Advertisement

Can rheumatologists stop causing demyelinating disease?

  • David Baker
    Correspondence
    Corresponding author.
    Affiliations
    Barts and The London School of Medicine and Dentistry, Blizard Institute, Queen Mary University of London, E1 2AT, United Kingdom
    Search for articles by this author
  • Charalambos Hadjicharalambous
    Affiliations
    Barts and The London School of Medicine and Dentistry, Blizard Institute, Queen Mary University of London, E1 2AT, United Kingdom
    Search for articles by this author
  • Sharmilee Gnanapavan
    Affiliations
    Barts and The London School of Medicine and Dentistry, Blizard Institute, Queen Mary University of London, E1 2AT, United Kingdom

    Clinical Board:Medicine (Neuroscience), The Royal London Hospital, Barts Health NHS Trust, London, United Kingdom
    Search for articles by this author
  • Gavin Giovannoni
    Affiliations
    Barts and The London School of Medicine and Dentistry, Blizard Institute, Queen Mary University of London, E1 2AT, United Kingdom

    Clinical Board:Medicine (Neuroscience), The Royal London Hospital, Barts Health NHS Trust, London, United Kingdom
    Search for articles by this author

      Highlights

      • Tumour necrosis factor inhibitors and other rheumatoid arthritis treatments can infrequently induce demyelination disease.
      • Disease modifying anti-rheumatoid drugs may increase pathogenic memory B cell responses and inhibit potentially pathogenic ectopic B cell follicles.
      • Poor central nervous penetration of disease modifying anti-rheumatoid drugs may not limit brain located ectopic B cell follicles, whilst inhibiting joint disease

      Abstract

      Background

      Perhaps the most informative experiments in human disease are clinical trials and notably, responses to specific therapies can be highly-informative to help understand disease pathogenesis. There are reagents that inhibit a variety of different autoimmune conditions, such as CD20 memory B cell depleters that are active in both multiple sclerosis (MS), rheumatoid arthritis (RA) and other conditions, suggesting influences on common immune mechanisms in different diseases. However, a notable exception seemed to be the use of tumour necrosis factor (TNF) inhibitors that limits RA, yet seem to, rarely, trigger demyelination and induce MS. This was first seen with TNF-inhibiting monoclonal antibodies and TNF-receptor-immunoglobulin fusion proteins. However, this is also seen with tyrosine and Janus kinase inhibitors that inhibit RA, yet induce demyelinating disease in some individuals

      Purpose

      To provide an overview, from a B cell centric perspective, that may underpin the biology that links arthritis treatments to the development of demyelinating disease.

      Conclusions

      It is apparent that the disease modifying anti-rheumatoid drugs that cause demyelination share a number of common features. These agents tend to inhibit TNF-receptor signalling, augment or exhibit limited inhibitor activity on class-switched memory B cells and importantly appear to be relatively excluded from the central nervous system (CNS). They will thus not target ectopic B cell follicles in the CNS, unlike that occurring in peripheral autoimmunity as seen with anti-TNF treatments in RA. Agents such as ibudilast and some Janus kinase inhibitors that inhibit TNF and clearly penetrate the CNS do not appear to induce demyelination and may even be neuroprotective. It remains to be established whether selection or development of CNS penetrant agents may avoid CNS-complications of treatments for RA. Clearly, further studies are warranted

      Graphical abstract

      Keywords

      Abbreviations:

