Chemosensory Dysfunction and Oral Disorders Affect Oral Health-Related Quality Of Life in Patients with Primary Sjögren's Syndrome

Background: The aim of this study was to evaluate chemosensory function and oral disorders in patients with primary Sjögren's syndrome (pSS) and to compare these findings with those of age- and gender-matched healthy controls. Methods : Olfactory and gustatory function, dysgeusia, burning sensations in the tongue (BST), halitosis, and oral health-related quality of life (OHRQoL) using the short-form Oral Health Impact Profile (OHIP-14) were evaluated in 58 patients with primary Sjögren’s syndrome (pSS) and 55 age-and gender-matched healthy controls. Results: Patients with pSS had significantly lower self-reported visual analogue scale (VAS) smell score (8.6±2.2 vs. 9.6±0.7, p=0.016) and VAS taste score (9.5±0.7 vs. 8.5±2.1, p=0.014) than healthy controls. A greater proportion of patients with pSS had anosmia (3.8% vs. 0.0%) or hyposmia (36.5% vs. 13.2%) and ageusia for basic tastes: sweetness (34.0% vs. 7.5%), sourness (10.6 % vs. 0.0), saltiness (10.0% vs. 5.7%) or bitterness (19.1% vs. 1.9%). A higher proportion of pSS patients complained of dysgeusia (52.6% vs. 9.4%, p<0.0001) and BST (45.6% vs. 0.0%, p<0.0001) while similar number of pSS patients and controls reported halitosis (31.6% vs. 28.3%, p=0.434). The mean OHIP-14 score was significantly higher in patients with pSS (6.8±7.0 vs. 2.3±8.5, p<0.001) indicating patients’ poorer OHRQoL compared to controls. Conclusions: The majority of patients with pSS had impaired chemosensory function and indicators of oral health in comparison to the age- and gender-matched healthy

with another disease of connective tissue [1].
The pathogenesis of SS is complex. Genetic background and environmental factors including infections, stress and hormonal factors contribute to the pathogenesis of Sjögren's syndrome with the important role of the immune cells of innate and adaptive immunity such as, dendritic cells (DCs), T and B cells. The hallmarks of SS are lymphocytic infiltration of the exocrine glands and the presence of circulating autoantibodies (anti-Ro/SS-A and anti-La/SS-B) [2]. Moreover, patients with pSS have autoantibodies directed against muscarinic acetylcholine type 3 receptors (M3R) which functionally inhibit salivary secretion [3]. Genetic susceptibility to pSS is evidenced by the presence of single nucleotide polymorphisms (SNPs) in human leukocyte antigen (HLA) alleles (HLA-DRA, HLA-DQB1, HLA-DQA1), STAT4, IRF5, IL-12A and TNIP1, genes involved in the function of innate and adaptive immune cells [4]. Moreover, several candidate genes that regulate matrix metalloproteinase 9 (MMP9) expression, the enzyme that degrades the salivary gland structures, have been identified in patients with pSS [5].
American-European consensus group (AECG) classification criteria are used for establishing the diagnosis of Sjögren syndrome [6]. There is no cure for SS. The treatment of patients with SS is mainly symptomatic and the use of substitution therapy with artificial tears and saliva is recommended. Management of oral manifestations includes intense oral hygiene, prevention of oral infections and their treatment, use of artificial saliva, and local and systematic stimulation of salivary secretion [7]. Biological drugs could block several immune pathways or cytokines involved in the pathogenesis of SS, such as BAFF-APRIL and muscle pain as important signs and symptoms of the disease. However, some of the most important consequences of the nose and mouth dryness, the chemosensory dysfunction, as well as some of the important aspects of the oral disorders, dysgeusia, burning sensations in the tongue (BST), halitosis, and poorer oral health-related quality of life (OHRQoL) are often neglected. Moreover, some of the physicians and patients do not even realize that above mentioned chemosensory dysfunction and oral disorders are directly related to the pSS. The data regarding chemosensory dysfunction and other oral disorders, such as dysgeusia, burning sensations in the tongue and mouth in patients with pSS are limited. Therefore, it is of high importance to assess the impaired olfactory and gustatory functions, and occurrence of oral disorders in patients with pSS.
Patients with Sjögren's syndrome commonly experience oral symptoms and they are often firstly examined by a dentist. Having in mind that prevention and early treatment are crucial for the maintenance of oral health in patients with pSS, dental professionals should recognize the signs and symptoms of xerostomia and immediately connect them to SS. Early and appropriate treatment of patients with pSS is important to prevent the development of chemosensory dysfunction and oral disorders. Oral hygiene and regular dentist care are of importance. In cases of dysgeusia and burning mouth disorder, tricyclic antidepressants and clonazepam can be helpful, but can also potentiate mouth dryness in patients with pSS [21]. In case of severe dysgeusia topical anaesthetics like lidocaine gel is indicated [22]. Artificial saliva may be helpful in patients with xerostomia [23].
Additionally, strategies that capitalize on non-olfactory components of food flavour (altering food texture, primary taste qualities, temperature, and colour) should be implemented to help maintain food enjoyment. Foods and beverages that are salty, sweet, or that stimulate the trigeminal nerve (e.g., black or red pepper, carbonation) may provide another dimension to the eating experience.
Enhancing the olfactory component of food flavour can also improve food intake in patients with olfactory dysfunction. These compensatory strategies may help improve dietary choices and maintain both food enjoyment and nutritional health.
The aim of this study was to evaluate olfactory and gustatory function, dysgeusia, burning sensation in the tongue (BST), halitosis, and OHRQoL in patients with primary Sjögren's syndrome and to compare these findings with those of age-and gender-matched healthy controls.

