Sage Journals: Discover world-class research

Abstract

Background:

Olfactory threshold (OT) is associated with short-term inflammatory activity in relapsing multiple sclerosis (RMS).

Objective:

We aimed to investigate OT for prediction of treatment response in RMS.

Methods:

In this 5-year prospective study on 123 RMS patients, OT was measured at disease-modifying treatment (DMT) initiation (M0), after 3 months (M3), and 12 months (M12) by Sniffin’ Sticks test. Primary endpoint was defined as an absence of relapse during the observation period, with Expanded Disability Status Scale (EDSS) progression and magnetic resonance imaging (MRI) activity being the secondary endpoints. Optimal cutoff values were determined by receiver operating characteristic analyses and their predictive value assessed by multivariable Cox regression models.

Results:

Higher OT scores at M0, M3, and M12 were independently associated with decreased relapse probability with the strongest risk reduction at M3 (hazard ratio (HR) = 0.44, p < 0.001). Improvement of OT scores from M0 to M3 (ΔOT_M3) was also associated with reduced relapse risk (HR = 0.12, p < 0.001). OT score > 6.5 at M3 was the strongest predictor of relapse freedom (HR = 0.10, p < 0.001) with high diagnostic accuracy (positive predictive value (PPV) = 87%), closely followed by ΔOT_M3 ⩾ 0.5 (HR = 0.12, p < 0.001, PPV = 86%).

Conclusions:

OT is an independent predictor of freedom of disease activity upon DMT initiation within 5 years and may be a useful biomarker of treatment response.

Keywords

Multiple sclerosis olfactory threshold disease-modifying treatment relapse MRI treatment response

Get full access to this article

View all access options for this article.

References

Compston

Coles

. Multiple sclerosis. Lancet 2002; 359: 1221–1231.

Cree

BAC

Mares

Hartung

H-P

. Current therapeutic landscape in multiple sclerosis. Curr Opin Neurol 2019; 32: 365–377.

Giovannoni

. Disease-modifying treatments for early and advanced multiple sclerosis. Curr Opin Neurol 2018; 31(3): 233–243.

Bsteh

Hegen

Dosser

, et al. To treat or not to treat: Sequential individualized treatment evaluation in relapsing multiple sclerosis. Mult Scler Relat Dis 2019; 40: 101908.

Hegen

Bsteh

Berger

. “No evidence of disease activity”: Is it an appropriate surrogate in multiple sclerosis. Eur J Neurol 2018; 25(9): 1107.e101.

Lutterotti

Vedovello

Reindl

, et al. Olfactory threshold is impaired in early, active multiple sclerosis. Mult Scler 2011; 17(8): 964–969.

Bsteh

Hegen

Ladstätter

, et al. Change of olfactory function as a marker of inflammatory activity and disability progression in MS. Mult Scler J 2017; 25: 267–274.

Bsteh

Berek

Hegen

, et al. Smelling multiple sclerosis: Different qualities of olfactory function reflect either inflammatory activity or neurodegeneration. Mult Scler J 2018; 336: 8814113.

Schmidt

Goktas

Harms

, et al. Structural correlates of taste and smell loss in encephalitis disseminata. PLoS ONE 2011; 6(5): e19702.

10.

Bsteh

Steiger

Tuovinen

, et al. Impairment of odor discrimination and identification is associated with disability progression and gray matter atrophy of the olfactory system in MS. Mult Scler J 2019; 336: 382010.

11.

Bsteh

Hegen

Ladstätter

, et al. Transient impairment of olfactory threshold in acute multiple sclerosis relapse. Mult Scler Relat Disord 2018; 23: 74–77.

12.

Polman

Reingold

Banwell

, et al. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol 2011; 69(2): 292–302.

13.

Sormani

Gasperini

Romeo

, et al. Assessing response to interferon-β in a multicenter dataset of patients with MS. Neurology 2016; 87: 134–140.

14.

Hummel

Kobal

Gudziol

, et al. Normative data for the “Sniffin’ sticks” including tests of odor identification, odor discrimination, and olfactory thresholds: An upgrade based on a group of more than 3,000 subjects. Eur Arch Otorhinolaryngol 2007; 264(3): 237–243.

