10.14639/0392-100X-N1344
Objective. To evaluate the olfactory function in primary Sjögren’s syndrome (pSS) patients and investigate its correlation with dry eye parameters.Methods. Thirty-eight pSS patients (49.47 ± 10.06 years) and 20 healthy volunteers (47.40 ± 8.92 years) were enrolled in the study. All participants underwent ENT and eye examinations including a modified Connecticut Chemosensory Clinical Research Center (CCCRC) test, tear break-up time (TBUT), ocular surface staining (OSS) and Schirmer test. The parameters were compared between the two groups using Student-t test, and Pearson test was used to evaluate the correlations.Results. Mean Schirmer and TBUT values were 2.39 ± 1.48 mm/5 min and 3.66 ± 1.5 sec in pSS and 18.30 ± 6.16 mm/5 min and 14.60 ± 3.64 sec in healthy subjects (p &lt; 0.001, both). There was a significant decrease in mean odour threshold, odour identification, CCCRC and VAS scores in the pSS group (p &lt; 0.001). Dry eye parameters showed moderate correlations with CCCRC parameters (r = 0.4-0.6, p &lt; 0.001) and olfaction VAS score (r = 0.4-0.75, p &lt; 0.05).Conclusions. There is a mild clinical impairment in smell sense in patients with pSS which seems to be correlated with dry eye parameters. Therefore, smell complaints should be queried in pSS patients suffering from severe dry eye.
text/xml
1827-675X
1344
en
Mete K. Bozkurt
http://creativecommons.org/licenses/by-nc-nd/4.0
ACTA Otorhinolaryngologica Italica
CCCRC
Olfactory dysfunction in primary Sjogren’s syndrome and its correlation with dry eye
Text.Serial.Journal
https://www.actaitalica.it/
41
Rhinology
2021-11-05
2020-12-29
2021-11-02
2021-11-02
443-449
1
Mete K. Bozkurt
2021/11/05
10.14639/0392-100X-N1344
443
Selcuk University School of Medicine, Otolaryngology Dept., Konya, Turkey
1827-675X
CCCRC
449
Olfactory dysfunction in primary Sjogren’s syndrome and its correlation with dry eye
https://www.actaitalica.it/article/download/1344/680
41
ACTA OTORHINOLARYNGOLOGICA ITALICA 2021;41:443-449; doi: 10.14639/0392-100X-N1344




Rhinology


Olfactory dysfunction in primary Sjogren’s syndrome
and its correlation with dry eye
Difunzione olfattiva nella sindrome di Sjogren e correlazione con la xeroftalmia
Yunus E. Topan1, Banu Bozkurt2, Sema Yılmaz3, Çağdaş Elsürer1, Sona Gorcuyeva2, Mete K. Bozkurt1
1
 Selcuk University School of Medicine, Otolaryngology Dept., Konya, Turkey; 2 Selcuk University School of Medicine, Ophthalmology
Dept., Konya, Turkey; 3 Selcuk University School of Medicine, Rheumatology Dept., Konya, Turkey


