Zainab Assy

MAPPING REGIONAL ORAL DRYNESS: new perspectives on dry mouth and dry mouth interventions Zainab Assy

Mapping regional oral dryness: new perspectives on dry mouth and dry mouth interventions The research described in this thesis was conducted at the Academic Centre for Dentistry Amsterdam department Oral Biochemistry, Amsterdam, the Netherlands. An unrestricted research grant from the Nederlands Tijdschrift voor Tandheelkunde (NTVT, grant number OZB2018.01) was received by Z. Assy to perform all described research. Printing of this thesis was financially supported by: Nationale Vereniging Sjögrenpatiënten (NVSP), and Research Institute of the Academic Centre for Dentistry Amsterdam DOI: http://doi.org/10.5463/thesis.91 Zainab Assy Department of Oral Biochemistry Provided by thesis specialist Ridderprint, ridderprint.nl Author: Zainab Assy Printing: Ridderprint Cover, layout and design: Wessel Bosscher, persoonlijkproefschrift.nl ISBN:978-94-6458-944-3 Copyright 2023 © ZAINAB ASSY The Netherlands. All rights reserved. No parts of this thesis may be reproduced, stored in a retrieval system or transmitted in any form by any means without permission of the author.

VRIJE UNIVERSITEIT MAPPING REGIONAL ORAL DRYNESS: NEW PERSPECTIVES ON DRY MOUTH AND DRY MOUTH INTERVENTIONS ACADEMISCH PROEFSCHRIFT ter verkrijging van de graad Doctor of Philosophy aan de Vrije Universiteit Amsterdam, op gezag van de rector magnificus prof.dr. J.J.G. Geurts, in het openbaar te verdedigen ten overstaan van de promotiecommissie van de Faculteit der Tandheelkunde op woensdag 22 maart 2023 om 9.45 uur in een bijeenkomst van de universiteit, De Boelelaan 1105 door Zainab Assy geboren te Bagdad, Irak

promotoren: prof.dr. F.J. Bikker dr. H.S. Brand copromotor: dr. D.H.J. Jager promotiecommissie: prof.dr. M.L. Laine prof.dr. A. Vissink prof.dr. T. Forouzanfar prof.dr. W.M. Thomson prof.dr. B. O’Connell paranymphs Sherien EL Asadi Eliška Hartlová

This thesis is dedicated to my mum, Alia Hussein

TABLE OF CONTENTS Introduction page Chapter 1 General introduction, aim and outline of thesis 9 Perceived intra-oral dryness Chapter 2 Regional differences in perceived oral dryness as determined with a newly developed questionnaire, the Regional Oral Dryness Inventory 27 Chapter 3 Differences in perceived intra-oral dryness in various dry-mouth patients as determined using the Regional Oral Dryness Inventory 47 Intra-oral surfacea area and salivary distribution Chapter 4 Determination of intra-oral surface areas by cone-beam computed tomography analysis and their relation with anthropometric measurements of the head 77 Chapter 5 Correlations of palatal surface area with anthropometric dimensions of head and face 95 Chapter 6 Salivary film thickness and MUC5B levels at various intra-oral surfaces 111 Interventions to relieve oral dryness Chapter 7 The relationship between the severity of oral dryness and the use of dry-mouth interventions by various subgroups of dry-mouth patients 137 Chapter 8 The association between oral dryness and use of dry-mouth interventions in Sjögren’s syndrome patients 161 Chapter 9 Preferences of Sjögren’s syndrome patients regarding potential new saliva substitutes 185 Discussion and summary Chapter 10 General discussion 205 Chapter 11 Summary 217 Chapter 12 Nederlandse samenvatting 223 Appendices 229 Contributions of the authors 230 Acknowlegdements 233 About the author 236 List of publications 237

INTRODUCTION

1 General introduction, aim and outline of the thesis

10 Chapter 1 GENERAL INTRODUCTION Human saliva is produced by three pairs of major salivary glands and multiple minor salivary glands. The major salivary glands are the parotid, the submandibular, and the sublingual glands. The parotid glands mostly secrete serous saliva. The submandibular glands secrete both mucinous and serous saliva. The sublingual glands and the minor salivary glands secrete only mucinous saliva [1]. The minor glands comprise approximately 600– 1000 glands, distributed throughout the mouth except for the anterior part of the palate [2, 3]. Only recently, and surprisingly to many in the salivary and anatomical fields, a report was published in 2020 describing the location of a potential ‘new’ salivary gland, the ‘tubarial gland’ [4]. The glands were proposed to be situated close to the torus tubarius, a structure in the human nasopharynx composed of cartilage, which supports the auditory tube. Though, it is questioned whether the tubarial glands are bona fide salivary glands and the quest to their identity is currently under investigation [5-7]. The major salivary glands are responsible for 90% of the total volume of saliva, while the minor glands are responsible for <10% of the total secretion. Although the contribution of these minor glands is limited quantitatively, the ingredients in saliva secreted by these glands are essential for the local protection and moistening of the mucosal surface [2]. The salivary flow is regulated by the autonomic nervous system, with the parasympathetic response primarily responsible for stimulating secretion of watery saliva and the sympathetic system involved in salivary protein production [8, 9]. Healthy, unstimulated salivary secretion rates vary between 800 and 1500 mL per day or 0.25-0.35mL/min, but can increase upon stimulation, e.g. by chewing and taste, up to 1.0-3.0 mL/min [1, 10, 11]. The salivary flow rate and salivary composition are dependent upon the type and duration of the stimulus, and the glands that secrete the saliva [8]. Besides, the circadian rhythm affects the salivary secretion rate as well [10, 12]. This circadian rhythm has a high amplitude with a peak in saliva secretion in the late afternoon, while the flow rate is virtually negligible during sleep [10]. Saliva is considered as fundamental for the maintenance of the oral cavity homeostasis [2], due to its multiple functions including moistening and lubrication, microbial homeostasis, wound healing, tooth mineralization, and pH buffering (Figure 1) [10, 11, 13]. Additionally, saliva is involved in digestion and taste perception [10]. Although saliva consists of 99% water, its functions are effectuated by a great variety of compounds including ions, peptides and proteins such as glycoproteins and immunoglobulins (Figure 1) [14].

