Autoimmunity Reviews 17 (2018) 405–412

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Autoimmunity Reviews

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Review

Olfactory function in systemic lupus erythematosus and systemic

sclerosis. A longitudinal study and review of the literature☆
Mariana Freschi Bombini a,c,d,1, Fernando Augusto Peres b,c,d,1, Aline Tamires Lapa c,d,f,
Nailú Angélica Sinicato c,d,f, Beatriz Ricato Quental c,d, Ágatha de Souza Melo Pincelli c,d, Tiago Nardi Amaral b,c,d,e,
Caroline Cristina Gomes j, Ana Paula del Rio e, João Francisco Marques-Neto e, Lilian T.L. Costallat e,
Paula Teixeira Fernandes g, Fernando Cendes h, Leticia Rittner i, Simone Appenzeller c,d,e,⁎
a
Physiopathology Graduate Program, School of Medical Sciences, University of Campinas, Brazil
b
Medicine Graduate Program, School of Medical Sciences, University of Campinas, Brazil
c
Rheumatology Lab, School of Medical Sciences, University of Campinas, Brazil
d
Autoimmunity Lab School of Medical Sciences, University of Campinas, Brazil
e
Department of Medicine, Rheumatology Unit, School of Medical Sciences, University of Campinas, Brazil
f
Child and Adolescent Health Graduate Program, School of Medical Sciences, University of Campinas, Brazil
g
Department of Sports Sciences, School of Physical Education, University of Campinas, Brazil
h
Medical Imaging Computing Laboratory, School of Electrical and Computer Engineering, University of Campinas, Brazil
i
Department of Neurology, School of Medical Sciences, University of Campinas, Brazil
j
Undergraduate medical student-School of Medical Science-University of Campinas, Brazil

a r t i c l e i n f o a b s t r a c t

Article history: Background/purpose: To evaluate olfactory function in systemic lupus erythematosus (SLE), systemic sclerosis
Received 23 November 2017 (SSc) and healthy controls over a 2-year period, and to determine the association of olfactory dysfunction with
Accepted 28 November 2017 age, disease activity, disease damage, treatment, anxiety and depression symptoms and limbic structures
Available online 11 February 2018 volumes.
Methods: Consecutive SLE and SSc patients were enrolled in this study. Clinical, laboratory disease activity and
Keywords:
damage were assessed according to diseases specific guidelines. Olfactory functions were evaluated using the
Sense of smell
Olfaction
Sniffin' Sticks test (TDI). Volumetric magnetic resonance imaging (MRI) was obtained in a 3T Phillips scanner.
Olfactory dysfunction Amygdalae and hippocampi volumes were analyzed using FreeSurfer® software.
Autoimmunity Results: We included 143 SLE, 57 SSc and 166 healthy volunteers. Olfactory dysfunction was observed in 78
Central nervous system diseases (54.5%) SLE, 35 (59.3%) SSc patients and in 24 (14.45%) controls (p b 0.001) at study entry. SLE and SSc patients
Systemic lupus erythematosus had significantly lower mean in all three phases (TDI) of the olfactory assessment when compared with healthy
Systemic sclerosis volunteers. In SLE, the presence of olfactory dysfunction was associated with older age, disease activity, higher
anxiety and depression symptoms score, smaller left hippocampus volume, smaller left and right amygdalae vol-
ume and the presence of anti-ribosomal P (anti-P) antibodies. In SSc the presence of olfactory impairment was
associated with older age, disease activity, smaller left and right hippocampi volumes and smaller right amygdala
volume. Olfactory function was repeated after a 2-year period in 90 SLE, 35 SSc and 62 controls and was stable in
all three groups.
Conclusion: Both SLE and SSc patients with longstanding disease had significant reduction in all stages of TDI that
maintained stable over a 2-year period. Olfactory dysfunction was associated with age, inflammation and hippo-
campi and amygdalae volumes. In SLE, additional association with anti-P, anxiety and depression symptoms was
observed.
© 2018 Published by Elsevier B.V.

☆ Grants: Fundação de Amparo à Pesquisa do Estado de São Paulo-Brasil (FAPESP 2008/02917-0 and 2011/03788-2, FAPESP-CEPID 2013/07559-3), Conselho Nacional Pesquisa
Desenvolvimento-Brasil CNPq (300447/2009-4 and 471343/2011-0 and 302205/2012-8 and 473328/2013-5 and 157534/2015-4, 401477/2016-9), PANLAR.
⁎ Corresponding author at: Department of Medicine, School of Medical Sciences, State University of Campinas, Cidade Universitária, Campinas CEP 13083-970, SP, Brazil.
E-mail address: appenzel@unicamp.br (S. Appenzeller).
1
Mariana Freschi Bombini and Fernando Augusto Peres contributed equally to the work and should both considered first authors.

