Journal of Neurology

, Volume 253, Issue 1, pp 98–108

The window of therapeutic opportunity in multiple sclerosis

Evidence from monoclonal antibody therapy
  • A. J. Coles
  • A. Cox
  • E. Le Page
  • J. Jones
  • S. A. Trip
  • J. Deans
  • S. Seaman
  • D. H. Miller
  • G. Hale
  • H. Waldmann
  • D. A. Compston
ORIGINAL COMMUNICATION

Abstract

From 1991–2002, we treated 58 patients with multiple sclerosis (MS) using the humanised monoclonal antibody, Campath–1H, which causes prolonged T lymphocyte depletion. Clinical and surrogate markers of inflammation were suppressed. In both the relapsing–remitting (RR) and secondary progressive (SP) stages of the illness, Campath–1H reduced the annual relapse rate (from 2.2 to 0.19 and from 0.7 to 0.001 respectively; both p < 0.001). Remarkably, MRI scans of patients with SP disease, treated with Campath–1H 7 years previously, showed no new lesion formation. However, despite these effects on inflammation, disability was differently affected depending on the phase of the disease. Patients with SPMS showed sustained accumulation of disability due to uncontrolled progression marked by unrelenting cerebral atrophy, attributable to ongoing axonal loss. The rate of cerebral atrophy was greatest in patients with established cerebral atrophy and highest inflammatory lesion burden before treatment (2.3 versus 0.7 ml/year; p = 0.04). In contrast, patients with RR disease showed an impressive reduction in disability at 6 months after Campath–1H (by a mean of 1.2 EDSS points) perhaps owing to a suppression of on–going inflammation in these patients with unusually active disease. In addition, there was a further significant, albeit smaller, mean improvement in disability up to 36 months after treatment.We speculate that this represents the beneficial effects of early rescue of neurons and axons from a toxic inflammatory environment, and that prevention of demyelination will prevent long–term axonal degeneration. These concepts are currently being tested in a controlled trial comparing Campath–1H and IFN–beta in the treatment of drug–naïve patients with early, active RR MS.