11 General introduction, aim and outline of the thesis Figure 1: Overview of salivary functions, modified from Vila et al. [13]. Aetiologies of salivary dysfunction Under various conditions the salivary gland function can be partially or totally impaired, resulting in a quantitative and/or qualitative change in the output of saliva (salivary gland dysfunction) [15]. This can be attributed to various aetiologies. The most common aetiology is the intake of multiple medications (polypharmacy), especially of (combinations of) antidepressants, anxiolytics, opiates, antihypertensives, diuretics and antihistamines [15]. Over 500 medications are known to cause or increase oral dryness as a side-effect [11]. These medications affect the salivary secretory mechanisms in various ways; some have anticholinergic or sympathomimetic actions that affect the neural control of salivary glands. Others have a cytotoxic effect on the salivary glands, or they have a diuretic effect that depletes body fluids, or damage the ion-transport pathways in the acinar cells [16, 17]. It has been suggested that the number of medications administered is more significant in the aetiology of oral dryness than specific types of medication [11]. Also, numerous diseases and medical conditions are associated with salivary gland dysfunction (Table 1) [16, 18]. These conditions can result in e.g. dysfunctions in neurotransmitter receptors, destruction of glandular parenchyma, immune dysregulations that may interfere with the secretion process or alterations in fluid composition and electrolytes [16]. One of the disorders with a very high association with salivary dysfunction is Sjögren’s syndrome, an autoimmune disease that affects the integrity of exocrine glands, mainly the salivary and lacrimal glands. Also, endocrine disorders (such as diabetes mellitus), neurologic disorders (such as depression), genetic disorders 1

12 Chapter 1 Table 1: Systemic disorders that may be associated with salivary dysfunction. Based on Saleh et al. [16] and Coke et al. [18] Rheumatological chronic inflammatory disorders Sjögren’s syndrome Rheumatoid arthritis Juvenile idiopathic arthritis Systemic lupus erythematosus Primary biliary cirrhosis Endocrine disorders Diabetes mellitus Hyperthyroidism Hypothyroidism Neurologic disorders Depression Parkinson’s disease Genetic disorders Agenesis of salivary glands Ectodermic dysplasia Prader-Willi syndrome Down syndrome Familial amyloidotic polyneuropathy Gaucher disease Papillon-Lefèvre syndrome Hereditary hemochromatosis Metabolic disorders Dehydration Chronic renal failure Bulimia Anaemia Alcohol abuse Infectious disorders HIV/AIDS HCV infection COVID Others Fibromyalgia Graft-versus-host disease Sarcoidosis Chronic pancreatitis

13 General introduction, aim and outline of the thesis (such as agenesis of the salivary glands), metabolic disorders (such as dehydration), infectious disorders (such as HIV and COVID) and other diseases (such as fibromyalgia) are associated with impaired salivary function [16]. In addition, salivary gland dysfunction is common in patients who have received radiotherapy of the head and neck region. In these patients, the development of salivary gland dysfunction depends on the cumulative dose of radiation and the volume of salivary gland tissue included in the field of radiation [15]. Additionally, various other factors can inhibit the secretion of saliva, such as tobacco smoking, using alcohol, the wearing of complete dentures, heavy snoring, and mouth breathing due to functional impairment of the upper airways [11, 19]. Also, periods of acute anxiety and stress can induce transient oral dryness due to predominant activation of the sympathetic stimulation [9]. Finally, during the physiological process of aging unfavorable changes in the number of secretory cells (acini) within the salivary glands may develop which also induce reduced secretion and/or a dry mouth. This problemmainly affects menopausal women and individuals older than 65 years [11]. However, the literature also depicts that these dry-mouth symptoms are not solely explained by the physiological processes of aging, but can also be caused by age-related increase in the number of medications used [11]. 1

14 Chapter 1 Consequences of impaired salivary function There is hyposalivation when the unstimulated salivary flow rate is <0.1 mL/ min or <0.7 mL/min under stimulated conditions [16]. The overall prevalence of hyposalivation in older people is approximately 33% [20]. Persistent and severe hyposalivation commonly results in mucosal changes, an increased caries activity, oral fungal infections and a proclivity towards acute gingivitis [15, 21]. In addition, consequences such as disturbed taste sensation, impaired lubrication, dysphagia, difficulty with chewing, difficulty with speaking, fetor ex ore, fissures and ruptures of the lips are also very common. These consequences may lead to behavioral changes like avoiding certain foods. In turn, changes in dietary intake may result in nutritional deficiencies and atrophy of the masticatory muscles and decreased masticatory ability [15, 19]. Consequently, hyposalivation and its related symptoms and clinical consequences often have negative effects on social functioning, quality of life in general and oral health in particular [15, 22, 23]. Also xerostomia, the subjective sensation of dry mouth that in most cases is present throughout the day [15], is sometimes associated with hyposalivation. The prevalence of xerostomia ranges between 1-65%, dependent on parameters studies such as study sample, gender, age, used medications, and used diagnostic tool [8, 19, 24-26]. In the general population, this prevalence is estimated to be approximately 20%, with increased prevalence in females (up to 30%) and in the elderly (up to 50%) [8, 19, 24]. Discomfort, especially disturbed sleep at night, is the most common symptom associated with xerostomia [11]. Current diagnostic tools for xerostomia and hyposalivation In order to prevent the negative consequences of xerostomia and hyposalivation a careful and systematic diagnosis of their respective cause(s), symptoms and signs is essential. Also, analysis of glandular function and inspecting the salivary glands is supportive in dry-mouth diagnostics. Currently, several tools are available. Firstly, there are various questionnaires for the assessment of xerostomia. One of the most frequently used questionnaires, and also internationally validated, is the Xerostomia Inventory (XI) developed by Thomson et al. [27]. The XI consists of 11-items on a 5-point Likert scale, summated into a single continuous scale score for the severity of xerostomia [28, 29]. Van der Putten et al. proposed a shorter version of the Xerostomia Inventory: the Summated Xerostomia Inventory-Dutch. In this questionnaire, five items of the original XI were used, with a 3 point-Likert scale [28, 29]. On the other hand, Fox et al. developed a questionnaire with four items about

