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161 results on '"Stuve O"'

1. Intractable and highly active relapsing multiple sclerosis – role of alemtuzumab

Author

Dubey D, Cano CA, and Stuve O

Subjects
Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571, Neurology. Diseases of the nervous system, RC346-429
Abstract

Divyanshu Dubey,1 Christopher A Cano,1 Olaf Stuve1–3 1Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, 2Neurology Section, VA North Texas Health Care System, Medical Service, Dallas, TX, USA; 3Department of Neurology, Klinikum rechts der Isar, Technische Universität München, Munich, Germany Abstract: Alemtuzumab is a humanized recombinant monoclonal antibody that was recently approved by the US Food and Drug Administration and the European Medicines Agency for the management of relapsing forms of multiple sclerosis (MS). It has been utilized for the management of chronic lymphocytic leukemia, bone marrow and renal transplantation, or graft versus host disease. Because of its immunomodulatory properties, it was brought into clinical development in MS. One Phase II (CAMMS223) and two Phase III clinical trials (CARE-MSI and -II) have evaluated the safety and efficacy of alemtuzumab in patients with relapsing–remitting MS. Even though its efficacy profile and long-lasting effect have attracted much interest among physicians and patients, it has significant potential adverse effects that may limit its use to patients with active disease. Here, we review the history of drug development of alemtuzumab. Furthermore, we outline the postulated mechanisms of action, clinical evidence, and safety of alemtuzumab for its use as a disease-modifying agent in active and highly active MS. Keywords: alemtuzumab, multiple sclerosis, monoclonal antibody, CD52, idiopathic thrombocytopenic purpura

Published
2015

2. B lymphocytes in neuromyelitis optica.

Author

Zamvil, Scott, Yeaman, Michael, Von Buedingen, Hans-Christian, Bennett, JL, O'Connor, KC, Bar-Or, A, Zamvil, SS, Hemmer, B, Tedder, TF, von, H-C, Stuve, O, Yeaman, MR, and Smith, TJ

Abstract

Neuromyelitis optica (NMO) is an inflammatory autoimmune disorder of the CNS that predominantly affects the spinal cord and optic nerves. A majority (approximately 75%) of patients with NMO are seropositive for autoantibodies against the astrocyte water ch

Published
2015

6. Tumefactive demyelination following herbal supplement use: Cause or coincidence?

Author

Dubey, D., Golden, E., Suss, A., Cano, C., Krishnan, G., and Stuve, O.

Subjects
Ethnic, cultural, racial issues/studies, Social sciences, Women's issues/gender studies
Abstract

Byline: D. Dubey, E. Golden, A. Suss, C. Cano, G. Krishnan, O. Stuve Sir, A 32-year-old male presented with right-sided facial droop (lower-half) and dysarthria. He reported onset of speech [...]

Published
2016

7. Genome sequencing uncovers phenocopies in primary progressive multiple sclerosis

Author

Jia, X, Madireddy, L, Caillier, S, Santaniello, A, Esposito, F, Comi, G, Stuve, O, Zhou, Y, Taylor, B, Kilpatrick, T, Martinelli-Boneschi, F, Cree, BAC, Oksenberg, JR, Hauser, SL, Baranzini, SE, Jia, X, Madireddy, L, Caillier, S, Santaniello, A, Esposito, F, Comi, G, Stuve, O, Zhou, Y, Taylor, B, Kilpatrick, T, Martinelli-Boneschi, F, Cree, BAC, Oksenberg, JR, Hauser, SL, and Baranzini, SE

Abstract

OBJECTIVE: Primary progressive multiple sclerosis (PPMS) causes accumulation of neurological disability from disease onset without clinical attacks typical of relapsing multiple sclerosis (RMS). However, whether genetic variation influences the disease course remains unclear. We aimed to determine whether mutations causative of neurological disorders that share features with multiple sclerosis (MS) contribute to risk for developing PPMS. METHODS: We examined whole-genome sequencing (WGS) data from 38 PPMS and 81 healthy subjects of European ancestry. We selected pathogenic variants exclusively found in PPMS patients that cause monogenic neurological disorders and performed two rounds of replication genotyping in 746 PPMS, 3,049 RMS, and 1,000 healthy subjects. To refine our findings, we examined the burden of rare, potentially pathogenic mutations in 41 genes that cause hereditary spastic paraplegias (HSPs) in PPMS (n = 314), secondary progressive multiple sclerosis (SPMS; n = 587), RMS (n = 2,248), and healthy subjects (n = 987) genotyped using the MS replication chip. RESULTS: WGS and replication studies identified three pathogenic variants in PPMS patients that cause neurological disorders sharing features with MS: KIF5A p.Ala361Val in spastic paraplegia 10; MLC1 p.Pro92Ser in megalencephalic leukodystrophy with subcortical cysts, and REEP1 c.606 + 43G>T in Spastic Paraplegia 31. Moreover, we detected a significant enrichment of HSP-related mutations in PPMS patients compared to controls (risk ratio [RR] = 1.95; 95% confidence interval [CI], 1.27-2.98; p = 0.002), as well as in SPMS patients compared to controls (RR = 1.57; 95% CI, 1.18-2.10; p = 0.002). Importantly, this enrichment was not detected in RMS. INTERPRETATION: This study provides evidence to support the hypothesis that rare Mendelian genetic variants contribute to the risk for developing progressive forms of MS. Ann Neurol 2018;83:51-63.

Published
2018

8. Siponimod versus placebo in secondary progressive multiple sclerosis (EXPAND): a double-blind, randomised, phase 3 study

