Effect of disease-modifying drugs on cortical lesions and atrophy in relapsing–remitting multiple sclerosis

Objective: To measure the effects of disease-modifying drugs (DMDs) on the development of cortical lesions (CL) and cortical atrophy in patients with relapsing–remitting multiple sclerosis (RRMS). Methods: RRMS patients (n = 165) were randomized to subcutaneous (sc) interferon (IFN) beta-1a (44 mcg three times weekly), intramuscular (im) IFN beta-1a (30 mcg weekly) or glatiramer acetate (GA; 20 mg daily). The reference population comprised 50 untreated patients. Clinical and MRI examinations were performed at baseline, 12 months and 24 months. Results: One hundred and forty-one treated patients completed the study. After 12 months, 37/50 (74%) of untreated patients developed ≥1 new CL (mean 1.6), compared with 30/47 (64%) of im IFN beta-1a-treated patients (mean 1.2, p = 0.021), 24/48 (50%) of GA-treated patients (mean 0.8, p = 0.001) and 12/46 (26%) of sc IFN beta-1a-treated patients (mean 0.4, p < 0.001). After 24 months, ≥1 new CL was observed in 41/50 (82%) of untreated (mean 3.0), 34/47 (72%) of im IFN beta-1a-treated (mean 1.6, p < 0.001), 30/48 (62%) of GA-treated (mean 1.3, p < 0.001) and 24/46 (52%) of sc IFN beta-1a-treated patients (mean 0.8, p < 0.001). Mean grey matter fraction decrease in DMD-treated patients at 24 months ranged from 0.7 to 0.8 versus 1.0 in untreated patients (p = 0.023). Conclusions: Disease-modifying drugs significantly decreased new CL development and cortical atrophy progression compared with untreated patients, with faster and more pronounced effects seen with sc IFN beta-1a than with im IFN beta-1a or GA.

[1]  J. Tukey Comparing individual means in the analysis of variance. , 1949, Biometrics.

[2]  Rohit Bakshi,et al.  Gray matter involvement in multiple sclerosis , 2007, Neurology.

[3]  Frederik Barkhof,et al.  Extensive Hippocampal Demyelination in Multiple Sclerosis , 2007, Journal of neuropathology and experimental neurology.

[4]  B. Trapp,et al.  Subpial Demyelination in the Cerebral Cortex of Multiple Sclerosis Patients , 2003, Journal of neuropathology and experimental neurology.

[5]  F. Barkhof The clinico‐radiological paradox in multiple sclerosis revisited , 2002, Current opinion in neurology.

[6]  S. Reingold,et al.  Diagnostic criteria for multiple sclerosis: 2005 revisions to the “McDonald Criteria” , 2005, Annals of neurology.

[7]  Hans Lassmann,et al.  Cortical demyelination and diffuse white matter injury in multiple sclerosis. , 2005, Brain : a journal of neurology.

[8]  M. Calabrese,et al.  Magnetic resonance evidence of cortical onset of multiple sclerosis , 2009, Multiple sclerosis.

[9]  J. De Keyser,et al.  Treatment with interferon beta-1b delays conversion to clinically definite and McDonald MS in patients with clinically isolated syndromes , 2006, Neurology.

[10]  J. Stockman Effect of glatiramer acetate on conversion to clinically definite multiple sclerosis in patients with clinically isolated syndrome (PreCISe study): a randomised, double-blind, placebo-controlled trial , 2011 .

[11]  Hans Lassmann,et al.  Cortical demyelination in multiple sclerosis: A substrate for cognitive deficits? , 2006, Journal of the Neurological Sciences.

[12]  D S Goodin,et al.  Report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and the MS Council for Clinical Practice Guidelines , 2001 .

[13]  Richard A. C. Hughes,et al.  PRISMS-4: Long-term efficacy of interferon-&bgr;-1a in relapsing MS , 2001, Neurology.

[14]  Chiara Romualdi,et al.  Detection of cortical inflammatory lesions by double inversion recovery magnetic resonance imaging in patients with multiple sclerosis. , 2007, Archives of neurology.

[15]  M. Filippi,et al.  250 μg or 500 μg interferon beta-1b versus 20 mg glatiramer acetate in relapsing-remitting multiple sclerosis: a prospective, randomised, multicentre study , 2009, The Lancet Neurology.

[16]  Marco Rovaris,et al.  Effect of early interferon treatment on conversion to definite multiple sclerosis: a randomised study , 2001, The Lancet.

[17]  A J Thompson,et al.  Gray and white matter volume changes in early RRMS , 2005, Neurology.

[18]  C. Poser,et al.  Diagnostic criteria for multiple sclerosis , 2001, Clinical Neurology and Neurosurgery.

[19]  R. Rudick,et al.  Brain atrophy as an outcome measure for multiple sclerosis clinical trials , 2009, Neurology.