https://doi.org/10.1016/j.autrev.2018.02.002
1568-9972/© 2018 Published by Elsevier B.V.
406 M.F. Bombini et al. / Autoimmunity Reviews 17 (2018) 405–412

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 406
2. Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 406
2.1. Subjects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 406
2.2. Exclusion criteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 406
2.3. Disease related features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 406
2.4. CNS manifestations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 407
2.5. Mood and anxiety evaluation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 407
2.6. Olfactory functions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 407
2.7. Magnetic resonance imaging acquisition and analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 407
2.8. Statistical analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 407
2.9. Literature review . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 407
3. Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 407
3.1. SLE cohort . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 407
3.2. SSc cohort . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 409
4. Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 410
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 410

1. Introduction
Central nervous system (CNS) manifestations are often observed in
autoimmune rheumatic diseases, and are associated with higher mor-
tality and worse quality of life [1–4].
Neurologic, neurodegenerative and autoimmune diseases can pres-
ent with olfactory dysfunction. In some instances, olfactory impairment
can precede cognitive or motor dysfunction by several years and have
been associated with anxiety, depression and other neuropsychiatric
manifestations [5–57].
In SLE, changes in the sense of smell were associated with disease ac-
tivity and neuropsychiatric manifestations [21,22]. In SSc, the presence
of olfactory dysfunction was associated with depression [11]. In multi-
ple sclerosis (MS) smell abnormalities were associated with disease
burden, lesion load and structural magnetic resonance imaging (MRI)
abnormalities [24,40,44,58,59]. However, so far, no study has analyzed
olfactory function over a 2-year period and MRI findings in rheumatic
autoimmune patients.
Therefore, the aim of our study was to access olfactory function in
SLE and SSc patients over a 2-year period and to determine clinical, lab-
oratory and MRI findings associated with its occurrence. In addition, we
present a review of the literature of previous studies analyzing olfactory
impairment in autoimmune diseases to discuss physiopathological
mechanisms associated with its occurrence.
2. Methods
2.1. Subjects
Consecutive adult SLE [60] and SSc [61] patients followed at the
Rheumatology outpatient clinic of the University of Campinas, between
March 2011 and September 2016 were invited to participate in this lon-
gitudinal study.
Healthy volunteers were included as a control group. The healthy
controls were matched for sex, and demographic background and had
no a history of any chronic disease (including a personal history of auto-
immune diseases). Patients and controls were evaluated at study entry
and after a 2-year interval.
Ethical approval was obtained from the Institutional Review Board
of the University of Campinas and all subjects provided a volunteer-
written informed consent to participate.
2.2. Exclusion criteria
We excluded patients and controls with head injuries, nasofacial
surgeries, active nasal-sinus infections, allergic diseases, active smokers
and stroke, since these diseases could affect an appropriate interpreta-
tion of results. A total of 20 SLE, 37 SSc, and 5 controls were excluded.
2.3. Disease related features
The medical histories, clinical and serological features of each patient
were reviewed in medical charts. The variables included were age at
onset of disease (defined as the age at which the first symptoms clearly
attributable to SLE or SSc occurred), age at diagnosis [defined as the age
when patients fulfilled classification of SLE [60] or SSc [61] and the pres-
ence of autoantibodies. Antinuclear antibodies (ANAs) were deter-