Author

Kappos, L., Bar-Or, A., Cree, B. A. C., Fox, R. J., Giovannoni, G., Gold, R., Vermersch, P., Arnold, D. L., Arnould, S., Scherz, T., Wolf, C., Wallstrom, E., Dahlke, F., Achiron, A., Achtnichts, L., Agan, K., Akman-Demir, G., Allen, A. B., Antel, J. P., Antiguedad, A. R., Apperson, M., Applebee, A. M., Ayuso, G. I., Baba, M., Bajenaru, O., Balasa, R., Balci, B. P., Barnett, M., Bass, A., Becker, V. U., Bejinariu, M., Bergh, F. T., Bergmann, A., Bernitsas, E., Berthele, A., Bhan, V., Bischof, F., Bjork, R. J., Blevins, G., Boehringer, M., Boerner, T., Bonek, R., Bowen, J. D., Bowling, A., Boyko, A. N., Boz, C., Bracknies, V., Braune, S., Brescia Morra, V., Brochet, B., Brola, W., Brownstone, P. K., Brozman, M., Brunet, D., Buraga, I., Burnett, M., Buttmann, M., Butzkueven, H., Cahill, J., Calkwood, J. C., Camu, W., Cascione, M., Castelnovo, G., Centonze, D., Cerqueira, J., Chan, A., Cimprichova, A., Cohan, S., Comi, G., Conway, J., Cooper, J. A., Corboy, J., Correale, J., Costell, B., Cottrell, D. A., Coyle, P. K., Craner, M., Cui, L., Cunha, L., Czlonkowska, A., da Silva, A. M., de Sa, J., de Seze, J., Debouverie, M., Debruyne, J., Decoo, D., Defer, G., Derfuss, T., Deri, N. H., Dihenia, B., Dioszeghy, P., Donath, V., Dubois, B., Duddy, M., Duquette, P., Edan, G., Efendi, H., Elias, S., Emrich, P. J., Estruch, B. C., Evdoshenko, E. P., Faiss, J., Fedyanin, A. S., Feneberg, W., Fermont, J., Fernandez, O. F., Ferrer, F. C., Fink, K., Ford, H., Ford, C., Francia, A., Freedman, M., Frishberg, B., Galgani, S., Garmany, G. P., Gehring, K., Gitt, J., Gobbi, C., Goldstick, L. P., Gonzalez, R. A., Grandmaison, F., Grigoriadis, N., Grigorova, O., Grimaldi, L. M. E., Gross, J., Gross-Paju, K., Gudesblatt, M., Guillaume, D., Haas, J., Hancinova, V., Hancu, A., Hardiman, O., Harmjanz, A., Heidenreich, F. R., Hengstman, G. J. D., Herbert, J., Herring, M., Hodgkinson, S., Hoffmann, O. M., Hofmann, W. E., Honeycutt, W. D., Hua, L. H., Huang, D., Huang, Y., Hupperts, R., Imre, P., Jacobs, A. K., Jakab, G., Jasinska, E., Kaida, K., Kalnina, J., Kaprelyan, A., Karelis, G., Karussis, D., Katz, A., Khabirov, F. A., Khatri, B., Kimura, T., Kister, I., Kizlaitiene, R., Klimova, E., Koehler, J., Komatineni, A., Kornhuber, A., Kovacs, K., Koves, A., Kozubski, W., Krastev, G., Krupp, L. B., Kurca, E., Lassek, C., Laureys, G., Lee, L., Lensch, E., Leutmezer, F., Li, H., Linker, R. A., Linnebank, M., Liskova, P., Llanera, C., Lu, J., Lutterotti, A., Lycke, J., Macdonell, R., Maciejowski, M., Maeurer, M., Magzhanov, R. V., Maida, E. -M., Malciene, L., Mao-Draayer, Y., Marfia, G. A., Markowitz, C., Mastorodimos, V., Matyas, K., Meca-Lallana, J., Merino, J. A. G., Mihetiu, I. G., Milanov, I., Miller, A. E., Millers, A., Mirabella, M., Mizuno, M., Montalban, X., Montoya, L., Mori, M., Mueller, S., Nakahara, J., Nakatsuji, Y., Newsome, S., Nicholas, R., Nielsen, A. S., Nikfekr, E., Nocentini, U., Nohara, C., Nomura, K., Odinak, M. M., Olsson, T., van Oosten, B. W., Oreja-Guevara, C., Oschmann, P., Overell, J., Pachner, A., Panczel, G., Pandolfo, M., Papeix, C., Patrucco, L., Pelletier, J., Piedrabuena, R., Pless, M., Polzer, U., Pozsegovits, K., Rastenyte, D., Rauer, S., Reifschneider, G., Rey, R., Rizvi, S. A., Robertson, D., Rodriguez, J. M., Rog, D., Roshanisefat, H., Rowe, V., Rozsa, C., Rubin, S., Rusek, S., Sacca, F., Saida, T., Salgado, A. V., Sanchez, V. E. F., Sanders, K., Satori, M., Sazonov, D. V., Scarpini, E. A., Schlegel, E., Schluep, M., Schmidt, S., Scholz, E., Schrijver, H. M., Schwab, M., Schwartz, R., Scott, J., Selmaj, K., Shafer, S., Sharrack, B., Shchukin, I. A., Shimizu, Y., Shotekov, P., Siever, A., Sigel, K. -O., Silliman, S., Simo, M., Simu, M., Sinay, V., Siquier, A. E., Siva, A., Skoda, O., Solomon, A., Stangel, M., Stefoski, D., Steingo, B., Stolyarov, I. D., Stourac, P., Strassburger-Krogias, K., Strauss, E., Stuve, O., Tarnev, I., Tavernarakis, A., Tello, C. R., Terzi, M., Ticha, V., Ticmeanu, M., Tiel-Wilck, K., Toomsoo, T., Tubridy, N., Tullman, M. J., Tumani, H., Turcani, P., Turner, B., Uccelli, A., Urtaza, F. J. O., Vachova, M., Valikovics, A., Walter, S., Van Wijmeersch, B., Vanopdenbosch, L., Weber, J. R., Weiss, S., Weissert, R., West, T., Wiendl, H., Wiertlewski, S., Wildemann, B., Willekens, B., Visser, L. H., Vorobeychik, G., Xu, X., Yamamura, T., Yang, Y. N., Yelamos, S. M., Yeung, M., Zacharias, A., Zelkowitz, M., Zettl, U., Zhang, M., Zhou, H., Zieman, U., Ziemssen, T., Bergmann A., Haas J., Mirabella M. (ORCID:0000-0002-7783-114X), Terzi M., Kappos, L., Bar-Or, A., Cree, B. A. C., Fox, R. J., Giovannoni, G., Gold, R., Vermersch, P., Arnold, D. L., Arnould, S., Scherz, T., Wolf, C., Wallstrom, E., Dahlke, F., Achiron, A., Achtnichts, L., Agan, K., Akman-Demir, G., Allen, A. B., Antel, J. P., Antiguedad, A. R., Apperson, M., Applebee, A. M., Ayuso, G. I., Baba, M., Bajenaru, O., Balasa, R., Balci, B. P., Barnett, M., Bass, A., Becker, V. U., Bejinariu, M., Bergh, F. T., Bergmann, A., Bernitsas, E., Berthele, A., Bhan, V., Bischof, F., Bjork, R. J., Blevins, G., Boehringer, M., Boerner, T., Bonek, R., Bowen, J. D., Bowling, A., Boyko, A. N., Boz, C., Bracknies, V., Braune, S., Brescia Morra, V., Brochet, B., Brola, W., Brownstone, P. K., Brozman, M., Brunet, D., Buraga, I., Burnett, M., Buttmann, M., Butzkueven, H., Cahill, J., Calkwood, J. C., Camu, W., Cascione, M., Castelnovo, G., Centonze, D., Cerqueira, J., Chan, A., Cimprichova, A., Cohan, S., Comi, G., Conway, J., Cooper, J. A., Corboy, J., Correale, J., Costell, B., Cottrell, D. A., Coyle, P. K., Craner, M., Cui, L., Cunha, L., Czlonkowska, A., da Silva, A. M., de Sa, J., de Seze, J., Debouverie, M., Debruyne, J., Decoo, D., Defer, G., Derfuss, T., Deri, N. H., Dihenia, B., Dioszeghy, P., Donath, V., Dubois, B., Duddy, M., Duquette, P., Edan, G., Efendi, H., Elias, S., Emrich, P. J., Estruch, B. C., Evdoshenko, E. P., Faiss, J., Fedyanin, A. S., Feneberg, W., Fermont, J., Fernandez, O. F., Ferrer, F. C., Fink, K., Ford, H., Ford, C., Francia, A., Freedman, M., Frishberg, B., Galgani, S., Garmany, G. P., Gehring, K., Gitt, J., Gobbi, C., Goldstick, L. P., Gonzalez, R. A., Grandmaison, F., Grigoriadis, N., Grigorova, O., Grimaldi, L. M. E., Gross, J., Gross-Paju, K., Gudesblatt, M., Guillaume, D., Haas, J., Hancinova, V., Hancu, A., Hardiman, O., Harmjanz, A., Heidenreich, F. R., Hengstman, G. J. D., Herbert, J., Herring, M., Hodgkinson, S., Hoffmann, O. M., Hofmann, W. E., Honeycutt, W. D., Hua, L. H., Huang, D., Huang, Y., Hupperts, R., Imre, P., Jacobs, A. K., Jakab, G., Jasinska, E., Kaida, K., Kalnina, J., Kaprelyan, A., Karelis, G., Karussis, D., Katz, A., Khabirov, F. A., Khatri, B., Kimura, T., Kister, I., Kizlaitiene, R., Klimova, E., Koehler, J., Komatineni, A., Kornhuber, A., Kovacs, K., Koves, A., Kozubski, W., Krastev, G., Krupp, L. B., Kurca, E., Lassek, C., Laureys, G., Lee, L., Lensch, E., Leutmezer, F., Li, H., Linker, R. A., Linnebank, M., Liskova, P., Llanera, C., Lu, J., Lutterotti, A., Lycke, J., Macdonell, R., Maciejowski, M., Maeurer, M., Magzhanov, R. V., Maida, E. -M., Malciene, L., Mao-Draayer, Y., Marfia, G. A., Markowitz, C., Mastorodimos, V., Matyas, K., Meca-Lallana, J., Merino, J. A. G., Mihetiu, I. G., Milanov, I., Miller, A. E., Millers, A., Mirabella, M., Mizuno, M., Montalban, X., Montoya, L., Mori, M., Mueller, S., Nakahara, J., Nakatsuji, Y., Newsome, S., Nicholas, R., Nielsen, A. S., Nikfekr, E., Nocentini, U., Nohara, C., Nomura, K., Odinak, M. M., Olsson, T., van Oosten, B. W., Oreja-Guevara, C., Oschmann, P., Overell, J., Pachner, A., Panczel, G., Pandolfo, M., Papeix, C., Patrucco, L., Pelletier, J., Piedrabuena, R., Pless, M., Polzer, U., Pozsegovits, K., Rastenyte, D., Rauer, S., Reifschneider, G., Rey, R., Rizvi, S. A., Robertson, D., Rodriguez, J. M., Rog, D., Roshanisefat, H., Rowe, V., Rozsa, C., Rubin, S., Rusek, S., Sacca, F., Saida, T., Salgado, A. V., Sanchez, V. E. F., Sanders, K., Satori, M., Sazonov, D. V., Scarpini, E. A., Schlegel, E., Schluep, M., Schmidt, S., Scholz, E., Schrijver, H. M., Schwab, M., Schwartz, R., Scott, J., Selmaj, K., Shafer, S., Sharrack, B., Shchukin, I. A., Shimizu, Y., Shotekov, P., Siever, A., Sigel, K. -O., Silliman, S., Simo, M., Simu, M., Sinay, V., Siquier, A. E., Siva, A., Skoda, O., Solomon, A., Stangel, M., Stefoski, D., Steingo, B., Stolyarov, I. D., Stourac, P., Strassburger-Krogias, K., Strauss, E., Stuve, O., Tarnev, I., Tavernarakis, A., Tello, C. R., Terzi, M., Ticha, V., Ticmeanu, M., Tiel-Wilck, K., Toomsoo, T., Tubridy, N., Tullman, M. J., Tumani, H., Turcani, P., Turner, B., Uccelli, A., Urtaza, F. J. O., Vachova, M., Valikovics, A., Walter, S., Van Wijmeersch, B., Vanopdenbosch, L., Weber, J. R., Weiss, S., Weissert, R., West, T., Wiendl, H., Wiertlewski, S., Wildemann, B., Willekens, B., Visser, L. H., Vorobeychik, G., Xu, X., Yamamura, T., Yang, Y. N., Yelamos, S. M., Yeung, M., Zacharias, A., Zelkowitz, M., Zettl, U., Zhang, M., Zhou, H., Zieman, U., Ziemssen, T., Bergmann A., Haas J., Mirabella M. (ORCID:0000-0002-7783-114X), and Terzi M.

