Możliwości farmakoterapii w hamowaniu progresji niezależnej od rzutów w stwardnieniu rozsianym Artykuł przeglądowy
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Opublikowane:
wrz 30, 2024
Słowa kluczowe:
stwardnienie rozsiane, progresja niezależna od aktywności rzutowej, PIRA, farmakoterapia, leki modyfikujące przebieg choroby, neurodegeneracja, remielinizacja
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Abstrakt
Artykuł przedstawia przegląd aktualnych farmakoterapeutycznych możliwości hamowania progresji niezależnej od rzutów w stwardnieniu rozsianym. Omówiono zmianę paradygmatu w leczeniu stwardnienia rozsianego, która wynika z rosnącej świadomości zjawiska progresji niezależnej od aktywności rzutowej. Przedstawiono mechanizmy działania wielu leków (w tym ofatumumabu, okrelizumabu, siponimodu, natalizumabu, ibudilastu, simwastatyny, biotyny, masytynibu i innych) oraz wyniki badań klinicznych. Złożoność patofizjologii progresji niezależnej od aktywności rzutowej przekłada się na potrzebę wielokierunkowego podejścia terapeutycznego. Opracowywanie skutecznych terapii jest utrudnione z uwagi na złożoność patomechanizmów w przebiegu choroby i potrzebę prowadzenia długoterminowych obserwacji. Omówiono także ewolucję metod oceny progresji choroby i znaczenie identyfikacji wiarygodnych biomarkerów. Obiecującymi kierunkami są możliwość stosowania terapii skojarzonych i personalizacja leczenia.
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Bibliografia
1. Lublin FD, Reingold SC, Cohen JA et al. Defining the clinical course of multiple sclerosis: The 2013 revisions. Neurology. 2014; 83(3): 278-86.
2. University of California, San Francisco MS-EPIC Team; Cree BAC, Hollenbach JA, Bove R et al. Silent progression in disease activity–free relapsing multiple sclerosis. Annals of Neurology. 2019; 85(5): 653-66.
3. Kappos L, Wolinsky JS, Giovannoni G et al. Contribution of Relapse-Independent Progression vs Relapse-Associated Worsening to Overall Confirmed Disability Accumulation in Typical Relapsing Multiple Sclerosis in a Pooled Analysis of 2 Randomized Clinical Trials. JAMA Neurol. 2020; 77(9): 1132.
4. Giovannoni G, Popescu V, Wuerfel J et al. Smouldering multiple sclerosis: the ‘real MS’. Ther Adv Neurol Disord. 2022; 15: 175628642110667.
5. Lublin FD, Häring DA, Ganjgahi H et al. How patients with multiple sclerosis acquire disability. Brain. 2022; 145(9): 3147-61.
6. Lassmann H. Pathogenic Mechanisms Associated With Different Clinical Courses of Multiple Sclerosis. Front Immunol. 2019; 9: 3116.
7. Sugimoto K, Nishioka R, Ikeda A et al. Activated microglia in a rat stroke model express NG2 proteoglycan in peri-infarct tissue through the involvement of TGF-β1. Glia. 2014; 62(2): 185-98.
8. Mei F, Lehmann-Horn K, Shen YAA et al. Accelerated remyelination during inflammatory demyelination prevents axonal loss and improves functional recovery. eLife. 2016; 5: e18246.
9. Sedel F, Bernard D, Mock DM et al. Targeting demyelination and virtual hypoxia with high-dose biotin as a treatment for progressive multiple sclerosis. Neuropharmacology. 2016; 110: 644-53.
10. Friese MA, Craner MJ, Etzensperger R et al. Acid-sensing ion channel-1 contributes to axonal degeneration in autoimmune inflammation of the central nervous system. Nat Med. 2007; 13(12): 1483-9.
11. Scolding NJ, Pasquini M, Reingold SC, Cohen JA; International Conference on Cell-Based Therapies for Multiple Sclerosis; International Conference on Cell-Based Therapies for Multiple Sclerosis; International Conference on Cell-Based Therapies for Multiple Sclerosis. Cell-based therapeutic strategies for multiple sclerosis. Brain. 2017; 140(11): 2776-96.
12. Magliozzi R, Howell OW, Nicholas R et al. Inflammatory intrathecal profiles and cortical damage in multiple sclerosis. Annals of Neurology. 2018; 83(4): 739-55.