15 General introduction, aim and outline of the thesis the severity of dry mouth, which may predict hyposalivation [28]. For this questionnaire a binary scale is used [28, 29]. Eisbruch et al. evaluated the grade of xerostomia through a validated scale: subjective grade 1: no disability; grade 2: dryness requiring additional fluids for swallowing; and grade 3: dryness causing dietary alterations, interference with sleep, speaking, or other activities [28, 29]. In turn, Pai et al. developed an 8-item visual analog scale (VAS) to assess xerostomia [28, 29]. Finally, Suh et al. developed a questionnaire with a combination of a binary scale, categorical scoring scale and VAS [30]. Yet, at the moment there is no clear scientific consensus on the best form of grading xerostomia, mainly due to differences in opinion about the best way to obtain information from the patient [16]. In the past, Navazesh and co-workers developed a clinical scale consisting of four clinical measures; dryness of lips, dryness of buccal mucosa, absence of saliva produced by gland palpation, and total DMFT (decayed, missing, and filled teeth). Together, these four measures could successfully predict the presence or absence of salivary gland hypofunction [31]. More recently, the clinical oral dryness score (CODS) has been designed to objectively quantify clinical signs of reduced salivary secretion [32, 33]. The CODS has been developed to help oral health professionals with the objective and quick determination of salivary gland function in a clinical setting [32, 33]. The CODS is based on clinical and visual inspection of the mouth to inspect for various signs of oral dryness such as the presence of frothy saliva and stickiness of the dental mirror to the tongue or the buccal mucosa [32, 33]. In turn, measurement of the salivary flow rate is the objective tool for hyposalivation. It is relatively easy to perform and requires little time [28]. Salivary flow rates can be determined by various methods, either by collection of unstimulated and stimulated whole saliva or by collection of saliva from specific salivary glands [29]. By draining saliva passively into a pre-weighed cup unstimulated whole saliva can be collected (draining method) [28]. Alternatively, Leal et al. suggested the use of pre-weighed cotton rolls for collection of saliva from the orifices of the ducts of the major salivary glands. After a specific time, the cotton rolls are weighed again and saliva flow can be calculated. Also, absorbent strips can be used, which can be placed at various intra-oral locations to determine salivary flow [28]. Other methods to assess the unstimulated whole salivary flow rate include the so called ‘spitting method’ and the ‘suction method’ [28]. Stimulated salivary flow rate is determined while the patient chews an unflavored gum base or paraffin wax (1–2 g) for 1 or several minutes. Otherwise, saliva production can be stimulated with a solution 1

16 Chapter 1 of 2% citric acid applied on the sides of the tongue at intervals of 30 seconds [28]. Despite this wide range of techniques, accurate assessment of dry mouth according to the quantity of saliva might be difficult as salivary quantity and flow rate vary dramatically within and between individuals. Additional biochemical and mechanical measurements could support diagnostic tests for dry mouth. To understand the salivary quality, it is important to investigate both the compositional feature and mechanical properties of saliva, such as adsorption, rheological and tribological properties [30]. Salivary gland function can also be measured by scintigraphy, in which a radionuclide is injected intravenously and subsequently this radionuclide is taken up by the salivary glands and then secreted [8]. Measurement of uptake and secretion into the oral cavity can determine the presence and extent of functional salivary tissue [8]. Additionally, a number of other imaging techniques can help in identifying salivary gland abnormalities, for example magnetic resonance imaging (MRI). MRI can identify solid and cystic masses in the glands. Sialography is a radiographic examination of the salivary glands to visualize the anatomy of ducts, acinar integrity, calcifications, and some tumors [8]. It usually involves the injection of a small amount of contrast medium into the salivary duct of a single gland, followed by routine X-ray projections. Investigating the medical history of dry-mouth patients contributes to proper diagnosis. A detailed inventory of present symptoms, type and number of xerogenicmedications used, the presence of systemic and oral diseases, and previous dry-mouth therapies is important in this process [29]. This information also helps to investigate the potential underlying influence of condition like psychiatric and cardiovascular diseases [29]. The European Medical RiskRelated History questionnaire is a good example of an internationally validated patient-administered questionnaire that is used to retrieve information about the health status of a patient [34, 35]. Furthermore, an extra-oral and intra-oral examination should also be part of the examination of the patient. This should include the inspection and palpation of the salivary glands, expulsion (“milking”) of saliva from the major salivary duct orifices (at rest and after a stimulus), and inspection of the oral mucosa and the dentition [29]. Finally, salivary gland biopsy provides a definitive diagnosis of glandular pathology. A labial minor salivary gland biopsy is more commonly and easily performed than a biopsy of the major salivary glands [8]. Although, recent literature discusses parotid biopsies as an alternative for minor salivary gland biopsies [26, 36]. As the sensitivity and specificity of parotid and labial biopsies for diagnosing Sjögren’s syndrome