Key words

multiple sclerosis Campath–1H cerebral atrophy 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Annunziata P, Lore F, Venturini E, Morana P, Guarino E, Borghi S, Guazzi GC (1999) Early synthesis and correlation of serum anti–thyroid antibodies with clinical parameters in multiple sclerosis. J Neurol Sci 168:32–36CrossRefPubMedGoogle Scholar
  2. 2.
    Bechtold DA, Kapoor R, Smith KJ (2004) Axonal protection using flecainide in experimental autoimmune encephalomyelitis. Ann Neurol 55:607–616CrossRefPubMedGoogle Scholar
  3. 3.
    Brady ST, Witt AS, Kirkpatrick LL, de Waegh SM, Readhead C, Tu PH, Lee VM (1999) Formation of compact myelin is required for maturation of the axonal cytoskeleton. J Neurosci 19:7278–7288PubMedGoogle Scholar
  4. 4.
    Brex PA, Ciccarelli O, O’Riordan JI, Sailer M, Thompson AJ, Miller DH (2002) A longitudinal study of abnormalities on MRI and disability from multiple sclerosis. N Engl J Med 346:158–164CrossRefPubMedGoogle Scholar
  5. 5.
    Broadley SA, Deans J, Sawcer SJ, Clayton D, Compston DA (2000) Autoimmune disease in first–degree relatives of patients with multiple sclerosis. A UK survey. Brain 123:1102–1111CrossRefPubMedGoogle Scholar
  6. 6.
    Chard DT, Brex PA, Ciccarelli O, Griffin CM, Parker GJ, Dalton C, Altmann DR, Thompson AJ, Miller DH (2003) The longitudinal relation between brain lesion load and atrophy in multiple sclerosis: a 14 year follow up study. J Neurol Neurosurg Psychiatry 74:1551–1554CrossRefPubMedGoogle Scholar
  7. 7.
    Colello RJ, Pott U, Schwab ME (1994) The role of oligodendrocytes and myelin on axon maturation in the developing rat retinofugal pathway. J Neurosci 14:2594–2605Google Scholar
  8. 8.
    Coles AJ, Paolillo A, Molyneux PD, Wing M, Hale G, Miller DH, Waldmann H, Compston DA (1998) Monoclonal antibody treatment exposes three mechanisms underlying the clinical course of multiple sclerosis. Ann Neurol 44:464Google Scholar
  9. 9.
    Coles AJ, Wing M, Molyneux P, Paolillo A, Davie C, Hale G, Miller DH, Waldmann H, Compston A (1999) Monoclonal antibody treatment exposes three mechanisms underlying the clinical course of multiple sclerosis. Ann Neurol 46:296–304CrossRefPubMedGoogle Scholar
  10. 10.
    Coles AJ, Wing MG, Smith S, Corradu F, Greer S, Taylor CJ, Weetman AP, Hale G, Chatterjee KC, Waldmann H, Compston A (1999) Pulsed monoclonal antibody treatment and thyroid autoimmunity in multiple sclerosis. Lancet 354:691–1695CrossRefPubMedGoogle Scholar
  11. 11.
    Comi G, Filippi M, Barkhof F, Durelli L, Edan G, Fernandez O, Hartung H, Seeldrayers P, Sorensen PS, Rovaris M, Martinelli V, Hommes OR (2001) Effect of early interferon treatment on conversion to definite multiple sclerosis: a randomised study. Lancet 357:1576–1582CrossRefPubMedGoogle Scholar
  12. 12.
    Comi G, Filippi M, Barkhof F, Durelli L, Edan G, Fernandez O, Hartung H, Seeldrayers P, Sorensen PS, Rovaris M, Martinelli V, Hommes OR (2001) Effect of early interferon treatment on conversion to definite multiple sclerosis: a randomised study. Lancet 357:1576–1582CrossRefPubMedGoogle Scholar
  13. 13.
    Compston A, Coles A (2002) Multiple sclerosis. Lancet 359:1221–1231CrossRefPubMedGoogle Scholar
  14. 14.
    Confavreux C, Vukusic S, Moreau T, Adeleine P (2000) Relapses and progression of disability in multiple sclerosis. N Engl J Med 343:1430–1438CrossRefPubMedGoogle Scholar
  15. 15.
    Confavreux C, Vukusic S, Adeleine P (2003) Early clinical predictors and progression of irreversible disability in multiple sclerosis: an amnesic process. Brain 126:770–782CrossRefPubMedGoogle Scholar
  16. 16.
    Cox AL, Thompson S, Hale G, Waldmann H, Compston DA, Coles AJ (2003) Lymphocyte depletion in multiple sclerosis induces a relative increase in regulatory T cells. Immunology 110, s1:81Google Scholar
  17. 17.
    Davie CA, Hawkins CP, Barker GJ, Brennan A, Tofts PS, Miller DH, McDonald WI (1994) Serial proton magnetic resonance spectroscopy in acute multiple sclerosis lesions. Brain 117:49–58PubMedGoogle Scholar
  18. 18.
    Durelli L, Ferrero B, Oggero A, Verdun E, Ghezzi A, Montanari E, Zaffaroni M (2001) Liver and thyroid function and autoimmunity during interferon–beta 1b treatment for MS. Neurology 57:1363–1370PubMedGoogle Scholar
