Evolution of MS lesions to black holes under DNA vaccine treatment

Deutsche Zeitschrift für Nervenheilkunde - Tập 259 - Trang 1375-1382 - 2012
Athina Papadopoulou1, Stefanie von Felten2, Stefan Traud3, Amena Rahman4, Joanne Quan4, Robert King4, Hideki Garren4, Lawrence Steinman5, Gary Cutter6, Ludwig Kappos1, Ernst Wilhelm Radue3
1Neurology Clinic, Department of Neurology, University Hospital Basel, Basel, Switzerland
2Clinical Trial Unit, University Hospital Basel, Basel, Switzerland
3Medical Image Analysis Center (MIAC), University Hospital Basel, Basel, Switzerland
4Bayhill Therapeutics, Palo Alto, USA
5Stanford University, Stanford, USA
6Department of Biostatistics, University of Alabama, Birmingham, USA

Tóm tắt

Persistent black holes (PBH) are associated with axonal loss and disability progression in multiple sclerosis (MS). The objective of this work was to determine if BHT-3009, a DNA plasmid-encoding myelin basic protein (MBP), reduces the risk of new lesions becoming PBH, compared to placebo, and to test if pre-treatment serum anti-MBP antibody levels impact on the effect of BHT-3009 treatment. In this retrospective, blinded MRI study, we reviewed MRI scans of 155 MS patients from a double-blind, randomized, phase II trial with three treatment arms (placebo, 0.5 and 1.5 mg BHT-3009). New lesions at weeks 8 and 16 were tracked at week 48 and those appearing as T1-hypointense were classified as PBH. A subset of 46 patients with available pre-treatment serum anti-MBP IgM levels were analyzed separately. Overall, there was no impact of treatment on the risk for PBH. However, there was a significant interaction between anti-MBP antibodies and treatment effect: patients receiving 0.5 mg BHT-3009 showed a reduced risk of PBH with higher antibody levels compared to placebo (p < 0.01). Although we found no overall reduction of the risk for PBH in treated patients, there may be an effect of low-dose BHT-3009, depending on the patients’ pre-treatment immune responses.