Study participants
The study was performed at the Outpatient Clinic of the Institute of Rheumatology, University of Belgrade, Serbia. Fifty eight patients with primary SS, all fulfilling the American-European Consensus (AEC) classification criteria [6], and fifty five healthy controls of similar age and gender were enrolled in this comparative cross-sectional study. Some of the healthy volunteers were recruited from the healthy staff of the Institute of Rheumatology. Together with other recruited healthy subjects they completed a health questionnaire. All study participants had given their informed consent according to the Declaration of Helsinki, and the study was approved by the Local Ethics Committee at the Institute of Rheumatology.
The patients with pSS were aged from 25 to 77 years and were randomly and continuously recruited into the study from the Outpatient clinic of the Institute of Rheumatology. The exclusion criteria for the patients were inflammatory rheumatic diseases or systemic connective tissue diseases, active infections, malignant diseases, metabolic diseases or any other condition that may affect oral health, quality of life or patient capability to participate in the study by the investigator's opinion. The exclusion criteria for the healthy controls were subjective mouth and eye dryness, presence of chronic rheumatic, metabolic or malignant diseases.

Clinical assessment
Patients' disease characteristics (activity of pSS, extraglandular manifestations), medical history, chronic diseases, use of medications, and lifestyle habits (such as smoking) were recorded. Objective xerophthalmia was assessed by Schirmer's I test and Rose Bengal score determination. Oral involvement was evaluated by salivary scintigraphy of the major salivary glands. Salivary gland scintigraphy was performed with radioactive technetium-99m (Tc99m) pertechnetate. The difference between the maximum and minimum excretion after being stimulated by vitamin C divided by the maximum counts was defined as the excretion rate. It was classed as normal if excretion level was ≥50% or dysfunctional if excretion level was <50% [24,25].
Labial salivary gland (LSG) biopsies were performed in patients with pSS. The changes observed in 4mm 2 of salivary gland tissue were scored from 0 to 4, according to the semiquantitative scoring method of Chisholm and Mason [26]. Grade 0 was given based on absence of inflammatory infiltrate; grade 1 on the presence of slight infiltrate; grade 2 on the presence of moderate infiltrate of focus score < 1 (focus score is defined as number of aggregates of ≥ 50 lymphocytes per 4 mm2 of tissue).
Grades 3 and 4 were given if focus scores were ≥ 1. Grades 3 and 4 were defined as pathological findings.

Laboratory assessment
Routine laboratory and immunoserological tests were carried out on all patients; antinuclear antibodies (ANA; positive if titre>1:80) were measured by indirect immunofluorescence on the HEp-2 cell line substrate (Organtec Diagnostica, Germany). The serum levels of rheumatoid factor (IgM-RF) were determined by laser nephelometry whereas anti-extractable nuclear antigen antibodies anti-Ro/SS-A and anti-La/SS-B were detected by enzyme-linked immunosorbent assay (ELISA; Organtec Diagnostica) [24,25].