  19. 19.
    Durelli L, Oggero A, Verdun E, Isoardo GL, Barbero P, Bergamasco B, Brossa PC, Ghigo E, Maccario M, Faggiano F (2001) Thyroid function and antithyroid antibodies in MS patients screened for interferon treatment. A multicenter study. J Neurol Sci 193:17–22CrossRefPubMedGoogle Scholar
  20. 20.
    Ferguson B, Matyszak MK, Esiri MM, Perry VH (1997) Axonal damage in acute multiple sclerosis lesions. Brain 120:393–399CrossRefPubMedGoogle Scholar
  21. 21.
    Filippi M, Rovaris M, Iannucci G, Mennea S, Sormani MP, Comi G (2000) Whole brain volume changes in patients with progressive MS treated with cladribine. Neurology 55:1714–1718PubMedGoogle Scholar
  22. 22.
    Gilleece MH, Dexter TM (1993) Effect of Campath–1H antibody on human hematopoietic progenitors in vitro. Blood 82:807–812PubMedGoogle Scholar
  23. 23.
    Golde S, Chandran S, Brown GC, Compston A (2002) Different pathways for iNOS–mediated toxicity in vitro dependent on neuronal maturation and NMDA receptor expression. J Neurochem 82:269–282CrossRefPubMedGoogle Scholar
  24. 24.
    Griffiths I, Klugmann M, Anderson T, Yool D, Thomson C, Schwab MH, Schneider A, Zimmermann F, McCulloch M, Nadon N, Nave KA (1998) Axonal swellings and degeneration in mice lacking the major proteolipid of myelin. Science 280:1610–1613CrossRefPubMedGoogle Scholar
  25. 25.
    Hale G, Waldmann H (1996) Recent results using CAMPATH–1 antibodies to control GVHD and graft rejection. Bone Marrow Transpl 17:305–308Google Scholar
  26. 26.
    Hartung HP, Gonsette R, Konig N, Kwiecinski H, Guseo A, Morrissey SP, Krapf H, Zwingers T (2002) Mitoxantrone in progressive multiple sclerosis: a placebo–controlled, double–blind, randomised, multicentre trial. Lancet 360:2018–2025CrossRefPubMedGoogle Scholar
  27. 27.
    Heesen C, Gbadamosi J, Schoser BG, Pohlau D (2001) Autoimmune hyperthyroidism in multiple sclerosis under treatment with glatiramer acetate – a case report. Eur J Neurol 8:199CrossRefPubMedGoogle Scholar
  28. 28.
    Heinzlef O, Alamowitch S, Sazdovitch V, Chillet P, Joutel A, Tournier–Lasserve E, Roullet E (2000) Autoimmune diseases in families of French patients with multiple sclerosis. Acta Neurol Scand 101:36–40CrossRefPubMedGoogle Scholar
  29. 29.
    Henderson RD, Saltissi D, Pender MP (1998) Goodpasture’s syndrome associated with multiple sclerosis. Acta Neurol Scand 98:134–135PubMedGoogle Scholar
  30. 30.
    Ioppoli C, Meucci G, Mariotti S, Martino E, Lippi A, Gironelli L, Pinchera A, Muratorio A (1990) Circulating thyroid and gastric parietal cell autoantibodies in patients with multiple sclerosis. Ital J Neurol Sci 11:31–36PubMedGoogle Scholar
  31. 31.
    Isaacs JD, Hale G, Waldmann H, Dick AD, Haynes R, Forrester JV, Watson P, Meyer PAR (1995) Monoclonal antibody therapy of chronic intraocular inflammation using Campath–1H3. Br J Ophthalmol 79:1054–1055PubMedGoogle Scholar
  32. 32.
    Isaacs JD, Hazleman BL, Chakravarty K, Grant JW, Hale G, Waldmann H (1996) Monoclonal antibody therapy of diffuse cutaneous scleroderma with CAMPATH–1H. J Rheumatol 23:1103–1106PubMedGoogle Scholar
  33. 33.
    Isaacs JD, Manna VK, Rapson N, Bulpitt KJ, Hazleman BL, Matteson EL, St. Clair EW, Schnitzer TJ, Johnston JM (1996) CAMPATH–1H in rheumatoid arthritis–an intravenous dose–ranging study. Br J Rheumatol 35:231–240PubMedGoogle Scholar
  34. 34.
    Isaacs JD, Watts RA, Hazleman BL, Hale G, Keogan MT, Cobbold SP, Waldmann H (1992) Humanised monoclonal antibody therapy for rheumatoid arthritis. Lancet 340:748–752CrossRefPubMedGoogle Scholar
  35. 35.
    Kaplan MR, Meyer Franke A, Lambert S, Bennett V, Duncan ID, Levinson SR, Barres BA (1997) Induction of sodium channel clustering by oligodendrocytes. Nature 386:724–728CrossRefPubMedGoogle Scholar
  36. 36.
    Kapoor R, Davies M, Blaker PA, Hall SM, Smith KJ (2003) Blockers of sodium and calcium entry protect axons from nitric oxide–mediated degeneration. Ann Neurol 53:174–180CrossRefPubMedGoogle Scholar
  37. 37.
    Killick SB, Marsh JC, Hale G, Waldmann H, Kelly SJ, Gordon Smith EC (1997) Sustained remission of severe resistant autoimmune neutropenia with Campath–1H. Br J Haematol 97:306–308PubMedGoogle Scholar
