno, Italy
84.
Sacco  KA , Abraham  RS .  Consequences of B-cell-depleting therapy: hypogammaglobulinemia and impaired B-cell reconstitution.   Immunotherapy. 2018;10(8):713-728. doi:10.2217/imt-2017-0178PubMedGoogle Scholar
85.
Tallantyre  EC , Whittam  DH , Jolles  S ,  et al.  Secondary antibody deficiency: a complication of anti-CD20 therapy for neuroinflammation.   J Neurol. 2018;265(5):1115-1122. doi:10.1007/s00415-018-8812-0PubMedGoogle Scholar
86.
Montalban  X , Wolinsky  JS , Arnold  DL ,  et al.  Safety and efficacy of evobrutinib, a Bruton’s tyrosine kinase inhibitor in relapsing multiple sclerosis over 2.5 years of the open-label extension to a phase II trial (P5-4.001).   Neurology. 2022;98(18 Suppl):2812.Google Scholar
87.
Woyach  JA , Ruppert  AS , Heerema  NA ,  et al.  Ibrutinib regimens versus chemoimmunotherapy in older patients with untreated CLL.   N Engl J Med. 2018;379(26):2517-2528. doi:10.1056/NEJMoa1812836PubMedGoogle Scholar
88.
Costello  F , Stüve  O , Weber  MS , Zamvil  SS , Frohman  E .  Combination therapies for multiple sclerosis: scientific rationale, clinical trials, and clinical practice.   Curr Opin Neurol. 2007;20(3):281-285. doi:10.1097/WCO.0b013e328122de1bPubMedGoogle Scholar
89.
Rubenstein  JL , Fridlyand  J , Abrey  L ,  et al.  Phase I study of intraventricular administration of rituximab in patients with recurrent CNS and intraocular lymphoma.   J Clin Oncol. 2007;25(11):1350-1356. doi:10.1200/JCO.2006.09.7311PubMedGoogle Scholar
90.
Topping  J , Dobson  R , Lapin  S ,  et al.  The effects of intrathecal rituximab on biomarkers in multiple sclerosis.   Mult Scler Relat Disord. 2016;6:49-53. doi:10.1016/j.msard.2016.01.001PubMedGoogle Scholar
91.
Martin  E , Aigrot  MS , Grenningloh  R ,  et al.  Bruton’s tyrosine kinase inhibition promotes myelin repair.   Brain Plast. 2020;5(2):123-133. doi:10.3233/BPL-200100PubMedGoogle Scholar
AMA CME Accreditation Information

Credit Designation Statement: The American Medical Association designates this Journal-based CME activity activity for a maximum of 1.00  AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Successful completion of this CME activity, which includes participation in the evaluation component, enables the participant to earn up to:

  • 1.00 Medical Knowledge MOC points in the American Board of Internal Medicine's (ABIM) Maintenance of Certification (MOC) program;;
  • 1.00 Self-Assessment points in the American Board of Otolaryngology – Head and Neck Surgery’s (ABOHNS) Continuing Certification program;
  • 1.00 MOC points in the American Board of Pediatrics’ (ABP) Maintenance of Certification (MOC) program;
  • 1.00 Lifelong Learning points in the American Board of Pathology’s (ABPath) Continuing Certification program; and
  • 1.00 CME points in the American Board of Surgery’s (ABS) Continuing Certification program

It is the CME activity provider's responsibility to submit participant completion information to ACCME for the purpose of granting MOC credit.

Close
Want full access to the AMA Ed Hub?
After you sign up for AMA Membership, make sure you sign in or create a Physician account with the AMA in order to access all learning activities on the AMA Ed Hub
Buy this activity
Close
Want full access to the AMA Ed Hub?
After you sign up for AMA Membership, make sure you sign in or create a Physician account with the AMA in order to access all learning activities on the AMA Ed Hub
Buy this activity
Close
With a personal account, you can:
  • Access free activities and track your credits
  • Personalize content alerts
  • Customize your interests
  • Fully personalize your learning experience
Education Center Collection Sign In Modal Right
Close

Name Your Search

Save Search
With a personal account, you can:
  • Access free activities and track your credits
  • Personalize content alerts
  • Customize your interests
  • Fully personalize your learning experience
Close
Close

Lookup An Activity

or

My Saved Searches

You currently have no searches saved.

Close

My Saved Courses

You currently have no courses saved.

Close