      CNS (central nervous system (CNS)), CSF (cerebrospinal fluid), DMARDS (disease modifying anti-rheumatoid drugs), MS (multiple sclerosis, rheumatoid, arthritis, TNF, tumour necrosis factor)
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Multiple Sclerosis and Related Disorders
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Adlowitz D.G.
        • Barnard J.
        • Biear J.N.
        • Cistrone C.
        • Owen T.
        • Wang W.
        • Palanichamy A.
        • Ezealah E.
        • Campbell D.
        • Wei C.
        • Looney R.J.
        • Sanz I.
        • Anolik J.H.
        Expansion of activated peripheral blood memory B cells in rheumatoid arthritis, impact of B cell depletion therapy, and biomarkers of response.
        PLoS One. 2015; 10e0128269
        • Ammar M.
        • Louati N.
        • Frikha I.
        • Medhaffar M.
        • Ghozzi H.
        • Elloumi M.
        • Menif H.
        • Zeghal K.
        • Ben Mahmoud L.
        Overexpression of P-glycoprotein and resistance to Imatinib in chronic myeloid leukemia patients.
        J. Clin. Lab. Anal. 2020; 34: e23374
        • Anagnostou T.
        • Litzow M.R.
        Spotlight on ponatinib in the treatment of chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia: patient selection and perspectives.
        Blood Lymphat. Cancer. 2017; 8: 1-9
        • Andersson M.
        • Svenungsson E.
        • Khademi M.
        • Lampa J.
        • Brundin L.
        • Wallström E.
        No signs of immunoactivation in the cerebrospinal fluid during treatment with infliximab.
        Ann. Rheum. Dis. 2006; 65: 1237-1240
        • Araki M.
        • Matsuoka T.
        • Miyamoto K.
        • Kusunoki S.
        • Okamoto T.
        • Murata M.
        • Miyake S.
        • Aranami T.
        • Yamamura T.
        Efficacy of the anti-IL-6 receptor antibody tocilizumab in neuromyelitis optica: a pilot study.
        Neurology. 2014; 82: 1302-1306
        • Arnaud L.
        • Lebrun-Vignes B.
        • Salem J.E.
        Checkpoint inhibitor-associated immune arthritis.
        Ann. Rheum. Dis. 2019; 78: e68
        • Atzeni F.
        • Nucera V.
        • Gerratana E.
        • Cirillo M.
        • Marino F.
        • Miceli G.
        • Sangari D.
        • Boccassini L.
        • Masala I.F.
        Concerns about the safety of anti-TNF agents when treating rheumatic diseases.
        Expert Opin. Drug Saf. 2020; 19 (Jun): 695-705
        • Baker D.
        • Butler D.
        • Scallon B.J.
        • O'Neill J.K.
        • Turk J.L.
        • Feldmann M.
        Control of established experimental allergic encephalomyelitis by inhibition of tumor necrosis factor (TNF) activity within the central nervous system using monoclonal antibodies and TNF receptor-immunoglobulin fusion proteins.
        Eur. J. Immunol. 1994; 24: 2040-2048
        • Baker D.
        • Marta M.
        • Pryce G.
        • Giovannoni G.
        Schmierer K memory B cells are major targets for effective immunotherapy in relapsing multiple sclerosis.
        EBioMedicine. 2017; 16: 41-50
        • Baker D.
        • Pryce G.
        • Amor S.
        • Giovannoni G.
        • Schmierer K.
        Learning from other autoimmunities to understand targeting of B cells to control multiple sclerosis.
        Brain. 2018; 141: 2834-2847
        • Barkhof F.
        • Hulst H.E.
        • Drulovic J.
        • Uitdehaag B.M.
        • Matsuda K.
        • Landin R.
        MN166-001 Investigators. Ibudilast in relapsing-remitting multiple sclerosis: a neuroprotectant?.
        Neurology. 2010; 74: 1033-1040
        • Beauchemin P.
        • Carruthers R.
        MS arising during Tocilizumab therapy for rheumatoid arthritis.
        Mult. Scler. 2016; 22: 254-256
        • Berraondo P.
        Mechansism of action for different checkpoint inhibitors.
        HemaSphere. 2019; 3: 28-30
        • Bielekova B.
        • Richert N.
        • Howard T.
        • Packer A.N.
        • Blevins G.
        • Ohayon J.
        • McFarland H.F.
        • Stürzebecher C.S.
        • Martin R.
        Treatment with the phosphodiesterase type-4 inhibitor rolipram fails to inhibit blood-brain barrier disruption in multiple sclerosis.
        Mult. Scler. 2009; 15: 1206-1214
        • Bronte V.
        • Ugel S.
        • Tinazzi E.
        • Vella A.
        • De Sanctis F.
        • Canè S.
        • Batani V.
        • Trovato R.
        • Fiore A.
        • Petrova V.
        • Hofer F.
        • Barouni R.M.
        • Musiu C.
        • Caligola S.
        • Pinton L.
        • Torroni L.
        • Polati E.
        • Donadello K.
        • Friso S.
        • Pizzolo F.
        • Iezzi M.
        • Facciotti F.
        • Pelicci P.G.
        • Righetti D.
        • Bazzoni P.
        • Rampudda M.
        • Comel A.
        • Mosaner W.