Abstract

Background: No treatment has consistently shown efficacy in slowing disability progression in patients with secondary progressive multiple sclerosis (SPMS). We assessed the effect of siponimod, a selective sphingosine 1-phosphate (S1P) receptor1,5 modulator, on disability progression in patients with SPMS. Methods: This event-driven and exposure-driven, double-blind, phase 3 trial was done at 292 hospital clinics and specialised multiple sclerosis centres in 31 countries. Using interactive response technology to assign numbers linked to treatment arms, patients (age 18–60 years) with SPMS and an Expanded Disability Status Scale score of 3·0–6·5 were randomly assigned (2:1) to once daily oral siponimod 2 mg or placebo for up to 3 years or until the occurrence of a prespecified number of confirmed disability progression (CDP) events. The primary endpoint was time to 3-month CDP. Efficacy was assessed for the full analysis set (ie, all randomly assigned and treated patients); safety was assessed for the safety set. This trial is registered with ClinicalTrials.gov, number NCT01665144. Findings: 1651 patients were randomly assigned between Feb 5, 2013, and June 2, 2015 (1105 to the siponimod group, and 546 to the placebo group). One patient did not sign the consent form, and five patients did not receive study drug, all of whom were in the siponimod group. 1645 patients were included in the analyses (1099 in the siponimod group and 546 in the placebo). At baseline, the mean time since first multiple sclerosis symptoms was 16·8 years (SD 8·3), and the mean time since conversion to SPMS was 3·8 years (SD 3·5); 1055 (64%) patients had not relapsed in the previous 2 years, and 918 (56%) of 1651 needed walking assistance. 903 (82%) patients receiving siponimod and 424 (78%) patients receiving placebo completed the study. 288 (26%) of 1096 patients receiving siponimod and 173 (32%) of 545 patients receiving placebo had 3-month CDP (hazard ratio 0·79, 95% CI 0·65–0·95; relative

Published
2018

10. Five-year outcomes of halt-MS: high-dose immunosuppressive therapy and autologous hematopoietic cell transplantation for severe relapsing-remitting multiple sclerosis

Author

Nash, R, Hutton, G, Racke, M, Poppat, U, Devine, S, Georges, G, Griffith, L, Muraro, P, Openshaw, H, Sayre, P, Stuve, O, Arnold, D, McConville, K, Wundes, A, Kraft, G, and Bowen, J

Subjects
Transplantation, Science & Technology, Oncology, Immunology, Biophysics, 1103 Clinical Sciences, Hematology, Life Sciences & Biomedicine
Published
2016

12. consideration on discontinuing natalizumab for the treatment of multiple sclerosis

Author

BERGER JR, CENTONZE D, CONFAVREUX C, CUTTER G, GIOVANNONI G, GOLD R, HARTUNG HP, LUBLIN F, MIRAVALLE A, MONTALBAN X, O' CONNOR P, OLSSON T, POLMAN CH, STUVE O, WOLINSKY JS, ZIEMSSEN T., COMI , GIANCARLO, Berger, Jr, Centonze, D, Comi, Giancarlo, Confavreux, C, Cutter, G, Giovannoni, G, Gold, R, Hartung, Hp, Lublin, F, Miravalle, A, Montalban, X, O' CONNOR, P, Olsson, T, Polman, Ch, Stuve, O, Wolinsky, J, and Ziemssen, T.

Published
2010

13. Therapeutic considerations for disease progression in multiple sclerosis: evidence, experience, and future expectations

Author

Frohman EM, Stuve O, Havrdova E, Corboy J, Achiron A, Zivadinov R, Sorensen PS, Phillips JT, Weinshenker B, Hawker K, Hartung HP, Steinman L, Zamvil S, Cree BAC, Hauser S, Weiner H, Racke MK, FILIPPI , MASSIMO, Frohman, Em, Stuve, O, Havrdova, E, Corboy, J, Achiron, A, Zivadinov, R, Sorensen, P, Phillips, Jt, Weinshenker, B, Hawker, K, Hartung, Hp, Steinman, L, Zamvil, S, Cree, Bac, Hauser, S, Weiner, H, Racke, Mk, and Filippi, Massimo

Published
2005

14. Treatment of Neuromyelitis Optica: Review and Recommendations

Author

Kimbrough, D, Fujihara, K, Jacob, A, Lana-Peixoto, M, Isabel Leite, M, Levy, M, Marignier, R, Nakashima, I, Palace, J, De Seze, J, Stuve, O, Tenembaum, SN, Traboulsee, A, Waubant, E, Weinshenker, BG, Wingerchuk, D, and Biorepository, Guthy Jackson Charitable Foundation Clinical Consortium and

Subjects
medicine.medical_specialty, Neuromyelitis optica, business.industry, Multiple sclerosis, Azathioprine, General Medicine, medicine.disease, Dermatology, Article, Transverse myelitis, Neurology, Prednisone, Immunology, Demyelinating disease, medicine, Optic neuritis, Rituximab, Neurology (clinical), business, medicine.drug
Abstract

Neuromyelitis optica (NMO) is an autoimmune demyelinating disease preferentially targeting the optic nerves and spinal cord. Once regarded as a variant of multiple sclerosis (MS), NMO is now recognized to be a different disease with unique pathology and immunopathogenesis that does not respond to traditional MS immunomodulators such as interferons. Preventive therapy in NMO has focused on a range of immunosuppressive medications, none of which have been validated in a rigorous randomized trial. However, multiple retrospective and a few recent prospective studies have provided evidence for the use of six medications for the prevention of NMO exacerbations: azathioprine, rituximab, mycophenolate mofetil, prednisone, methotrexate and mitoxantrone. This review provides a comprehensive analysis of each of these medications in NMO and concludes with a set of recommended consensus practices. Copyright 2012 Elsevier B.V.