[20]  P. Vermersch,et al.  A placebo-controlled trial of oral cladribine for relapsing multiple sclerosis. , 2010, The New England journal of medicine.

[21]  H P Hartung,et al.  Treatment with interferon beta-1b delays conversion to clinically definite and McDonald MS in patients with clinically isolated syndromes , 2006, Neurology.

[22]  M. Filippi,et al.  Cortical lesions in primary progressive multiple sclerosis , 2009, Neurology.

[23]  A. Compston,et al.  Recommended diagnostic criteria for multiple sclerosis: Guidelines from the international panel on the diagnosis of multiple sclerosis , 2001, Annals of neurology.

[24]  E. Portaccio,et al.  Evidence for relative cortical sparing in benign multiple sclerosis: a longitudinal magnetic resonance imaging study , 2009, Multiple sclerosis.

[25]  Ludwig Kappos,et al.  A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. , 2010, The New England journal of medicine.

[26]  D. Paty,et al.  Interferon beta‐1b is effective in relapsing‐remitting multiple sclerosis , 1993, Neurology.

[27]  M. Calabrese,et al.  Extensive cortical inflammation is associated with epilepsy in multiple sclerosis , 2008, Journal of Neurology.

[28]  Rohit Bakshi,et al.  The measurement and clinical relevance of brain atrophy in multiple sclerosis , 2006, The Lancet Neurology.

[29]  M. Rovaris,et al.  Regional brain atrophy evolves differently in patients with multiple sclerosis according to clinical phenotype. , 2005, AJNR. American journal of neuroradiology.

[30]  J H Simon,et al.  Intramuscular interferon beta-1a therapy initiated during a first demyelinating event in multiple sclerosis. CHAMPS Study Group. , 2000, The New England journal of medicine.

[31]  Xavier Montalban,et al.  Daclizumab in active relapsing multiple sclerosis (CHOICE study): a phase 2, randomised, double-blind, placebo-controlled, add-on trial with interferon beta , 2010, The Lancet Neurology.

[32]  D. Louis Collins,et al.  Relating neocortical pathology to disability progression in multiple sclerosis using MRI , 2004, NeuroImage.

[33]  G Cazzato,et al.  A longitudinal study of brain atrophy and cognitive disturbances in the early phase of relapsing-remitting multiple sclerosis , 2001, Journal of neurology, neurosurgery, and psychiatry.

[34]  M. Filippi,et al.  A 3‐year magnetic resonance imaging study of cortical lesions in relapse‐onset multiple sclerosis , 2009, Annals of neurology.

[35]  A. Thompson,et al.  Magnetic resonance imaging in monitoring the treatment of multiple sclerosis: concerted action guidelines. , 1991, Journal of neurology, neurosurgery, and psychiatry.

[36]  Frederik Barkhof,et al.  Grey matter pathology in multiple sclerosis , 2008, The Lancet Neurology.

[37]  Ludwig Kappos,et al.  Effect of early versus delayed interferon beta-1b treatment on disability after a first clinical event suggestive of multiple sclerosis: a 3-year follow-up analysis of the BENEFIT study , 2007, The Lancet.

[38]  F. Barkhof,et al.  Comparison of subcutaneous interferon beta-1a with glatiramer acetate in patients with relapsing multiple sclerosis (the REbif vs Glatiramer Acetate in Relapsing MS Disease [REGARD] study): a multicentre, randomised, parallel, open-label trial , 2008, The Lancet Neurology.

[39]  C. Granger,et al.  Intramuscular interferon beta‐1a for disease progression in relapsing multiple sclerosis , 1996, Annals of neurology.

[40]  H. Panitch,et al.  Full results of the Evidence of Interferon Dose-Response-European North American Comparative Efficacy (EVIDENCE) study: a multicenter, randomized, assessor-blinded comparison of low-dose weekly versus high-dose, high-frequency interferon beta-1a for relapsing multiple sclerosis. , 2007, Clinical therapeutics.

[41]  Alan J. Thompson,et al.  Localization of grey matter atrophy in early RRMS , 2006, Journal of Neurology.

[42]  Interferon beta-1b in the treatment of multiple sclerosis: final outcome of the randomized controlled trial. The IFNB Multiple Sclerosis Study Group and The University of British Columbia MS/MRI Analysis Group. , 1995, Neurology.

[43]  F. Barkhof,et al.  Accumulation of cortical lesions in MS: relation with cognitive impairment , 2009, Multiple sclerosis.

[44]  D. Paty,et al.  Magnetic resonance imaging results of the PRISMS trial: A randomized, double‐blind, placebo‐controlled study of interferon‐β1a in relapsing‐remitting multiple sclerosis , 1999 .

[45]  Massimo Filippi,et al.  Cortical lesions and atrophy associated with cognitive impairment in relapsing-remitting multiple sclerosis. , 2009, Archives of neurology.