        • Lunardi C.
        • Olivieri O.
        Baricitinib restrains the immune dysregulation in patients with severe COVID-19.
        J. Clin. Invest. 2020; 130: 6409-6416
        • Canete J.D.
        • Celis R.
        • Moll C.
        • Izquierdo E.
        • Marsal S.
        • Sanmarti R.
        • et al.
        Clinical significance of synovial lymphoid neogenesis and its reversal after anti-tumour necrosis factor alpha therapy in rheumatoid arthritis.
        Ann. Rheum. Dis. 2009; 68: 751-756
        • Chen Y.
        • Agarwal S.
        • Shaik N.M.
        • Chen C.
        • Yang Z.
        • Elmquist W.F.
        P-glycoprotein and breast cancer resistance protein influence brain distribution of dasatinib.
        J. Pharmacol. Exp. Ther. 2009; 330: 956-963
        • Cohen S.B.
        • Emery P.
        • Greenwald M.W.
        • Dougados M.
        • Furie R.A.
        • Genovese M.C.
        • Keystone E.C.
        • Loveless J.E.
        • Burmester G.R.
        • Cravets M.W.
        • Hessey E.W.
        • Shaw T.
        • Totoritis M.C.
        • REFLEX Trial Group
        Rituximab for rheumatoid arthritis refractory to anti-tumor necrosis factor therapy: Results of a multicenter, randomized, double-blind, placebo-controlled, phase III trial evaluating primary efficacy and safety at twenty-four weeks.
        Arthritis Rheum. 2006; 54: 2793-2806
        • Corsiero E.
        • Nerviani A.
        • Bombardieri M.
        • Pitzalis C.
        Ectopic lymphoid structures: powerhouse of.
        Autoimmun. Front. Immunol. 2016; 7: 430
        • Das R.
        • Bar N.
        • Ferreira M.
        • Newman A.M.
        • Zhang L.
        • Bailur J.K.
        • Bacchiocchi A.
        • Kluger H.
        • Wei W.
        • Halaban R.
        • Sznol M.
        • Dhodapkar M.V.
        • Dhodapkar K.M.
        Early B cell changes predict autoimmunity following combination immune checkpoint blockade.
        J. Clin. Invest. 2018; 128: 715-720
        • de Lavallade H.
        • Khoder A.
        • Hart M.
        • Sarvaria A.
        • Sekine T.
        • Alsuliman A.
        • Mielke S.
        • Bazeos A.
        • Stringaris K.
        • Ali S.
        • Milojkovic D.
        • Foroni L.
        • Chaidos A.
        • Cooper N.
        • Gabriel I.
        • Apperley J.
        • Belsey S.
        • Flanagan R.J.
        • Goldman J.
        • Shpall E.J.
        • Kelleher P.
        • Marin D.
        • Rezvani K.
        Tyrosine kinase inhibitors impair B-cell immune responses in CML through off-target inhibition of kinases important for cell signaling.
        Blood. 2013; 122: 227-238
        • Dobson R.
        • Giovannoni G.
        Multiple sclerosis - a review.
        Eur. J. Neurol. 2019; 26: 27-40
        • Duchow A.
        • Bellmann-Strobl J.
        Satralizumab in the treatment of neuromyelitis optica spectrum disorder.
        Neurodegener. Dis. Manag. 2021; 11: 49-59
        • Elliott M.J.
        • Maini R.N.
        • Feldmann M.
        • Kalden J.R.
        • Antoni C.
        • Smolen J.S.
        • Leeb B.
        • Breedveld F.C.
        • Macfarlane J.D.
        • Bijl H.
        • et al.
        Randomised double-blind comparison of chimeric monoclonal antibody to tumour necrosis factor alpha (cA2) versus placebo in rheumatoid arthritis.
        Lancet. 1994; 344: 1105-1110
        • Elsbernd P.M.
        • Hoffman W.R.
        • Carter J.L.
        • Wingerchuk D.M.
        Interleukin-6 inhibition with tocilizumab for relapsing MOG-IgG associated disorder (MOGAD): a case-series and review.
        Mult. Scler. Relat. Disord. 2020; 48 (16)102696https://doi.org/10.1016/j.msard.2020.102696
        • Fox R.J.
        • Coffey C.S.
        • Conwit R.
        • Cudkowicz M.E.
        • Gleason T.
        • Goodman A.
        • Klawiter E.C.
        • Matsuda K.
        • McGovern M.
        • Naismith R.T.
        • Ashokkumar A.
        • Barnes J.
        • Ecklund D.
        • Klingner E.
        • Koepp M.
        • Long J.D.
        • Natarajan S.
        • Thornell B.
        • Yankey J.
        • Bermel R.A.
        • Debbins J.P.
        • Huang X.
        • Jagodnik P.
        • Lowe M.J.
        • Nakamura K.
        • Narayanan S.
        • Sakaie K.E.
        • Thoomukuntla B.
        • Zhou X.
        • Krieger S.
        • Alvarez E.
        • Apperson M.
        • Bashir K.
        • Cohen B.A.
        • Coyle P.K.
        • Delgado S.
        • Dewitt L.D.
        • Flores A.
        • Giesser B.S.
        • Goldman M.D.
        • Jubelt B.
        • Lava N.
        • Lynch S.G.
        • Moses H.
        • Ontaneda D.
        • Perumal J.S.
        • Racke M.
        • Repovic P.
        • Riley C.S.
        • Severson C.
        • Shinnar S.
        • Suski V.
        • Weinstock-Guttman B.
        • Yadav V.