Published
2012

15. Disability outcome measures in multiple sclerosis clinical trials: current status and future prospects

Author

Cohen, Jeffrey A., Reingold, Stephen C., Polman, Chris H., International Advisory Committee On Clinical Trials In Multiple Sclerosis Polman, Wolinsky Js C. H., Barkhof, F., Balcer, L. J., Banwell, B., Calabresi, P., Clanet, M., Cohen, J. A., Comi, G., Cutter, G. R., Freedman, M. S., Goodman, A. D., Kappos, L., Kieseier, B. C., Lubetzki, C., Lublin, F. D., Miller, A., Montalban, X., O'Connor, P., Petkau, J., Pozzilli, Carlo, Reingold, S. C., Sørensen, P. S., Sormani, M. P., Stuve, O., Thompson, A. J., Wolinsky, Jerry S., Neurology, and NCA - Multiple Sclerosis and Other Neuroinflammatory Diseases

Subjects
medicine.medical_specialty, Activities of daily living, Multiple Sclerosis, MEDLINE, Alternative medicine, Retina, Disability Evaluation, Quality of life (healthcare), Activities of Daily Living, Medicine, Humans, Intensive care medicine, Randomized Controlled Trials as Topic, Neurologic Examination, Expanded Disability Status Scale, business.industry, Multiple sclerosis, Brain, medicine.disease, Magnetic Resonance Imaging, Clinical trial, Multiple sclerosis functional composite, Physical therapy, Disease Progression, Neurology (clinical), business, Biomarkers, Tomography, Optical Coherence
Abstract

Many of the available disability outcome measures used in clinical trials of multiple sclerosis are insensitive to change over time, inadequately validated, or insensitive to patient-perceived health status or quality of life. Increasing focus on therapies that slow or reverse disability progression makes it essential to refine existing measures or to develop new tools. Major changes to the expanded disability status scale should be avoided to prevent the loss of acceptance by regulators as a measure for primary outcomes in trials that provide substantial evidence of effectiveness. Rather, we recommend practical refinements. Conversely, although substantial data support the multiple sclerosis functional composite as an alternative measure, changes to its component tests and scoring method are needed. Novel approaches, including the use of composite endpoints, patient-reported outcomes, and measurement of biomarkers, show promise as adjuncts to the current disability measures, but are insufficiently validated to serve as substitutes. A collaborative approach that involves academic experts, regulators, industry representitives, and funding agencies is needed to most effectively develop disability outcome measures.

Published
2012

18. Defining the clinical course of multiple sclerosis: The 2013 revisions

Author

Lublin, F. D., primary, Reingold, S. C., additional, Cohen, J. A., additional, Cutter, G. R., additional, Sorensen, P. S., additional, Thompson, A. J., additional, Wolinsky, J. S., additional, Balcer, L. J., additional, Banwell, B., additional, Barkhof, F., additional, Bebo, B., additional, Calabresi, P. A., additional, Clanet, M., additional, Comi, G., additional, Fox, R. J., additional, Freedman, M. S., additional, Goodman, A. D., additional, Inglese, M., additional, Kappos, L., additional, Kieseier, B. C., additional, Lincoln, J. A., additional, Lubetzki, C., additional, Miller, A. E., additional, Montalban, X., additional, O'Connor, P. W., additional, Petkau, J., additional, Pozzilli, C., additional, Rudick, R. A., additional, Sormani, M. P., additional, Stuve, O., additional, Waubant, E., additional, and Polman, C. H., additional

Published
2014
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19. OP007 Anti-MAdCAM monoclonal antibody PF-00547659 does not affect immune surveillance in the central nervous system of anti-TNF and immunosuppressant experienced Crohn's disease patients who are anti-TNF inadequate responders: Results from the TOSCA study

Author

D'Haens, G., primary, Vermeire, S., additional, Cataldi, F., additional, Vogelsang, H., additional, Allez, M., additional, Desreumaux, P., additional, Van Gossum, A., additional, Baumgart, D., additional, Sandborn, W.J., additional, Gorelick, K.J., additional, Ransohoff, R., additional, Stuve, O., additional, Cheng, J., additional, Rivers, S., additional, Comer, G.M., additional, Jin, B., additional, Pradhan, V., additional, Hassan-Zahraee, M., additional, Kaminski, A., additional, and Reinisch, W., additional

Published
2014
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22. BAF312, a Selective Sphingosine-1-Phosphate Receptor Modulator Improves MRI and Clinical Outcomes in Relapsing-Remitting Multiple Sclerosis (RRMS) (S30.001)

Author

Stuve, O., primary, Selmaj, K., additional, Li, D., additional, Hartung, H.-P., additional, Hemmer, B., additional, Kappos, L., additional, Freedman, M., additional, Rieckmann, P., additional, Montalban, X., additional, Zhang Auberson, L., additional, Pohlmann, H., additional, Mercier, F., additional, Dahlke, F., additional, and Wallstrom, E., additional

Published
2012
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23. Memantine for cognitive impairment in multiple sclerosis: a randomized placebo-controlled trial

Author

Lovera, JF, primary, Frohman, E., additional, Brown, TR, additional, Bandari, D., additional, Nguyen, L., additional, Yadav, V., additional, Stuve, O., additional, Karman, J., additional, Bogardus, K., additional, Heimburger, G., additional, Cua, L., additional, Remingon, G., additional, Fowler, J., additional, Monahan, T., additional, Kilcup, S., additional, Courtney, Y., additional, McAleenan, J., additional, Butler, K., additional, Wild, K., additional, Whitham, R., additional, and Bourdette, D., additional

Published
2010
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26. Immunologic, clinical, and radiologic status 14 months after cessation of natalizumab therapy

Author

Stuve, O., primary, Cravens, P. D., additional, Frohman, E. M., additional, Phillips, J. T., additional, Remington, G. M., additional, von Geldern, G., additional, Cepok, S., additional, Singh, M. P., additional, Cohen Tervaert, J. W., additional, De Baets, M., additional, MacManus, D., additional, Miller, D. H., additional, Radu, E. W., additional, Cameron, E. M., additional, Monson, N. L., additional, Zhang, S., additional, Kim, R., additional, Hemmer, B., additional, and Racke, M. K., additional

Published
2008
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30. Folgen des Absetzens von Natalizumab auf die Krankheitsaktivität und das Immunsystem bei der Multiplen Sklerose

Author

Stuve, O, primary, Cravens, P, additional, Frohman, E, additional, Phillips, J, additional, Marra, C, additional, Miller, D, additional, Radü, EW, additional, von Geldern, G, additional, Cepok, S, additional, Monson, N, additional, Cohen Tervaert, J, additional, De Baets, M, additional, Kim, R, additional, Racke, M, additional, and Hemmer, B, additional

Published
2007
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38. Critical appraisal of the role of fingolimod in the treatment of multiple sclerosis

Author

Warnke C, Stüve O, Hartung HP, Fogdell-Hahn A, and Kieseier B

Subjects
Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571, Neurology. Diseases of the nervous system, RC346-429
Abstract

Clemens Warnke1,2, Olaf Stüve3,4, Hans-Peter Hartung1, Anna Fogdell-Hahn2, Bernd C Kieseier11Department of Neurology, Heinrich-Heine-University, Düsseldorf, Germany; 2Department of Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden; 3Department of Neurology, Dallas Veterans Affairs Medical Center, TX, USA; 4Department of Neurology, University of Texas Southwestern Medical Center at Dallas, TX, USAAbstract: This review summarizes Phase III clinical trial data available for fingolimod. The main purpose is to evaluate the benefit-risk profile of fingolimod, the first oral compound available for treatment of multiple sclerosis (MS) and just recently approved by the European authorities. The authors place this evaluation in the context of the known safety and efficacy profile of established compounds for therapy of MS to outline the current and future potential of fingolimod. The authors conclude that only long-term safety data from post-marketing surveillance plans, together with additional head-to-head studies, would allow evidence-based treatment decisions. Furthermore, risk-profile analyses including patient history, exposure data to certain pathogens, and genetic analyses may potentially help to choose the right drug for individual patients in the future. Until these approaches toward an individualized medicine have been validated, treatment decisions for one or the other compound will have to be based partly on class IV evidence. Therefore, a close dialog with the well-informed patient, secured by effective risk mitigation plans, is required to choose the compound.Keywords: FTY720, oral drug, spingosine 1-phosphate receptor

Published
2011

39. Anti-MAdCAM-1 therapy does not affect immune surveillance in the central nervous system

Author

Stuve, O., D Haens, G., Reinisch, W., Vermeire, S., Vogelsang, H., Allez, M., Pierre DESREUMAUX, Gossum, A., Baumgart, D. C., Hassan-Zahraee, M., Cheng, J., Zhang, Y., Sandborn, W., Kaminski, A., Ahmad, A., Pradhan, V., Cataldi, F., Clare, R., and Gorelick, K.