13. Ontaneda D, Thompson AJ, Fox RJ et al. Progressive multiple sclerosis: prospects for disease therapy, repair, and restoration of function. The Lancet. 2017; 389(10076): 1357-66.
14. Barro C, Benkert P, Disanto G et al. Serum neurofilament as a predictor of disease worsening and brain and spinal cord atrophy in multiple sclerosis. Brain. 2018; 141(8): 2382-91.
15. Hauser SL, Bar-Or A, Cohen JA et al. Ofatumumab versus Teriflunomide in Multiple Sclerosis. N Engl J Med. 2020; 383(6): 546–57.
16. Gärtner J, Hauser SL, Bar-Or A et al. Efficacy and safety of ofatumumab in recently diagnosed, treatment-naive patients with multiple sclerosis: Results from ASCLEPIOS I and II. Mult Scler. 2022; 28(10): 1562-75.
17. Bar-Or A, Hauser SL, Cohen JA et al. Early Initiation of Ofatumumab Delays Disability Progression in People With Relapsing Multiple Sclerosis: 6-Year Results From ALITHIOS Open-Label Extension Study. In 2024.
18. Gingele S, Jacobus TL, Konen FF et al. Ocrelizumab Depletes CD20+ T Cells in Multiple Sclerosis Patients. Cells. 2018; 8(1): 12.
19. Montalban X, Hauser SL, Kappos L et al. Ocrelizumab versus Placebo in Primary Progressive Multiple Sclerosis. N Engl J Med. 2017; 376(3): 209-20.
20. Wolinsky JS, Arnold DL, Brochet B et al. Long-term follow-up from the ORATORIO trial of ocrelizumab for primary progressive multiple sclerosis: a post-hoc analysis from the ongoing open-label extension of the randomised, placebo-controlled, phase 3 trial. The Lancet Neurology. 2020; 19(12): 998-1009.
21. Gergely P, Nuesslein-Hildesheim B, Guerini D et al. The selective sphingosine 1-phosphate receptor modulator BAF312 redirects lymphocyte distribution and has species-specific effects on heart rate. British J Pharmacology. 2012; 167(5): 1035-47.
22. Kappos L, Bar-Or A, Cree BAC et al. Siponimod versus placebo in secondary progressive multiple sclerosis (EXPAND): a double-blind, randomised, phase 3 study. The Lancet. 2018; 391(10127): 1263-73.
23. Benedict RHB, Tomic D, Cree BA et al. Siponimod and Cognition in Secondary Progressive Multiple Sclerosis: EXPAND Secondary Analyses. Neurology. 2021; 96(3): e376-86.
24. Arnold DL, Piani-Meier D, Bar-Or A et al. Effect of siponimod on magnetic resonance imaging measures of neurodegeneration and myelination in secondary progressive multiple sclerosis: Gray matter atrophy and magnetization transfer ratio analyses from the EXPAND phase 3 trial. Mult Scler. 2022; 28(10): 1526-40.
25. Polman CH, O’Connor PW, Havrdova E et al. A Randomized, Placebo-Controlled Trial of Natalizumab for Relapsing Multiple Sclerosis. N Engl J Med. 2006; 354(9): 899-910.
26. Kapoor R, Ho PR, Campbell N et al. Effect of natalizumab on disease progression in secondary progressive multiple sclerosis (ASCEND): a phase 3, randomised, double-blind, placebo-controlled trial with an open-label extension. The Lancet Neurology. 2018; 17(5): 405-15.
27. Giovannoni G, Cutter G, Sormani MP et al. Is multiple sclerosis a length-dependent central axonopathy? The case for therapeutic lag and the asynchronous progressive MS hypotheses. Multiple Sclerosis and Related Disorders. 2017; 12: 70-8.
28. Gibson LCD, Hastings SF, McPhee I et al. The inhibitory profile of Ibudilast against the human phosphodiesterase enzyme family. European Journal of Pharmacology. 2006; 538(1-3): 39-42.
29. Fox RJ, Coffey CS, Conwit R et al. Phase 2 Trial of Ibudilast in Progressive Multiple Sclerosis. N Engl J Med. 2018; 379(9): 846-55.
30. Fox RJ, Coffey CS, Cudkowicz ME et al. Design, rationale, and baseline characteristics of the randomized double-blind phase II clinical trial of ibudilast in progressive multiple sclerosis. Contemporary Clinical Trials. 2016; 50: 166-77.