        • Zabeti A.
        • NN102/SPRINT-MS Trial Investigators
        Phase 2 trial of ibudilast in progressive multiple sclerosis.
        N. Engl. J. Med. 2018; 379: 846-855
        • Fresegna D.
        • Bullitta S.
        • Musella A.
        • Rizzo F.R.
        • De Vito F.
        • Guadalupi L.
        • Caioli S.
        • Balletta S.
        • Sanna K.
        • Dolcetti E.
        • Vanni V.
        • Bruno A.
        • Buttari F.
        • Stampanoni Bassi M.
        • Mandolesi G.
        • Centonze D.
        • Gentile A.
        Re-examining the role of TNF in MS.
        Pathog. Ther. Cells. 2020; 9: 2290
        • Friedman J.E.
        • Zabriskie J.
        • Bourganskaia E.
        A pilot study of pentoxifylline in multiple sclerosis.
        Arch. Neurol. 1996; 53: 956-957
        • Fujimoto T.
        • Sakoda S.
        • Fujimura H.
        • Yanagihara T.
        Ibudilast, a phosphodiesterase inhibitor, ameliorates experimental autoimmune encephalomyelitis in Dark August rats.
        J. Neuroimmunol. 1999; 95: 35-42
        • Genain C.P.
        • Roberts T.
        • Davis R.L.
        • Nguyen M.H.
        • Uccelli A.
        • Faulds D.
        • Li Y.
        • Hedgpeth J.
        • Hauser S.L.
        Prevention of autoimmune demyelination in non-human primates by a cAMP-specific phosphodiesterase inhibitor.
        Proc. Natl. Acad. Sci. U S A. 1995; 92: 3601-3605
        • Ghosh N.
        • Tiongson M.D.
        • Stewart C.
        • Chan K.K.
        • Jivanelli B.
        • Cappelli L.
        • Bass A.R.
        Checkpoint inhibitor-associated arthritis: a systematic review of case reports and case series.
        J. Clin. Rheumatol. 2020; https://doi.org/10.1097/RHU.0000000000001370
        • Giovannoni G.
        • Butzkueven H.
        • Dhib-Jalbut S.
        • Hobart J.
        • Kobelt G.
        • Pepper G.
        • Sormani M.P.
        • Thalheim C.
        • Traboulsee A.
        Vollmer T Brain health: time matters in multiple sclerosis.
        Mult. Scler. Relat. Disord. 2016; 9: S5-S48
        • Gonzalez Vicent M.
        • Molina B.
        • Fabregat M.
        • Segura M.
        • Diaz M.A.
        Toxoplasmosis and secondary Guillain-Barré associated with ruxolitinib as graft-versus-host disease treatment.
        Pediatr. Blood Cancer. 2019; 66 (Jan): e27446
        • Gregory A.P.
        • Dendrou C.A.
        • Attfield K.E.
        • Haghikia A.
        • Xifara D.K.
        • Butter F.
        • Poschmann G.
        • Kaur G.
        • Lambert L.
        • Leach O.A.
        • Prömel S.
        • Punwani D.
        • Felce J.H.
        • Davis S.J.
        • Gold R.
        • Nielsen F.C.
        • Siegel R.M.
        • Mann M.
        • Bell J.I.
        • McVean G.
        • Fugger L.
        TNF receptor 1 genetic risk mirrors outcome of anti-TNF therapy in multiple sclerosis.
        Nature. 2012; 488: 508-511
        • Harrington R.
        • Al Nokhatha S.A.
        • Conway R.
        JAK inhibitors in rheumatoid arthritis: an evidence-based review on the emerging clinical data.
        J. Inflamm. Res. 2020; 13 (Sep 14): 519-531
        • Hauser S.L.
        • Bar-Or A.
        • Comi G.
        • Giovannoni G.
        • Hartung H.P.
        • Hemmer B.
        • Lublin F.
        • Montalban X.
        • Rammohan K.W.
        • Selmaj K.
        • Traboulsee A.
        • Wolinsky J.S.
        • Arnold D.L.
        • Klingelschmitt G.
        • Masterman D.
        • Fontoura P.
        • Belachew S.
        • Chin P.
        • Mairon N.
        • Garren H.
        • Kappos L.
        OPERA I and OPERA II clinical investigators. Ocrelizumab versus interferon Beta-1a in relapsing multiple sclerosis.
        N Engl. J. Med. 2017; 376: 221-234
        • Hoshino H.
        • Shirai Y.
        • Konishi H.
        • Yamamura T.
        • Shimizu N.
        Efficacy of tocilizumab for fulminant multiple sclerosis with a tumefactive cervical lesion: a 12-year-old boy.
        Mult. Scler. Relat. Disord. 2020; 37 (Jan)101460https://doi.org/10.1016/j.msard.2019.101460
        • Illei G.G.
        • Shirota Y.
        • Yarboro C.H.
        • Daruwalla J.
        • Tackey E.
        • Takada K.
        • Fleisher T.
        • Balow J.E.
        • Lipsky P.E.
        Tocilizumab in systemic lupus erythematosus: data on safety, preliminary efficacy, and impact on circulating plasma cells from an open-label phase I dosage-escalation study.
        Arthritis Rheum. 2010; 62: 542-552
        • Inoue H.
        • Taji H.
        • Yamada K.
        • Iriyama C.
        • Saito T.
        • Kato H.
        • Yanada M.
        • Yamamoto K.
        • Matsukawa N.
        Dasatinib-induced reversible demyelinating peripheral neuropathy and successful conversion to nilotinib in chronic myelogenous leukemia.