mined by indirect immunofluorescence using Hep 2 substrate, and
regarded as positive if higher than 1:40. Anti-double stranded DNA
(anti-dsDNA) antibodies were determined by indirect immunofluores-
cence using Crithidia as substrate and considered positive if higher
than 1:20. Precipitating antibodies to extractable nuclear antigens
(ENAs), including Ro (SSA), LA (SSB), topoisomerase I and Sm were de-
tected by a standardized ELISA method, and considered positive if
higher than 1:40. Anticardiolipin antibodies (aCLs) of the IgG and IgM
isotypes were measured by an ELISA method [62]. The lupus anticoagu-
lant (LA) activity was detected by coagulation assays in platelet-free
plasma obtained by double centrifugation, following the recommenda-
tion of the subcommittee on LA of the Scientific and Standardization
Committee of the International Society of Thrombosis and Homeostasis
[63]. These measurements were carried out twice, at an interval of
12 weeks.
Anti-ribosomal P antibodies (anti-P) were evaluated in SLE patients
and controls at study entry. A blood sample was collected from all par-
ticipants at the day of study entry and centrifuged at 3000 rpm for
15 min after being allowed to clot for 30 min at room temperature.
Sera were separated as soon as possible from the clot of red cells after
centrifugation. Separated sera were kept in aliquots at −80 °C until
the time of assay. Commercially available kits from INOVA QUANTA
LiteTM Ribosome P, San Diego, California, USA were used for analysis.
This kit uses synthetic 22 amino acid C-terminal peptide. The samples
were classified as positive if N20 units.
At time of study entry and subsequent evaluation, all patients were
evaluated by a rheumatologist (TNA, SA, LTL) who performed a neuro-
logical and clinical examination. In SLE, disease activity was measured
by Systemic Lupus Erythematosus Disease Activity Index (SLEDAI)
[64]. Scores N 3 were considered active disease [65]. Cumulative SLE-
related damage was determined in all patients using the Systemic
Lupus International Collaborating Clinics (SLICC)/ACR Damage Index
(SDI). Damage was considered if scores ≥ 1 [66]. In SSc, disease activity
was evaluated by the Valentine's activity index [67] and disease severity
was evaluated by the Medsger's severity index [68].
 M.F. Bombini et al. / Autoimmunity Reviews 17 (2018) 405–412
2.4. CNS manifestations
The involvement of the central nervous system (CNS) and peripheral
nervous system (PNS) were clinically evaluated in each patient and con-
trol. In SLE, neurological and psychiatric involvement was defined ac-
cording to ACR case definitions and divided into the categories present
or absent [69].
2.5. Mood and anxiety evaluation
All subjects completed the Beck Depression Inventory (BDI) [70,71]
and Beck Anxiety Inventory (BAI) [72] at study entry. These scales con-
sist of 21 items, each describing common symptom of depression/anxi-
ety. The respondent is asked to rate how much he or she has been
bothered by each symptom over the past month on a 4-point scale rang-
ing from 0 to 3. The items are summed to obtain a total score that can
range from 0 to 63. The cutoffs used for the BDI were: 0–13: no/minimal
symptoms; 14–19: mild symptoms; 20–28: moderate symptoms; and
29–63: severe symptoms of depression and for the BAI: 0–7: no/mini-
mal symptoms; 8–15: mild symptoms; 16–25: moderate symptoms;
26–63: severe symptoms of anxiety.
2.6. Olfactory functions
Olfactory assessment was performed using the Sniffin' Sticks kit
(SST) (Burghart Medizintechnik, Wedel, Germany) [73–75]. The test
consists of a pen-like odor dispensing device. It classifies three stages
of smell as threshold (T), discrimination (D), and identification (I) of
odors [75]. Each stage can be scored from 0 to 16 and the total score
of all stages ranges from 0 to 48 points. Olfactory impairment/dysfunc-
tion was considered when the total score (TDI) was b30 [73].
2.7. Magnetic resonance imaging acquisition and analysis
All patients and controls included in the study underwent magnetic
resonance imaging (MRI) with a Philips 3T scanner at study entry and
after a 2-year interval. Sagittal T1-weighted images (3D acquisitions ob-
tained in the sagittal plane “gradient echo” T1 weighted with 1 mm
thickness, angle of excitation of 35°, TR = 22 ms, TE = 9 ms, matrix