31. Greenwood J, Steinman L, Zamvil SS. Statin therapy and autoimmune disease: from protein prenylation to immunomodulation. Nat Rev Immunol. 2006; 6(5): 358-70.
32. Chataway J, Schuerer N, Alsanousi A et al. Effect of high-dose simvastatin on brain atrophy and disability in secondary progressive multiple sclerosis (MS-STAT): a randomised, placebo-controlled, phase 2 trial. The Lancet. 2014; 383(9936): 2213-21.
33. Chan D, Binks S, Nicholas JM et al. Effect of high-dose simvastatin on cognitive, neuropsychiatric, and health-related quality-of-life measures in secondary progressive multiple sclerosis: secondary analyses from the MS-STAT randomised, placebo-controlled trial. The Lancet Neurology. 2017; 16(8): 591-600.
34. Tourbah A, Lebrun-Frenay C, Edan G et al. MD1003 (high-dose biotin) for the treatment of progressive multiple sclerosis: A randomised, double-blind, placebo-controlled study. Mult Scler. 2016; 22(13): 1719-31.
35. Cree BAC, Cutter G, Wolinsky JS et al. Safety and efficacy of MD1003 (high-dose biotin) in patients with progressive multiple sclerosis (SPI2): a randomised, double-blind, placebo-controlled, phase 3 trial. The Lancet Neurology. 2020; 19(12): 988-97.
36. Dubreuil P, Letard S, Ciufolini M et al. Masitinib (AB1010), a Potent and Selective Tyrosine Kinase Inhibitor Targeting KIT. Bauer JA, editor. PLoS ONE. 2009; 4(9): e7258.
37. Vermersch P, Brieva-Ruiz L, Fox RJ et al. Efficacy and Safety of Masitinib in Progressive Forms of Multiple Sclerosis: A Randomized, Phase 3, Clinical Trial. Neurol Neuroimmunol Neuroinflamm. 2022; 9(3): e1148.
38. Chataway J, De Angelis F, Connick P et al. Efficacy of three neuroprotective drugs in secondary progressive multiple sclerosis (MS-SMART): a phase 2b, multiarm, double-blind, randomised placebo-controlled trial. The Lancet Neurology. 2020; 19(3): 214-25.
39. Packer L, Witt EH, Tritschler HJ. Alpha-lipoic acid as a biological antioxidant. Free Radical Biology and Medicine. 1995; 19(2): 227-50.
40. Marracci GH, Jones RE, McKeon GP et al. Alpha lipoic acid inhibits T cell migration into the spinal cord and suppresses and treats experimental autoimmune encephalomyelitis. Journal of Neuroimmunology. 2002; 131(1-2): 104-14.
41. Spain R, Powers K, Murchison C et al. Lipoic acid in secondary progressive MS: A randomized controlled pilot trial. Neurol Neuroimmunol Neuroinflamm. 2017; 4(5): e374.
42. Loy BD, Fling BW, Horak FB et al. Effects of lipoic acid on walking performance, gait, and balance in secondary progressive multiple sclerosis. Complementary Therapies in Medicine. 2018; 41: 169-74.
43. Mei F, Fancy SPJ, Shen YAA et al. Micropillar arrays as a high-throughput screening platform for therapeutics in multiple sclerosis. Nat Med. 2014; 20(8): 954-60.
44. Green AJ, Gelfand JM, Cree BA et al. Clemastine fumarate as a remyelinating therapy for multiple sclerosis (ReBUILD): a randomised, controlled, double-blind, crossover trial. The Lancet. 2017; 390(10111): 2481-9.
45. Hartley MD, Altowaijri G, Bourdette D. Remyelination and Multiple Sclerosis: Therapeutic Approaches and Challenges. Curr Neurol Neurosci Rep. 2014; 14(10): 485.
46. Mahad DH, Trapp BD, Lassmann H. Pathological mechanisms in progressive multiple sclerosis. The Lancet Neurology. 2015; 14(2): 183-93.
47. Lassmann H, Van Horssen J, Mahad D. Progressive multiple sclerosis: pathology and pathogenesis. Nat Rev Neurol. 2012; 8(11): 647-56.
48. Ontaneda D, Fox RJ, Chataway J. Clinical trials in progressive multiple sclerosis: lessons learned and future perspectives. The Lancet Neurology. 2015; 14(2): 208-23.
49. Sormani M, Signori A, Siri P et al. Time to first relapse as an endpoint in multiple sclerosis clinical trials. Mult Scler. 2013; 19(4): 466-74.