        Intern. Med. 2020; 59: 2419-2421
        • Ishida T.
        • Akagawa N.
        • Miyata T.
        • Tominaga N.
        • Iizuka T.
        • Higashihara M.
        • Suzuki T.
        • Miyazaki K.
        Dasatinib-associated reversible demyelinating peripheral polyneuropathy in a case of chronic myeloid leukemia.
        Int. J. Hematol. 2018; 107: 373-377
        • Judge C.
        • Moheb N.
        • Melinosky C.
        Nilotinib-associated demyelinating disease (p2.2-093).
        Neurology. 2019; 92 (P2.2-093)
        • Jung Y.J.
        • Tweedie D.
        • Scerba M.T.
        • Greig N.H.
        Neuroinflammation as a factor of neurodegenerative disease: thalidomide analogs as treatments.
        Front. Cell Dev. Biol. 2019; 7: 313
        • Kemanetzoglou E.
        • Andreadou E.
        CNS demyelination with TNF-alpha Blockers.
        Curr. Neurol. Neurosci. Rep. 2017; 17: 36
        • Kikuchi H.
        • Aramaki K.
        • Hirohata S.
        Effect of infliximab in progressive neuro-Behçet's syndrome.
        J. Neurol. Sci. 2008; 272: 99-105
        • Kleinschnitz C.
        • Meuth S.G.
        Wiendl H the trials and errors in MS therapy.
        Int. MS J. 2008; 15: 79-90
        • Kleiter I.
        • Ayzenberg I.
        • Araki M.
        • Yamamura T.
        • Gold R.
        • Tocilizumab M.S.
        • NMOSD
        Mult. Scler. 2016; 22: 1891-1892
        • Koo B.S.
        • Jo S.
        • Kwon E.
        • Shin J.H.
        • Hur J.W.
        • Kim T.H.
        Effect of biologics in the level of cytokines in the synovial fluid of patients with ankylosing spondylitis.
        Korean J. Intern. Med. 2020; 35: 465-473
        • Kraft P.
        • Schwarz T.
        • Göb E.
        • Heydenreich N.
        • Brede M.
        • Meuth S.G.
        • Kleinschnitz C.
        The phosphodiesterase-4 inhibitor rolipram protects from ischemic stroke in mice by reducing blood-brain-barrier damage, inflammation and thrombosis.
        Exp. Neurol. 2013; 247: 80-90
        • Krueger J.
        • Clark J.D.
        • Suárez-Fariñas M.
        • Fuentes-Duculan J.
        • Cueto I.
        • Wang C.Q.
        • Tan H.
        • Wolk R.
        • Rottinghaus S.T.
        • Whitley M.Z.
        • Valdez H.
        • von Schack D.
        • O'Neil S.P.
        • Reddy P.S.
        • Tatulych S.
        • A3921147 Study Investigators
        Tofacitinib attenuates pathologic immune pathways in patients with psoriasis: a randomized phase 2 study.
        J. Allergy Clin. Immunol. 2016; 137: 1079-1090
        • Kumar N.
        • Abboud H.
        Iatrogenic CNS demyelination in the era of modern biologics.
        Mult. Scler. 2019; 25: 1079-1085
        • Kunkl M.
        • Frascolla S.
        • Amormino C.
        • Volpe E.
        • Tuosto L.T.
        Helper cells: the modulators of inflammation in multiple sclerosis.
        Cells. 2020; 9: 482
        • Leandro M.J.
        • Cambridge G.
        • Ehrenstein M.R.
        • Edwards J.C.
        Reconstitution of peripheral blood B cells after depletion with rituximab in patients with rheumatoid arthritis.
        Arthritis Rheum. 2006; 54: 613-620
        • Leandro M.J.
        Anti-tumour necrosis factor therapy and B cells in rheumatoid arthritis.
        Arthritis Res. Ther. 2009; 11: 128
        • Ledeboer A.
        • Hutchinson M.R.
        • Watkins L.R.
        • Johnson K.W.
        Ibudilast (AV-411). A new class therapeutic candidate for neuropathic pain and opioid withdrawal syndromes.
        Expert Opin. Investig. Drugs. 2007; 16: 935-950
        • Magliozzi R.
        • Howell O.
        • Vora A.
        • Serafini B.
        • Nicholas R.
        • Puopolo M.
        • Reynolds R.
        • Aloisi F.
        Meningeal B-cell follicles in secondary progressive multiple sclerosis associate with early onset of disease and severe cortical pathology.
        Brain. 2007; 130: 1089-1104
        • Massoud F.
        • Ismail I.I.
        • Al-Hashel J.Y.
        • Abboud H.
        CNS demyelination during tofacitinib therapy: first report.
        Mult. Scler. Relat. Disord. 2020; 46102568https://doi.org/10.1016/j.msard.2020.102568
        • Mavropoulos A.
        • Zafiriou E.
        • Simopoulou T.
        • Brotis A.G.
        • Liaskos C.
        • Roussaki-Schulze A.
        • Katsiari C.G.
        • Bogdanos D.P.
        • Sakkas L.I.
        Apremilast increases IL-10-producing regulatory B cells and decreases proinflammatory T cells and innate cells in psoriatic arthritis and psoriasis.
        Rheumatology. 2019; 58: 2240
        • Mizwicki M.T.
        • Fiala M.
        • Magpantay L.
        Tocilizumab attenuates inflammation in ALS patients through inhibition of IL6 receptor signaling.
        Am. J. Neurodegener. Dis. 2012; 1: 305-315
        • Moser T.
        • Akgün K.