256 × 220, FOV = 230 × 250 mm, 1 × 1 pixel) were used for analysis.
Automated segmentations of hippocampi and amygdalae volumes
were performed using Freesurfer software [76].
2.8. Statistical analysis
The demographic, clinic, and laboratory characteristics were ana-
lyzed by mean and standard deviation (SD) for continuous variables
or frequency; categorical variables were expressed as percentages. The
Pearson Qui-squared test or the Fisher's exact tests were used for cate-
gorical variables. The Shapiro-Wilk test was used to verify normality.
Comparisons between variables were performed through the Student
t-test for parametric data or the Mann-Whitney test for non-
parametric continuous variables. Values of p ≤ 0.05 were considered
Table 1
Olfactory functions in SLE, SSc and controls.
Olfactory function SLE
(N = 143)
Number (%) of olfactory dysfunction 78 (54.5%)
Threshold mean (±SD) 7.11 (3.07)
Discrimination mean (±SD) 10.79 (2.38)
Identification mean (±SD) 10.88 (2.08)
Total mean (±SD) 28.79 (4.98)
⁎ Comparisons between SLE and controls p b 0.05.
#
Comparisons between SSc and controls p b 0.05.
$
Comparisons between SLE and SSc p b 0.05.
407
significant. All statistical analyses were performed in the SPSS software,
version 17.0.
2.9. Literature review
A comprehensive literature review was performed in Pubmed and
Web of Science using terms: smell, olfaction, odors, rheumatic disease,
autoimmune disease, systemic lupus erythematosus, systemic sclerosis,
Sjogren syndrome, rheumatoid arthritis, antiphospholipid syndrome,
multiple sclerosis, myasthenia gravis, neuromyelitis optica,
antiphospholipid disease, Behçet disease and ANCA-associated vasculi-
tis. Only articles in English from 1972 to 2017 were included in the re-
view. We excluded articles including animal model (N = 7), review
article (N = 8), conference and meeting abstract (N = 6), duplicate
(N = 2) and articles not in English (N = 7).
3. Results
3.1. SLE cohort
We included 143 [133 (93%) women; mean age = 40.32 (SD ±
11.23)] consecutive SLE patients. The mean disease duration was
9.3 years (SD ± 5.1). The control group consisted of 166 controls [145
(87%) women; p = 0.071] with a mean age of 42.51 years (SD ±
12.07) (p = 0.18).
Forty-eight (36.0%) SLE patients had active disease (SLEDAI ≥ 3) and
68 (47.5%) had cumulative damage (SDI ≥ 1).
At the time of study entry, 91 (63.3%) SLE patients had anxiety
symptoms [mean BAI scores = 16.02 (SD = 13.38)], compared to 45
(27.1%) of controls (p b 0.001) [mean BAI scores = 6.80 (SD = 9.59);
p b 0.001]. Depressive symptoms were observed in 60 (41.9%) of SLE pa-
tients [mean BDI scores = 14.07 (SD = 11.17)] and in 34 (20.48%) of
controls (p b 0.001) [mean BDI scores = 6.54 (SD = 8.04); p b 0.001].
Anti-P antibodies were observed in 22 (15.38%) of SLE patients and in
none of the controls (p = 0.002).
Olfactory dysfunction was observed in 78 (54.5%) SLE patients and in
24 (14.45%) controls (p b 0.001). In addition to lower TDI scores [mean
SLE scores = 28.79 (SD ± 4.98) vs mean controls scores = 34.31 (SD ±
3.50); p b 0.001], SLE patients had significantly lower scores in all three
subtest of SST when compared to controls (Table 1).
SLE patients with olfactory dysfunction were significantly older
[mean age = 42.77 (SD ± 11.81) vs 36.61 (SD ± 11.12) years; p =
0.0017], had more disease activity [mean SLEDAI scores = 4.73 (SD ±
4.61) vs 2.73 (SD ± 1.65); p = 0.009], higher BAI scores [mean BAI
score 15.85 (SD ± 14.98) vs 8.22 (SD ± 9.50); p b 0.001], higher BDI
scores [mean BDI score 15.98 (SD ± 11.74) vs 8.52 (SD ± 7.63); p b
0.001], smaller left hippocampus volume [mean volume 3695.36 mm3
(SD ± 451.87) vs 3926.73 mm3 (SD ± 492.92); p = 0.0042], smaller
left amygdala volume [mean volume 1583.91 mm3 (SD ± 232.28) vs
1711.65 mm3 (SD ± 332.51); p = 0.001], smaller right amygdala vol-
ume [mean volume 1698.73 mm3 (SD ± 296.01) vs 1891.22 mm3 (SD
± 298.13); p = 0.0002] and had more frequently anti-P antibodies (p
= 0.016) when compared to SLE patients without olfactory
SSc Controls
(N = 59) (N = 166)
35 (59.32%) 24 (14.45%)⁎,#
5.64 (2.38)$ 8.48 (3.60)⁎,#
9.71 (2.30) 11.69 (2.20)⁎,#
10.16 (1.78) 11.85 (2.13)⁎,#
25.52 (3.42)$ 32.03 (5.39)⁎,#
408 M.F. Bombini et al. / Autoimmunity Reviews 17 (2018) 405–412