50. Goldman MD, LaRocca NG, Rudick RA et al. Evaluation of multiple sclerosis disability outcome measures using pooled clinical trial data. Neurology. 2019; 93(21): e1921-31.
51. De Stefano N, Stromillo ML, Giorgio A et al. Establishing pathological cut-offs of brain atrophy rates in multiple sclerosis. J Neurol Neurosurg Psychiatry. 2016; 87(1): 93-9.
52. Kappos L, De Stefano N, Freedman MS et al. Inclusion of brain volume loss in a revised measure of ‘no evidence of disease activity’ (NEDA-4) in relapsing–remitting multiple sclerosis. Mult Scler. 2016; 22(10): 1297-305.
53. Khurana V, Sharma H, Afroz N et al. Patient-reported outcomes in multiple sclerosis: a systematic comparison of available measures. Euro J Neurology. 2017; 24(9): 1099-107.
2. University of California, San Francisco MS-EPIC Team; Cree BAC, Hollenbach JA, Bove R et al. Silent progression in disease activity–free relapsing multiple sclerosis. Annals of Neurology. 2019; 85(5): 653-66.
3. Kappos L, Wolinsky JS, Giovannoni G et al. Contribution of Relapse-Independent Progression vs Relapse-Associated Worsening to Overall Confirmed Disability Accumulation in Typical Relapsing Multiple Sclerosis in a Pooled Analysis of 2 Randomized Clinical Trials. JAMA Neurol. 2020; 77(9): 1132.
4. Giovannoni G, Popescu V, Wuerfel J et al. Smouldering multiple sclerosis: the ‘real MS’. Ther Adv Neurol Disord. 2022; 15: 175628642110667.
5. Lublin FD, Häring DA, Ganjgahi H et al. How patients with multiple sclerosis acquire disability. Brain. 2022; 145(9): 3147-61.
6. Lassmann H. Pathogenic Mechanisms Associated With Different Clinical Courses of Multiple Sclerosis. Front Immunol. 2019; 9: 3116.
7. Sugimoto K, Nishioka R, Ikeda A et al. Activated microglia in a rat stroke model express NG2 proteoglycan in peri-infarct tissue through the involvement of TGF-β1. Glia. 2014; 62(2): 185-98.
8. Mei F, Lehmann-Horn K, Shen YAA et al. Accelerated remyelination during inflammatory demyelination prevents axonal loss and improves functional recovery. eLife. 2016; 5: e18246.
9. Sedel F, Bernard D, Mock DM et al. Targeting demyelination and virtual hypoxia with high-dose biotin as a treatment for progressive multiple sclerosis. Neuropharmacology. 2016; 110: 644-53.
10. Friese MA, Craner MJ, Etzensperger R et al. Acid-sensing ion channel-1 contributes to axonal degeneration in autoimmune inflammation of the central nervous system. Nat Med. 2007; 13(12): 1483-9.
11. Scolding NJ, Pasquini M, Reingold SC, Cohen JA; International Conference on Cell-Based Therapies for Multiple Sclerosis; International Conference on Cell-Based Therapies for Multiple Sclerosis; International Conference on Cell-Based Therapies for Multiple Sclerosis. Cell-based therapeutic strategies for multiple sclerosis. Brain. 2017; 140(11): 2776-96.
12. Magliozzi R, Howell OW, Nicholas R et al. Inflammatory intrathecal profiles and cortical damage in multiple sclerosis. Annals of Neurology. 2018; 83(4): 739-55.
13. Ontaneda D, Thompson AJ, Fox RJ et al. Progressive multiple sclerosis: prospects for disease therapy, repair, and restoration of function. The Lancet. 2017; 389(10076): 1357-66.
14. Barro C, Benkert P, Disanto G et al. Serum neurofilament as a predictor of disease worsening and brain and spinal cord atrophy in multiple sclerosis. Brain. 2018; 141(8): 2382-91.
15. Hauser SL, Bar-Or A, Cohen JA et al. Ofatumumab versus Teriflunomide in Multiple Sclerosis. N Engl J Med. 2020; 383(6): 546–57.
16. Gärtner J, Hauser SL, Bar-Or A et al. Efficacy and safety of ofatumumab in recently diagnosed, treatment-naive patients with multiple sclerosis: Results from ASCLEPIOS I and II. Mult Scler. 2022; 28(10): 1562-75.