Assessment of chemosensory and oral disorders
The participants were instructed not to eat, drink, or smoke for 1 h before their appointment at the Institute of Rheumatology. A detailed medical history was recorded and participants were examined by specialists in rheumatology and dentistry.
The olfactory and gustatory assessments were carried out as described below. Before olfactory testing, subjects were asked to score their own general subjective smell perception on a visual analogue scale (VAS) from 0 to 10, where self-reported smell score 0 = no smell perception and 10 = very good smell perception. In cognitive evaluation of olfactory function an identification test with 12 odor pens (Sniffin'Sticks-Screening; BurghartMesstechnik, Wedel, Germany) was used. The pens were positioned under the subject's nose, approximately 2 cm from either nostril, for a maximum of 4sec.
The subjects were instructed to choose from the three possible answers (anosmic/hyposmic -0 points, or normosmic-1 point) for each of a 12 odors on a multiple-choices scoring card [27]. The answers chosen by every individual were recorded on a protocol sheet, and the data were scored for each of them. A normative classification was used to define anosmic (score: 0-5), hyposmic (score: 6-9), and normosmic (score: 10-12) subjects.
Before gustatory testing, subjects were asked to score their subjective taste perception on a VAS of 0-10, where self-reported taste score 0 = no taste perception and score 10 = very good taste perception. A gustatory assessment was performed after the subjects were given a detailed explanation of the testing procedure. Gustatory function was evaluated using taste strips with four basic taste qualities sweet, sour, salty and bitter [28]. Taste strips (length 8 cm, tip area2 cm 2 ; Burghart Messtechnik, Wedel, Germany) were gently rubbed onto the anterior tip of the extended tongue. The taste qualities were presented in a random manner. A chart with names of the four taste qualities was placed in front of the subjects during testing in order to ask the subjects to identify the taste of the strip. The subjects were allowed to rinse their mouths with water during the gustatory testing. The semi-quantitative evaluation for each of four taste qualities was performed as follows: 0=loss of ability to taste, 1 = reduced ability to taste and 2 = normal ability to taste. This protocol resulted in a total of maximum score 8, for each subject.
The subjects of this study completed a questionnaire for the assessment of dysgeusia, burning sensation in the tongue (BST), and halitosis. In addition they described their experience of these conditions using open-ended questions. They completed oral health-related quality of life (OHRQoL) questionnaire using the 14-item short form of the Oral Health Impact Profile (OHIP-14) [29][30][31].
Serbian source version of OHIP-14 was produced after the questionnaire had undergone back translation, linguistic and cultural validation. The total OHIP-14 sum score ranges from 0 to56, giving an overall indication of the patient's OHRQoL. A high OHIP-14 score indicates a poor OHRQoL.
Disease activity and the presence of extraglandular manifestations were estimated using the EULAR index of disease activity (ESSDAI, range 0-123) [32,33]. The subjective evaluation of the dryness intensity, joint pain and fatigue were assessed using EULAR SS Patient Reported Index (ESPRI, range 0-10) [31].

Statistical analyses
Statistical analysis was done using the Statistical Package for the Social Sciences (SPSS) version 16.0. Independent samples t-test was used for comparing normally distributed continuous variables in both patient and control groups. A chi-square test was used to compare dichotomous variables. Odds ratios (ORs) with 95% confidence intervals (CIs) for smell or taste alterations in patients with pSS and healthy controls were determined. P values < 0.05 were considered statistically significant.

Demographical and clinical characteristics of patients with primary Sjögren's syndrome and healthy controls
The characteristics of patients with pSS and healthy controls are shown in Table 1

Olfactory function
The pSS group had a significantly lower mean self-reported smell score on VAS than healthy controls (8.6±2.2 vs. 9.6±0.7, p=0.016). Similarly, olfactory testing showed that the patients with pSS were significantly more anosmic and hyposmic and fewer of them were normosmic in comparison with healthy controls, as shown in Fig 1.
Gustatory testing categorized significantly more patients with pSS as ageusic/hypogeusic and significantly fewer with normal sense of taste than in the control group as shown in Table 2.