Table 2
Literature review of olfactory impairment in autoimmune disease.

Author N patients/N Smell test/smell Olfactory results Correlations, association or conclusion

controls analysis

SSc Amital [11] 20/21 ♀ Sniffin' Sticks TDI 3 of 20 (15%) SSc hyposmia TDI score correlate inversely with BDI-II
TDI SSc b controls
SSj Su [12] 15♀/32 Sniffin' Sticks TDI SSj = BMS
Midilli [13] 70♀ e 7♂/77 5 component smell SSj = controls Smell disorder was associated with nasal polyposis
D
Kamel [14] 25♀ e 3♂/37 UPSIT UPST SSj b UPST controls T and age. Taste and smell thresholds were correlated
Weiffenbach 30♀/60♀ UPSIT UPSIT SSj b controls
[15]
Rasmussen [16] 36♀/36 Elsberg's No differences between groups No correlation with mucociliary clearance
olfactomer
Jones [17] 14♀ and 7♂/16 T: dilutions of All SSj had hyposmia Hyposmia, inflammatory changes in the nasal mucous
pyridine, membrane, and nasal accumulation of 99mTcO4 in SSj
nitrobenzene and
thiophene
Henkin [18] 29♀ T: for pyridine, 45% hyposmia. Cyclophosphamide improved smell function
nitrobenzene,
thiophene
Mikulicz's Takano [19] 17♂ and 27♀ T&T olfactometer 45% patients had olfactory abnormalities IgG4-positive plasmacytes in the nasal mucosa with
disease olfactory abnormalities
RA Steinbach [20] 75♀ and 26♂ Sniffin' Sticks TDI TDI and THR RA b control. Age, disease activity and severity
SLE Cavaco [21] 81♀ e 4♂/85 BSIT BSIT SLE and NPSLE b BSIT controls NPSLE: more olfactory dysfunctions than controls or
non-NPSLE patients
Shoenfeld [22] 41♀ e 9♂/50 Sniffin' Sticks TDI TDI SLE b control TDI with SLEDAI and NP manifestations
MS Uecker [23] 15♀ e 5♂ Sniffin' Sticks TDI 50% hyposmia No significant change during D correlated negatively with number of relapses; VAS
the follow-up. correlated with the TDI score of the longitudinally
tested patients
Good [24] 52♀ e 21♂/52♀ UPSIT, ODT UPSIT MS b control ODT correlation with lesion volume
e 21♂ 37% smell loss
5Jordy [25] 72♀ e 28♂/55♀ CCCRC Olfactory alteration MS (32%) b controls Age and EDSS
e 45♂ (3%).
Kandemir [26] 14♀ and 6 BSIT The total smell scores MS b controls no difference in total smell scores and disease
♂/20 duration or relapse
Caglayan [27] 21♀ and 8♂/30 Sniffin' Sticks TDI T patients b controls T, I, TDI correlation with age. I and TDI with MMSE and
EDSS.
Samkoff [28] 11♀ and 5♂/14 UPSIT UPSIT score patients = controls Negative correlation between UPSIT scores and EDSS
Caminiti [29] 19♀ e 11♂/18♀ OERPs 7/30 patients did not show OERP. 16/23 Disease duration, EDSS and OERPs
e 12♂ patients had amplitude significantly lower
than control group
Erb [30] 24♀ e 6♂/30 Sniffin' Sticks TDI TH and DIS MS = controls. No correlation between the FA reduction in lesions
and the EDSS or the TDI score. I: correlation with FA
values of lesions in the olfactory brain
Dahlslett [31] 20♀ e 10♂/30 OERP, Sniffin' OERP 23.8% hyposmia. TDI score inversely correlated with EDSS score; I:
Sticks TDI TDI 40% hyposmia. TDI MS b control inversely correlated with disease duration and EDSS
Silva [32] 153/165 B-SIT B-SIT MS b control. Age, disease duration, education, EDSS, depression
and MMSE.
Goektas [33] 25♀ and Sniffin' Sticks TDI 44% olfactory alteration OB volume correlated with olfactory function. I:
11♂/36 correlated with neurological scores.
Erb-Eigner [34] 30/12 Sniffin' Sticks TDI TDI, TH, ID MS b controls TDI score increased with decreased FA, increased MD
and increased RD. FA decreased in olfactory
structures. TDI correlated with EDSS
Lutterotti [35] 35♀ and Sniffin' Sticks TDI TDI, TH, ID MS b control TDI and disease activity and disease duration b 2
15♂/30 38% MS hyposmia ID years. TH and disease active and inflammation. ID and
8% MS hyposmia DIS negative correlation with disease duration.
48% MS hyposmia TH
26% hyposmia TDI
Fleiner [36] 11♀ and 5♂/16 Sniffin' Sticks TDI MS: 50% hyposmia The EDSS score inversely correlated with the
identification subtest
Zorzon [37] 25♀ and 15♂ CC-SIT 12.5% olfactory abnormal. Sex, age, disease duration, disability, anxiety,
40/40 CC-SIT MS score b control depression, lesion load. Correlation between CC-SIT
score and olfactory brain lesion load, and negative
correlation EDSS.
Zivadinov [38] 25♀ and CC-SIT CCSIT MS b controls CC-SIT score with symptoms of anxiety, depression
15♂/40 and severity of neurological impairment
Doty [39] 3♀ and 2♂ UPSIT 3 of 5 patients had moderate microsmia. Olfactory loss associated with fluctuations in plaque
numbers in inferior frontal and temporal lobes.
Doty [40] 17♀ and 9♂ UPSIT 38.5% of MS with olfactory loss Negative correlation with lesion load
Hawkes [41] 43♀ and UPSIT, OEP 15% patients had abnormal UPSIT. UPSIT scores correlated with EDSS. UPSIT scores with
29♂/96 25% patients had abnormal OEP. the H2S-evoked response.
Constantinescu 2♀ case report UPSIT Both patients with olfactory symptoms. The fluctuation of olfactory function in parallel with
[42] disease activity
Ansari [43] 40♀/24 T: serial binary Threshold MS = control T: with degree of disability, treatment.
dilutions of amyl
acetate and
nitrobenzene
 M.F. Bombini et al. / Autoimmunity Reviews 17 (2018) 405–412 409

