Top

Published in:

01-04-2015 | Original Communication

Uric acid in relapsing–remitting multiple sclerosis: a 2-year longitudinal study

Authors: Marcello Moccia, Roberta Lanzillo, Teresa Costabile, Cinzia Russo, Antonio Carotenuto, Gabriella Sasso, Emanuela Postiglione, Carla De Luca Picione, Michele Vastola, Giorgia Teresa Maniscalco, Raffaele Palladino, Vincenzo Brescia Morra

Published in: Journal of Neurology | Issue 4/2015

Abstract

Uric acid (UA) is reduced in multiple sclerosis (MS), and possibly relates to MS outcomes, with lower UA levels in subjects experiencing a relapse or presenting higher disability scores. The present retrospective longitudinal study evaluated UA variations in MS, in relation to clinical relapses, disability progression, and cognitive functions. We included 141 subjects with relapsing–remitting MS (RRMS) and performed expanded disability status scale (EDSS), symbol digit modalities test (SDMT) and UA evaluation at baseline visit and after 2-year follow-up. Paired t test showed significantly lower UA levels after 2-year follow-up than at baseline (3.987 ± 1.135 and 4.167 ± 1.207 mg/dL, respectively) (p = 0.001). The difference in UA levels between 2-year follow-up and baseline related to EDSS sustained progression (p < 0.001; OR = 0.099), and presented a trend for clinical relapses at logistic regression (p = 0.211; OR = 0.711) and for the time to relapse at Cox regression (p = 0.236; HR = 0.792). Analysis of variance showed reduced baseline UA levels in subjects with impaired SDMT at baseline (p = 0.045; adjusted R ² = 0.473) and after 2-year follow-up (p = 0.034; adjusted R ² = 0.470). This is the first study showing a progressive reduction of UA levels during the course of RRMS, suggesting a progressive decrease of antioxidant reserves, in relation to relapse risk, disability progression and cognitive function.

Schreibelt G, van Horssen J, van Rossum S, Dijkstra CD, Drukarch B, de Vries HE (2007) Therapeutic potential and biological role of endogenous antioxidant enzymes in multiple sclerosis pathology. Brain Res Rev 56(2):322–330. doi:10.1016/j.brainresrev.2007.07.005 CrossRefPubMed

Hooper DC, Bagasra O, Marini JC, Zborek A, Ohnishi ST, Kean R, Champion JM, Sarker AB, Bobroski L, Farber JL, Akaike T, Maeda H, Koprowski H (1997) Prevention of experimental allergic encephalomyelitis by targeting nitric oxide and peroxynitrite: implications for the treatment of multiple sclerosis. Proc Natl Acad Sci USA 94(6):2528–2533PubMedCentralCrossRefPubMed

Hooper DC, Scott GS, Zborek A, Mikheeva T, Kean RB, Koprowski H, Spitsin SV (2000) Uric acid A peroxynitrite scavenger inhibits CNS inflammation blood– CNS barrier permeability changes and tissue damage in mouse model of multiple sclerosis. FASEB J 14(5):691–698PubMed

Squadrito GL, Cueto R, Splenser AE, Valavanidis A, Zhang H, Uppu RM, Pryor WA (2000) Reaction of uric acid with peroxynitrite and implications for the mechanism of neuroprotection by uric acid. Arch Biochem Biophys 376(6):333–337. doi:10.1006/abbi.2000.1721 CrossRefPubMed

Scott GS, Spitsin SV, Kean RB, Mikheeva T, Koprowski H, Hooper DC (2002) Therapeutic intervention in experimental allergic encephalomyelitis by administration of uric acid precursors. Proc Natl Acad Sci USA 99(25):16303–16308. doi:10.1073/pnas.212645999 PubMedCentralCrossRefPubMed

Hooper DC, Spitsin S, Kean RB, Champion JM, Dickson GM, Chaudhry I, Koprowski H (1998) Uric acid, a natural scavenger of peroxynitrite, in experimental allergic encephalomyelitis and multiple sclerosis. Proc Natl Acad Sci USA 95(2):675–680PubMedCentralCrossRefPubMed

