Chemosensory dysfunction, Oral disorders and Oral health-related quality of life in patients with primary Sjögren’s syndrome: comparative cross-sectional study

This comparative cross-sectional study was performed at the Outpatient Clinic of the Institute of Rheumatology, University of Belgrade, Serbia. The period of recruitment was from the end of 2017 till the beginning of 2019. All fifty-eight patients with primary SS met the American–European Consensus (AEC) classification criteria [18]. These criteria include subjective symptoms of ocular dryness; subjective symptoms of oral dryness; objective measururement of ocular dryness by Schirmer’s test or corneal staining; salivary gland biopsy with focus score > 2; salivary scintigraphy showing reduced salivary flow (1.5 mL in 15 min) and/or diffuse sialectasias and positive autoantibodies against SS-A and/or SS-B. Patients were diagnosed with primary SS if 4 out of 6 criteria were met; either salivary gland pathology symptoms or the presence of autoantibodies against SS-A/SS-B are necessary for the diagnosis. If the patients had already been diagnosed with rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) or scleroderma prior to developing their sicca symptoms, they were diagnosed with secondary SS.

Fifty-five healthy controls of similar age and gender-matched were enrolled in this comparative cross-sectional study. The majority 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. [Mirjana Šijan Gobeljić], [Vera Milić,] and [Nemanja Damjanov] prepared study material, collected data and did all the analyses.

The patients with pSS were aged 25–77 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, in the investigator’s opinion, could make a patient ineligible to participate in the study. The exclusion criteria for the healthy controls were subjective mouth and eye dryness, presence of chronic rheumatic, metabolic or malignant diseases.

Disease characteristics (activity of pSS, extraglandular manifestations), patient’s medical history, chronic diseases, use of medications, and unhealty lifestyle habits (such as smoking) were recorded. Schirmer’s I test and Rose Bengal score were used for evaluation of objective xerophthalmia. Compromised function of the major salivary glands was assessed by salivary scintigraphy using radioactive technetium-99 m (Tc99m) pertechnetate, as easy, reproducible and well tolerated techique. Excretion rate was defined as the difference between maximum and minimum excretion after being stimulated by vitamin C, divided by the maximum counts. The excretion level ≥ 50% was classified as normal or dysfunctional if it was < 50% [19, 20].

Labial salivary gland (LSG) biopsies were performed in patients with pSS. The degrees of lymphocytic infiltration of the salivary gland tissue sections (4mm²) were scored from 0 to 4, according to the semiquantitative scoring method of Chisholm and Mason [21]. Grade 0 denoted the absence of inflammatory infiltrate; grade 1 slight presence of infiltrate; grade 2 moderate presence of 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, which are defined as pathological findings corresponded to focus scores ≥1.

Laboratory assessment of study participants included routine laboratory and immunoserological tests. Antinuclear antibodies (ANA; positive if titers > 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. Anti-Ro/SS-A and anti-La/SS-B antibodies were detected by enzyme-linked immunosorbent assay (ELISA; Organtec Diagnostica) [19, 20].

The participants were instructed not to eat, drink, or smoke for at least 1 h before their appointment at the Institute of Rheumatology. A detailed personal medical history was recorded. Also, the participants were examined by specialists in rheumatology and dentistry.

The olfactory and gustatory assessments were carried out as described below. Before olfactory testing, the 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 was scored as 0 = no smell perception up to 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 4 s. The subjects were instructed to choose from the three possible answers (anosmic/hyposmic – 0 points, or normosmic–1 point) for each of 12 odors on a multiple-choice scoring card [22]. The answers chosen by each individual participant were recorded on a protocol sheet, and the data were scored separately 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, the subjects were asked to score their subjective taste perception on VAS of 0–10, where self-reported taste score 0 meant no taste perception and score 10 meant very good taste perception. A gustatory assessment was performed after the subjects had been 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 [23]. The taste strips (length 8 cm, tip area2 cm²; Burghart Messtechnik, Wedel, Germany) were gently rubbed onto the anterior tip of the extended tongue. Different 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. 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 maximum score of 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 [9, 10, 12]. In addition, they described their experience of these conditions using open-ended questions. They also completed oral health-related quality of life (OHRQoL) questionnaire using the 14-item short form of the Oral Health Impact Profile (OHIP-14) [24‐26]. Serbian version of OHIP-14 was produced after the questionnaire had undergone back translation, linguistic and cultural validation. It had to be linguistically validated (and psychometrically tested) since no Serbian version had been available. Specifically, the questionnaire was translated from English into Serbian by two independent translators. Pretesting of the resulting questionnaire was conducted on a sample of 10 patients before it was used in this study in order to avoid a possible misinterpretation of any of the questions. The translated version proved to be accurate and well understood by the patients, so no further cultural modification seemed to be necessary.

The total OHIP-14 sum score ranged from 0 to 56, giving an overall indication of the patient’s OHRQoL. A high OHIP-14 score indicated a poor OHRQoL.