  38. 38.
    Kotter MR, Zhao C, van Rooijen N, Franklin RJ (2005) Macrophage–depletion induced impairment of experimental CNS remyelination is associated with a reduced oligodendrocyte progenitor cell response and altered growth factor expression. Neurobiol Dis 18:166–175CrossRefPubMedGoogle Scholar
  39. 39.
    Kuhlmann T, Lingfeld G, Bitsch A, Schuchardt J, Bruck W (2002) Acute axonal damage in multiple sclerosis is most extensive in early disease stages and decreases over time. Brain 125:2202–2212CrossRefPubMedGoogle Scholar
  40. 40.
    Leary SM, Miller DH, Stevenson VL, Brex PA, Chard DT, Thompson AJ (2003) Interferon beta–1a in primary progressive MS: an exploratory, randomized, controlled trial. Neurology 60:44–51PubMedGoogle Scholar
  41. 41.
    Lim SH, Hale G, Marcus RE, Waldmann H, Baglin TP (1993) CAMPATH–1 monoclonal antibody therapy in severe refractory autoimmune thrombocytopenic purpura. Br J Haematol 84:542–544PubMedGoogle Scholar
  42. 42.
    Lockwood CM, Thiru S, Stewart S, Hale G, Isaacs J, Wraight P, Elliott J, Waldmann H (1996) Treatment of refractory Wegener's granulomatosis with humanized monoclonal antibodies. QJM 89:903–912PubMedGoogle Scholar
  43. 43.
    Losseff NA, Wang L, Lai HM, Yoo DS, Gawne Cain ML, McDonald WI, Miller DH, Thompson AJ (1996) Progressive cerebral atrophy in multiple sclerosis. A serial MRI study. Brain 119:2009–2019PubMedGoogle Scholar
  44. 44.
    Matthews JN, Altman DG, Campbell MJ, Royston P (1990) Analysis of serial measurements in medical research. BMJ 300:230–235PubMedGoogle Scholar
  45. 45.
    McDonald WI, Compston A, Edan G, Goodkin D, Hartung HP, Lublin FD, McFarland HF, Paty DW, Polman CH, Reingold SC, Sandberg–Wollheim M, Sibley W, Thompson A, van den Noort S, Weinshenker BY, Wolinsky JS (2001) Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the diagnosis of multiple sclerosis. Ann Neurol 50:121–127CrossRefPubMedGoogle Scholar
  46. 46.
    Meyer Franke A, Kaplan MR, Pfrieger FW, Barres BA (1995) Characterization of the signaling interactions that promote the survival and growth of developing retinal ganglion cells in culture. Neuron 15:805–819CrossRefGoogle Scholar
  47. 47.
    Miller DH, Molyneux PD, Barker GJ, MacManus DG, Moseley IF, Wagner K (1999) Effect of interferon–beta1b on magnetic resonance imaging outcomes in secondary progressive multiple sclerosis: results of a European multicenter, randomized, double–blind, placebo–controlled trial. European Study Group on Interferon–beta1b in secondary progressive multiple sclerosis. Ann Neurol 46:850–859CrossRefPubMedGoogle Scholar
  48. 48.
    Molyneux PD, Kappos L, Polman C, Pozzilli C, Barkhof F, Filippi M, Yousry T, Hahn D, Wagner K, Ghazi M, Beckmann K, Dahlke F, Losseff N, Barker GJ, Thompson AJ, Miller DH (2000) The effect of interferon beta–1b treatment on MRI measures of cerebral atrophy in secondary progressive multiple sclerosis. European Study Group on Interferon beta–1b in secondary progressive multiple sclerosis. Brain 123:2256–2263CrossRefPubMedGoogle Scholar
  49. 49.
    Monzani F, Caraccio N, Meucci G, Lombardo F, Moscato G, Casolaro A, Ferdeghini M, Murri L, Ferrannini E (1999) Effect of 1–year treatment with interferon–beta1b on thyroid function and autoimmunity in patients with multiple sclerosis. Eur J Endocrinol 141:325–331CrossRefPubMedGoogle Scholar
  50. 50.
    Moreau T, Thorpe J, Miller D, Moseley I, Hale G, Waldmann H, Clayton D, Wing M, Scolding N, Compston A (1994) Preliminary evidence from magnetic resonance imaging for reduction in disease activity after lymphocyte depletion in multiple sclerosis [published erratum appears in Lancet 1994 Aug 13, 344(8920):486]. Lancet 344:298–301PubMedGoogle Scholar
  51. 51.
    Nicholas RS, Compston A, Brown DR (2001) Inhibition of tumour necrosis factor–alpha (TNFalpha)–induced NFkappaB p52 converts the metabolic effects of microglial–derived TNFalpha on mouse cerebellar neurones to neurotoxicity. J Neurochem 76:1431–1438CrossRefPubMedGoogle Scholar
  52. 52.