Subjects
Immunology, Immunology and Allergy
Abstract

Background Blocking integrins can be associated with an increased risk of progressive multifocal encephalopathy (PML). MAdCAM-1 is an adhesion molecule that is not constitutively expressed in healthy CNS and considered mostly gut-selective. However, MAdCAM-1 is upregulated in choroid plexus epithelium during experimental autoimmune encephalomyelitis (EAE. PF-00547659 is a fully human mAb that is highly selective for MAdCAM-1. The purpose of this study was to investigate its effect on cellular elements of immune surveillance in the CNS and blood of patients with Crohn’s disease (CD). Methods All methods were tested in a control cohort of volunteers with CD (Cohort 1). Study patients (Cohort 2) had CD and prior treatment with anti-TNF and immunosuppressant therapies. Patients underwent a lumbar puncture (LP1) followed by 3 monthly injections of 225 mg PF-00547659. After the last dose, a LP2 was performed. CSF was analyzed within 24h by multi-parameter flow cytometry. Results In Cohort 1, the lymphocyte subset percentages were the same at both time points. Cohort 2 consisted of 30 patients in whom 2 LPs were performed. Their pre-treatment lymphocyte numbers were lower than those of subjects who had stopped immunosuppressants, but otherwise results were the same. CSF lymphocytes (cells per mL) shown as geometric means (CV%). LP1: 37 patients, total lymphocytes 391 (140%), CD3+/CD4+ cells 246 (152%), CD3+/CD8+ cells 100 (126%), CD4:CD8 ratio 2.46 (57%). LP2: 30 patients, total lymphocytes 513 (137%), CD3+/CD4+ cells 332 (143%), CD3+/CD8+ cells 123 (125%), CD4:CD8 ratio 2.69 (56%). Conclusion This is the first evidence that a therapeutic dose of anti-MAdCAM-1 mAb does not affect the number and composition of leukocytes in the CNS.

41. CCL2 upregulation triggers hypoxic preconditioning-induced protection from stroke

Author

Stowe Ann M, Wacker Bradley K, Cravens Petra D, Perfater Jennifer L, Li Min K, Hu Ruilong, Freie Angela B, Stüve Olaf, and Gidday Jeffrey M

Subjects
Neurology. Diseases of the nervous system, RC346-429
Abstract

Abstract Background A brief exposure to systemic hypoxia (i.e., hypoxic preconditioning; HPC) prior to transient middle cerebral artery occlusion (tMCAo) reduces infarct volume, blood-brain barrier disruption, and leukocyte migration. CCL2 (MCP-1), typically regarded as a leukocyte-derived pro-inflammatory chemokine, can also be directly upregulated by hypoxia-induced transcription. We hypothesized that such a hypoxia-induced upregulation of CCL2 is required for HPC-induced ischemic tolerance. Methods Adult male SW/ND4, CCL2-null, and wild-type mice were used in these studies. Cortical CCL2/CCR2 message, protein, and cell-type specific immunoreactivity were determined following HPC (4 h, 8% O2) or room air control (21% O2) from 6 h through 2 weeks following HPC. Circulating leukocyte subsets were determined by multi-parameter flow cytometry in naïve mice and 12 h after HPC. CCL2-null and wild-type mice were exposed to HPC 2 days prior to tMCAo, with immunoneutralization of CCL2 during HPC achieved by a monoclonal CCL2 antibody. Results Cortical CCL2 mRNA and protein expression peaked at 12 h after HPC (both p < 0.01), predominantly in cortical neurons, and returned to baseline by 2 days. A delayed cerebral endothelial CCL2 message expression (p < 0.05) occurred 2 days after HPC. The levels of circulating monocytes (p < 0.0001), T lymphocytes (p < 0.0001), and granulocytes were decreased 12 h after HPC, and those of B lymphocytes were increased (p < 0.0001), but the magnitude of these respective changes did not differ between wild-type and CCL2-null mice. HPC did decrease the number of circulating CCR2+ monocytes (p < 0.0001) in a CCL2-dependent manner, but immunohistochemical analyses at this 12 h timepoint indicated that this leukocyte subpopulation did not move into the CNS. While HPC reduced infarct volumes by 27% (p < 0.01) in wild-type mice, CCL2-null mice subjected to tMCAo were not protected by HPC. Moreover, administration of a CCL2 immunoneutralizing antibody prior to HPC completely blocked (p < 0.0001 vs. HPC-treated mice) the development of ischemic tolerance. Conclusions The early expression of CCL2 in neurons, the delayed expression of CCL2 in cerebral endothelial cells, and CCL2-mediated actions on circulating CCR2+ monocytes, appear to be required to establish ischemic tolerance to focal stroke in response to HPC, and thus represent a novel role for this chemokine in endogenous neurovascular protection.

Published
2012
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42. Lymph node-derived donor encephalitogenic CD4+ T cells in C57BL/6 mice adoptive transfer experimental autoimmune encephalomyelitis highly express GM-CSF and T-bet

Author

Lambracht-Washington Doris, Vinnakota Ramya, Herndon Emily, Ben Li-Hong, Zacharias Tresa E, Hussain Rehana Z, Cravens Petra D, Nessler Stefan, Zamvil Scott S, Eagar Todd N, and Stüve Olaf

Subjects
Neurology. Diseases of the nervous system, RC346-429
Abstract

Abstract Experimental autoimmune encephalomyelitis (EAE) is a relevant animal model for the human demyelinating inflammatory disorder of the central nervous system (CNS), multiple sclerosis (MS). Induction of EAE by adoptive transfer allows studying the role of the donor T lymphocyte in disease pathogenesis. It has been challenging to reliably induce adoptive transfer EAE in C57BL/6 (H-2b) mice. The goal of this study was to develop a reproducible and high yield protocol for adoptive transfer EAE in C57BL/6 mice. A step-wise experimental approach permitted us to develop a protocol that resulted in a consistent relatively high disease incidence of ~70% in recipient mice. Donor mice were immunized with myelin oligodendrocyte glycoprotein (MOG)p35-55 in complete Freund's adjuvant (CFA) followed by pertussis toxin (PT). Only lymph node cells (LNC) isolated at day 12 post immunization, and restimulated in vitro for 72 hours with 10 μg/mL of MOGp35-55 and 0.5 ng/mL of interleukin-12 (IL-12) were able to transfer disease. The ability of LNC to transfer disease was associated with the presence of inflammatory infiltrates in the CNS at day 12. Interferon gamma (IFNγ) was produced at comparable levels in cell cultures prepared from mice at both day 6 and day 12 post immunization. By contrast, there was a trend towards a negative association between IL-17 and disease susceptibility in our EAE model. The amount of GM-CSF secreted was significantly increased in the culture supernatants from cells collected at day 12 post immunization versus those collected at day 6 post-immunization. Activated CD4+ T cells present in the day 12 LNC cultures maintained expression of the transcription factor T-bet, which has been shown to regulate the expression of the IL-23 receptor. Also, there was an increased prevalence of MOGp35-55-specific CD4+ T cells in day 12 LNC after in vitro re-stimulation. In summary, encephalitogenic LNC that adoptively transfer EAE in C57BL/6 mice were not characterized by a single biomarker in our study, but by a composite of inflammatory markers. Our data further suggest that GM-CSF expression by CD4+ T cells regulated by IL-23 contributes to their encephalitogenicity in our EAE model.

Published
2011
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43. Mechanisms of action of disease-modifying agents and brain volume changes in multiple sclerosis

Author

Omar Khan, Hans Lassmann, Michael K. Racke, Olaf Stüve, Anthony T. Reder, Alireza Minagar, Michael G. Dwyer, Elliot M. Frohman, Robert Zivadinov, Massimo Filippi, Zivadinov, R, Reder, At, Filippi, Massimo, Minagar, A, Stuve, O, Lassmann, H, Racke, Mk, Dwyer, Mg, Frohman, En, and Khan, O.