SUMMARY
Objective. To evaluate the olfactory function in primary Sjögren’s syndrome (pSS) patients
and investigate its correlation with dry eye parameters.
Methods. Thirty-eight pSS patients (49.47 ± 10.06 years) and 20 healthy volunteers
(47.40 ± 8.92 years) were enrolled in the study. All participants underwent ENT and eye
examinations including a modified Connecticut Chemosensory Clinical Research Center
(CCCRC) test, tear break-up time (TBUT), ocular surface staining (OSS) and Schirmer test.
The parameters were compared between the two groups using Student-t test, and Pearson
test was used to evaluate the correlations.
Results. Mean Schirmer and TBUT values were 2.39 ± 1.48 mm/5 min and 3.66 ± 1.5 sec
in pSS and 18.30 ± 6.16 mm/5 min and 14.60 ± 3.64 sec in healthy subjects (p < 0.001,
both). There was a significant decrease in mean odour threshold, odour identification, CC-
CRC and VAS scores in the pSS group (p < 0.001). Dry eye parameters showed moderate
correlations with CCCRC parameters (r = 0.4-0.6, p < 0.001) and olfaction VAS score                Received: December 29, 2020
(r = 0.4-0.75, p < 0.05).                                                                          Accepted: June 4, 2021
Conclusions. There is a mild clinical impairment in smell sense in patients with pSS which
seems to be correlated with dry eye parameters. Therefore, smell complaints should be              Correspondence
queried in pSS patients suffering from severe dry eye.                                             Mete Kaan Bozkurt
KEY WORDS: primary Sjögren’s syndrome, dry eye, olfactory dysfunction, CCCRC                       Selcuk University, School of Medicine, Department
                                                                                                   of Otolaryngology Head & Neck Surgery, Konya,
                                                                                                   Turkey
RIASSUNTO                                                                                          Tel. +90 3322243947
Obiettivo. Valutare la funzione olfattiva nei pazienti con sindrome di Sjögren primaria            E-mail: metekaanbozkurt@gmail.com
(pSS) e indagare la sua correlazione con la xeroftalmia.
Metodi. Nello studio sono stati arruolati trentotto pazienti con pSS (49,47 ± 10,06 anni) e        Funding
20 volontari sani (47,40 ± 8,92 anni). Tutti i partecipanti sono stati sottoposti a vista ORL      None.
e oculistica, inclusiva del test del Connecticut Chemosensory Clinical Research Center
(CCCRC), Tear Break-up Time (TBUT), colorazione della superficie oculare (OSS) e test di           Conflict of interest
Schirmer. I parametri sono stati confrontati tra i due gruppi utilizzando il test t di Student e   The Authors declare no conflict of interest.
il test di Pearson è stato utilizzato per valutare le correlazioni.
Risultati. I valori medi di Schirmer e TBUT erano 2,39 ± 1,48 mm/5 min e 3,66 ± 1,5 sec              How to cite this article: Topan YE, Bozkurt B,
nel gruppo pSS e 18,30 ± 6,16 mm/5 min e 14,60 ± 3,64 sec nei soggetti sani (p < 0,001,              Yılmaz S, et al. Olfactory dysfunction in primary
entrambi). C’è stata una diminuzione statisticamente significativa della soglia media                Sjogren’s syndrome and its correlation with dry
dell’odore, dell’identificazione dell’odore, dei punteggi CCCRC e VAS nel gruppo pSS                 eye. Acta Otorhinolaryngol Ital 2021;41:443-449.
(p < 0,001). I parametri dell’occhio secco hanno mostrato correlazioni moderate con i                https://doi.org/10.14639/0392-100X-N1344
parametri CCCRC (r = 0,4-0,6, p < 0,001) e il punteggio VAS dell’olfatto (r = 0,4-0,75,
p < 0,05).                                                                                         © Società Italiana di Otorinolaringoiatria
Conclusioni. Esiste una lieve compromissione clinica del senso dell’olfatto nei pazienti           e Chirurgia Cervico-Facciale
con PSS che sembra essere correlata alla xeroftalmia. Pertanto, i disturbi dell’olfatto do-
vrebbero essere valutati nei pazienti con PSS che soffrono di grave secchezza oculare.                            OPEN ACCESS

                                                                                                   This is an open access article distributed in accordance with
PAROLE CHIAVE: sindrome di Sjögren primaria, xeroftalmia, disfunzione olfattiva,                   the CC-BY-NC-ND (Creative Commons Attribution-Non-
CCCRC                                                                                              Commercial-NoDerivatives 4.0 International) license. The
                                                                                                   article can be used by giving appropriate credit and mentio-
                                                                                                   ning the license, but only for non-commercial purposes and
                                                                                                   only in the original version. For further information: https://
                                                                                                   creativecommons.org/licenses/by-nc-nd/4.0/deed.en




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Y.E. Topan et al.