Toncev G, Milicic B, Toncev S, Samardzic G (2002) Serum uric acid levels in multiple sclerosis patients correlate with activity of disease and blood-brain barrier dysfunction. Eur J Neurol 9(3):221–226. doi:10.1046/j.1468-1331.2002.00384.x CrossRefPubMed

Toncev G, Milicic B, Toncev S, Samardzic G (2002) High-dose methylprednisolone therapy in multiple sclerosis increases serum uric acid levels. Clin Chem Lab Med 40(5):505–508. doi:10.1515/CCLM.2002.088 CrossRefPubMed

Dujmovic I, Pekmezovic T, Obrenovic R et al (2009) Cerebrospinal fluid and serum uric acid levels in patients with multiple sclerosis. Clin Chem Lab Med 47:848–853. doi:10.1515/CCLM.2009.192 CrossRefPubMed

10.

Spitsin S, Hooper DC, Mikheeva T, Koprowski H (2001) Uric acid levels in patients with multiple sclerosis: analysis in mono- and dizygotic twins. Mult Scler 7(3):165–166. doi:10.1177/135245850100700305 CrossRefPubMed

11.

Sotgiu S, Pugliatti M, Sanna A, Sotgiu A, Fois ML, Arru G, Rosati G (2002) Serum uric acid and multiple sclerosis. Neurol Sci 23(4):183–188. doi:10.1007/s100720200059 CrossRefPubMed

12.

Peng F, Zhang B, Zhong X, Li J, Xu G, Hu X, Qiu W (2008) Pei Z (2008) Serum uric acid levels of patients with multiple sclerosis and other neurological diseases. Mult Scler 14(2):188–196. doi:10.1177/1352458507082143 CrossRefPubMed

13.

Ashtari F, Bahar M, Aghaei M, Zahed A (2013) Serum uric acid level in patients with relapsing–remitting multiple sclerosis. J Clin Neurosci 20(5):676–678. doi:10.1016/j.jocn.2012.05.054 CrossRefPubMed

14.

Drulovic J, Dujmovic I, Stojsavljevic N, Mesaros S, Andjelković S, Miljković D, Perić V, Dragutinović G, Marinković J, Lević Z, Mostarica Stojković M (2001) Uric acid levels in sera from patients with multiple sclerosis. J Neurol 248(2):121–126CrossRefPubMed

15.

Knapp CM, Constantinescu CS, Tan JH, McLean R, Cherryman GR, Gottlob I (2004) Serum uric acid levels in optic neuritis. Mult Scler 10(3):278–280CrossRefPubMed

16.

Liu B, Shen Y, Xiao K, Tang Y, Cen L, Wei J (2012) Serum uric acid levels in patients with multiple sclerosis: a meta-analysis. Neurol Res 34(2):163–171. doi:10.1179/1743132811Y.0000000074 PubMed

17.

Moccia M, Lanzillo R, Palladino R, Russo C, Carotenuto A, Massarelli M, Vacca G, Vacchiano V, Nardone A, Triassi M, Morra VB (2014) Uric acid: a potential biomarker of multiple sclerosis and of its disability. Clin Chem Lab Med. doi:10.1515/cclm-2014-0744

18.

Guerrero AL, Gutiérrez F, Iglesias F, Martín-Polo J, Merino S, Martín-Serradilla JI, Laherrán E, Tejero MA (2011) Serum uric acid levels in multiple sclerosis patients inversely correlate with disability. Neurol Sci 32(2):347–350. doi:10.1007/s10072-011-0488-5 CrossRefPubMed

19.

Euser SM, Hofman A, Westendrop RGJ, Breteler MMB (2009) Serum uric acid and cognitive function and dementia. Brain 132(Pt 2):377–382. doi:10.1093/brain/awn316 PubMed

20.