Dysgeusia, burning sensation in the tongue, and halitosis
Complaints of dysgeusia, BST, and halitosis in the patients with pSS and healthy controls are shown in Table 3. Only five out of 53 healthy controls complained of dysgeusia, while more than half of patients with pSS (53%) reported dysgeusia. Thirty patients with pSS who complained of dysgeusia described the taste as metallic, sour, bitter, rotten or unpleasant. The majority of patients reported distorted bitter taste (36.7%), while all controls that reported dysgeusia (9.4%) complained of unpleasant taste.
The majority of patients with pSS (77%) and healthy controls (67%) experienced distorted taste as a daily problem.
While none of the controls complained of burning sensation of the tongue (BST), nearly half of patients with pSS reported BST (46%). The majority of patients with pSS (38%) experienced burning sensation in the tongue during the meals and 39% of them reported sour taste sensation as a type of BST.
About 32% of patients and 28% of controls complained of halitosis. Half of the pSS patients experiencing halitosis complained of halitosis as a persisting daily problem, similarly to the majority of healthy controls (80%) who also reported halitosis as a daily problem.
Odds ratios for the development of dysgeusia, BST and halitosis were determined in patients with SS and healthy controls and the results are presented in Table 3. In addition, patients with primary Sjögren's syndrome and positive findings of anosmia (40.4%) was significantly higher than healthy controls (13.2%) (Odds ratio: 5.2, 95% CI: 1.9-14.3, p < 0.001). The obtained results show that pSS is a risk factor for the development of dysgeusia, BST and anosmia.
The pSS group had a significantly higher mean OHIP-14 sum score than the control group (6.8±7.0 vs.2.3±8.5, p<0.001) (Fig 3). Scores in all domains of OHIP-14 (functional limitation, physical limitation, psychological limitation, and social limitation) were higher in pSS patients than in controls.
The pSS group had a significantly lower mean VASEQ5D sum score than the control group (6.7±2.0 vs. 8.3±1.0 <0.0001).