        • Proschmann U.
        • Sellner J.
        • Ziemssen T.
        The role of TH17 cells in multiple sclerosis: therapeutic implications.
        Autoimmun. Rev. 2020; 19102647
        • Naismith R.T.
        • Bermel R.A.
        • Coffey C.S.
        • Goodman A.D.
        • Fedler J.
        • Kearney M.
        • Klawiter E.C.
        • Nakamura K.
        • Narayanan S.
        • Goebel C.
        • Yankey J.
        • Klingner E.
        • Fox R.J.
        • SPRINT-MS investigators
        Effects of ibudilast on MRI measures in the phase 2 SPRINT-MS study.
        Neurology. 2020; https://doi.org/10.1212/WNL.0000000000011314
        • Novi G.
        • Bovis F.
        • Fabbri S.
        • Tazza F.
        • Gazzola P.
        • Maietta I.
        • Currò D.
        • Bruschi N.
        • Roccatagliata L.
        • Boffa G.
        • Lapucci C.
        • Pesce G.
        • Cellerino M.
        • Solaro C.
        • Laroni A.
        • Capello E.
        • Mancardi G.
        • Sormani M.
        • Inglese M.
        • Uccelli A.
        Tailoring B cell depletion therapy in MS according to memory B cell monitoring.
        Neurol. Neuroimmunol. Neuroinflamm. 2020; 7: e845
        • O'Connell J.
        • Porter J.
        • Kroeplien B.
        • Norman T.
        • Rapecki S.
        • Davis R.
        • McMillan D.
        • Arakaki T.
        • Burgin A.
        • Fox Iii D.
        • Ceska T.
        • Lecomte F.
        • Maloney A.
        • Vugler A.
        • Carrington B.
        • Cossins B.P.
        • Bourne T.
        • Lawson A.
        Small molecules that inhibit TNF signalling by stabilising an asymmetric form of the trimer.
        Nat. Commun. 2019; 10: 5795
        • Oke A.R.
        • Wheater M.
        • Karydis I.
        • Wallis D.
        Successful use of adalimumab in immune checkpoint inhibitor-associated inflammatory arthritis.
        Rheumatol. Adv. Pract. 2018; 2 (Jan 30): rky001
        • Oliveira M.C.B.
        • de Brito M.H.
        • Simabukuro M.M.
        Central nervous system demyelination associated with immune checkpoint inhibitors: review of the literature.
        Front. Neurol. 2020; 11 (Dec 11)538695https://doi.org/10.3389/fneur.2020.538695
        • Pardridge W.M.
        Blood-brain barrier and delivery of protein and gene therapeutics to brain.
        Front. Aging Neurosci. 2020; 11: 373
        • Pereira I.
        • Fialho S.
        • Castro G.
        • Zimmermann A.
        Imatinib mesylate induces clinical remission in rheumatoid arthritis.
        Jt. Bone Spine. 2010; 77: 372-373
        • Pfeuffer S.
        • Ruck T.
        • Kleinschnitz C.
        • Wiendl H.
        • Meuth S.G.
        Failed, interrupted and inconclusive trials on relapsing multiple sclerosis treatment: update 2010–2015.
        Expert Rev. Neurother. 2016; 16: 689-700
        • Porkka K.
        • Koskenvesa P.
        • Lundan T.
        • Rimpilainen J.
        • Mustjoki S.
        • Smykla R.
        • Wild R.
        • Luo R.
        • Arnan M.
        • Brethon B.
        • Eccersley L.
        • Hjorth-Hansen H.
        • Hoglund M.
        • Klamova H.
        • Knutsen H.
        • Parikh S.
        • Raffoux E.
        • Gruber F.
        • Brito-Babapulle F.
        • Dombret H.
        • Duarte R.F.
        • Elonen E.
        • Paquette R.
        • Zwaan C.M.
        • Lee F.Y.
        Dasatinib crosses the blood–brain barrier and is an efficient therapy for central nervous system Philadelphia chromosome-positive leukemia.
        Blood. 2008; 112: 1005-1112
        • Probert L.
        • Eugster H.P.
        • Akassoglou K.
        • Bauer J.
        • Frei K.
        • Lassmann H.
        Fontana A TNFR1 signalling is critical for the development of demyelination and the limitation of T-cell responses during immune-mediated CNS disease.
        Brain. 2000; 123: 2005-2019
        • Probert L.
        TNF and its receptors in the CNS: the essential, the desirable and the deleterious effects.
        Neuroscience. 2015; 302: 2-22
        • Pryce G.
        • Baker D.
        Oligoclonal bands in multiple sclerosis; Functional significance and therapeutic implications. Does the specificity matter?.
        Mult. Scler. Relat. Disord. 2018; 25: 131-137
        • Růžičková Š.
        • Cimburek Z.
        • Jarošová K.
        • Forejtová Š.
        • Vencovský J.
        Plasma cells as a marker predicting the outcome of anti-TNF therapy.
        Čes. Revmatol. 2007; 15: 179-184
        • Rafei H.
        • Jabbour E.J.
        • Kantarjian H.
        • Sinicrope K.D.
        • Kamiya-Matsuoka C.
        • Mehta R.S.
        • Daver N.G.
        • Kadia T.M.
        • Naqvi K.
        • Cortes J.
        • Konopleva M.
        Neurotoxic events associated with BCR-ABL1 tyrosine kinase inhibitors: a case series.