17. Bar-Or A, Hauser SL, Cohen JA et al. Early Initiation of Ofatumumab Delays Disability Progression in People With Relapsing Multiple Sclerosis: 6-Year Results From ALITHIOS Open-Label Extension Study. In 2024.
18. Gingele S, Jacobus TL, Konen FF et al. Ocrelizumab Depletes CD20+ T Cells in Multiple Sclerosis Patients. Cells. 2018; 8(1): 12.
19. Montalban X, Hauser SL, Kappos L et al. Ocrelizumab versus Placebo in Primary Progressive Multiple Sclerosis. N Engl J Med. 2017; 376(3): 209-20.
20. Wolinsky JS, Arnold DL, Brochet B et al. Long-term follow-up from the ORATORIO trial of ocrelizumab for primary progressive multiple sclerosis: a post-hoc analysis from the ongoing open-label extension of the randomised, placebo-controlled, phase 3 trial. The Lancet Neurology. 2020; 19(12): 998-1009.
21. Gergely P, Nuesslein-Hildesheim B, Guerini D et al. The selective sphingosine 1-phosphate receptor modulator BAF312 redirects lymphocyte distribution and has species-specific effects on heart rate. British J Pharmacology. 2012; 167(5): 1035-47.
22. Kappos L, Bar-Or A, Cree BAC et al. Siponimod versus placebo in secondary progressive multiple sclerosis (EXPAND): a double-blind, randomised, phase 3 study. The Lancet. 2018; 391(10127): 1263-73.
23. Benedict RHB, Tomic D, Cree BA et al. Siponimod and Cognition in Secondary Progressive Multiple Sclerosis: EXPAND Secondary Analyses. Neurology. 2021; 96(3): e376-86.
24. Arnold DL, Piani-Meier D, Bar-Or A et al. Effect of siponimod on magnetic resonance imaging measures of neurodegeneration and myelination in secondary progressive multiple sclerosis: Gray matter atrophy and magnetization transfer ratio analyses from the EXPAND phase 3 trial. Mult Scler. 2022; 28(10): 1526-40.
25. Polman CH, O’Connor PW, Havrdova E et al. A Randomized, Placebo-Controlled Trial of Natalizumab for Relapsing Multiple Sclerosis. N Engl J Med. 2006; 354(9): 899-910.
26. Kapoor R, Ho PR, Campbell N et al. Effect of natalizumab on disease progression in secondary progressive multiple sclerosis (ASCEND): a phase 3, randomised, double-blind, placebo-controlled trial with an open-label extension. The Lancet Neurology. 2018; 17(5): 405-15.
27. Giovannoni G, Cutter G, Sormani MP et al. Is multiple sclerosis a length-dependent central axonopathy? The case for therapeutic lag and the asynchronous progressive MS hypotheses. Multiple Sclerosis and Related Disorders. 2017; 12: 70-8.
28. Gibson LCD, Hastings SF, McPhee I et al. The inhibitory profile of Ibudilast against the human phosphodiesterase enzyme family. European Journal of Pharmacology. 2006; 538(1-3): 39-42.
29. Fox RJ, Coffey CS, Conwit R et al. Phase 2 Trial of Ibudilast in Progressive Multiple Sclerosis. N Engl J Med. 2018; 379(9): 846-55.
30. Fox RJ, Coffey CS, Cudkowicz ME et al. Design, rationale, and baseline characteristics of the randomized double-blind phase II clinical trial of ibudilast in progressive multiple sclerosis. Contemporary Clinical Trials. 2016; 50: 166-77.
31. Greenwood J, Steinman L, Zamvil SS. Statin therapy and autoimmune disease: from protein prenylation to immunomodulation. Nat Rev Immunol. 2006; 6(5): 358-70.
32. Chataway J, Schuerer N, Alsanousi A et al. Effect of high-dose simvastatin on brain atrophy and disability in secondary progressive multiple sclerosis (MS-STAT): a randomised, placebo-controlled, phase 2 trial. The Lancet. 2014; 383(9936): 2213-21.
33. Chan D, Binks S, Nicholas JM et al. Effect of high-dose simvastatin on cognitive, neuropsychiatric, and health-related quality-of-life measures in secondary progressive multiple sclerosis: secondary analyses from the MS-STAT randomised, placebo-controlled trial. The Lancet Neurology. 2017; 16(8): 591-600.
34. Tourbah A, Lebrun-Frenay C, Edan G et al. MD1003 (high-dose biotin) for the treatment of progressive multiple sclerosis: A randomised, double-blind, placebo-controlled study. Mult Scler. 2016; 22(13): 1719-31.