17 General introduction, aim and outline of the thesis are comparable. In addition, parotid gland incision biopsy can overcome most of the disadvantages of labial gland excision biopsy [26, 36]. Taken together for a systematic and detailed investigation of xerostomia, hyposalivation, salivary gland function and gland inspection, the use of a combination of diagnostic tools (both objective and subjective parameters) is recommended. Dry-mouth interventions Effective management of dry-mouth complaints is important in order to improve the quality of life of those who seek treatment for their symptoms and to minimize associated oral problems [24]. In some patients it may be possible tomanage the problems associated with a dry mouth through optimal management of the underlying condition(s); for example, an adjustment of the medication used or its dosage. In individuals with mild symptoms sucking ice chips, frequent sipping of water, and reducing or avoiding irritants, such as alcohol, caffeine, smoking or hot, spicy foods may provide sufficient relief for their symptoms [24]. When there is some residual salivary function, saliva secretion can be stimulated with the use of topical sialagogues, such as using sugar-free chewing gums and lozenges [37]. Systemic pharmacotherapies with parasympathomimetic activity including pilocarpine and cevimeline could also stimulate the salivary secretion [37, 38]. Other interventions such as acupuncture, salivary neuro-electrostimulation and sialendoscopy have also been used to increase saliva production and, in some cases, might also lessen the associated dry-mouth symptoms [37, 39, 40]. Especially in Sjögren’s syndrome patients, sialendoscopy of the major salivary glands showed promising results as it increased the salivation and reduced oral dryness up to at least 60weeks [40]. However, when the salivary secretion is irreversibly impaired, e.g. as a consequence of radiotherapy, then salivary substitutes could be used as dry-mouth interventions. Examples of salivary substitutes are mouth washes, mouth gels and oral sprays [24, 37]. These substitutes help to moisturize the mucosa in absence of saliva [24]. State of the art in dry-mouth diagnostics and dry-mouth interventions Despite the wide range of questionnaires and clinical tests available, an accurate diagnosis of dry mouth is still challenging, due to the complex aetiology of dry mouth and the various potential underlying mechanisms. Besides, the current diagnostic methods map dry-mouth symptoms in general terms, but they do not adequately reveal the complexity of this problem and they are also not entirely discriminating. To illustrate, the total salivary flow rate 1

18 Chapter 1 measures only the whole saliva secretion, but this flow rate does not provide information on the extent of the moisturizing effect of saliva. For this reason, hyposalivation and xerostomia are not correlated per se [23, 41]. Moreover, the sensation of a dry mouth is not only related to the reduction in salivary secretion rate, but possibly also to the unequal thickness of the saliva film on both soft and hard oral tissue surfaces [23]. The salivary film thickness could influence the moisturizing effect of saliva, and consequently the surface over which saliva is spread can influence the salivary film thickness and possibly also its moisturizing effect. An important gap in the scientific literature is a dry-mouth questionnaire which explores the perceived dryness at various intra-oral locations, specifically various mucosal surfaces such as the tongue or palate. And, although, a large number of studies have shown that the salivary film is not equally distributed within the oral cavity [33, 42-49], a questionnaire to determine dryness at specific oral locations is still lacking. For this reason, it is envisaged that a questionnaire to determine dryness at specific oral locations could increase our understanding about the distribution of saliva in the oral cavity and the relation with perceived dryness. Additionally, such a new questionnaire could even contribute to determining the cause of oral dryness in specific patient groups. In addition, as the (size of) surface area plays a role in the distribution of saliva, measurement of the oral surface areas could be an important additional tool during the diagnosis of oral dryness. Nowadays, various interventions are available to relieve oral dryness. The reasons that affect the use of dry-mouth interventions by patients are not fully understood yet. In previous research it was shown that age, gender and the presence of a dental prothesis could affect the use of dry-mouth interventions in Sjögren’s syndrome patients [50]. However, it is still unclear whether the severity of intra-oral dryness could also affect the use of drymouth interventions. For this reason, factors that affect the choice of dry-mouth interventions will be further explored. Aimand outline of the thesis The overall aimof this thesiswas to improve the current, available diagnostic tools for drymouth by developing a newmethod for measuring the perceived dryness at specific various intra-oral locations and to investigate the effect of intra-oral surface areas on the distribution of saliva within the oral cavity. Additionally, the use of dry-mouth interventions by various dry-mouth patients will be investigated to understand which factors affect the use of these interventions. In this thesis, eight research chapters are divided into three main themes:

19 General introduction, aim and outline of the thesis 1) perceived intra-oral dryness (Chapters 2, and 3); 2) intra-oral surface area and salivary distribution (Chapters 4, 5 and 6); and 3) interventions to relieve oral dryness (Chapters 7, 8 and 9). In Chapter 2, a novel questionnaire, the Regional Oral Dryness Inventory (RODI) was developed to quantify the severity of dryness at various locations in the mouth. Next, this questionnaire was validated in various groups of dry-mouth patients aiming to differentiate between causes of oral dryness (Chapter 3). As the size of the surface area of the intra-oral regions, the palate, can possibly influence the distribution and average thickness of the salivary film, in Chapter 4 intra-oral surface areas were quantified using cone-beam computed tomography (CBCT). Besides, potential correlations between intraoral surface areas and facial anthropomorphic measurements were analyzed which would enable easy and safe chair-side approximation of intra-oral surface areas. In Chapter 5 the relation between the palate surface area, measured using an intra-oral scanner, and anthropometric measurements of the head and face was validated in living subjects. In Chapter 6, palatal surface area measurements were explored in healthy volunteers in combination with measurements of the salivary film and the salivary consistency, especially the concentration of a salivary mucin, at various intra-oral locations. The aim of Chapter 7 was to investigate the use of dry-mouth interventions by subgroups of patients with different causes of oral dryness and explored the possible relation of the applied interventions with intra-oral dryness and salivary flow rate. In accordance with this study, Chapter 8 has a similar aim, but focuses on Sjögren’s syndrome patients specifically. The purpose of Chapter 9 was to explore the preferences of Sjögren’s syndrome patients regarding various product characteristics of potential new saliva substitutes, important functions of possible substitutes, objections against certain ingredients, desired flavors for the substitutes, objections against potential side-effects of saliva substitutes, and the preferred method of administration. 1