        Leuk. Lymphoma. 2019; 60: 3292-3295
        • Reinwald M.
        • Schleyer E.
        • Kiewe P.
        • Blau I.W.
        • Burmeister T.
        • Pursche S.
        • Neumann M.
        • Notter M.
        • Thiel E.
        • Hofmann W.K.
        • Kolb H.J.
        • Burdach S.
        • Bender H.U.
        Efficacy and pharmacologic data of second-generation tyrosine kinase inhibitor nilotinib in BCR-ABL-positive leukemia patients with central nervous system relapse after allogeneic stem cell transplantation.
        Biomed. Res. Int. 2014; 2014637059
        • Rekhi E.
        • pryce A.
        • Sohal M.
        • Dassan P.
        CNS demyelination in patients on nilotinib treatment for CML.
        J. Neurol. Neurosurg. Psychiat. 2016; 87 (e1.62-e1)
        • Richardson P.J.
        • Ottaviani S.
        • Prelle A.
        • Stebbing J.
        • Casalini G.
        • Corbellino M.
        CNS penetration of potential anti-COVID-19 drugs.
        J. Neurol. 2020; 267 (Jul): 1880-1882
        • Rieckmann P.
        • Weber F.
        • Günther A.
        • Martin S.
        • Bitsch A.
        • Broocks A.
        • Kitze B.
        • Weber T.
        • Börner T.
        Poser S pentoxifylline, a phosphodiesterase inhibitor, induces immune deviation in patients with multiple sclerosis.
        J. Neuroimmunol. 1996; 64: 193-200
        • Rizzi M.
        • Lorenzetti R.
        • Fischer K.
        • Staniek J.
        • Janowska I.
        • Troilo A.
        • Strohmeier V.
        • Erlacher M.
        • Kunze M.
        • Bannert B.
        • Kyburz D.
        • Voll R.E.
        • Venhoff N.
        • Thiel J.
        Impact of tofacitinib treatment on human B-cells in vitro and in vivo.
        J. Autoimmun. 2017; 77 (Feb): 55-66
        • Rolan P.
        • Gibbons J.A.
        • He L.
        • Chang E.
        • Jones D.
        • Gross M.I.
        • Davidson J.B.
        • Sanftner L.M.
        • Johnson K.W.
        Ibudilast in healthy volunteers: safety, tolerability and pharmacokinetics with single and multiple doses.
        Br. J. Clin. Pharmacol. 2008; 66: 792-801
        • Rolfes L.
        • Pawlitzki M.
        • Pfeuffer S.
        • Huntemann N.
        • Wiendl H.
        • Ruck T.
        Meuth SG failed, interrupted, or inconclusive trials on immunomodulatory treatment strategies in multiple sclerosis: update 2015–2020.
        BioDrugs. 2020; 34: 587-610
        • Roll P.
        • Muhammad K.
        • Schumann M.
        • Kleinart S.
        • Einsele H.
        • Dörner T.
        • Tony H.P.
        In vivo effects of the anti-interleukin-6 receptor inhibitor tocilizumab on the B cell compartment.
        Arthritis Rheum. 2011; 63: 1255
        • Rotstein D.L.
        • Sawicka K.
        • Bharatha A.
        • Montalban X.
        • Lipton J.H.
        CNS demyelination after initiating the tyrosine kinase inhibitor imatinib: a report of two cases.
        Mult. Scler. 2020; 26: 1121-1124
        • Ruddle N.H.
        • Bergman C.M.
        • McGrath K.M.
        • Lingenheld E.G.
        • Grunnet M.L.
        • Padula S.J.
        • Clark R.B.
        An antibody to lymphotoxin and tumor necrosis factor prevents transfer of experimental allergic encephalomyelitis.
        J. Exp. Med. 1990; 172: 1193-1200
        • Salinas G.F.
        • De Rycke L.
        • Barendregt B.
        • Paramarta J.E.
        • Hreggvidsdottir H.
        • Cantaert T.
        • van der Burg M.
        • Tak P.P.
        • Baeten D.
        Anti-TNF treatment blocks the induction of T cell-dependent humoral responses.
        Ann. Rheum. Dis. 2013; 72: 1037-1943
        • Scott L.J.
        Tocilizumab: a review in rheumatoid arthritis.
        Drugs. 2017; 77: 1865-1879
        • Sefia E.
        • Pryce G.
        • Meier U.C.
        • Giovannoni G.
        • Baker D.
        Depletion of CD20 B cells fails to inhibit relapsing mouse experimental autoimmune encephalomyelitis.
        Mult. Scler. Relat. Disord. 2017; 14: 46-50
        • Sengul Samanci N.
        • Ozan T.
        • Çelik E.
        • Demirelli F.H.
        Optic neuritis related to atezolizumab treatment in a patient with metastatic non-small-cell lung cancer.
        JCO Oncol. Pract. 2020; 16: 96-98
        • Smolen J.S.
        • Genovese M.C.
        • Takeuchi T.
        • Hyslop D.L.
        • Macias W.L.
        • Rooney T.
        • Chen L.
        • Dickson C.L.
        • Riddle Camp J.
        • Cardillo T.E.
        • Ishii T.
        • Winthrop K.L.
        Safety profile of baricitinib in patients with active rheumatoid arthritis with over 2 years median time in treatment.
        J. Rheumatol. 2019; 46: 7-18
        • Sommer N.
        • Löschmann P.A.
        • Northoff G.H.
        • Weller M.
        • Steinbrecher A.
        • Steinbach J.P.
        • Lichtenfels R.