35. Cree BAC, Cutter G, Wolinsky JS et al. Safety and efficacy of MD1003 (high-dose biotin) in patients with progressive multiple sclerosis (SPI2): a randomised, double-blind, placebo-controlled, phase 3 trial. The Lancet Neurology. 2020; 19(12): 988-97.
36. Dubreuil P, Letard S, Ciufolini M et al. Masitinib (AB1010), a Potent and Selective Tyrosine Kinase Inhibitor Targeting KIT. Bauer JA, editor. PLoS ONE. 2009; 4(9): e7258.
37. Vermersch P, Brieva-Ruiz L, Fox RJ et al. Efficacy and Safety of Masitinib in Progressive Forms of Multiple Sclerosis: A Randomized, Phase 3, Clinical Trial. Neurol Neuroimmunol Neuroinflamm. 2022; 9(3): e1148.
38. Chataway J, De Angelis F, Connick P et al. Efficacy of three neuroprotective drugs in secondary progressive multiple sclerosis (MS-SMART): a phase 2b, multiarm, double-blind, randomised placebo-controlled trial. The Lancet Neurology. 2020; 19(3): 214-25.
39. Packer L, Witt EH, Tritschler HJ. Alpha-lipoic acid as a biological antioxidant. Free Radical Biology and Medicine. 1995; 19(2): 227-50.
40. Marracci GH, Jones RE, McKeon GP et al. Alpha lipoic acid inhibits T cell migration into the spinal cord and suppresses and treats experimental autoimmune encephalomyelitis. Journal of Neuroimmunology. 2002; 131(1-2): 104-14.
41. Spain R, Powers K, Murchison C et al. Lipoic acid in secondary progressive MS: A randomized controlled pilot trial. Neurol Neuroimmunol Neuroinflamm. 2017; 4(5): e374.
42. Loy BD, Fling BW, Horak FB et al. Effects of lipoic acid on walking performance, gait, and balance in secondary progressive multiple sclerosis. Complementary Therapies in Medicine. 2018; 41: 169-74.
43. Mei F, Fancy SPJ, Shen YAA et al. Micropillar arrays as a high-throughput screening platform for therapeutics in multiple sclerosis. Nat Med. 2014; 20(8): 954-60.
44. Green AJ, Gelfand JM, Cree BA et al. Clemastine fumarate as a remyelinating therapy for multiple sclerosis (ReBUILD): a randomised, controlled, double-blind, crossover trial. The Lancet. 2017; 390(10111): 2481-9.
45. Hartley MD, Altowaijri G, Bourdette D. Remyelination and Multiple Sclerosis: Therapeutic Approaches and Challenges. Curr Neurol Neurosci Rep. 2014; 14(10): 485.
46. Mahad DH, Trapp BD, Lassmann H. Pathological mechanisms in progressive multiple sclerosis. The Lancet Neurology. 2015; 14(2): 183-93.
47. Lassmann H, Van Horssen J, Mahad D. Progressive multiple sclerosis: pathology and pathogenesis. Nat Rev Neurol. 2012; 8(11): 647-56.
48. Ontaneda D, Fox RJ, Chataway J. Clinical trials in progressive multiple sclerosis: lessons learned and future perspectives. The Lancet Neurology. 2015; 14(2): 208-23.
49. Sormani M, Signori A, Siri P et al. Time to first relapse as an endpoint in multiple sclerosis clinical trials. Mult Scler. 2013; 19(4): 466-74.
50. Goldman MD, LaRocca NG, Rudick RA et al. Evaluation of multiple sclerosis disability outcome measures using pooled clinical trial data. Neurology. 2019; 93(21): e1921-31.
51. De Stefano N, Stromillo ML, Giorgio A et al. Establishing pathological cut-offs of brain atrophy rates in multiple sclerosis. J Neurol Neurosurg Psychiatry. 2016; 87(1): 93-9.
52. Kappos L, De Stefano N, Freedman MS et al. Inclusion of brain volume loss in a revised measure of ‘no evidence of disease activity’ (NEDA-4) in relapsing–remitting multiple sclerosis. Mult Scler. 2016; 22(10): 1297-305.
53. Khurana V, Sharma H, Afroz N et al. Patient-reported outcomes in multiple sclerosis: a systematic comparison of available measures. Euro J Neurology. 2017; 24(9): 1099-107.