Tài liệu tham khảo

Barkhof F, Brueck W, De Groot C et al (2003) Remyelinated lesions in multiple sclerosis magnetic resonance image appearance. Arch Neurol 60:1073–1081 Bitsch A, Kuhlmann T, Stadelmann C, Lassmann H, Lucchinetti C, Bruck W (2001) A longitudinal MRI study of histopathologically defined hypointense multiple sclerosis lesions. Ann Neurol 49:793–796 Brueck W, Bitsch A, Kolenda H, Brück Y, Stiefel M, Lassmann H (1997) Inflammatory central nervous system demyelination: correlation of magnetic resonance imaging findings with lesion pathology. Ann Neurol 42:783–793 van Walderveen MA, Kamphorst W, Scheltens P et al (1998) Histopathologic correlate of hypointense lesions on T1-weighted spin-echo MRI in multiple sclerosis. Neurology 50:1282–1288 Bitsch A, Bruhn H, Vougioukas V et al (1999) Inflammatory CNS demyelination: histopathologic correlation with in vivo quantitative proton MR spectroscopy. Am J Neuroradiol 20:1619–1627 Karampekios S, Papanikolaou N, Papadaki E et al (2005) Quantification of magnetization transfer rate and native T1 relaxation time of the brain: correlation with magnetization transfer ratio measurements in patients with multiple sclerosis. Neuroradiology 47:189–196 Levesque I, Sled JG, Narayanan S et al (2005) The role of edema and demyelination in chronic T1 black holes: a quantitative magnetization transfer study. J Magn Reson Imaging 21:103–110 Otaduy MC, Callegaro D, Bacheschi LA, Leite CC (2006) Correlation of magnetization transfer and diffusion magnetic resonance imaging in multiple sclerosis. Mult Scler 12:754–759 Rovira A, Alonso J, Cucurella G et al (1999) Evolution of multiple sclerosis lesions on serial contrast-enhanced T1-weighted and magnetization-transfer MR images. Am J Neuroradiol 20:1939–1945 van Waesberghe JH, van Buchem MA, Filippi M et al (1998) MR outcome parameters in multiple sclerosis: comparison of surface-based thresholding segmentation and magnetization transfer ratio histographic analysis in relation to disability (a preliminary note). Am J Neuroradiol 19:1857–1862 van Walderveen MA, Barkhof F, Pouwels PJ, van Schijndel RA, Polman CH, Castelijns JA (1999) Neuronal damage in T1-hypointense multiple sclerosis lesions demonstrated in vivo using proton magnetic resonance spectroscopy. Ann Neurol 46:79–87 Iannucci G, Minicucci L, Rodegher M, Sormani MP, Comi G, Filippi M (1999) Correlations between clinical and MRI involvement in multiple sclerosis: assessment using T(1), T(2) and MT histograms. J Neurol Sci 171:121–129 Minneboo A, Uitdehaag BM, Jongen P et al (2009) Association between MRI parameters and the MS severity scale: a 12 year follow-up study. Mult Scler 15:632–637 Nijeholt GJ, van Walderveen MA, Castelijns JA et al (1998) Brain and spinal cord abnormalities in multiple sclerosis. Correlation between MRI parameters, clinical subtypes and symptoms. Brain 121(Pt 4):687–697 Rovaris M, Comi G, Rocca MA et al (1999) Relevance of hypointense lesions on fast fluid-attenuated inversion recovery MR images as a marker of disease severity in cases of multiple sclerosis. Am J Neuroradiol 20:813–820 Sailer M, Losseff NA, Wang L, Gawne-Cain ML, Thompson AJ, Miller DH (2001) T1 lesion load and cerebral atrophy as a marker for clinical progression in patients with multiple sclerosis. A prospective 18 months follow-up study. Eur J Neurol 8:37–42 Truyen L, van Waesberghe JH, van Walderveen MA et al (1996) Accumulation of hypointense lesions (“black holes”) on T1 spin-echo MRI correlates with disease progression in multiple sclerosis. Neurology 47:1469–1476 van Walderveen MA, Barkhof F, Hommes OR et al (1995) Correlating MRI and clinical disease activity in multiple sclerosis: relevance of hypointense lesions on short-TR/short-TE (T1-weighted) spin-echo images. Neurology 45:1684–1690 van Walderveen MA, Truyen L, van Oosten BW et al (1999) Development of hypointense lesions on T1-weighted spin-echo magnetic resonance images in multiple sclerosis: relation to inflammatory activity. Arch Neurol 56:345–351 van Walderveen MA, Lycklama ANG, Ader HJ et al (2001) Hypointense lesions on T1-weighted spin-echo magnetic resonance imaging: relation to clinical characteristics in subgroups of patients with multiple sclerosis. Arch Neurol 58:76–81 Zivadinov R, Leist TP (2005) Clinical-magnetic resonance imaging correlations in multiple sclerosis. J Neuroimaging 15:10S–21S van Waesberghe JH, van Walderveen MA, Castelijns JA et al (1998) Patterns of lesion development in multiple sclerosis: longitudinal observations with T1-weighted spin-echo and magnetization transfer MR. Am J Neuroradiol 19:675–683 Rovira A, Leon A (2008) MR in the diagnosis and monitoring of multiple sclerosis: an overview. Eur J Radiol 67:409–414 Dalton CM, Miszkiel KA, Barker GJ et al (2004) Effect of natalizumab on conversion of gadolinium enhancing lesions to T1 hypointense lesions in relapsing multiple sclerosis. J Neurol 251:407–413 Filippi M, Rovaris M, Rocca MA, Sormani MP, Wolinsky JS, Comi G (2001) Glatiramer acetate reduces the proportion of new MS lesions evolving into “black holes”. Neurology 57:731–733 Barkhof F, Hulst HE, Drulovic J, Uitdehaag BM, Matsuda K, Landin R (2010) MN166-001 Investigators. Ibudilast in relapsing-remitting multiple sclerosis: a neuroprotectant? Neurology 74(13):1033–1040 MacManus DG, Miller D, Kappos L, et al (2008) The effect of BG00012 on conversion of gadolinium-enhancing lesions to T1-hypointense lesions. Mult Scler 14:163 Garren H, Robinson WH, Krasulova E et al (2008) Phase 2 trial of a DNA vaccine encoding myelin basic protein for multiple sclerosis. Ann Neurol 63:611–620 Garren H, Robinson WH, Rahman A, King R, Utz PJ, Steinman L (2010) Baseline plasma anti-MBP antibody levels correlate with subject response to BHT-3009, a novel, antigen-specific tolerizing DNA vaccine therapy for MS patients. Mult Scler p417 Frohman EM, Racke MK, Raine CS (2006) Multiple sclerosis—the plaque and its pathogenesis. N Engl J Med 354:942–955 Sospedra M, Martin R (2005) Immunology of multiple sclerosis. Annu Rev Immunol 23:683–747 Genain CP, Cannella B, Hauser SL, Raine CS (1999) Identification of autoantibodies associated with myelin damage in multiple sclerosis. Nat Med 5:170–175 Bielekova B, Goodwin B, Richert N et al (2000) Encephalitogenic potential of the myelin basic protein peptide (amino acids 83–99) in multiple sclerosis: results of a phase II clinical trial with an altered peptide ligand. Nat Med 6:1167–1175 Cadavid D, Cheriyan J, Skurnick J, Lincoln JA, Wolansky LJ, Cook SD (2009) New acute and chronic black holes in patients with multiple sclerosis randomised to interferon beta-1b or glatiramer acetate. J Neurol Neurosurg Psychiatry 80:1337–1343 Dalton CM, Miszkiel KA, Barker GJ et al (2004) Effect of natalizumab on conversion of gadolinium enhancing lesions to T1 hypointense lesions in relapsing multiple sclerosis. J Neurol 251:407–413