        • Meyermann R.
        • Riethmüller A.
        • Fontana A.
        • et al.
        The antidepressant rolipram suppresses cytokine production and prevents autoimmune encephalomyelitis.
        Nat. Med. 1995; 1: 244-248
        • Takahashi N.
        • Miura M.
        • Scott S.
        • Saitoh H.
        • Motegi M.
        • Fujishima N.
        • kameoka Y.
        • Tagawa H.
        • Hirokawa M.
        • Sawada K.
        Dasatinib cerebrospinal fluid concentration and plasma pharmacokinetics: potential for central nervous system prophylaxis in philadelphia chromosome-positive leukemia.
        Blood. 2010; 116: 1807
        • Takemura S.
        • Klimiuk P.A.
        • Braun A.
        • Goronzy J.J.
        • Weyand C.M.
        T cell activation in rheumatoid synovium is B cell dependent.
        J. Immunol. 2001; 167: 4710-4718
        • Tanaka Y.
        • McInnes I.B.
        • Taylor P.C.
        • Byers N.L.
        • Chen L.
        • de Bono S.
        • Issa M.
        • Macias W.L.
        • Rogai V.
        • Rooney T.P.
        • Schlichting D.E.
        • Zuckerman S.H.
        • Emery P.
        Characterization and changes of lymphocyte subsets in baricitinib-treated patients with rheumatoid arthritis: an integrated analysis.
        Arthritis Rheumatol. 2018; 70: 1923-1932
        • Taylor T.R.P.
        • Galloway J.
        • Davies R.
        • Hyrich K.
        • Dobson R.
        Demyelinating events following initiation of anti-TNFα therapy in the British society for rheumatology biologics registry in rheumatoid arthritis.
        Neurol. Neuroimmunol. Neuroinflamm. 2021; 8: e992
        • Simuni T.
        • Fiske B.
        • Merchant K.
        • Coffey C.S.
        • Klingner E.
        • Caspell-Garcia C.
        • Lafontant D.E.
        • Matthews H.
        • Wyse R.K.
        • Brundin P.
        • Simon D.K.
        • Schwarzschild M.
        • Weiner D.
        • Adams J.
        • Venuto C.
        • Dawson T.M.
        • Baker L.
        • Kostrzebski M.
        • Ward T.
        • Rafaloff G.
        • Parkinson Study Group NILO-PD Investigators and Collaborators
        Efficacy of Nilotinib in Patients With Moderately Advanced Parkinson Disease: A Randomized Clinical Trial.
        JAMA Neurol. 2021; 78: 312-320
        • Trantham T.
        • Auten J.
        • Muluneh B.
        • Van Deventer H.J.
        Ruxolitinib for the treatment of lymphoma-associated hemophagocytic lymphohistiocytosis: a cautionary tale.
        Oncol. Pharm. Pract. 2020; 26: 1005-1008
        • van Oosten B.W.
        • Barkhof F.
        • Truyen L.
        • Boringa J.B.
        • Bertelsmann F.W.
        • von Blomberg B.M.
        • Woody J.N.
        • Hartung H.P.
        • Polman C.H.
        Increased MRI activity and immune activation in two multiple sclerosis patients treated with the monoclonal anti-tumor necrosis factor antibody cA2.
        Neurology. 1996; 47: 1531-1534
        • Vernon M.R.
        • Pearson L.
        • Atallah E.J.
        Resolution of rheumatoid arthritis symptoms with imatinib mesylate.
        Clin. Rheumatol. 2009; 15: 26
        • Wolf A.M.
        • Wolf D.
        • Rumpold H.
        • Ludwiczek S.
        • Enrich B.
        • Gastl G.
        • Weiss G.
        • Tilg H.
        The kinase inhibitor imatinib mesylate inhibits TNF alpha production in vitro and prevents TNF-dependent acute hepatic inflammation.
        Proc. Natl. Acad. Sci. U S A. 2005; 102: 13622-13627
        • Wolff N.C.
        • Richardson J.A.
        • Egorin M.
        • Ilaria R.L.
        The CNS is a sanctuary for leukemic cells in mice receiving imatinib mesylate for Bcr/Abl-induced leukemia.
        Blood. 2003; 101: 5010-5013
        • Yamamura T.
        • Kleiter I.
        • Fujihara K.
        • Palace J.
        • Greenberg B.
        • Zakrzewska-Pniewska B.
        • Patti F.
        • Tsai C.P.
        • Saiz A.
        • Yamazaki H.
        • Kawata Y.
        • Wright P.
        • De Seze J.
        Trial of Satralizumab in neuromyelitis optica spectrum disorder.
        N. Engl. J. Med. 2019; 381: 2114-2124
        • Zbaar S.A.
        Serum level of TNF-alpha in patients with chronic myeloid leukemia on Imatinib therapy.
        Tikr. Med. J. 2017; 22: 54-60
        • Zhang C.
        • Zhang M.
        • Qiu W.
        • Ma H.
        • Zhang X.
        • Zhu Z.
        • Yang C.S.
        • Jia D.
        • Zhang T.X.
        • Yuan M.
        • Feng Y.
        • Yang L.
        • Lu W.
        • Yu C.
        • Bennett J.L.
        • Shi F.D.
        • TANGO Study Investigators
        Safety and efficacy of tocilizumab versus azathioprine in highly relapsing neuromyelitis optica spectrum disorder (TANGO): an open-label, multicentre, randomised, phase 2 trial.
        Lancet Neurol. 2020; 19: 391-401