Disease activity and the presence of extraglandular manifestations were estimated by the EULAR index of disease activity (ESSDAI, range 0–123) [27, 28]. The subjective evaluation of the dryness intensity, joint pain and fatigue were assessed with the use of EULAR SS Patient Reported Index (ESPRI, range 0–10) [29].

Statistical analysis was conducted using the Statistical Package for the Social Sciences (SPSS) version 16.0. The sample sizing procedure was as follows: we defined our Population Size and set our Confidence Level to be 95%, which corresponds to a Z-score of 1.96. Based on the relevant literature, we used 0.5 for SD value, which was an adequate number for our sample size. After defining these values, we used the Sample size formula: Necessary Sample Size = (Z-score)2 * StdDev*(1-StdDev) / (margin of error)_2.

Normality of the data was assessed by Kolmogorov-Smirnov normality test. Independent samples t-test was used to compare 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.

The characteristics of patients with pSS and healthy controls are shown in Table 1. The patients with pSS and the healthy controls had a comparable mean age (p = 0.917). The majority of subjects in either group were females (p = 0.244). The two groups did not differ significantly in smoking habits (p = 0.560). In comparison with patients with pSS none of the healthy controls had subjective experience of ocular dryness (< 0.0001), oral dryness (< 0.0001), dysphagia (< 0.0001), nasal dryness (< 0.0001), dyspareunia (< 0.0001), salivary gland enlargement (< 0.0001) or Reynaud phenomenon (< 0.0001). The mean disease duration in patients with pSS was 7.65 ± 5.85 years, ranging from 1 to 22 years. The majority of patients with pSS (43%) had moderate disease activity as estimated by ESSDAI EULAR index of disease activity. More than half of patients (60%) reported that they were not satisfied with their current health status as assessed by EULAR SS Patient Reported Index ESSPRI. The vast majority of patients (more than 88%) had positive salivary gland scintigraphy, salivary gland biopsy and abnormal tear breaking-up time (BUT), Schirmer’s test and Rose Bengal score. The majority of patients (71%) were positive for antinuclear antibodies, SS-A autoantibodies (81%) and RF (69%). The mean value for erythrocyte sedimentation rate (ESR) was 25.7 mm/hour and it ranged from 2 to 88 mm/hour. Leucopenia was found in more than half of the patients (62%). Twenty–two patients with pSS (38%) were on corticosteroid therapy, whereas the majority among them (75%) took 10-50 mg of corticosteroids per day. The majority of patients (81%) used artificial tears, while only 4% of patients used artificial saliva, 46% received Chloroquine or Hydroxychloroquine, 3% Azathioprine and 2% Methotrexate. The majority of patients in this study received drugs that are not expected to have significant effect on chemosensory function.

The pSS group had a significantly lower mean self-reported smell score on VAS than healthy controls (8.57 ± 2.21 95% CI 7.99 to 9.15 vs. 9.56 ± 0.72 95% CI 9.36 to 9.76; p = 0.016; (Table 2). Similarly, olfactory testing showed that the patients with pSS were significantly more anosmic and hyposmic and significantly fewer of them were normosmic in comparison with healthy controls (χ² = 9.9; p = 0.002), as shown in Fig. 1.

The patients with pSS had a significantly lower mean self-reported taste score on VAS than healthy controls (8.48 ± 2.10 95% CI 7.93 to 9.04 vs. 9.54 ± 0.67 95% CI 9.35 to 9.73; p = 0.014). Gustatory testing showed that the pSS patient group had significantly lower mean taste scores than the control group (4.11 ± 1.82 95% CI 3.57 to 6.64 vs. 6.11 ± 1.93 95% CI 5.58 to 6.64; p < 0.0001) (Table 2). 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. Significantly more patients with pSS had impaired ability to taste sweet (p < 0.0001), sour (p = 0.054), salty (p = 0.018) and bitter (p = 0.001) than healthy controls.

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 (χ² = 23.6, p < 0.0001). 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. Similar proportions of the 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%) (χ² = 31.6, p < 0.0001). 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, but the difference between the two groups was not significant (χ² = 0.40, p = 0.434). 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 (p = 0.328).

Highly significant differences in frequency of self-reported complaints of dysgeusia among patients with pSS and controls and BST were observed, with no differencies in the presence of halitosis as shown in Fig. 2.

Odds ratios for the development of dysgeusia, BST and halitosis were determined in patients with SS and healthy controls and the results are given in Table 3. In addition, positive findings of anosmia (40.4%) were significantly higher among patients with primary Sjögren’s syndrome than among 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 (6.79 ± 7.03; 95% CI − 0.19 to 4.73 vs. 2.27 ± 8.46; 95% CI 4.90 to 8.67, 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 (6.67 ± 2.02 95% CI 6.13 to 7.22 vs. 8.28 ± 1.02 95% CI 7.99 to 8.57; p < 0.0001).