Table 2 (continued)

Author N patients/N Smell test/smell Olfactory results Correlations, association or conclusion

controls analysis

Li [44] 11♀ and T&T olfactometer 42.3% olfactory function deficits. T&T correlated with EDSS. Bulb olfactory was smaller
15♂/26 test kit Olfactory threshold MS = control in olfactory dysfunction.
Holinski [45] 13 ♀ and 7♂ OM 2/S 25% patient's hyposmic. Negative correlation of OB volume and H2S latencies.
olfactometer Hyposmic patients had smaller OB volume and higher
volume of lesions in OB.
Rolet [46] 36♀ and 14♂ Sniffin' Sticks TDI Olfactory dysfunction was 40% TH, 18% DIS I: correlation positivity with EDSS and negatively with
and 10% ID. medical record. TDI was inversely correlated with
disease progression.
Churg-Strauss Tallab [47] One ♂ case UPSIT, odor UPSIT = total anosmia. No
syndrome reports. memory; PEA – TH Odor memory = total anosmia.
(CSS) PEA – TH = anosmia.
Neuromyelitis Zhang [48] 49/26 T&T olfactometer NMOSDs: 53% olfactory dysfunction patients TH was positively correlated with serum aquaporin-4
optica with olfactory dysfunction had smaller OB antibodies. Both detection
volume than did patients without it or and recognition thresholds for olfaction were
controls. negatively correlated with OB volume
Myasthenia Tekeli [49] 8♀ and 22♂/30 Sniffin' sticks test MG patients showed significantly lower Olfactory loss correlated with the severity of the
gravis (MG) TDI olfactory and gustatory scores than controls. disease.
Leon-Sarmiento 27MG, 11 UPSIT MG UPSIT b control; polymiositis UPSIT b No relationships with thymectomy, time since
[50] polymiositis/27 controls diagnosis, type of treatment, or the presence of serum
anti-nicotinic or muscarinic antibodies.
BD Akyol [51] 50/46 Sniffin' Sticks TDI ID, TDI b control. No
Veyselle [52] 17♀ and CCCRC CCCRC BD b controls No
13♂/30
GPA Fasunla [53] 9♂, 7♀/16 Sniffin' Sticks TDI T, D, I, TDI b control.
Goktas [54] 5 ♀, 4♂ Sniffin' Sticks TDI One patient had anosmia (11%), four
patients had hyposmia (44%) and four
patients were normosmic (45%).
Zycinska [55] 31♀ and 12♂ Sniffin' Sticks TDI 74% olfactory dysfunction. TDI, T, I, D T and age.
patients b control Nasal inflammation and SST
Laudien [56] 44♀ and 32♂ Sniffin' Sticks TDI 14 (18.4%) olfactory dysfunction Psychophysical test and olfactory performance.
Proft [57] 17♀ and Sniffin' Sticks' TDI T, D, I, TDI b control TDI and D with CRP; D: lower scores with azathioprine
27♂/44 75% hyposmia.

♀: women; ♂: men; BD: Behçet disease; BSIT: brief smell identification test; CC-SIT: cultural smell identification test; CRP: C reactive protein; D: discrimination; FA: fraction anisotropy;
GPA: granulomatosis with polyangiitis; I: identification; MD: mean diffusivity; MMSE: mini mental state exam; MS: multiple sclerosis; OB: olfactory bulb; ODT: odor detection threshold;
OEP: olfactory evoked potentials; OERPs: olfactometer OM2S; PEA – TH: detection threshold with phenyl ethyl alcohol; RA: rheumatoid arthritis; RD: radial diffusivity; SLE: systemic lupus
erythematosus; SSj: Sjogren's syndrome; 99mTcO4: 99rntechnetium pertechnetate; T: threshold; TDI: total score Sniffin' Sticks' test; UPSIT: University of Pennsylvania smell identification
test.