Subjects
Multiple Sclerosis, Antibodies, Neoplasm, Anti-Inflammatory Agents, Inflammation, Antibodies, Monoclonal, Humanized, Natalizumab, Adrenal Cortex Hormones, Edema, medicine, Humans, Glatiramer acetate, Remyelination, Alemtuzumab, business.industry, Multiple sclerosis, Therapeutic effect, Antibodies, Monoclonal, Brain, Immunoglobulins, Intravenous, Glatiramer Acetate, Interferon-beta, Organ Size, medicine.disease, medicine.anatomical_structure, Immunology, Cladribine, Neurology (clinical), medicine.symptom, Atrophy, business, Peptides, medicine.drug
Abstract

Disease-modifying agents (DMAs), including interferon beta (IFNbeta) and glatiramer acetate (GA), are the mainstays of long-term treatment of multiple sclerosis (MS). Other potent anti-inflammatory agents like natalizumab and different types of chemotherapeutics are increasingly being used for treatment of MS, particularly in patients with breakthrough disease activity. Brain volume (BV) loss occurs early in the disease process, accelerates over time, and may be only partially affected by DMA therapy. Low-dose, low frequency IFNbeta administered once weekly and GA appear to partially reduce BV decline over the second and third years of treatment. High dose, high frequency IFNbeta demonstrated no clear effect on BV loss during this time period. Current evidence suggests that changes in BV after immunoablation may not be due entirely to the resolution of edema but may be related to potential chemotoxicity of high dose cyclophosphamide. Natalizumab reduces the development of BV decline in the second and third years of treatment. IV immunoglobulin showed a positive effect on decelerating BV reduction in relapsing and advanced stages of MS. These differences between DMAs may be explained by the extent of their therapeutic effects on inflammation and on the balance between inhibition or promotion of remyelination and neuronal repair in the CNS. We described the mechanisms of action by which DMAs induce accelerated, non-tissue-related BV loss (pseudoatrophy) in the short term but, in the long run, may still potentially lead to permanent BV decline. The effects of corticosteroid therapy on changes in BV in patients with MS help clarify the mechanisms through which potent anti-inflammatory treatments may prevent, stabilize, or induce BV loss.

Published
2008

44. Most patients with multiple sclerosis or a clinically isolated demyelinating syndrome should be treated at the time of diagnosis

Author

Howard L. Weiner, Michael J. Olek, Lawrence Steinman, Massimo Filippi, John R. Corboy, J. R. Richert, Olaf Stüve, Frederik Barkhof, Michael K. Racke, Cedric S. Raine, M. K. Sharief, Gary Cutter, Elliot M. Frohman, Eva Havrdova, Robert Zivadinov, A. Achiron, Fred D. Lublin, Frohman, Em, Havrdova, E, Lublin, F, Barkhof, F, Achiron, A, Sharief, Mk, Stuve, O, Racke, Mk, Steinman, L, Weiner, H, Olek, M, Zivadinov, R, Corboy, J, Raine, C, Cutter, G, Richert, J, and Filippi, Massimo

Subjects
Oncology, medicine.medical_specialty, Pathology, Neurology, Multivariate analysis, biology, business.industry, Multiple sclerosis, Incidence (epidemiology), medicine.disease, Natural history, Arts and Humanities (miscellaneous), Interferon, Predictive value of tests, Internal medicine, medicine, biology.protein, Neurology (clinical), Antibody, business, medicine.drug
Abstract

1aforearlymultiplesclerosis:CHAMPStrialsubgroup analyses. Ann Neurol. 2002;51:481-490. 42. Hadjimichael O, Vollmer TL. Adherence to injection therapy in multiple sclerosis: patients survey. Neurology. 1999;52:A549. 43. The IFNB Multiple Sclerosis Study Group and the University of British Columbia MS/MRI Analysis Group. Neutralizing antibodies during treatment of multiple sclerosis with interferon beta-1b: experience during the first three years. Neurology. 1996;47:889-894. 44. Malucchi S, Sala A, Gilli F, et al. Neutralizing antibodies reduce the efficacy of betaIFN during treatment of multiple sclerosis. Neurology. 2004; 62:2031-2037. 45. Rudick RA, Simonian NA, Alam JA, et al. Incidence and significance of neutralizing antibodies to interferon beta-1a in multiple sclerosis: Multiple Sclerosis Collaborative Research Group (MSCRG). Neurology. 1998;50:1266-1272. 46. Rice G. The significance of neutralizing antibodies inpatientswithmultiplesclerosis treatedwith interferon beta. Arch Neurol. 2001;58:1297-1298. 47. Weinshenker BG, Bass B, Rice GP, et al. The natural history of multiple sclerosis—a geographically based study, 2: predictive value of the early clinical course. Brain. 1989;112:1419-1428. 48. Weinshenker BG, Rice GPA, Noseworthy JH, et al. The natural history of multiple sclerosis—a geographically based study, 3: multivariate analysis of predictive factors and models of outcome. Brain. 1991;114:1045-1056. 49. Runmarker B, Andersson C, Oden A, Andersen O. Prediction of outcome in multiple sclerosis based on multivariate models. J Neurol. 1994;241: 597-604. 50. Confavreux C, Aimard G, Devic M. Course and prognosis of multiple sclerosis assessed by the computerized data processing of 349 patients. Brain. 1980;103:281-300.

Published
2006

45. Characterizing the mechanisms of progression in multiple sclerosis. Evidence and new hypotheses for future directions

Author

JT Phillips, John R. Corboy, Bernhard Hemmer, Nitin J. Karandikar, H.-P. Hartung, Stephen G. Waxman, Elliot M. Frohman, Michael K. Racke, Stephen L. Hauser, Jorge R. Oksenberg, J. Wilken, Bruce A.C. Cree, J. De Keyser, Lawrence Steinman, Olaf Stuve, Nancy L. Monson, Claudia F. Lucchinetti, Massimo Filippi, Frohman, Em, Filippi, Massimo, Stuve, O, Waxman, Sg, Corboy, J, Phillips, Jt, Lucchinetti, C, Wilken, J, Karandikar, N, Hemmer, B, Monson, N, Dekeyser, J, Hartung, H, Steinman, L, Oksenberg, Jr, Cree, Bac, Hauser, S, Racke, Mk, and Gerontology

Subjects
Multiple Sclerosis, Signs and symptoms, Disease, CD8(+) T-CELLS, MYELIN BASIC-PROTEIN, EXPERIMENTAL ALLERGIC ENCEPHALOMYELITIS, Research Support, Models, Biological, Disease course, Multiple Sclerosis/genetics/*immunology/*pathology, Arts and Humanities (miscellaneous), ALTERED PEPTIDE LIGAND, Models, N.I.H, medicine, Humans, Disease process, genetics, Non-U.S. Gov't, TUMOR-NECROSIS-FACTOR, business.industry, Multiple sclerosis, Disease progression, Neurosciences, Extramural, APOLIPOPROTEIN-E GENOTYPE, medicine.disease, Biological, CNS WHITE-MATTER, RECEPTOR ANTAGONIST GENES, MAJOR HISTOCOMPATIBILITY COMPLEX, Treatment intervention, EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS, Immune System, Inflammatory cascade, Disease Progression, Immune System/physiopathology, Neurology (clinical), business, Neuroscience
Abstract

Major advancements have been achieved in our ability to diagnose multiple sclerosis (MS) and to commence treatment intervention with agents that can favorably affect the disease course. Although MS exacerbations and the emergence of disability constitute the more conspicuous aspects of the disease process, evidence has confirmed that most of the disease occurs on a constitutive and occult basis. Disease-modifying therapies appear to be modest in the magnitude of their treatment effects, particularly in the progressive stage of the disease. Therapeutic strategies currently used for MS primarily target the inflammatory cascade. Several potential mechanisms appear to be involved in the progression of MS. Characterizing these mechanisms will result in a better understanding of the various forms of the disorder and how to effectively treat its clinical manifestations. It is our objective within this 2-part series on progression in MS to offer both evidence-based observations and hypothesis-driven expert perspectives on what constitutes the cause of progression in MS. We have chosen areas of inquiry that appear to have been most productive in helping us to better conceptualize the landscape of what MS looks like pathologically, immunologically, neuroscientifically, radiographically, and genetically. We have attempted to advance hypotheses focused on a deeper understanding of what contributes to the progression of this illness and to illustrate new technical capabilities that are catalyzing novel research initiatives targeted at achieving a more complete understanding of progression in MS.

Published
2005

46. Safety and efficacy of evobrutinib in relapsing multiple sclerosis (evolutionRMS1 and evolutionRMS2): two multicentre, randomised, double-blind, active-controlled, phase 3 trials.