Introduction                                                      ance and a decrease in olfactory sensation, via preventing
                                                                  the transport of olfactory molecules to the olfactory epithe-
Primary Sjogren’s syndrome (pSS) is a chronic, autoim-
                                                                  lium. In this study, we evaluated the olfactory function in
mune, systemic disease characterised by rhinitis sicca,           pSS patients using both a subjective Visual Analog Scale
symptoms of dry eyes and dry mouth driven by lymphocytes          (VAS) and a modified Connecticut Chemosensory Clinical
and autoantibodies targeting the exocrine glands, primarily       Research Center (CCCRC) test and compared these find-
the lacrimal and salivary glands 1-5. The revised international   ings with those age- and gender-matched healthy controls.
classification criteria for diagnosis of SS are typical ocular    We further investigated the correlation of smell dysfunction
and oral symptoms, ocular signs (Schirmer’s test and/or ocu-      with dry eye parameters.
lar staining score), reduced saliva secretion, histopathology
of minor salivary glands showing lymphocytic infiltration
and the presence of autoantibodies against Ro/SS-A and La/        Materials and methods
SS-B 6. The disease is named as primary SS (pSS) in the           The study was approved by the Selcuk University Research
absence of accompanying autoimmune connective tissue              Ethics Committee (2018/20) and followed the tenets of
disease, such as rheumatoid arthritis (RA), systemic lupus        1964 Helsinki Declaration. A total of 38 patients diagnosed
erythematosus (SLE) and scleroderma. The prevalence of            with pSS in the Rheumatology Department of Selcuk Uni-
pSS is estimated to be 0.06% 7. The disorder mainly affects       versity Medical Faculty, all fulfilling the American-Euro-
women, with a female to male ratio as nine. As a result of        pean Consensus classification criteria 6 and age- and sex-
permenant destruction of lacrimal gland acini and ducts, tear     matched 20 healthy volunteers were included in the study.
production is reduced and patients complain of dryness, dis-      Written informed consent was obtained from all partici-
comfort and foreign body sensation in the eye, visual fluc-       pants. Patients were using systemic immunosupressive/im-
tuation with blinking, blurred vision and impaired quality        munoregulatory treatment including steroids, hydroxyclo-
of life (QOL) 5,8. In addition, SS can lead to corneal ulcers,    roquine and methothrexate. Exclusion criteria were history
scleritis, uveitis, retinal vasculitis and optic neuritis.        of head trauma or stroke, chemotherapy or radiotherapy
Senses of smell and taste are very important for nutrition,       in head and neck region, hepatitis C infection, AIDS, pre-
in terms of recognition of foods, being one of the first warn-    existing lymphoma, sarcoidosis, graft versus host disease,
ing systems against chemicals, avoiding detrimental effects       nasal polyposis, advanced septal deviation, active upper
of these substances and involuntary ingestion and early           respiratory tract infection, allergic rhinitis, use of anticho-
digestion of dietary substances. Smell sensory processing         linergic drugs, previous nasal surgery, current smoking and
system can detect and discriminate thousands of low mo-           chronic alcohol use. Patients with secondary SS were not
lecular mass compounds (odourants). Via biochemical and           included in the study.
electrophysiological processes, the molecular information
converts into smell sensation 9.                                  ENT examination
Olfaction affects eating behaviour, digestive system physi-       Both sides of nasal cavities were evaluated endoscopi-
ology, gastric secretion and nervous system 9. Olfactory          cally using a Storz 0° endoscope. AR was performed with
dysfunction can manifest as reduced ability, disturbance or       RhinoMetrics® SRE2000 (Lynge, Denmark). The nasal
absence of smell. Olfaction can be impaired by transmis-          volume from 0 to 2.2 cm (VOL1), from 2.2 cm to 5.4 cm
sional pathologies of nasal and paranasal sinuses, sensori-       (VOL2), total nasal volume from 0 to 5.4 cm (TVOL), the
neural pathologies influencing the olfactory epithelium and       minimum cross-sectional area of the anterior (MCA1) and
bulbus, aging, chronic smoking, alcohol abuse, metabolic          the minimum cross-sectional area of the posterior (MCA2)
and autoimmune diseases and olfactory dysfunction has a           were measured from each nasal cavity within the distance
negative effect on QOL 10,11.                                     of 2.2 and 5.4 cm from the nostrils. The test was repeated 3
Saliva and nasal mucus are important in maintaining nor-          times and mean values were recorded. Subjects were asked
mal taste and smell acuity through their effects on taste         to score their smell perception on VAS, where self-reported
buds imbedded in the oral epithelium and olfactory cells          smell was scored as 0 indicating no smell perception up
found in the nasal cavity. In SS, progressive involvement of      to 10 showing very good smell perception. Objective ol-
exocrine glands with loss of secretion might impair the spe-      factory function was evaluated by a modified CCCRC test
cial senses of smell and taste. Patients with SS frequently       which includes a butanol threshold test and odour identifi-
report dry mouth, taste impairment, nasal dryness, odour          cation test using common odours 17, which was validated
change, and hyposmia 12-16. Low production of nasal mu-           in Turkish population by Veyseller et al. 18. Threshold test-
cous might lead to nasal obstruction, increased nasal resist-     ing was performed with solutions of 1-butanol in deionised



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                                                                                              Olfactory dysfunction in primary Sjogren’s syndrome




