References
- Papers of special note have been highlighted as:
- * of interest to readers
- ** of considerable interest to readers
- Polman CH, Uitdehaag BM. Drug treatment of multiple sclerosis. BMJ. 2000;321(7259):490–494.
- Haggiag S, Ruggieri S, Gasperini C. Efficacy and safety of laquinimod in multiple sclerosis: current status. Ther Adv Neurol Disord. 2013;6(6):343–352.
- Patwardhan MB, Matchar DB, Samsa GP, et al. Cost of multiple sclerosis by level of disability: a review of literature. Mult Scler. 2005;11(2):232–239.
- Lucchinetti CF, Bruck W, Rodriguez M, et al. Distinct patterns of multiple sclerosis pathology indicates heterogeneity on pathogenesis. Brain Pathol. 1996;6(3):259–274.
- Ontaneda D, Fox RJ, Chataway J. Clinical trials in progressive multiple sclerosis: lessons learned and future perspectives. Lancet Neurol. 2015;14(2):208–223.
- Lugaresi A, di Ioia M, Travaglini D, et al. Risk-benefit considerations in the treatment of relapsing-remitting multiple sclerosis. Neuropsychiatr Dis Treat. 2013;9:893–914.
- Tanasescu R, Ionete C, Chou IJ, et al. Advances in the treatment of relapsing-remitting multiple sclerosis. Biomed J. 2014;37(2):41–49.
- Wolinsky JS, Narayana PA, Noseworthy JH, et al. Linomide in relapsing and secondary progressive MS: part II: MRI results. MRI Analysis Center of the University of Texas-Houston, Health Science Center, and the North American Linomide Investigators. Neurology. 2000;54(9):1734–1741.
- Tan IL, Lycklama a Nijeholt GJ, Polman CH, et al. Linomide in the treatment of multiple sclerosis: MRI results from prematurely terminated phase-III trials. Mult Scler. 2000;6(2):99–104.
- Yang J-S, Xu L-Y, Xiao B-G, et al. Laquinimod (ABR-215062) suppresses the development of experimental autoimmune encephalomyelitis, modulates the Th1/Th2 balance and induces the Th3 cytokine TGF-β in Lewis rats. J Neuroimmunol. 2004;156(1–2):3–9.
- Brück W, Wegner C. Insight into the mechanism of laquinimod action. J Neurol Sci. 2011;306(1–2):173–179.
- Fernandez O. Oral laquinimod treatment in multiple sclerosis. Neurologia. 2011;26(2):111–117.
- Constantinescu CS, Farooqi N, O’Brien K, et al. Experimental autoimmune encephalomyelitis (EAE) as a model for multiple sclerosis (MS). Br J Pharmacol. 2011;164(4):1079–1106.
- Wegner C, Stadelmann C, Pfortner R, et al. Laquinimod interferes with migratory capacity of T cells and reduces IL-17 levels, inflammatory demyelination and acute axonal damage in mice with experimental autoimmune encephalomyelitis. J Neuroimmunol. 2010;227(1–2):133–143.
- Ruffini F, Rossi S, Bergamaschi A, et al. Laquinimod prevents inflammation-induced synaptic alterations occurring in experimental autoimmune encephalomyelitis. Mult Scler. 2013;19(8):1084–1094.
*A study showing a potentially important neuroprotective effect of laquinimod.
- Schulze-Topphoff U, Shetty A, Varrin-Doyer M, et al. Laquinimod, a quinoline-3-carboxamide, induces type ii myeloid cells that modulate central nervous system autoimmunity. PLoS ONE. 2012;7(3):e33797.
**Evidence that laquinimod modulates primarily cells of the innate immune system and thus suppresses inflammation both in the periphery and in the CNS.
- Mishra MK, Wang J, Silva C, et al. Kinetics of proinflammatory monocytes in a model of multiple sclerosis and its perturbation by laquinimod. Am J Pathol. 2012;181(2):642–651.
- Toubi E, Nussbaum S, Staun-Ram E, et al. Laquinimod modulates B cells and their regulatory effects on T cells in Multiple Sclerosis. J Neuroimmunol. 2012;251(1–2):45–54.
- Zilkha-Falb R, Gurevich M, Hayardeny L, et al. The role of laquinimod in modulation of the immune response in relapsing–remitting multiple sclerosis: lessons from gene expression signatures. J Neuroimmunol. 2015;283:11–16.
- Jolivel V, Luessi F, Masri J, et al. Modulation of dendritic cell properties by laquinimod as a mechanism for modulating multiple sclerosis. Brain 2013;136:1048–1066.