Author

Montalban X, Vermersch P, Arnold DL, Bar-Or A, Cree BAC, Cross AH, Kubala Havrdova E, Kappos L, Stuve O, Wiendl H, Wolinsky JS, Dahlke F, Le Bolay C, Shen Loo L, Gopalakrishnan S, Hyvert Y, Javor A, Guehring H, Tenenbaum N, and Tomic D

Subjects
Humans, Adult, Double-Blind Method, Female, Male, Middle Aged, Young Adult, Treatment Outcome, Adolescent, Protein Kinase Inhibitors therapeutic use, Protein Kinase Inhibitors adverse effects, Agammaglobulinaemia Tyrosine Kinase antagonists & inhibitors, Piperidines, Hydroxybutyrates, Nitriles therapeutic use, Crotonates therapeutic use, Multiple Sclerosis, Relapsing-Remitting drug therapy, Toluidines therapeutic use, Pyrimidines therapeutic use
Abstract

Background: Evobrutinib, a Bruton's tyrosine kinase (BTK) inhibitor, has shown preliminary efficacy in people with relapsing multiple sclerosis in a phase 2 trial. Here, we aimed to compare the safety and efficacy of evobrutinib with the active comparator teriflunomide in people with relapsing multiple sclerosis., Methods: EvolutionRMS1 and evolutionRMS2 were two multicentre, randomised, double-blind, double-dummy, active-controlled, phase 3 trials conducted at 701 multiple sclerosis centres and neurology clinics in 52 countries. Adults aged 18-55 years with relapsing multiple sclerosis (Expanded Disability Status Scale [EDSS] score of 0·0-5·5) were included. Participants were randomly assigned (1:1) using a central interactive web response system to receive either evobrutinib (45 mg twice per day with placebo once per day) or teriflunomide (14 mg once per day with placebo twice per day), all taken orally and in an unfasted state, with randomisation stratified by geographical region and baseline EDSS. All study staff and participants were masked to the study interventions. The primary endpoint for each study was annualised relapse rate based on adjudicated qualified relapses up to 156 weeks, assessed in the full analysis set (defined as all randomly assigned participants) with a negative binomial model. These studies are registered with ClinicalTrials.gov (NCT04338022 for evolutionRMS1 and NCT04338061 for evolutionRMS2, both are terminated)., Findings: The primary analysis was done using data for 2290 randomly assigned participants collected from June 12, 2020, to Oct 2, 2023. 1124 participants were included in the full analysis set in evolutionRMS1 (560 in the evobrutinib group and 564 in the teriflunomide group) and 1166 in evolutionRMS2 (583 in each group). 751 (66·8%) participants were female and 373 (33·1%) were male in evolutionRMS1, whereas 783 (67·2%) were female and 383 (32·8%) were male in evolutionRMS2. Annualised relapse rate was 0·15 (95% CI 0·12-0·18 with evobrutinib vs 0·14 [0·11-0·18] with teriflunomide (adjusted RR 1·02 [0·75-1·39]; p=0·55) in evolutionRMS1 and 0·11 (0·09-0·13 vs 0·11 [0·09-0·13]; adjusted RR 1·00 [0·74-1·35]; p=0·51) in evolutionRMS2. The pooled proportion of participants with any treatment-emergent adverse event (TEAE) was similar between treatment groups (976 [85·6%] of 1140 with evobrutinib vs 999 [87·2%] of 1146 with teriflunomide). The most frequently reported TEAEs were COVID-19 (223 [19·6%] with evobrutinib vs 223 [19·5%] with teriflunomide), alanine aminotransferase increased (173 [15·2%] vs 204 [17·8%]), aspartate aminotransferase increased (110 [9·6%] vs 131 [11·4%]), and headache (175 [15·4%] vs 176 [15·4%]). Serious TEAE incidence rates were higher with evobrutinib than teriflunomide (86 [7·5%] vs 64 [5·6%]). Liver enzyme elevations at least 5 × upper limit of normal were more common with evobrutinib than with teriflunomide, particularly in the first 12 weeks (55 [5·0%] vs nine [<1%]). Three people who received evobrutinib and one who received teriflunomide met the biochemical definition of Hy's law; all cases resolved after discontinuation of treatment. There were two deaths (one in each group), neither related to study treatment., Interpretation: The efficacy of evobrutinib was not superior to that of teriflunomide. Together, efficacy and liver-related safety findings do not support the use of evobrutinib in people with relapsing multiple sclerosis., Funding: Merck., Competing Interests: Declaration of interests XM received speaking honoraria or travel expenses, or both, for participation in scientific meetings; and has been a steering committee member of clinical trials and participated in advisory boards with AbbVie, Actelion (Janssen [Johnson & Johnson]), Alexion (AstraZeneca), Bayer, Biogen, Celgene (Bristol Myers Squibb), EMD Serono, Immunic, Janssen (Johnson & Johnson), MedDay, Merck, Mylan, Nervgen, Novartis, Roche, Sandoz, Sanofi, Teva, TG Therapeutics, Excemed, Multiple Sclerosis International Federation, and National Multiple Sclerosis Society. PV received honoraria and consulting fees from AB Science, Ad Scientiam, Biogen, Celgene (Bristol Myers Squibb), Imcyse, Janssen (Johnson & Johnson), Merck, Novartis, Roche, and Sanofi; and received research support from Novartis, Roche, and Sanofi. DLA received personal compensation for serving as a consultant for Alexion (AstraZeneca), Biogen, Celgene, Eli Lilly, Frequency Therapeutics, Merck, Novartis, Roche, Sanofi, and Shionogi; and holds an equity interest in NeuroRx Research. AB-O holds the Melissa and Paul Anderson Chair; received research funding from the Canadian Institutes of Health Research, Juvenile Diabetes Research Foundation, Multiple Sclerosis Society of Canada, Multiple Sclerosis Scientific Foundation, National Institutes of Health, and National Multiple Sclerosis Society; was a speaker in sponsored meetings and received consulting fees from Accure, Actelion (Janssen [Johnson & Johnson]), Atara Biotherapeutics, Biogen, Celgene (Receptos [Bristol Myers Squibb]), EMD Serono, Gossamer Bio, GSK, Medimmune, Merck, Novartis, Roche, and Sanofi; and received grant support to the University of Pennsylvania from Biogen, EMD Serono, Merck, Billerica, Novartis, and Roche. BACC received personal compensation for consulting from Alexion, Atara, Autobahn, Avotres, Biogen, Boston Pharma, EMD Serono, Gossamer Bio, Hexal (Sandoz), Horizon, Immunic AG, Kyverna, Neuron23, Novartis, Sanofi, Siemens, and TG Therapeutics; and received research support from Genentech. AHC received funding for this study from the Hope Center for Neurological Disorders (Washington University, St Louis, MO, USA); a salary from the Manny and Rosalyn Rosenthal Dr John L Trotter Multiple Sclerosis Center Chair in Neuroimmunology of the Barnes-Jewish Hospital Foundation; grant support from the National Institutes of Health, US Department of Defense, and National Multiple Sclerosis Society USA; consulting fees from Genentech (Roche), TG Therapeutics, Bristol Myers Squibb, Janssen (Johnson & Johnson), and Novartis; payment or honoraria for lectures from the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) Forum 2024, University of Arizona, University of Maryland, University of South Alabama, University of Miami, Mayo Foundation, Consortium of Multiple Sclerosis Centers, and Biogen; payment or honoraria for writing chapters of the American Academy of Neurology; payment or honoraria for construction of continuing medical education talks and written documents from Catamount, Projects in Knowledge, Vindico Medical Education, and WebMD; payment or honoraria for preparation of educational materials from Indy Airone; financial support for attending scientific or medical meetings from EMD Serono, Novartis, Genentech, and Hoffmann-La Roche; financial support for attending advisory boards from Novartis, Genentech, Biogen, Bristol Myers Squibb, Janssen (Johnson & Johnson), TG Therapeutics, Octave, and Horizon; holds a patent (US patent 15060–630 [015875); participated on a data safety monitoring board or advisory board for Novartis for the ASCLEPIOS trials on ofatumumab, EMD Serono for the evolutionRMS trials on evobrutinib, and Genentech for the OBOE study on ocrelizumab; is the president of the board of governors for the Consortium of Multiple Sclerosis Centers; is on the programme nominating committee for ACTRIMS; was a member and chair of the Research Programs Advisory Committee for the National Multiple Sclerosis Society; is a member representing the National Multiple Sclerosis Society and a member of the nominating committee for the International Progressive Multiple Sclerosis Alliance; and received medical writing support from Genentech, EMD Serono, and Novartis. EKH received personal compensation for consulting, for serving on a scientific advisory board or data safety monitoring board, and for serving as an expert witness from Actelion (Janssen [Johnson & Johnson]), Biogen, Celgene, Merck, Novartis, Roche, and Sanofi. LK received research support to the institution (University Hospital Basel, Basel, Switzerland) including steering committee, advisory board, and consultancy fees from Actelion (Janssen [Johnson & Johnson]), Bayer, Biogen, Bristol Myers Squibb, GSK, Janssen (Johnson & Johnson), Japan Tobacco, Merck, Novartis, Roche, Sanofi, Santhera, and Shionogi, and TG Therapeutics; speaker fees from Bayer, Biogen, Merck, Novartis, Roche, and Sanofi; support of educational activities from Allergan, Bayer, Biogen, CSL Behring, Desitin, Merck, Novartis, Pfizer, Roche, Sanofi, Shire, and Teva; license fees for Neurostatus platform access; and grants from Bayer, Biogen, EU, InnoSwiss, Merck, Novartis, Roche, Swiss Multiple Sclerosis Society, and Swiss National Research Foundation. OS received personal compensation for consulting from EMD Serono, Novartis, and Octave Bioscience; grants from EMD Serono; and for serving as an editorial board member of Therapeutic Advances in Neurological Disorders. HW received personal compensation for consulting, for serving on a scientific advisory board, speaking and traveling or attending meetings from AbbVie, Actelion (Janssen [Johnson & Johnson]), Alexion (AstraZeneca), Argenx, Beckton Dickinson, Biogen, Bristol Myers Squibb (Celgene), EMD Serono, Fondazione Cariplo, Gossamer Bio, Idorsia, Immunic, Immunovant, Janssen (Johnson & Johnson), Lundbeck, Merck, Neurodiem, NexGen, Novartis, Ology, Roche, Sandoz, Sanofi, Teva, WebMD, and Worldwide Clinical Trials; contracted research with Alexion (AstraZeneca), Amicus Therapeutics, Argenx, Biogen, CSL Behring, Merck, Novartis, Roche, and Sanofi. JSW received personal compensation for consulting, serving on a scientific advisory board, speaking or other activities from Cleveland Clinic Foundation, EMD Serono, Inmagene, Novartis, Roche, Sandoz, and Zenas BioPharma; and royalties for out-licensing monoclonal antibodies through UTHealth from Millipore Corporation. FD provides consultancy to Merck through Impulze. CLB is an employee of Merck Santé. YH, HG, and SG are employees of Merck and own stock or stock options. AJ and DT are employees of Ares Trading. DT received stock or an ownership interest from Novartis. NT and LSL are employees of EMD Serono., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Published
2024
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47. Exploring the association of disease-modifying therapies for multiple sclerosis and BTK inhibitors with epilepsy.