water, decreasing in 8 steps. The test result was expressed                evaluate the correlation between smell test parameters and
as threshold score from 0 to 8. In the identification test, 8              dry eye tests and a p value < 0.05 was considered as statisti-
well-known odourants which contains peanut butter, soap,                   cally significant.
mothballs, Vicks, chocolate, coffee, cinnamon and baby
powder were presented within 180 ml opaque jars to the in-                 Results
tact trigeminal nerve function test person in the same man-
ner. As the ability to sense Vicks VapoRub indicates intact                The pSS group included 35 females (92.11%) and 3 males
trigeminal nerve function and was easily identified by all                 (7.89%) with a mean age of 49.47 ± 10.06 years (range
subjects, it was not included in the final score 18. Possible              26-73 years), and the control group included 19 females
scores ranged from 0 to 7 items correctly identified. Scores               (95%) and 1 male (5%) with a mean age of 47.40 ± 8.92
for both nostrils were averaged to arrive at the final score.              years (range 35-68 years). There were no differences be-
Butanol threshold and identification tests were averaged to                tween the two groups in terms of age and gender (p = 0.44
obtain a CCCRC score.                                                      and 0.57, respectively). The mean duration of SS diagnosis
                                                                           and treatment was found as 54.03 months (12 months-240
Eye examination                                                            months). The systemic medications were hydroxychloro-
All subjects underwent a detailed ophthalmological exami-                  quine, methotrexate, sulfasalazine, azathioprine and ster-
nation, including Schirmer test, tear break up time (TBUT)                 oids. Nine subjects in the pSS group (23.7%) and 4 subjects
test and ocular surface staining (OSS). Schirmer test is a                 in the control group (20%) were former smokers (p = 0.75).
standard measure of aqueous tear production and is safe,                   None of the healthy subjects had complaints of dry eye, dry
easy to perform and inexpensive. Whatman’s filter paper                    mouth, dysphagia, nasal dryness, taste or smell loss. Mean
(No. 41) of 5 x 35 mm length was placed in the outer 1/3                   Schirmer and TBUT values were significantly lower in pSS
portion of both lower eyelid fornices and the length of wet-               group (2.39 ± 1.48 mm/5 min and 3.66 ± 1.5 sec, respec-
ting was measured and ≤ 5 mm at the end of 5 minutes was                   tively) compared to healthy subjects (18.30 ± 6.16 mm/5
defined as definitely decreased tear production. TBUT is                   min and 14.60 ± 3.64 sec, respectively) (p < 0.001, both)
an indicator of tear film stability and commonly used in                   (Tab. I). According to the Oxford scale, the OSS was mild
the assessment of dry eye disease. Sodium fluorescein is                   in 15 pSS subjects (39.5%), moderate in 14 (36.8%) and
installed into the lower conjunctiva and the patient is asked              severe in 9 subjects (23.7%).
to look straight ahead and blink a few times. The tear film                The pSS subjects had a lower mean self-reported smell score
is observed under blue light and the time between the last                 on VAS than the control group (7.45 ± 1.01 and 9.35 ± 0.59,
blink and the first dry spot is recorded. More than 10 sec-                respectively) (p < 0.05). Mean odour threshold, odour iden-
onds is considered normal, 5 to 10 seconds marginal and                    tification and CCCRC scores were significantly lower in
< 5 seconds was considered as abnormal TBUT. According                     the pSS group (7.05 ± 0.73, 5.32 ± 0.99 and 6.05 ± 0.63, re-
to the Oxford Scale, the OSS was graded between stage 0                    spectively) than the control group (7.95 ± 0.22, 6.45 ± 0.60
and 5 and then categorised as mild (stage 0-1), moderate                   and 6.73 ± 0.30, respectively) (p < 0.001) (Tab. II). The post
(stage 2 or 3), or severe (stage 4-5).                                     hoc power was 99% (1-b > 0.99), which indicates that our
                                                                           results were highly reliable.
Statistical analysis                                                       Mean VAS score, odour threshold, odour identification
Statistical analysis was performed using SPSS 23.0 (SPSS/                  and CCCRC scores were found to be significantly lower
IBM, Inc., Chicago, IL, USA) for Microsoft Windows.                        in pSS patients with severe OSS (6.78 ± 0.83, 6.67 ± 0.87,
Data are expressed as mean ± standard deviation, range                     4.78 ± 0.97 and 5.67 ± 0.75, respectively) compared to mild
(min-max) and percentage. The parameters were compared                     OSS (7.73 ± 0.7, 7.33 ± 0.62, 5.87 ± 0.64 and 6.40 ± 0.34,
between pSS and healthy using Student-t test. Since the                    respectively) (p < 0.05, all), while only odour identifica-
data were normally distributed, Pearson’s test was used to                 tion and CCCRC scores differed between mild and moder-


Table I. Demographic data and dry eye test results.
                                                        pSS group n = 38               Controls n = 20                      p value
 Age (years) (min-max)                                49.47 ± 10.06 (26-73)          47.40 ± 8.92 (35-68)                    0.44
 Gender (female n/%)                                       35 (92.11%)                    19 (95%)                           0.57
 Schirmer test (mm/5min)                                2.39 ± 1.48 (1-7)            18.30 ± 6.16 (10-30)                   < 0.001
 TBUT (sec)                                              3.66 ± 1.5 (2-8)            14.60 ± 3.64 (10-21)                   < 0.001




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Y.E. Topan et al.




Table II. Olfactory test and acustic rhinometry results of pSS and control group (Mean ± SD).
                                                                     pSS group                           Control group              P value
 Odour threshold score                                           7.05 ± 0.73 (5-8)                     7.95 ± 0.22 (7-8)            < 0.001
 Odour identification score                                      5.32 ± 0.99 (3-7)                     6.45 ± 0.60 (5-7)            < 0.001
 CCCRC value                                                     6.05 ± 0.63 (4-7)                     6.73 ± 0.30 (6-7)            < 0.001
 Odour detection VAS score                                       7.45 ± 1.01(5-10)                     9.35 ± 0.59 (8-10)           < 0.001
 MCA1                                                         0.36 ± 0.17 (0.04-0.74)               0.40 ± 0.13 (0.16-0.74)          0.39
 MCA2                                                         0.42 ± 0.25 (0.04-1.44)               0.65 ± 0.31 (0.15-1.52)          0.004
 Right Vol1                                                   1.62 ± 0.58 (0.52-3.51)               1.83 ± 0.38 (1.28-2.52)          0.14
 Right Vol2                                                  5.11 ± 3.33 (0.51-16.42)               9.01 ± 5.13 (3.44-24.97)         0.001
 Right total volume                                          6.73 ± 3.74 (1.03-18.46)              10.81 ± 5.28 (5.13-26.89)         0.001
 Left Vol1                                                     1.81 ± 0.9 (0.77-3.65)               1.60 ± 0.49 (0.92-3.03)          0.19
 Left Vol2                                                   5.94 ± 2.53 (2.75-13.12)               7.34 ± 3.26 (2.30-14.44)         0.076
 Left total volume                                           7.75 ± 2.89 (3.52-16.77)               8.94 ± 3.6 (3.80-16.17)          0.18