Discussion
The data regarding the associations between chemosensory disturbances, BST, halitosis, salivary gland function, and OHRQoL in patients with SS are limited. The present study demonstrates that patients with pSS had impaired olfactory and gustatory functions, dysguesia and burning sensation of the tongue (BST) and poorer OHRQoL were more frequent among them in comparison with the healthy controls without sicca symptoms. No significant differences were found in the frequencies of halitosis between patients with pSS and the controls. Our findings are in agreement with other studies showing disturbed taste and smell functions in patients with SS [10,11,35,36].
In our study, gustatory dysfunction was found to be more frequently reported than olfactory dysfunction, which is consistent with some studies [10,11,36], but contradictory to one of them [35].
The possible explanation may be related to the difference in methods of testing smell function. In this study, detection of the cognitive smell function was performed using smell identification test, whereas in the study by Kamel et al. [35] the chemosensory threshold (which reflects peripheral sensory impairment) was assessed. Smell function would be ideally tested by assessing threshold, detection, and identification tests. However, only identification test was performed in this study. Our findings demonstrate that dysgeusia, BST, and halitosis were often reported among patients with pSS which is in line with the reported data [11]. However, in our study no differences were found in the occurrence of halitosis between pSS and the control group.
There are indications that the cause of smell and taste impairments, as well as a burning sensation in the mouth may be caused by hyposalivation [10,37,38]. However, some studies show that salivary factors are not responsible for taste performance [38]. A recent study demonstrated lower salivary secretion rates in patients with pSS, but only weak correlation was found between salivary secretion rates and the presence of oral disorders. These findings indicate that low salivary flow is not a causative factor for the oral disorders examined in the reported study [11].
In our study we observed the relatively high percentage of ageusic and hypogeusic patients within the group of patients with pSS. While ageusia is a rare condition, reported to account for less than 1% of patients with chemosensory dysfunction [39][40][41] the patients with pSS in this study were categorized as ageusic as they experienced the inability to taste basic tastes: sweetness (34%), sourness (11%), saltiness (10%) or bitterness (19%). Interestingly, between 40-50% of healthy controls were found to be hypogeusic regarding the evaluated four basic tastes. However, the number of patients with pSS with ageusia/hypogeusia was significantly higher compared to healthy controls.
As for olfactory function, anosmia is the most common complaint of patients with chemosensory disorders [37][38][39]. However, in the present study 3.8% of the patients with pSS were categorized as anosmic and 36.5% as hyposmic. The percentage of anosmic patients in our study was found to be lower than in the study conducted by Rusthen et al. [11] where 12.9% of patients with pSS were categorized as anosmic. Some studies indicate that about half of the patients with complaints of anosmia and hyposmia report change in food preferences reflected in higher consumption of sugar and seasonings [39][40][41] and stated that loss or reduced ability to taste affected their eating habits [42]. This could result in either an increase or a decrease in body weight as both an increase and a reduction in food intake was observed in patients with chemosensory disorders [41].
About half of the patients with pSS complained of BST, which was mainly related to food intake, while none of healthy controls experienced BST. Burning sensation in the mouth is frequently present in patients with SS [14]. More than half of the patients complained of dysgeusia with the distorted taste of bitterness occurring on a daily basis, while dysgeusia was reported by a less than 10% of healthy controls. The problem of chemosensory dysfunction and oral disorders, such as dysgeusia, burning sensations in the tongue and mouth in patients with pSS is underestimated and the data about the frequency and severity of these disorders are limited. In our study we observed higher percentage of ageusic and hypogeusic patients within the group of patients with pSS, compared to other authors. [39][40][41]. Patients with pSS in our study were categorized as ageusic as they experienced the inability to taste basic tastes: sweetness (34%), sourness (11%), saltiness (10%) or bitterness (19%). This difference in comparison with previous studies is suggesting that problem was underestimated, and needs to be more carefully addressed in the future. The findings of our study show that oral disorders occur on a daily basis in a large proportion of patients with pSS and highlight the need for more attention to be given to these oral problems.
Chemosensory and oral disorders, burning mouth syndrome in particular, usually reduce the patients' quality of life, and 'psychological dysfunction' is common in patients with this diagnosis [43].
Consistent with this, the present study showed poor OHRQoL as estimated by OHIP-14score. The OHIP-14 questionnaire is designed to examine certain aspects of OHRQoL and the improved questionnaire is needed for better assessments of chemosensory disorders and OHRQoL in patients with pSS [11].
Oral malodor is a problem that has received increasing attention over the last decades. In the present study, a third of the patients with pSS complained of halitosis, whereas similar proportion of healthy controls reported oral malodor. The main oral causes of this disorder are known as well as effective treatment strategies [44]. Interestingly, it has been reported that a third of the patients seeking treatment for halitosis do not actually have oral malodor caused by the production of volatile sulphur compounds, and therefore they cannot be categorized as 'genuine halitosis' patients [17]. This could be one of the explanations of a high percentage of healthy controls complaining of halitosis in our study. Possible underlying cause of the high occurrence of olfactory and gustatory dysfunctions in pSS patients could be found in systemic inflammatory mechanisms operating in pSS such as overexpression of interferon-inducible genes [19]. Toll-like receptor pathways and interferon pathways mediate the inflammatory responses in taste tissue in pSS and may interfere with normal taste transduction and taste-bud cell turnover [20].
A most recent study demonstrated significantly high occurrence of dysgeusia, burning mouth sensation, halitosis and reduced taste in non-SS sicca patients and patients with pSS. Although non-SS sicca patients do not fulfill Sjögren's syndrome classification criteria, they had similar or even worse oral complaints than the patients with pSS [45]. Generally it would have been desirable to have a second comparison group with patients with dry syndrome that was not secondary to an autoimmune disease (diabetes, menopause, hypothyroidism, radiotherapy, age, etc.) to demonstrate whether the differences are due to the autoimmune process or the damage caused by the dryness of the mouth. Not having this second comparison group is one of the weaknesses of our study. In our plans for future studies we will try to form this second comparison group to have better insight in the possible association of other autoimmune diseases and the chemosensory dysfunction and oral disorders.

Conclusion
The results obtained in this study showed that patients with pSS had impaired olfactory and gustatory function. The occurrence of oral disorders, such as dysgeusia, BST, and halitosis was frequently found in patients with pSS patients who reported poorer OHRQoL compared to age-and gender-matched healthy subjects. Therefore, the regular assessment of the chemosensory functions and oral disorders in patients with pSS should be performed. Future studies of habits related to oral hygiene and dietary intake are needed to ensure improved treatment of oral health problems in patients with pSS.

Ethics approval
All study participants had given their informed consent according to the Declaration of Helsinki, and   Values are given as mean±SD or n (%); Statistical analysis was performed using chi-square tests except for age (t-test); *(n=57); ** (n=56) Values are given as mean±SD or n (%); Statistical analysis was performed using chi-square test (gustatory function) and Mann-Whitney test (taste score VAS, taste score)  Oral health-related quality of life (OHRQoL) in patients with pSS and healthy controls Patients with pSS had a significantly higher mean OHIP-14 sum score using the short-form Oral Health Impact Profile (OHIP-14) questionnaire than healthy controls reflecting poorer OHRQoL (p<0.0001; Mann-Whitney U test)