    Paolillo A, Coles AJ, Molyneux P, Gawne Cain ML, MacManus D, Barker GJ, Compston A, Miller D (1999) Quantitative MRI in patients with secondary progressive multiple sclerosis treated with monoclonal antibody Campath–1H. Neurology 53:751–757PubMedGoogle Scholar
  53. 53.
    Redford EJ, Kapoor R, Smith KJ (1997) Nitric oxide donors reversibly block axonal conduction: demyelinated axons are especially susceptible. Brain 120:2149–2157PubMedGoogle Scholar
  54. 54.
    Rice GP, Filippi M, Comi G (2000) Cladribine and progressive MS: clinical and MRI outcomes of a multicenter controlled trial. Cladribine MRI Study Group. Neurology 54:1145–1155PubMedGoogle Scholar
  55. 55.
    Riechmann L, Clark M, Waldmann H, Winter G (1988) Reshaping human antibodies for therapy. Nature 332:323–327CrossRefPubMedGoogle Scholar
  56. 56.
    Rotondi M, Oliviero A, Profice P, Mone CM, Biondi B, Del Buono A, Mazziotti G, Sinisi AM, Bellastella A, Carella C (1998) Occurrence of thyroid autoimmunity and dysfunction throughout a nine–month follow–up in patients undergoing interferon–beta therapy for multiple sclerosis. J Endocrinol Invest 21:748–752PubMedGoogle Scholar
  57. 57.
    Sanchez I, Hassinger L, Paskevich PA, Shine HD, Nixon RA (1996) Oligodendroglia regulate the regional expansion of axon caliber and local accumulation of neurofilaments during development independently of myelin formation. J Neurosci 16:5095–5105PubMedGoogle Scholar
  58. 58.
    Simon JH, Jacobs L, Kinkel RP (2001) Transcallosal bands: a sign of neuronal tract degeneration in early MS? Neurology 57:1888–1890PubMedGoogle Scholar
  59. 59.
    Simon JH, Jacobs L, Kinkel RP (2001) Transcallosal bands: a sign of neuronal tract degeneration in early MS? Neurology 57:1888–1890PubMedGoogle Scholar
  60. 60.
    Smith KJ, Kapoor R, Hall SM, Davies M (2001) Electrically active axons degenerate when exposed to nitric oxide. Ann Neurol 49:470–476PubMedGoogle Scholar
  61. 61.
    Stadelmann C, Kerschensteiner M, Misgeld T, Bruck W, Hohlfeld R, Lassmann H (2002) BDNF and gp145trkB in multiple sclerosis brain lesions: neuroprotective interactions between immune and neuronal cells? Brain 125:75–85CrossRefPubMedGoogle Scholar
  62. 62.
    The CHAMPS Study Group (2000) Intramuscular interferon beta–1a therapy initiated during a first demyelinating event in multiple sclerosis. N Engl J Med 343:898–904Google Scholar
  63. 63.
    Trapp BD, Peterson J, Ransohoff RM, Rudick RA, Mork S, Bo L (1998) Axonal transection in the lesions of multiple sclerosis. N Engl J Med 338:278–285CrossRefPubMedGoogle Scholar
  64. 64.
    Verdun E, Isoardo G, Oggero A, Ferrero B, Ghezzi A, Montanari E, Zaffaroni M, Durelli L (2002) Autoantibodies in multiple sclerosis patients before and during IFN–beta 1b treatment: are they correlated with the occurrence of autoimmune diseases? J Interferon Cytokine Res 22:245–255CrossRefPubMedGoogle Scholar
  65. 65.
    Weinshenker BG, Bass B, Rice GP, Noseworthy J, Carriere W, Baskerville J, Ebers GC (1989) The natural history of multiple sclerosis: a geographically based study. 2. Predictive value of the early clinical course. Brain 112:1419–1428PubMedGoogle Scholar
  66. 66.
    Wilkins A, Chandran S, Compston A (2001) A role for oligodendrocytederived IGF–1 in trophic support of cortical neurons. Glia 36:48–57CrossRefPubMedGoogle Scholar
  67. 67.
    Wilkins A, Majed H, Layfield R, Compston A, Chandran S (2003) Oligodendrocytes promote neuronal survival and axonal length by distinct intracellular mechanisms: a novel role for oligodendrocyte–derived glial cell linederived neurotrophic factor. J Neurosci 23:4967–4974PubMedGoogle Scholar

Copyright information

© Steinkopff-Verlag 2005

Authors and Affiliations

  • A. J. Coles
    • 4
  • A. Cox
    • 4
  • E. Le Page
    • 4
  • J. Jones
    • 4
  • S. A. Trip
    • 1
  • J. Deans
    • 4
  • S. Seaman
    • 2
  • D. H. Miller
    • 1
  • G. Hale
    • 3
  • H. Waldmann
    • 3
  • D. A. Compston
    • 4
  1. 1.Institute of NeurologyUniversity College LondonLondonUK
  2. 2.MRC Biostatistics UnitCambridgeUK
  3. 3.Sir William Dunn School of PathologyUniversity of OxfordOxfordUK
  4. 4.Department of Clinical Neurosciences, Box 165Addenbrooke’s HospitalCambridge CB2 2QQUK

Personalised recommendations