title: The window of therapeutic opportunity in multiple sclerosis: evidence from monoclonal antibody therapy.
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.
authors.affiliation: Department of Clinical Neurosciences, Box 165, Addenbrooke's Hospital, Cambridge CB2 2QQ, UK. ajc1020@medschl.cam.ac.uk
authors.forename: Alasdair J
authors.initials: AJ
authors.lastname: Coles
authors.forename: Amanda
authors.initials: A
authors.lastname: Cox
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Le Page
authors.forename: Joanne
authors.initials: J
authors.lastname: Jones
authors.forename: S Anand
authors.initials: SA
authors.lastname: Trip
authors.forename: Jackie
authors.initials: J
authors.lastname: Deans
authors.forename: Shaun
authors.initials: S
authors.lastname: Seaman
authors.forename: David H
authors.initials: DH
authors.lastname: Miller
authors.forename: Geoff
authors.initials: G
authors.lastname: Hale
authors.forename: Herman
authors.initials: H
authors.lastname: Waldmann
authors.forename: D Alastair
authors.initials: DA
authors.lastname: Compston
mesh_terms: D000074323:Alemtuzumab; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000009:adverse effects; D061067:Antibodies, Monoclonal, Humanized; D000912:Antibodies, Neoplasm / Q000008:administration & dosage* / Q000009:adverse effects; D018501:Antirheumatic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D015551:Autoimmunity / Q000187:drug effects; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D004185:Disability Evaluation; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007223:Infant; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D009103:Multiple Sclerosis / Q000628:therapy*; D012189:Retrospective Studies; D055502:Secondary Prevention; D013997:Time Factors
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000912:Antibodies, Neoplasm; D018501:Antirheumatic Agents; D000074323:Alemtuzumab