Author

Shirani A, Saez-Calveras N, Antel JP, Yaqubi M, Moore W, Brewster AL, and Stuve O

Abstract

Background: Multiple lines of evidence suggest a role of inflammation in epilepsy. Seizure incidence in patients with multiple sclerosis (MS) is twofold to threefold higher than the age-matched general population., Objectives: To explore the association of MS disease-modifying therapies (DMTs) and FDA-approved Bruton tyrosine kinase inhibitors (for lymphocytic malignancies) with the occurrence of epilepsy using the US Food and Drug Administration Adverse Event Reporting System (FAERS) database., Design: Secondary analysis of the FAERS database., Methods: We conducted a disproportionality analysis of FAERS between 2003-Q4 and 2023-Q3. MS DMTs and the Bruton tyrosine kinase inhibitor, ibrutinib, were included in the analysis. An inverse association was defined by a 95% confidence interval (CI) upper limit of reporting odds ratio (ROR) <1., Results: We found an inverse association of ibrutinib, ocrelizumab, ofatumumab, rituximab, and teriflunomide with epilepsy. The strongest inverse association was seen with ibrutinib (ROR: 0.338; 95% CI: 0.218-0.524)., Conclusion: Our findings suggest the possibility of considering these medications for repurposing opportunities in epilepsy and support a potential pathogenic role of leukocyte subsets in seizure perpetuation., (© The Author(s), 2024.)

Published
2024
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49. Multiple sclerosis treatments a review of current biomedical engineering approaches.

Author

Mohseni SO, Au KM, Issa W, Ruan L, Stuve O, and Wang AZ

Subjects
Humans, Animals, Biomedical Engineering methods, Neural Stem Cells transplantation, Multiple Sclerosis therapy
Abstract

Multiple Sclerosis (MS) is an autoimmune condition targeting the central nervous system (CNS) characterized by focal demyelination with inflammation, causing neurodegeneration and gliosis. This is accompanied by a refractory period in relapsing MS or chronic progression in primary progressive MS. Current MS treatments target disease relapses and aim to reduce further demyelination and disability. These include the treatment of acute exacerbations through global immunomodulation upon corticosteroid administration, which are accompanied by adverse reactions. Disease modifying therapies (DMTs) which provide targeted immunosuppression of T and B cells, and sequestration of leukocytes out of CNS, have led to further improvements in demyelination prevention and disease burden reduction. Despite their efficacy, DMTs are ineffective in remyelination, pathology reversal and have minimal effects in progressive MS. The advent of modern biomedical engineering approaches in combination with a better understanding of MS pathology, has led to the development of novel, regenerative approaches to treatment. Such treatments utilize neural stem cells (NSCs) and can reduce disease relapses and reverse damage caused by the disease through localized tissue regeneration. While at initial stages, pre-clinical and clinical studies utilizing NSCs and immune modulation have shown promising outcomes in tissue regeneration, creating a potential new era in MS therapy., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Andrew Z. Wang has patent ENGINEERED CELLS FUNCTIONALIZED WITH IMMUNE CHECKPOINT MOLECULES AND USES THEREOF issued to The University of North Carolina at Chapel Hill. Kin Man Au has patent ENGINEERED CELLS FUNCTIONALIZED WITH IMMUNE CHECKPOINT MOLECULES AND USES THEREOF pending to The University of North Carolina at Chapel Hill. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Published
2025
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50. A review of Bruton's tyrosine kinase inhibitors in multiple sclerosis.

Author

Airas L, Bermel RA, Chitnis T, Hartung HP, Nakahara J, Stuve O, Williams MJ, Kieseier BC, and Wiendl H

Abstract

Bruton's tyrosine kinase (BTK) inhibitors are an emerging class of therapeutics in multiple sclerosis (MS). BTK is expressed in B-cells and myeloid cells, key progenitors of which include dendritic cells, microglia and macrophages, integral effectors of MS pathogenesis, along with mast cells, establishing the relevance of BTK inhibitors to diverse autoimmune conditions. First-generation BTK inhibitors are currently utilized in the treatment of B-cell malignancies and show efficacy in B-cell modulation. B-cell depleting therapies have shown success as disease-modifying treatments (DMTs) in MS, highlighting the potential of BTK inhibitors for this indication; however, first-generation BTK inhibitors exhibit a challenging safety profile that is unsuitable for chronic use, as required for MS DMTs. A second generation of highly selective BTK inhibitors has shown efficacy in modulating MS-relevant mechanisms of pathogenesis in preclinical as well as clinical studies. Six of these BTK inhibitors are undergoing clinical development for MS, three of which are also under investigation for chronic spontaneous urticaria (CSU), rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Phase II trials of selected BTK inhibitors for MS showed reductions in new gadolinium-enhancing lesions on magnetic resonance imaging scans; however, the safety profile is yet to be ascertained in chronic use. Understanding of the safety profile is developing by combining safety insights from the ongoing phase II and III trials of second-generation BTK inhibitors for MS, CSU, RA and SLE. This narrative review investigates the potential of BTK inhibitors as an MS DMT, the improved selectivity of second-generation inhibitors, comparative safety insights established thus far through clinical development programmes and proposed implications in female reproductive health and in long-term administration., (© The Author(s), 2024.)

Published
2024
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