ate OSS groups (p < 0.05). Schirmer test, TBUT and Ox-                           controls showed impairment in smell function. Kamel et
ford OSS score showed significant correlations with odour                        al. 14 assessed smell and taste perception using Universi-
threshold (r = 0.49, 0.55 and 0.40, p < 0.05 respectively),                      ty of Pennsylvania Smell Threshold test and impregnated
odour identification score (r = 0.6, 0.61 and 0.51, p < 0.001,                   taste strips of 4 tastes (sweet, sour, salty and bitter) in 28
respectively), CCCRC score (r = 0.56, 0.58 and 0.54,                             pSS patients and 37 healthy subjects. They showed one
p < 0.001, respectively) and olfaction VAS score (r = 0.75,                      point decrease in odour detection threshold and 3.5 point
0.75 and 0.43, p < 0.05). Disease duration showed nega-                          decrease in taste threshold in SS group compared to con-
tive correlation with odour threshold (r = -0.53, p < 0.001),                    trol group. Forty-three percent of SS patients were hy-
odour identification score (r = -0.48, p < 0.001), CC-                           posmic (< 4.5) compared with 19% of the healthy group
CRC score (r = -0.55, p < 0.001) and olfaction VAS score                         (p = 0.036). The authors concluded that clinically impair-
(r = -0.49, p < 0.001).                                                          ment of chemosensory perception occurred in SS subjects,
Among AR parameters, mean MCA2, right VOL2 and right                             which contributed to a reduced health related QOL evalu-
total volume were significantly lower in the pSS group                           ated by the Short Form 12 14. Decreased mucin (odourant
compared to the control group (p < 0.05). No correlations                        carrier), recurrent rhinosinusitis and immunological mech-
were found between AR parameters and CCCRC scores                                anisms were proposed to explain decreased smell and taste
(p > 0.05), while a mild correlation was found between ol-                       disorder in SS subjects. In the study of Rusthen et al. 15,
faction VAS score and MCA2 (r = 0.32, p = 0.014), right                          mean odour VAS score and odour identification were 6.7
VOL2 (r = 0.28, p = 0.031) and right total volume (r = 0.27,                     and 8.8 in pSS patients and 8.3 and 10.7 in healthy sub-
p = 0.039).                                                                      jects (p < 0.05) and 12.9% of the patients were classified as
                                                                                 anosmic. In the meta-analysis of Al-Ezzi et al. 16 based on
                                                                                 5 studies with 378 participants, standardised mean differ-
Discussion
                                                                                 ences (SMD) between pSS and healthy controls were -0.78
Sjogren’s syndrome has a negative impact on smell and                            (95% CI -1.29 to -0.27) for smell; -1.01 (95% CI -1.54
taste function 12-16. Henkin et al. 12 studied taste and smell                   to -0.49) for taste; -0.93 (95% CI -1.22 to -0.64) for total
thresholds and forced scaling levels in 29 patients with SS                      sexual function; -1.28 (95% CI -1.65 to -0.90) and -0.83
and and in 10 patients with various diseases of the parotid                      (95% CI -1.27 to -0.40) for physical and mental compo-
glands. They showed significant taste and smell loss in                          nent of the QOL respectively; and 0.61 (95% CI 0.02, 1.20)
patients with xerostomia and rhinitis sicca, and treatment                       and 0.79 (95% CI 0.43 to 1.15) for anxiety and depression,
with cyclophosphamide or X-ray were shown to improve                             respectively. The authors concluded that pSS deteriorates
taste or smell function if the clinical signs and symptoms                       smell, taste, sexual function and QOL in women. Singh et
of xerostomia or rhinitis sicca concomitantly improved.                          al. 19 investigated olfactory and gustatory function, salivary
Weiffenbach et al.13 used smell identification test in 30 pSS                    secretion rates, burning mouth sensation and halitosis in 58
patients and 60 healthy subjects and found decreased ol-                         pSS patients, 22 non-Sjogren’s syndrome sicca patients and
faction in 26.7% of pSS subjects, while only 6.6% of the                         57 age-matched healthy controls. Olfactory and gustatory



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                                                                                      Olfactory dysfunction in primary Sjogren’s syndrome