**Strong evidence of innate immune system modulation as an essential mechanism whereby laquinimod suppresses multiple sclerosis (MS).
- Blakemore WF. Observations on oligodendrocyte degeneration, the resolution of status spongiosus and remyelination in cuprizone intoxication in mice. J Neurocytol. 1972;1(4):413–426.
- Bruck W, Pfortner R, Pham T, et al. Reduced astrocytic NF-kappaB activation by laquinimod protects from cuprizone-induced demyelination. Acta Neuropathol. 2012;124(3):411–424.
- Raasch J, Zeller N, van Loo G, et al. IkappaB kinase 2 determines oligodendrocyte loss by non-cell-autonomous activation of NF-kappaB in the central nervous system. Brain. 2011;134(Pt 4):1184–1198.
- Wujek JR, Bjartmar C, Richer E, et al. Axon loss in the spinal cord determines permanent neurological disability in an animal model of multiple sclerosis. J Neuropathol Exp Neurol. 2002;61(1):23–32.
- Centonze D, Muzio L, Rossi S, et al. Inflammation triggers synaptic alteration and degeneration in experimental autoimmune encephalomyelitis. J Neurosci. 2009;29(11):3442–3452.
- Rossi S, Muzio L, De Chiara V, et al. Impaired striatal GABA transmission in experimental autoimmune encephalomyelitis. Brain Behav Immun. 2011;25(5):947–956.
- Thöne J, Ellrichmann G, Seubert S, et al. Modulation of autoimmune demyelination by laquinimod via induction of brain-derived neurotrophic factor. Am J Pathol. 2012;180(1):267–274.
**In vivo evidence that brain-derived neurotrophic factor mediates some of the neuroprotective properties of laquinimod.
- Thone J, Gold R. Laquinimod: a promising oral medication for the treatment of relapsing-remitting multiple sclerosis. Expert Opin Drug Metab Toxicol. 2011;7(3):365–370.
- Polman C, Barkhof F, Sandberg-Wollheim M, et al. Treatment with laquinimod reduces development of active MRI lesions in relapsing MS. Neurology. 2005;64(6):987–991.
*The first Phase II clinical trial of laquinimod in MS showing positive results on the primary outcome measure.
- Comi G, Pulizzi A, Rovaris M, et al. Effect of laquinimod on MRI-monitored disease activity in patients with relapsing-remitting multiple sclerosis: a multicentre, randomised, double-blind, placebo-controlled phase IIb study. Lancet. 2008;371(9630):2085–2092.
*A larger and longer Phase II trial than in reference 29, confirming the potential therapeutic benefit of laquinimod.
- Filippi M, Rovaris M, Capra R, et al. A multi-centre longitudinal study comparing the sensitivity of monthly MRI after standard and triple dose gadolinium-DTPA for monitoring disease activity in multiple sclerosis. Implications for phase II clinical trials. Brain. 1998;121(Pt 10):2011–2020.
- Comi G, Abramsky O, Arbizu T, et al. Oral laquinimod in patients with relapsing-remitting multiple sclerosis: 36-week double-blind active extension of the multi-centre, randomized, double-blind, parallel-group placebo-controlled study. Mult Scler. 2010;16(11):1360–1366.
- Comi G, Jeffery D, Kappos L, et al. Placebo-controlled trial of oral laquinimod for multiple sclerosis. N Engl J Med. 2012;366(11):1000–1009.
**The results of a very large Phase III trial of laquinimod for relapsing remitting MS showing stronger effects on disability than on relapses.
- Vollmer TL, Sorensen PS, Selmaj K, et al. A randomized placebo-controlled phase III trial of oral laquinimod for multiple sclerosis. J Neurol. 2014;261(4):773–783.
- clinicaltrials.gov. The efficacy and safety and tolerability of laquinimod in subjects with relapsing remitting multiple sclerosis (RRMS) (CONCERTO) [cited 2015 Jul 28]. Available from: https://clinicaltrials.gov/ct2/show/NCT01707992.
- Barkhof F, Giovannoni G, Hartung HP, et al. ARPEGGIO: a randomized, placebo-controlled study to evaluate oral laquinimod in patients with primary progressive multiple sclerosis (PPMS). American Academy of Neurology; 2015 Apr 6. Washington (DC): Washington Convention Centre; 2015. p. Supplement P7.210.
- clinicaltrials.gov. A phase 2 clinical study in subjects with primary progressive multiple sclerosis to assess the efficacy, safety and tolerability of two oral doses of laquinimod either of 0.6 mg/Day or 1.5mg/Day (experimental drug) as compared to placebo [cited 2015 Jul 27]. Available from: https://clinicaltrials.gov/ct2/show/NCT02284568.