impairment. No differences in sex, disease duration, right hippocampus
volume, current prednisone dose, use of immunosuppressant medica-
tion and frequency of antiphospholipid antibodies was observed be-
tween SLE patients with and without olfactory dysfunction.
The olfactory performance remained stable over 2-year period in 90
patients evaluated. The patients did not present significant differences
in the threshold stage [mean score 6.83 (SD ± 3.31) vs 5.91(SD ±
2.23); p = 0.067), identification stage [mean score 10.92 (SD ± 2.18)
vs 10.12 (SD ± 1.90) p = 0.198], discrimination stage [mean score
11.06 (SD ± 2.43) vs 10.67 (SD ± 2.29) p = 0.319], and TDI [mean
score 28.82 (SD ± 5.33) vs 27.73 (SD ± 4.53); p = 0.317] at study
entry and follow-up period.
In 62 controls, olfactory performance also remained stable over 2-
year period. The controls did not present significant differences in the
threshold stage [mean score 8.39 (SD ± 3.52) vs 8.27(SD ± 3.42); p
= 0.851), identification stage [mean score 11.62 (SD ± 2.09) vs 11.63
(SD ± 2.13) p = 1], discrimination stage [mean score 11.87 (SD ±
1.98) vs 11.85 (SD ± 2.1) p = 0.92], and TDI [mean score 32.65 (SD
± 4.82) vs 32.64 (SD ± 4.71); p = 0.55] at study entry and follow-up
period.
3.2. SSc cohort
We included 57 [52 (92%) women; mean age of 47.99 years (SD ±
13.15) consecutive SSc patients. The mean disease duration was
8 years (SD ± 5.1) years. Twelve (20.3%) patients had active disease at
study entry.
At the time of study entry, 39 (66.1%) SSc patients had anxiety symp-
toms [mean BAI scores = 14.22 (SD = 12.21)] and 21 (35.6%) SSc had
depressive symptoms [mean BDI scores = 13.25 (SD = 8.99)]. Com-
pared to controls, SSc had significant higher BAI (p b 0.001) and BDI
(p b 0.001) scores.
Olfactory dysfunction was more frequently observed in SSc patients
[35 (59.3%); p b 0.001] when compared to controls. In addition to lower
score in TDI scores, SSc patients had significantly lower scores in all
three subtest of SST when compared to controls (Table 1).
SSc patients with olfactory impairment were significant older [mean
age = 49.41 (SD ± 10.4) vs 42.73 (SD ± 9.29) years; p = 0.02], had
more disease activity [mean scores = 2.11 (SD ± 1.65) vs 1.23 (SD ±
1.20); p = 0.023], smaller left hippocampus volume [mean volume
3032.6 mm3 (SD ± 706.44) vs 3632.49 mm3 (SD ± 709.63); p =
0.0034], smaller right hippocampus volume [mean volume
3168.32 mm3 (SD ± 667.08) vs 3791.26 mm3 (SD ± 759.27); p =
0.003], and smaller right amygdala volume [mean volume
1476.00 mm3 (SD ± 366.55) vs 1743.13 mm3 (SD ± 384.4); p =
0.01] when compared to SSc patients without olfactory impairment.
No differences in sex, disease duration, left amygdala volume, BAI,
BDI, current prednisone dose, use of immunosuppressant medication
and frequency of autoantibodies was observed between SSc patients
with and without olfactory dysfunction.
The olfactory performance remained stable over a 2-year period in
35 patients evaluated. The patients did not present significant differ-
ences in the threshold [mean score 6.06 (SD ± 3.17) vs 6.20 (SD ±
3.96); p = 0.84), identification [10.02 (SD ± 1.99) vs 11.08 (SD ±
2.14); p = 0.66), discrimination [10.42 (SD ± 2.77) vs 10.25 (SD ±
410 M.F. Bombini et al. / Autoimmunity Reviews 17 (2018) 405–412
2.96); p = 0.60], and TDI [26.54 (SD ± 6.52) vs 26.43 (SD ± 6.79); p =
0.59] stages.
4. Discussion
In our study, we observed that olfactory impairment was signifi-
cantly more common in SLE and SSc patients than in controls. In addi-
tion, we observed a significant reduction in all three stages of SST test
in SLE and SSc when compared to controls. Although the frequency of
olfactory impairment was similar between SLE and SSc, differences in
total scores and threshold stage were observed between groups.
Previous studies reported higher frequencies of olfactory dysfunc-
tion in SLE and SSc patients when compared to controls, however, no
differences in the three stages between patients and controls has been
observed [11,21,22]. This difference can be due to the larger sample
size of patients and controls in this study, when compared to previous
studies [11,21,22]. We observed higher anxiety and depression scores
only in SLE patients with olfactory dysfunction. Such association was
not observed in SSc. Similar results have been observed in animal
models and human studies.
In animal models, depression was associated with a significant
decrease in the number of neurons in the olfactory system and
periventricular region [77–80]. Reduction of the sense of smell and de-
pression could be induced in animal models by passive transfer of
anti-P antibodies into the CNS of mice [81,82]. In addition, immunosup-
pression altered sense of smell in mice [83]; and intracerebroventricular
infusion of cerebrospinal fluid from patients induced both dysfunction
in smell and spatial learning/memory in lupus-prone mice [84]. In SLE
we observed an association of olfactory impairment and anti-P antibod-
ies. No association of olfactory impairment and the use of immunosup-
pressants were observed in SLE and SSc.
Depression has also been linked to increased pro-inflammatory
cytokines such as interleukin 6 (IL6), tumor necrosis factor (TNF-α)
[85], and interleukin 1β (IL1β) [86,87]. Increased levels of pro-
inflammatory cytokines reduce hippocampi and amygdalae
neurogenesis, impair the proliferation of olfactory neurons, and increase
emotional instability [88]. Both innate and adaptive immune systems