functions were assessed using self-reported perception of           wetting distances of 6 to 18 mm are considered normal,
sense of smell and taste on VAS, 12-stick identification test       which means most of the the SS subjects included in the
and taste strips. Patients with pSS had a mild impairment in        study of Eren et al. 23 might not have severe dryness in the
smell sense compared to the control group (median 10/12             nasal mucosa. They found a trend toward a positive corre-
and 11/12, respectively, p = 0.007) and median gustatory            lation between olfactory function and intranasal Schirmer
and VAS scores were lower in patients with pSS (median              test scores, but it was not statistically significant.
20 and 7, respectively) than the healthy subjects (median           In our study, olfactory function was evaluated in 38 patients
26 and 8, respectively) (p < 0.05). A recent study by Šijan         diagnosed with pSS and the results were compared with
Gobeljić et al. 20 showed that patients with pSS had signifi-       age and sex-matched 20 healthy subjects. Mean subjective
cantly lower self-reported VAS smell score (8.6 ± 2.2) and          odour detection VAS score was 7.45 in pSS and 9.35 in the
VAS taste score (8.5 ± 2.1) than healthy controls (9.6 ± 0.7,       control group (p < 0.05). Using CCCRC test, mean odour
p = 0.016 and 9.5 ± 0.7, p = 0.014, respectively). Using            threshold, odour identification and CCCRC scores were
Sniffin Sticks test and taste strips, 3.8% of patients were         significantly lower in the pSS group (p < 0.001). However,
shown to have anosmia with scores between 0-5, 36.5%                the difference between the groups is around one point in all
had hyposmia with scores between 6-9, 34.0% had ageusia             parameters which in fact may not be noticed by the patient.
for sweetness, 10.6% for sourness, 10.0% for saltiness and          Most of the AR parameters did not differ between pSS and
19.1% for bitterness. Several factors may contribute to the         the control group and no correlations were found between
olfactory dysfunction in the SS patients, such as nasal dry-        AR parameters and smell tests (p > 0.05), which supports
ness, decreased mucin (an odourant carrier) and recurrent           the hypothesis that olfactory dysfunction in pSS is not due
rhinosinusitis 14. In case of decreased nasal secretion, ol-        to obstructive causes.
factory molecules can not dissolve within mucus and their           Mean CCCRC parameters in our control group was higher
transport to the olfactory epithelium is disturbed. Secretory       than normative values of 426 Turkish healthy volunteers 18,
immunoglobulins, distributed on the mucous film lining              which accepted maximum threshold scoring as 7, while it
the respiratory epithelium, neutralise viruses and bacterial        was 8 in our study. In addition, 37.1% of those subjects
surface antigens, favouring their phagocytosis. Decreased           were smokers, while none of our subjects were current
nasal mucous leads to a disruption in defense barrier and           smokers.
causes recurrent airway infections. Nasal dryness might             In the literature, there is no study investigating the rela-
also lead to epistaxis, crust formation and nasal blockage,         tionship between dry eye and olfactory function tests. In
all of which contribute to impaired olfactory function.             our study, the decrease in mean VAS score, odour thresh-
However, there are also contradictory studies, which did            old, odour identification and CCCRC scores were more
not reveal olfactory dysfunction in subjects with SS. In the        remarkable in pSS patients with severe OSS (6.78 ± 0.83,
study of Rasmussen et al. 21, although 39% of pSS patients          6.67 ± 0.87, 4.78 ± 0.97 and 5.67 ± 0.75, respectively) com-
complained of dryness in the nose and 44% of nasal crust            pared to mild OSS (7.73 ± 0.7, 7.33 ± 0.62, 5.87 ± 0.64 and
formation, no significant difference was found between              6.40 ± 0.34, respectively) (p < 0.05, all). The Schirmer test,
pSS and healthy subjects in odour detection using coffee            TBUT and OSS score showed significant correlations with
or mucociliary clearance. In the study of Midilli et al. 22,        CCCRC test parameters and olfaction VAS score, which
which investigated nasal and paranasal findings in 77 pSS           shows that smell loss was more remarkable in SS patients
patients and 77 control subjects, no significant differences        suffering from severe dry eye disease. In clinical practice,
were found in nasal clearance analysis with saccharin test          a good correlation was found between ocular and oral in-
and 5 component smell discrimination test between patients          volvement in patients with pSS. In pSS patients, Tashbayev
with SS and healthy subjects. In the studies of Rasmussen           et al. 24, showed that subjective oral dryness significantly
et al. 21 and Midilli et al. 22, olfactory dysfunction was evalu-   correlated with ocular dryness and stimulated saliva se-
ated with more simpler smell tests and no information was           cretion rate was significantly correlated with Schirmer I
given about the severity of disease in pSS participants. In         (r = 0.419). Ocular dryness might also be associated with
a recent study by Eren et al. 23, nasal dryness, postnasal          nasal dryness, which might be the cause of smell loss in
drip, and a decreased smell sense were remarkable in the            SS patients. One of our limitations was the relatively small
SS group (p < 0.05). Intranasal Schirmer test scores were           number of patients in the study; however, the post-hoc
lower in patients with SS (8.4 and 8 mm, in right and left          power was greater than 80% (1-b > 0.99), which indicates
nasal cavities) compared to healthy controls (11.7 mm,              that the results were highly reliable. The lack of measure-
both nasal cavities) (p = 0.041); however CCCRC scores              ments of salivary secretion rate, mucociliary function and
did not differ between the 2 groups. Intranasal Schirmer            nasal Schirmer test were other limitations, which will be