Moccia M, Picillo M, Erro R, Vitale C, Longo K, Amboni M, Santangelo G, Spina E, De Rosa A, De Michele G, Santoro L, Barone P, Pellecchia MT (2014) Is serum uric acid related to non-motor symptoms in de-novo Parkinson’s disease patients? Parkinsonism Relat Disord 20(7):772–775. doi:10.1016/j.parkreldis.2014.03.016 CrossRefPubMed

21.

Poser CM, Paty DW, Scheinberg L, McDonald WI, Davis FA, Ebers GC, Johnson KP, Sibley WA, Silberberg DH, Tourtellotte WW (1983) New diagnostic criteria for multiple sclerosis: guidelines for research protocols. Ann Neurol 13(3):227–231CrossRefPubMed

22.

Lublin FD, Reingold SC, Cohen JA, Cutter GR, Sørensen PS, Thompson AJ, Wolinsky JS, Balcer LJ, Banwell B, Barkhof F, Bebo B Jr, Calabresi PA, Clanet M, Comi G, Fox RJ, Freedman MS, Goodman AD, Inglese M, Kappos L, Kieseier BC, Lincoln JA, Lubetzki C, Miller AE, Montalban X, O’Connor PW, Petkau J, Pozzilli C, Rudick RA, Sormani MP, Stüve O, Waubant E, Polman CH (2014) Defining the clinical course of multiple sclerosis: the 2013 revisions. Neurology 83(3):278–286. doi:10.1212/WNL.0000000000000560 PubMedCentralCrossRefPubMed

23.

Polman CH, Reingold SC, Banwell B, Clanet M, Cohen JA, Filippi M, Fujihara K, Havrdova E, Hutchinson M, Kappos L, Lublin FD, Montalban X, O’Connor P, Sandberg-Wollheim M, Thompson AJ, Waubant E, Weinshenker B, Wolinsky JS (2011) Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol 69(2):292–302. doi:10.1002/ana.22366 PubMedCentralCrossRefPubMed

24.

Constantinescu CS, Freitag P, Kappos L (2000) Increase in serum levels of uric acid, an endogenous antioxidant, under treatment with glatiramer acetate for multiple sclerosis. Mult Scler 6(6):378–381. doi:10.1177/135245850000600603 CrossRefPubMed

25.

Kurtzke JF (1983) Rating neurological impairment in multiple sclerosis: an expanded disability scale (EDSS). Neurology 33:1444–1452CrossRefPubMed

26.

Ebers GC, Heigenhauser L, Daumer M, Lederer C, Noseworthy JH (2008) Disability as an outcome in MS clinical trials. Neurology 71(9):624–631. doi:10.1212/01.wnl.0000313034.46883 CrossRefPubMed

27.

Nocentini U, Giordano A, Di Vincenzo S, Panella M, Pasqualetti P (2006) The Symbol Digit Modalities Test-Oral version: Italian normative data. Funct Neurol 21(2):93–96

28.

Amato MP, Portaccio E, Goretti B, Zipoli V, Ricchiuti L, De Caro MF, Patti F, Vecchio R, Sorbi S, Trojano M (2006) The Rao’s Brief Repeatable Battery and Stroop Test: normative values with age, education and gender corrections in an Italian population. Mult Scler 12(6):787–793. doi:10.1177/1352458506070933 CrossRefPubMed

29.

Zoccolella S, Tortorella C, Iaffaldano P, Direnzo V, D'Onghia M, Luciannatelli E, Paolicelli D, Livrea P, Trojano M (2012) Low serum urate levels are associated to female gender in multiple sclerosis patients. PLoS One 7(7):e40608. doi:10.1371/journal.pone.0040608 PubMedCentralCrossRefPubMed

30.

Van Schependom J, D’hooghe MB, Cleynhens K, D’hooge M, Haelewyck MC, De Keyser J, Nagels G (2014) The symbol digit modalities test as sentinel test for cognitive impairment in multiple sclerosis. Eur J Neurol 21(9):1219–1225. doi:10.1111/ene.12463 (e71–e72)CrossRefPubMed

31.