15.

Zou

Yue

. Using confidence intervals to compare several correlated areas under the receiver operating characteristic curves. Stat Med 2013; 32: 5077–5090.

16.

Council National Research. The prevention and treatment of missing data in clinical trials. Washington, DC: National Academies Press, 2010.

17.

Trapp

Peterson

Ransohoff

, et al. Axonal transection in the lesions of multiple sclerosis. N Engl J Med 1998; 338: 278–285.

18.

Río

Castilló

Rovira

, et al. Measures in the first year of therapy predict the response to interferon beta in MS. Mult Scler 2009; 15(7): 848–853.

19.

Sormani

Rio

Tintorè

, et al. Scoring treatment response in patients with relapsing multiple sclerosis. Mult Scler J 2012; 19: 605–612.

20.

Freedman

Selchen

Arnold

, et al. Treatment optimization in MS: Canadian MS Working Group updated recommendations. Can J Neurol Sci 2013; 40(3): 307–323.

21.

Uher

Havrdova

Sobisek

, et al. Is no evidence of disease activity an achievable goal in MS patients on intramuscular interferon beta-1a treatment over long-term follow-up. Mult Scler 2017; 23(2): 242–252.

22.

Prosperini

Mancinelli

Giglio

, et al. Interferon beta failure predicted by EMA criteria or isolated MRI activity in multiple sclerosis. Mult Scler J 2014; 20: 566–576.

23.

Moscavitch

S-D

Szyper-Kravitz

Shoenfeld

. Autoimmune pathology accounts for common manifestations in a wide range of neuro-psychiatric disorders: The olfactory and immune system interrelationship. Clin Immunol 2009; 130(3): 235–243.

24.

Doty

Mannon

, et al. Olfactory dysfunction in multiple sclerosis. N Engl J Med 1997; 336: 1918–1919.

25.

Erb

Bohner

Harms

, et al. Olfactory function in patients with multiple sclerosis: A diffusion tensor imaging study. J Neurol Sci 2012; 316: 56–60.

26.

Rolet

Magnin

Millot

, et al. Olfactory dysfunction in multiple sclerosis: Evidence of a decrease in different aspects of olfactory function. Eur Neurol 2013; 69(3): 166–170.

27.

Tanik

Serin

Celikbilek

, et al. Olfactory bulb and olfactory sulcus depths are associated with disease duration and attack frequency in multiple sclerosis patients. J Neurol Sci 2015; 358: 1–4.

28.

Holinski

Schmidt

Dahlslett

, et al. MRI study: Objective olfactory function and CNS pathologies in patients with multiple sclerosis. Eur Neurol 2014; 72(3–4): 157–162.

29.

Shoenfeld

. To smell autoimmunity: Anti-P-ribosomal autoantibodies, depression, and the olfactory system. J Autoimmun 2007; 28(2–3): 165–169.

30.

Bsteh

Hegen

Altmann

, et al. Inner nuclear layer and olfactory threshold are interlinked and reflect inflammatory activity in multiple sclerosis. Mult Scler J Exp Transl Clin 2020; 6(3): 945738.

31.

Schmidt

Göktas

Jarius

, et al. Olfactory dysfunction in patients with neuromyelitis optica. Mult Scler Int 2013; 2013: 654501.

32.

Shoenfeld

Agmon-Levin

Flitman-Katzevman

, et al. The sense of smell in systemic lupus erythematosus. Arthritis Rheum 2009; 60(5): 1484–1487.

33.

Berek

Bsteh

Auer

, et al. Kappa-free light chains in CSF predict early multiple sclerosis disease activity. Neurol Neuroimmunol Neuroinflamm 2021; 8(4): e1005.

34.

Herz

Reen

Barker

, et al. The influence of circadian timing on olfactory sensitivity. Chem Senses 2017; 43: 45–51.

Supplementary Material

Please find the following supplemental material available below.

For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.

For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.

0.00 MB

0.02 MB

0.14 MB

1.37 MB

Olfactory threshold predicts treatment response in relapsing multiple sclerosis

Abstract

Background:

Objective:

Methods:

Results:

Conclusions:

Keywords

Get full access to this article

References

Supplementary Material