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evaluated in a further study. Rheumatologists always refer       related. Olfactory dysfunction was more remarkable in pSS
pSS patients to ophthalmologists for evaluation of dry eye       patients with moderate-severe ocular staining. Therefore,
severity and ocular side effects of medications used in SS,      smell complaints must be queried in SS patients suffering
mainly the adverse effects of hydroxychloroquine. Dry eye        dry eye.
tests, especially Schirmer test, is routine in these patients,
while ENT referral, nasal and ocular dryness tests are not       Acknowledgements
always performed, generally done as part of an investiga-
tion. Therefore, dry eye is an indicator of pSS severity and     We thank Asistant Prof. Umut Ece Arslan, Hacettepe Uni-
deterioration in dry eye test parameters might be a marker       versity, Public Health Institute, Ankara, for her assistance
for nasal involvement and smell impairment.                      in statistical analysis.
There are also complex interactions and some similarities
between autoimmunity and the olfactory system. Patients          References
with SLE, Sjogren’s syndrome, polydermatomyositis and            1
                                                                      Kabasakal Y, Kitapçıoğlu G, Karabulut G, et al. Criteria sets for
hereditary angioedema were shown to have disturbances in              primary Sjogren’s syndrome are not adequate for those presenting
olfactory functions 25. Genetics, hormonal and environmen-            with extraglandular organ involvements as their dominant clinical
tal factors may play a role in this relationship. Olfactory           features. Rheumatol Int 2017;37:675-684. https://doi.org/10.1007/
                                                                      s00296-017-3691-8
receptor gene clusters are located in proximity to MHC-          2
                                                                      Patel R, Shahane A. The epidemiology of Sjögren’s syndrome. Clin
complex, a key locus for autoimmune disorders, suggest-               Epidemiol 2014;6:247-255. https://doi.org/10.2147/CLEP.S47399
ing both physical and functional linkage between smell loss      3
                                                                      Vivino FB. Sjogren’s syndrome: clinical aspects. Clin Immunol
and autoimmunity 25,26.                                               2017;182:48-54. https://doi.org/10.1016/j.clim.2017.04.005
In the study of Shoenfeld et al. 27, using the Sniffin’ Sticks   4
                                                                      Fox PC. Autoimmune diseases and Sjogren’s syndrome: an autoim-
test, patients with SLE were found to have a significant              mune exocrinopathy. Ann N Y Acad Sci 2007;1098:15-21. https://doi.
decrease in smell abilities compared with controls as 46%             org/10.1196/annals.1384.003
vs 25% were hyposmic and 10% vs none were anosmic,
                                                                 5
                                                                      Bjordal O, Norheim KB, Rødahl E, et al. Primary Sjögren’s syn-
                                                                      drome and the eye. Surv Ophthalmol 2020;65:119-132. https://doi.
respectively. Magnetic resonance imaging (MRI) studies                org/10.1016/j.survophthal.2019.10.004
have shown involvement of the limbic system and func-            6
                                                                      Vitali C, Bombardieri S, Jonsson R, et al. Classification criteria for
tional areas of olfactory system, including amygdala and              Sjögren’s syndrome: a revised version of the European criteria pro-
hippocampus might support this clinical observation. Im-              posed by the American-European Consensus Group. Ann Rheum Dis
                                                                      2002;61:554-558. https://doi.org/10.1136/ard.61.6.554
mune-mediated mechanisms and drugs might be respon-
                                                                 7
                                                                      Qin B, Wang J, Yang Z, et al. Epidemiology of primary
sible for olfactory impairment. Bombini et al. 28 using the
                                                                      Sjögren’s syndrome: a systematic review and meta-analysis.
Sniffin’ Sticks test found olfactory dysfunction in 54.5% of          Ann Rheum Dis 2015;74:1983-1989. https://doi.org/10.1136/
143 SLE, 59.3% of 57 systemic sclerosis (SSc) and 14.45%              annrheumdis-2014-205375
of 166 healthy volunteers (p < 0.001) at study entry. Ol-        8
                                                                      Akpek EK, Bunya VY, Saldanha IJ. Sjögren’s syndrome: more than
factory dysfunction was found to be associated with age,              just dry eye. Cornea 2019;38:658-661. https://doi.org/10.1097/
                                                                      ICO.0000000000001865
disease activity, inflammation and smaller hippocampi and        9
                                                                      Hasin-Brumshtein Y, Lancet D, Olender T. Human olfaction: from
amygdalae volumes using volumetric MRI and FreeSurfer®                genomic variation to phenotypic diversity. Trends Genet 2009;25:178-
software. Mikulicz’s disease is an immunoglobulin IgG4                184. https://doi.org/10.1016/j.tig.2009.02.002
systemic disease. In the study by Takano et al. 29, of 44 pa-    10
                                                                      Wrobel BB, Leopold DA. Clinical assessment of patients with smell
tients, 45% had olfactory dysfunction even though they had            and taste disorders. Otolaryngol Clin North Am 2004;37:1127-1142.
no obstructive and inflammatory disease in nasal cavities             https://doi.org/10.1016/j.otc.2004.06.010
and sinuses. In subjects with olfactory dysfunction, there
                                                                 11
                                                                      Doty RL, Bromley SM. Effects of drugs on olfaction and taste. Otolar-
                                                                      yngol Clin North Am 2004;37:1229-1254. https://doi.org/10.1016/j.
were IgG4 positive plasmacytes in the nasal mucosa, which             otc.2004.05.002
might support a linkage between smell loss and autoim-           12
                                                                      Henkin RI, Talal N, Larson AL, et al. Abnormalities of taste and smell
munity.                                                               in Sjogren’s syndrome. Ann Intern Med 1972;76:375-383. https://doi.
                                                                      org/10.7326/0003-4819-76-3-375
                                                                 13
                                                                      Weiffenbach JM, Fox PC. Odor identification ability among patients
Conclusions                                                           with Sjögren’s syndrome. Arthritis Rheum 1993;36:1752-1754. htt-
                                                                      ps://doi.org/10.1002/art.1780361218
Our study showed that patients with pSS have a mild im-
                                                                 14
                                                                      Kamel UF, Maddison P, Whitaker R. Impact of primary Sjogren’s
pairment in smell. Herein, we evaluated for the first time
                                                                      syndrome on smell and taste: effect on quality of life. Rheumatology
the relationship between dry eye tests and olfactory func-            (Oxford) 2009;48:1512-1514. https://doi.org/10.1093/rheumatology/
tion parameters and showed that they were moderately cor-             kep249