Moccia M, Picillo M, Erro R, Vitale C, Longo K, Amboni M, Santangelo G, Palladino R, Capo G, Orefice G, Barone P, Pellecchia MT (2015) Presence and progression of non-motor symptoms in relation to uric acid in de novo Parkinson’s disease. Eur J Neurol 22(1):93–98. doi:10.1111/ene.12533 CrossRefPubMed

32.

Miller E, Walczak A, Saluk J, Ponczek MB, Majsterek I (2012) Oxidative modification of patient’s plasma proteins and its role in pathogenesis of multiple sclerosis. Clin Biochem 45(1–2):26–30. doi:10.1016/j.clinbiochem.2011.09.021 CrossRefPubMed

33.

Bowman GL, Shannon J, Frei B, Kaye JA, Quinn JF (2010) Uric acid as a CNS antioxidant. J Alzheimers Dis 19(4):1331–1336. doi:10.3233/JAD-2010-1330 PubMedCentralPubMed

34.

Niklasson F, Hetta J, Degrell I (1988) Hypoxanthine, xanthine, urate and creatinine concentration gradients in cerebrospinal fluid. Ups J Med Sci 93(3):225–232CrossRefPubMed

35.

Karg E, Klivényi P, Németh I, Bencsik K, Pintér S, Vécsei L (1999) Nonenzymatic antioxidants of blood in multiple sclerosis. J Neurol 246(7):533–539CrossRefPubMed

36.

Amorini AM, Petzold A, Tavazzi B, Eikelenboom J, Keir G, Belli A, Giovannoni G, Di Pietro V, Polman C, D’Urso S, Vagnozzi R, Uitdehaag B, Lazzarino G (2009) Increase of uric acid and purine compounds in biological fluids of multiple sclerosis patients. Clin Biochem 42(10–11):1001–1006. doi:10.1016/j.clinbiochem.2009.03.020 CrossRefPubMed

37.

Rentzos M, Nikolaou C, Anagnostouli M, Rombos A, Tsakanikas K, Economou M, Dimitrakopoulos A, Karouli M, Vassilopoulos D (2006) Serum uric acid and multiple sclerosis. Clin Neurol Neurosurg 108(6):527–531. doi:10.1016/j.clineuro.2005.08.004 CrossRefPubMed

38.

Muñoz García D, Midaglia L, Martinez Vilela J, Marín Sánchez M, López González FJ, Arias Gómez M, Dapena Bolaño D, Iglesias Castañón A, Alonso Alonso M, Romero López J (2014) Associated Inosine to interferon: results of a clinical trial in multiple sclerosis. Acta Neurol Scand. doi:10.1111/ane.12333 PubMed

Title: Uric acid in relapsing–remitting multiple sclerosis: a 2-year longitudinal study
Authors: Marcello Moccia
Roberta Lanzillo
Teresa Costabile
Cinzia Russo
Antonio Carotenuto
Gabriella Sasso
Emanuela Postiglione
Carla De Luca Picione
Michele Vastola
Giorgia Teresa Maniscalco
Raffaele Palladino
Vincenzo Brescia Morra
Publication date: 01-04-2015
Publisher: Springer Berlin Heidelberg
Published in: Journal of Neurology / Issue 4/2015
Print ISSN: 0340-5354
Electronic ISSN: 1432-1459
DOI: https://doi.org/10.1007/s00415-015-7666-y

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Uric acid in relapsing–remitting multiple sclerosis: a 2-year longitudinal study

Abstract

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 4/2015

A novel autosomal dominant leukodystrophy with specific MRI pattern

Long-term outcome of 424 childhood-onset myasthenia gravis patients

Clinical and molecular aspects of 30 patients with late-onset Pompe disease (LOPD): unusual features and response to treatment

Clinical routine use of dopamine transporter imaging in 516 consecutive patients

Clinical and experimental studies of potentially pathogenic brain-directed autoantibodies: current knowledge and future directions

Can MS lesion stages be distinguished with MRI? A postmortem MRI and histopathology study