20 Chapter 1 REFERENCES 1. Turner MD. Hyposalivation and Xerostomia: Etiology, Complications, and Medical Management. Dent Clin North Am. 2016;60(2):435-43. 2. de Paula F, Teshima THN, Hsieh R, Souza MM, Nico MMS, Lourenco SV. Overview of Human Salivary Glands: Highlights of Morphology and Developing Processes. Anat Rec (Hoboken). 2017;300(7):1180-8. 3. Hamada T, Kawazoe Y, Sekino K, Nagasawa T, Tsuru H. Palatal gland distribution. J Dent Res. 1974;53(4):944. 4. Valstar MH, de Bakker BS, Steenbakkers R, de Jong KH, Smit LA, Klein Nulent TJW, et al. The tubarial salivary glands: A potential new organ at risk for radiotherapy. Radiother Oncol. 2021;154:292-8. 5. Nascimento JJC, Ribeiro ECO, Silva-Neto EJ. Letter to the Editor regarding “The tubarial salivary glands: A potential new organ at risk for radiotherapy”. Radiother Oncol. 2021;154:323. 6. Bikker FJ, Vissink A. Letter to the editor concerning Valstar et al., [Radiother Oncol 2020 Sep 23;S0167-8140(20)30809-4. doi: 10.1016/j.radonc.2020.09.034]. Radiother Oncol. 2021;154:318. 7. Valstar MH, de Bakker BS, Steenbakkers R, de Jong KH, Smit LA, Klein Nulent TJW, et al. The tubarial glands paper: A starting point. A reply to comments. Radiother Oncol. 2021;154:308-11. 8. Napeñas JJ, Brennan MT, Fox PC. Diagnosis and treatment of xerostomia (dry mouth). Odontology. 2009;97(2):76-83. 9. Guggenheimer J, Moore PA. Xerostomia: etiology, recognition and treatment. J Am Dent Assoc. 2003;134(1):61-9; quiz 118-9. 10. Dawes C, Pedersen AM, Villa A, Ekstrom J, Proctor GB, Vissink A, et al. The functions of human saliva: A review sponsored by the World Workshop on Oral Medicine VI. Arch Oral Biol. 2015;60(6):863-74. 11. Tanasiewicz M, Hildebrandt T, Obersztyn I. Xerostomia of Various Etiologies: A Review of the Literature. Adv Clin Exp Med. 2016;25(1):199-206. 12. Dawes C. Circadian rhythms in human salivary flow rate and composition. J Physiol. 1972;220(3):529-45. 13. Vila T, Rizk AM, Sultan AS, Jabra-Rizk MA. The power of saliva: Antimicrobial and beyond. PLoS Pathog. 2019;15(11):e1008058. 14. Humphrey SP, Williamson RT. A review of saliva: normal composition, flow, and function. J Prosthet Dent. 2001;85(2):162-9. 15. Pedersen AML, Sørensen CE, Proctor GB, Carpenter GH, Ekström J. Salivary secretion in health and disease. J Oral Rehabil. 2018;45(9):730-46. 16. Saleh J, Figueiredo MA, Cherubini K, Salum FG. Salivary hypofunction: an update on aetiology, diagnosis and therapeutics. Arch Oral Biol. 2015;60(2):242-55. 17. Ying Joanna ND, Thomson WM. Dry mouth - An overview. Singapore Dent J. 2015;36:12-7. 18. Coke CJ, Davison B, Fields N, Fletcher J, Rollings J, Roberson L, et al. SARS-CoV-2 Infection and Oral Health: Therapeutic Opportunities and Challenges. J Clin Med. 2021;10(1).

21 General introduction, aim and outline of the thesis 19. Millsop JW, Wang EA, Fazel N. Etiology, evaluation, and management of xerostomia. Clin Dermatol. 2017;35(5):468-76. 20. Pina GMS, Mota Carvalho R, Silva BSF, Almeida FT. Prevalence of hyposalivation in older people: A systematic review and meta-analysis. Gerodontology. 2020;37(4):317-31. 21. Porter SR, Scully C, Hegarty AM. An update of the etiology and management of xerostomia. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2004;97(1):28-46. 22. Roblegg E, Coughran A, Sirjani D. Saliva: An all-rounder of our body. Eur J Pharm Biopharm. 2019;142:133-41. 23. Kho HS. Understanding of xerostomia and strategies for the development of artificial saliva. Chin J Dent Res. 2014;17(2):75-83. 24. Furness S, Worthington HV, Bryan G, Birchenough S, McMillan R. Interventions for the management of dry mouth: topical therapies. Cochrane Database Syst Rev. 2011(12):Cd008934. 25. Quock RL. Xerostomia: current streams of investigation. Oral Surg Oral Med Oral Pathol Oral Radiol. 2016;122(1):53-60. 26. Delli K, Spijkervet FK, Kroese FG, Bootsma H, Vissink A. Xerostomia. Monogr Oral Sci. 2014;24:109-25. 27. Thomson WM, Chalmers JM, Spencer AJ, Williams SM. The Xerostomia Inventory: a multi-itemapproach tomeasuring drymouth. Community Dent Health. 1999;16(1):127. 28. Villa A, Connell CL, Abati S. Diagnosis and management of xerostomia and hyposalivation. Ther Clin Risk Manag. 2015;11:45-51. 29. Villa A, Wolff A, Aframian D, Vissink A, Ekström J, Proctor G, et al. World Workshop on Oral Medicine VI: a systematic review of medication-induced salivary gland dysfunction: prevalence, diagnosis, and treatment. Clin Oral Investig. 2015;19(7):156380. 30. Hu J, Andablo-Reyes E, Mighell A, Pavitt S, Sarkar A. Dry mouth diagnosis and saliva substitutes-A review from a textural perspective. J Texture Stud. 2021;52(2):141-56. 31. Navazesh M, Christensen C, Brightman V. Clinical criteria for the diagnosis of salivary gland hypofunction. J Dent Res. 1992;71(7):1363-9. 32. Jager DHJ, Bots CP, Forouzanfar T, Brand HS. Clinical oral dryness score: evaluation of a new screening method for oral dryness. Odontology. 2018;106(4):439-44. 33. Osailan SM, Pramanik R, Shirlaw P, Proctor GB, Challacombe SJ. Clinical assessment of oral dryness: development of a scoring system related to salivary flow and mucosal wetness. Oral Surg Oral Med Oral Pathol Oral Radiol. 2012;114(5):597-603. 34. Smeets EC, de Jong KJ, Abraham-Inpijn L. Detecting the medically compromised patient in dentistry by means of the medical risk-related history. A survey of 29,424 dental patients in The Netherlands. Prev Med. 1998;27(4):530-5. 35. Abraham-Inpijn L, Russell G, Abraham DA, Backman N, Baum E, Bullon-Fernandez P, et al. A patient-administered Medical Risk Related History questionnaire (EMRRH) for use in 10 European countries (multicenter trial). Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2008;105(5):597-605. 36. Delli K, Vissink A, Spijkervet FK. Salivary gland biopsy for Sjögren’s syndrome. Oral Maxillofac Surg Clin North Am. 2014;26(1):23-33. 1