are up regulated in SLE and SSc patients, resulting in the production of
several pro-inflammatory cytokines and autoantibodies [89,90]. Several
other studies have shown an association between pro-inflammatory cy-
tokines and olfactory impairment and pro-inflammatory cytokines and
depression [91].
Thus, both human and animal studies report the interaction be-
tween inflammation, autoantibodies, depression, and olfactory impair-
ment. In our study, we observed an association between olfactory
impairment and disease activity, which can indirectly result from an in-
crease in the levels of cytokines in both SLE and SSc. Association of olfac-
tory abnormalities and disease activity has been shown in SLE before,
however, this association has never been studied in SSc [22].
The association of depression and olfactory impairment can be ex-
plained by the fact that brain areas linked to olfaction are involved in
neuropsychiatric disorders. In our study, we observed significant reduc-
tion in hippocampi and amygdalae volumes of SLE and SSc patients with
olfactory impairment. In MS, several studies have shown an association
of olfactory dysfunction with lesion load and structural abnormalities in
MRI [24,40,44,58,59]. However, this is the first study to analyze hippo-
campi and amygdalae volumes in SLE and SSc patients with and without
olfactory dysfunction.
The olfactory system can be evaluated through several methods,
however quantitative testing is essential to determine both the validity
and nature of a patient's complaint and to accurately monitor changes in
function over time [92]. In addition, sensitivity, reliability and practical-
ity are important issues to be considered when choosing an olfactory
test [92]. In the literature, we identified tests ranging from brief tests
of odor identification to sophisticated olfactometers yoked to electro-
physiological recording of odor-induced changes at the level of the
olfactory epithelium (the electro-olfactogram; EOG) and cortex (odor
event-related potentials; OERPs) [74,92–100]. Psychophysical tests are
more practical and less costly to use in clinical practice and research
[92,93]. Shorter test generally have less sensitivity and reliability
[93,101].In addition, few tests have performed cross-cultural adaptation
since smell recognition has an important cultural aspect [95].
The main differences in psychophysical tests include testing time,
price and evaluation of peripheral and central aspects of olfaction. “Pe-
ripheral” process (ability to detect an odor, threshold), involvement of
the nasal epithelium; “central” process (identification and discrimina-
tion) require complex skills including cognitive and verbal process
[102–104]. The presence of smaller hippocampi land amygdalae vol-
umes in SLE and SSc patients with olfactory impairment when com-
pared to patients without olfactory impairment corroborates these
results and emphasizes the importance of using a method to evaluate
smell that tests both central and peripheral processes. Unfortunately,
cognitive testing was not available in all participants of the studies
and no conclusive results could be drawn.
We choose to use the SST test due to its ability in identifying differ-
ent aspects of smell dysfunction, such as threshold, identification and
discrimination, in addition to be able to compare our results to previous
studies in autoimmune rheumatic diseases [11,22].
We observed that olfactory function maintained stable over a 2-year
period in SLE and SSc patients and controls. This is the first study to eval-
uate olfactory function over a 2-year period in longstanding rheumatic
autoimmune diseases. In MS, one study has observed stable olfactory
function over a 3-year period [23].
We observed that both SLE and SSc patients with olfactory dysfunc-
tion were older than patients without olfactory dysfunction. Age related
changes have also been observed in other cohorts and in healthy popu-
lation [14,20,22,25,37,105,106]. Contrary to results of the literature that
observed differences between sex in smell function, we did not observe
such difference [92,97]. However, only a small amount of men was in-
cluded in our study.
Olfactory dysfunction was observed in 14.5% of our healthy control
group. In a large US cross- sectional study including 3519 individuals,
estimated olfactory impairment was 13.5% [107]. Although different
smell identification methods were used, we can assume that the preva-
lence of smell abnormalities in our control group is comparable to other
healthy individuals.
In the literature review we identified 47 studies that analyzed smell
abnormalities in a standardized method in autoimmune disease
(Table 2). Results are difficult to compare due to different methods
used to evaluate smell abnormalities and different outcomes. In general
we observe a reduction of olfactory function in autoimmune
diseases associated with age [14,20,25,27,32,37,55], disease activ-
ity or severity [20,22,25,35,38,46,49] and MRI abnormalities
[24,26,30,33,34,37,39,40,42,44,45,47,48].
In summary, this is the first study to evaluate olfactory function over
a 2-year period and determine the association of olfactory dysfunction
and age, disease activity and brain structures involved in the limbic sys-
tem in both SLE and SSc. Association of olfactory dysfunction, mood dis-
orders and anti-P antibodies was observed only in SLE, confirming
results from animal models.
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