Abhishek Gulati (1,2), Francesca Bagnato (3,4), Pablo Villoslada (5), Nieves Velez de Mendizabal (1,2)
(1) Indiana University School of Medicine, Indianapolis, IN, USA; (2) Indiana Clinical and Translational Sciences Institute (CTSI), Indianapolis, IN, USA; (3) Neuroimmunology Branch, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD, USA; (4) Department of Neurology, University of Maryland, Baltimore, MD, USA; (5) Center for Neuroimmunology, Institute of Biomedical Research August Pi Sunyer (IDIBAPS), Hospital Clinic of Barcelona, Barcelona, Spain
Background: Multiple sclerosis (MS) is a chronic autoimmune disease that may affect both white matter and gray matter [1-3]. The acute focal inflammatory events in the white matter are evident on magnetic resonance imaging (MRI) as contrast enhancing lesions (CELs). A negative binomial distribution model was recently used to best describe the CEL generation and resolution in the absence of treatment [4]. Interferon beta-1b (IFN-beta-1b) is widely used for the treatment of relapsing-remitting (RR) MS. Despite being first-line treatment, IFN-beta-1b is considered only partially effective in reducing CEL activity [2].
Objectives: The aims of this work are (1) to characterize the effect of IFN-beta-1b in preventing CEL formation and (2) to investigate its ability in promoting CEL resolution.
Methods: Nine patients with RRMS, not receiving any immunomodulatory treatment but steroids to treat clinical exacerbations, underwent monthly MRIs for 48 months [5]. The number of CELs was monthly recorded. Monthly CELs were also available from 6-months pre-therapy and 36-months therapy phases from another group of 15 RRMS patients [6]. Therapy consisted of subcutaneous administration of 250 µg IFN-beta-1b every other day for 36 months as well as steroids to treat clinical exacerbations. Using the previously published negative binomial distribution model [4] as the baseline model, effect of IFN-beta-1b was evaluated on all the model parameters using different time functions. The analyses were performed using NONMEM version 7.2 [7].
Results: IFN-beta-1b produced an expected decrease in the predicted numbers of CELs (λ) by λ0 inhibition. No effect was identified on the Markovian elements that also define λ. The findings imply that the IFN-beta-1b might prevent the formation of new CELs but does not affect their resolution.
Conclusions: A previous study by our group [4] indicated that the use of steroids contributes to the resolution of existing CELs, but does not reduce the development of new CELs. Interestingly, the analyses performed in this study complement these findings, indicating that the use of IFN-beta-1b reduces the formation of new CELs but does not promote disappearance of already-formed CELs. These results suggest that the design of optimal therapies combining IFN-beta-1b and steroids might affect the occurrence and resolution of inflammation more effectively.
References:
[1] Calabresi PA. Diagnosis and management of multiple sclerosis. American family physician. 2004;70(10):1935-44.
[2] Goldenberg MM. Multiple sclerosis review. P & T : a peer-reviewed journal for formulary management. 2012;37(3):175-84.
[3] Weinshenker BG. Epidemiology of multiple sclerosis. Neurologic clinics. 1996;14(2):291-308.
[4] Velez de Mendizabal N, Hutmacher MM, Troconiz IF, Goni J, Villoslada P, Bagnato F, et al. Predicting Relapsing-Remitting Dynamics in Multiple Sclerosis Using Discrete Distribution Models: A Population Approach. Plos One. 2013;8(9).
[5] Bagnato F, Jeffries N, Richert ND, Stone RD, Ohayon JM, McFarland HF, et al. Evolution of T1 black holes in patients with multiple sclerosis imaged monthly for 4 years. Brain : a journal of neurology. 2003;126(Pt 8):1782-9.
[6] Chiu AW, Richert N, Ehrmantraut M, Ohayon J, Gupta S, Bomboi G, et al. Heterogeneity in response to interferon beta in patients with multiple sclerosis: a 3-year monthly imaging study. Archives of neurology. 2009;66(1):39-43.
[7] Beal S, Sheiner LB, Boeckmann A, Bauer RJ. NONMEM User’s Guides. (1989-2011), ICON Development Solutions, Ellicott City, MD, USA. 2011.
Reference: PAGE 23 () Abstr 3086 [www.page-meeting.org/?abstract=3086]
Poster: Drug/Disease modeling - CNS