22 Chapter 1 37. Al Hamad A, Lodi G, Porter S, Fedele S, Mercadante V. Interventions for dry mouth and hyposalivation in Sjögren’s syndrome: A systematic review and meta-analysis. Oral Dis. 2019;25(4):1027-47. 38. Furness S, Bryan G, McMillan R, Worthington HV. Interventions for the management of dry mouth: non-pharmacological interventions. Cochrane Database Syst Rev. 2013(8):Cd009603. 39. Aframian DJ, Baaton S, Mazor S, Nadler C, Keshet N, Haviv Y, et al. Improvement of dry mouth following intraductal irrigation of salivary glands. Oral Dis. 2019;25(7):1735-43. 40. Karagozoglu KH, Vissink A, Forouzanfar T, de Visscher J, Maarse F, Brand HS, et al. Sialendoscopy increases saliva secretion and reduces xerostomia up to 60 weeks in Sjögren’s syndrome patients: a randomized controlled study. Rheumatology (Oxford). 2021;60(3):1353-63. 41. Fox PC, Busch KA, BaumBJ. Subjective reports of xerostomia and objectivemeasures of salivary gland performance. J Am Dent Assoc. 1987;115(4):581-4. 42. Won S, Kho H, Kim Y, Chung S, Lee S. Analysis of residual saliva and minor salivary gland secretions. Arch Oral Biol. 2001;46(7):619-24. 43. DiSabato-Mordarski T, Kleinberg I. Measurement and comparison of the residual saliva on various oral mucosal and dentition surfaces in humans. Arch Oral Biol. 1996;41(7):655-65. 44. Wolff M, Kleinberg I. Oral mucosal wetness in hypo- and normosalivators. Arch Oral Biol. 1998;43(6):455-62. 45. Chaudhury NM, Proctor GB, Karlsson NG, Carpenter GH, Flowers SA. Reduced Mucin-7 (Muc7) Sialylation and Altered Saliva Rheology in Sjögren’s Syndrome Associated Oral Dryness. Mol Cell Proteomics. 2016;15(3):1048-59. 46. Chaudhury NM, Shirlaw P, Pramanik R, Carpenter GH, Proctor GB. Changes in Saliva Rheological Properties and Mucin Glycosylation in Dry Mouth. J Dent Res. 2015;94(12):1660-7. 47. Osailan S, Pramanik R, Shirodaria S, Challacombe SJ, Proctor GB. Investigating the relationship between hyposalivation and mucosal wetness. Oral Dis. 2011;17(1):109-14. 48. Pramanik R, Osailan SM, Challacombe SJ, Urquhart D, Proctor GB. Protein and mucin retention on oral mucosal surfaces in dry mouth patients. Eur J Oral Sci. 2010;118(3):245-53. 49. Challacombe S, Bds P, Bsc P. Clinical Scoring Scales for Assessment of Dry Mouth. 2015. p. 119-32. 50. Brand HS, Bots CP, Veerman ECI. Therapies for xerostomia in Sjögren’s disease are age- and gender-dependent. J Dent Res. 2011;90(Special Issue A):1347.

23 General introduction, aim and outline of the thesis 1

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25 PERCEIVED INTRA-ORAL DRYNESS

2 Regional differences in perceived oral dryness as determined with a newly developed questionnaire, the Regional Oral Dryness Inventory Z. Assy D. H. J. Jager E. Mashhour F. J. Bikker H. S. Brand Clinical Oral Investigations, 2020 Nov; 24(11):4051-4060.

Chapter 2 ABSTRACT Objectives Several questionnaires, such as the internationally validated and frequently used Xerostomia Inventory (XI), havebeendeveloped toquantify the subjective feelingof adrymouth. Thesequestionnaires quantify theoverall perceptionof drymouthbut lack the possibility to differentiate between various intra-oral regions. In this light, a novel questionnaire, theRegional Oral Dryness Inventory (RODI), whichquantifies the severity of dryness at various locations in themouth, was evaluated. Material andmethod A retrospective case report studywas designed. Datawere collected frompatients who visited the salivaclinic for Special CareDentistry inAmsterdam. Data, including the saliva secretion rates, RODI scores, the Xerostomia Inventory (XI) score, and Clinical Oral Dryness Score (CODS), wereextracted fromtheelectronichealth record systemOase Dental. Results A total of 337 patients participated in this study with an average age of 54 ± 17 years. The majority of the patients were female (68.5%). The perceived dryness as determinedby theRODIwas thehighest for theposteriorpalateand the lowest for the floor of themouth. Thehighest correlationswere foundbetween the corresponding regions in the RODI and regionally related individual items of the XI and CODS. Conclusion There isasignificant difference indry-mouth feelingat different intra-oral locations. Clinical relevance Regional evaluation of xerostomia with the RODI might improve diagnosis of xerostomia by helping to discriminate between different potential causes of oral dryness in patients and for evaluating the efficacy of mouth-moistening products. The RODI is highlyaccessibleandeasy toperformindental practices during routine clinical assessment. Keywords Drymouth, Xerostomia, Salivaryflowrate, Xerostomia Inventory, Clinical Oral Dryness Score 28