448
                                                                                                      Olfactory dysfunction in primary Sjogren’s syndrome




15
     Rusthen S, Young A, Herlofson BB, et al. Oral disorders, saliva secre-    22
                                                                                    Midilli R, Gode S, Oder G, et al. Nasal and paranasal involvement
     tion, and oral health-related quality of life in patients with primary         in primary Sjogren`s syndrome. Rhinology 2013;51:265-267. https://
     Sjögren’s syndrome. Eur J Oral Sci 2017;125:265-271. https://doi.              doi.org/10.4193/Rhino13.001
     org/10.1111/eos.12358                                                     23
                                                                                    Eren E, Balcı K, Gerçik Ö, et al. Does nasal secretion decrease in
16
     Al-Ezzi MY, Pathak N, Tappuni AR, et al. Primary Sjögren’s syn-                Sjögren syndrome and does this affect nasal function? Laryngoscope
     drome impact on smell, taste, sexuality and quality of life in female          2021;131:370-373. https://doi.org/10.1002/lary.29022
     patients: a systematic review and meta-analysis. Mod Rheumatol            24
                                                                                    Tashbayev B, Rusthen S, Young A, et al. Interdisciplinary, com-
     2017;27:623-629. https://doi.org/10.1080/14397595.2016.1249538
                                                                                    prehensive oral and ocular evaluation of patients with primary
17
     Cain WS, Gent JF, Goodspeed RB, et al. Evaluation of olfac-                    Sjögren’s syndrome. Sci Rep 2017;7:10761. https://doi.org/10.1038/
     tory dysfunction in the Connecticut Chemosensory Clini-                        s41598-017-10809-w
     cal Research Center. Laryngoscope 1988;98:83-88. https://doi.
     org/10.1288/00005537-198801000-00017
                                                                               25
                                                                                    Perricone C, Shoenfeld N, Agmon-Levin N, et al. Smell and auto-
                                                                                    immunity: a comprehensive review. Clin Rev Allergy Immunol
18
     Veyseller B, Ozucer B, Karaaltin AB, et al. Connecticut (CCCRC)                2013;45:87-96. https://doi.org/10.1007/s12016-012-8343-x
     olfactory test: normative values in 426 healthy volunteers. Indian J
     Otolaryngol Head Neck Surg 2014;66:31-34. https://doi.org/10.1007/
                                                                               26
                                                                                    Doherty PC. On the nose: shared themes for the sensory and im-
     s12070-013-0632-z                                                              mune self. Nat Immunol 2003;4:1043-1045. https://doi.org/10.1038/
                                                                                    ni1103-1043
19
     Singh PB, Young A, Homayouni A, et al. Distorted taste and ımpaired
     oral health in patients with sicca complaints. Nutrients 2019;11:264.
                                                                               27
                                                                                    Shoenfeld N, Agmon-Levin N, Flitman-Katzevman I, et al. The
     https://doi.org/10.3390/nu11020264                                             sense of smell in systemic lupus erythematosus. Arthritis Rheum
                                                                                    2009;60:1484-1487. https://doi.org/10.1002/art.24491
20
     Šijan Gobeljić M, Milić V, Pejnović N, et al. Chemosensory dys-
     function, oral disorders and oral health-related quality of life in pa-   28
                                                                                    Bombini MF, Peres FA, Lapa AT, et al. Olfactory function in systemic
     tients with primary Sjögren’s syndrome: comparative cross-sectional            lupus erythematosus and systemic sclerosis. A longitudinal study and
     study. BMC Oral Health 2020;20:187. https://doi.org/10.1186/                   review of the literature. Autoimmun Rev 2018;17:405-412. https://
     s12903-020-01169-5                                                             doi.org/10.1016/j.autrev.2018.02.002
21
     Rasmussen N, Brofeldt S, Manthorpe R. Smell and nasal findings in         29
                                                                                    Takano K, Yamamoto M, Kondo A, et al. A clinical study of olfactory
     patients with primary Sjögren’s syndrome. Scand J Rheumatol Suppl              dysfunction in patients with Mikulicz’s disease. Auris Nasus Larynx
     1986;61:142-145.                                                               2011;38:347-351. https://doi.org/10.1016/j.anl.2010.11.008




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