29 Regional differences in perceived oral dryness INTRODUCTION Saliva is a multi-functional fluid which provides mucosal lubrication and moistening, and protection of the teeth and oral mucosa surface, and plays an important role in digestion, protecting oral tissues, swallowing, taste, and speaking [1, 2]. Therefore, an adequate saliva flow is important for the maintenance of oral health [3, 4]. Saliva flow can be impaired due to many factors. A reduction in saliva secretion rate can be the result of xerogenic medications, radiotherapy of the head and neck, or systemic diseases such as Sjögren’s syndrome [5–7]. Patients suffering from a reduced salivary flow rate may complain about taste alterations, swallowing difficulties, and a burning sensation in the mouth. Other oral complications include increased risk of ulcerations, caries, gingivitis, periodontitis, and oral Candida spp. infections [8, 9]. A reduced salivary flow rate is known as hyposalivation and can objectively be determined by sialometry. Hyposalivation is defined as a salivary flow rate is < 0.1 mL/min at rest or < 0.7 mL/min upon stimulation [8]. In contrast, the subjective sensation of a dry mouth experienced by the patient is called xerostomia [9, 10], which can only be determined with self-reported questionnaires [11–15]. Over the past decades, several questionnaires have been developed to quantify the overall feeling of a dry mouth [11–15]. For example, the Xerostomia Inventory (XI) is an internationally validated and frequently used questionnaire with 11 items on a 5-point Likert scale to quantify the severity of the xerostomia [11]. The sensation of a dry mouth is not solitarily related to the reduction in salivary secretion rate changes but might also be related to the unequal thickness of the saliva film on both soft and hard oral tissue surfaces [16]. To exemplify, the salivary film that remains in the oral cavity after swallowing is the thickest at the dorsal area of the tongue and the thinnest at the hard palate [17–21]. In addition, differences in salivary composition have also been implicated in the perception of dry mouth [19–21]; the salivary mucin MUC5B retains large amounts of water and contributes to the generation of a hydrophilic gel essential for lubrication of the oral epithelium [22–24]. Moreover, MUC5B is the main component that determines the viscoelasticity of saliva [24]. Local variations in the MUC5B concentration have been reported with higher intensity on the hard palate than other oral surfaces [18]. In light of these local variations [17, 18, 21], the palate may be more frequently related to xerostomia complaints than other areas, e.g., the tongue [19]. 2

30 Chapter 2 So far, xerostomia questionnaires were aimed to quantify the overall feeling of mouth dryness and not the perceived xerostomia at different intraoral locations. Therefore, the purpose of this study is to evaluate a recently developed questionnaire, Regional Oral Dryness Inventory (RODI), which quantifies the severity of dryness at various locations in the mouth. MATERIALS AND METHODS Study design A retrospective case report study was designed. Data were collected from patients older than 18 years, who visited the saliva clinic for Special Care Dentistry in Amsterdam. These patients were referred to the saliva clinic by dentists, general physicians, and medical specialists between January 2014 and April 2019. All the patients included in this study had saliva-related and/ or dry-mouth complaints. The Ethics Review Committee of the Academic Centre for Dentistry Amsterdam (ACTA) confirmed that the Medical Research Involving Human Subjects Act (WMO) does not apply to this study (protocol number 201910). The reporting of this study conforms to the STROBE statement [25]. All the questionnaires and clinical parameters have been collected and interpreted by a single practitioner (DHJJ). A standardized protocol is used for this process, which takes approximately 45 min. All the procedures described in the present study are part of the regular patient care routine in the saliva clinic. Data collectionmethods The relevant data were extracted by one abstractor (EM) from the electronic health record systemOase Dental (VST Software B.V., Haarlem, The Netherlands). Patients were included when most of the relevant data were present in the record of the patient. The extracted data were registered pseudonymized in a Microsoft Excel under a code number so that the data can no longer be traced back to the patients. The following clinical data were retrieved: gender, age, the Xerostomia Inventory (XI) score, Clinical Oral Dryness Score (CODS), scores on the newly developed Regional Oral Dryness Inventory, and the secretion rates of unstimulated whole saliva (UWS), chewing-stimulated whole saliva (CH-SWS), and citric acid–stimulated whole saliva (A-SWS). Random checks were done after data entry, by two researchers (EM and ZA), to verify correct transfer of data from the medical record to the case reports. This was performed according to the 100-20 rule in which 100% of the data is

31 Regional differences in perceived oral dryness checked in 20% of the case reports and 20% of the most important data are checked in 100% of the case reports [26]. Subjective oral dryness Before a patient visited the saliva clinic, he or she received several questionnaires by mail to fill out at home. These questionnaires included the Xerostomia Inventory (XI) which consists of 11 items on a 5-point Likert scale ranging from 1 = “never” to 5 = “very often.” The items are about oral dryness and mouth feel in the patients. Patients indicate in each item how often they suffer from problems with regard to mouth feel and oral dryness. The scores of the 11 items are summed resulting in a total XI score that ranges between 11 (no xerostomia) and 55 (extreme xerostomia) [11]. In addition, the patients received a newly developed Regional Oral Dryness Inventory (RODI) (Fig. 1). This questionnaire contains 9 schematic illustrations of different locations in the oral cavity. Four illustrations represent areas in the upper jaw: the upper lip, anterior part of the palate (including the rugae), inside part of the cheeks, and posterior part of the palate (from the rugae up to the end of the soft palate). Four illustrations represent areas in the lower jaw: the lower lip, floor of the mouth, posterior part of the tongue (from vallate papilla up to end of the tongue), and anterior part of the tongue (from tip of the tongue up to vallate papilla). Finally, one illustration represents the pharynx. At each location, the patient can indicate the severity of the perceived oral dryness using a 5-point Likert scale ranging from 1 = “no dryness” to 5 = “severe dryness.” Clinical oral dryness score During the visit to the saliva clinic, the Clinical Oral Dryness Score (CODS) was scored for all patients by a single examiner (DHJJ). The CODS was recorded before determining the salivary flow rates and analyzing the xerostomia questionnaires, so the examiner was not aware during the recording of the CODS whether a patient suffered from hyposalivation/ xerostomia or not. The examiner scored the patient’s mouth for the presence or absence of ten features of oral dryness: (1) mirror sticks to buccal mucosa; (2) mirror sticks to tongue; (3) tongue shows loss of papillae; (4) tongue lobulated/ fissured; (5) frothy saliva; (6) no saliva pooling in floor of mouth; (7) glassy appearance of other oral mucosa, especially palate; (8) debris on palate (excluding debris under dentures); (9) altered/smooth gingival architecture; and (10) active or recently restored (last 6 months) cervical caries (> 2 teeth) [27]. A specially designed form with illustrations of dry-mouth features from 2

32 Chapter 2 Fig. 1 The Regional Oral Dryness Inventory with the nine intra-oral regions and instructions. Regional Oral Dryness Inventory. The following questions are about dryness perception in the mouth during the last 4 weeks. The illustrations below show four different regions in the upper jaw, four different regions in the lower jaw, and an illustration of the throat. Please indicate the severity of dryness for each of these different locations on a scale from 1 to 5, where 1 = no dryness and 5 = severe dryness. It is advisable to answer spontaneously and not spend too much time considering your answer.

33 Regional differences in perceived oral dryness 2

34 Chapter 2 the original publication was used to score each feature [27]. The scores from the ten features were added together resulting in a total CODS ranging from 0 (no oral dryness) to 10 (extreme oral dryness). Sialometry The patients were instructed not to eat, drink, chew gum, brush teeth, use mouthwash, or smoke for at least 1 h before their visit to the saliva clinic. The procedure to determine the saliva secretion rate has been described by Jager and co-workers [28]. At the time of the collection of saliva, patients were placed in a quiet room and asked to sit in an upright position. The UWS was collected by the draining method in a pre-weighed plastic container [29]. To collect unstimulated saliva, patients were asked to immediately collect saliva after an initial swallow. Afterwards, they were asked to expectorate in the container as soon as they collected saliva. During saliva collection, the patients were not allowed to swallow. To collect CH-SWS, patients were asked to chew a 5 × 5-cm sheet of parafilm (Parafilm M, Pechiney, Chicago, IL, USA) with a frequency of approximately 60 chews per minute. The patients were instructed to expectorate the saliva every 30 s into a pre-weighed plastic container during a 5 min period. For stimulation of A-SWS secretion, a citric acid solution (2% w/v) was applied with cotton buds on the lateral borders of the tongue at 30 s intervals [30]. After the collection period was finished, the plastic containers were reweighed, and the collected volume was determined by subtracting the weight of the container prior to collection. The salivary flow was calculated by dividing the collected volume (assuming 1 g of saliva equals 1 mL) by collection time (min). Salivary flow rates were expressed in mL/min [29]. To determine whether patients suffered from hyposalivation, the following cut-off values were used: UWS < 0.10 mL/min, CH-SWS < 0.70 mL/min, and ASWS < 0.70 mL/min [8]. Data analysis The data were processed in Microsoft Excel and then converted into SPSS, version 25.0 (IBM Corp SPSS Statistics, Armonk, NY, USA) for the statistical analysis. The Shapiro– Wilk test was used to assess the normality of the data. The data were presented as median, and their interquartile range (IQR) as all parameters were not normally distributed. The mean and standard deviation were also reported to clarify relatively small differences. A Friedman test was conducted for the scores of the RODI and XI scores, followed by a Wilcoxon signed-rank test as post hoc procedure.

35 Regional differences in perceived oral dryness Possible relationships among the RODI scores of the nine intra-oral regions, and the relation of the RODI scores with XI scores, UWS, CH-SWS, and A-SWS salivary flow rates were analyzed with a bootstrapped Spearman rank correlation test (1000 × bootstrapping). The Spearman’s rho coefficient and bias-corrected accelerated (Bca) 95% confidence interval were extracted. A significance level (α) of 0.01 was chosen for the correlation test. The Mann-Whitney U test (significance level of α = 0.05) was performed to explore a possible relation between a positive CODS score and the associated region in the RODI. RESULTS A total of 337 patients participated in this study with an average age of 54 ± 17 years. The majority of the patients were female (68.5%). The RODI scores, XI scores, CODS and UWS, CH-SWS, and A-SWS salivary flow rates were not normally distributed (Shapiro–Wilk test; p < 0.01). Table 1 presents the different salivary flow rates of the study sample. Based on the UWS, CH-SWS, and A-SWS flow rates, respectively, 26.9%, 48.6%, and 13.1% of the study sample respectively suffered from hyposalivation. Regional Oral Dryness Inventory In Table 2, the median and the corresponding IQR, and mean with standard deviation are shown for each of the nine intraoral regions of the RODI. There was a significant difference in perceived oral dryness between the nine intraoral regions (Friedman test p < 0.05, followed by Wilcoxon signed-rank tests p < 0.05). The highest scores were obtained for the posterior palate, while the lowest scores were obtained for the floor of the mouth (Table 2). The scores of all regions correlated significantly with each other (Table 3) indicating that patients who suffer from severe xerostomia at one location in general also have high levels of xerostomia at other intra-oral locations. The correlation coefficient varied between 0.51 (pharynx with lower lip) and 0.82 (lower lip and upper lip). Four different regions have a correlation coefficient ≥ 0.75: the lower lip and upper lip, the posterior palate and posterior tongue, the anterior tongue and posterior tongue, and the floor of the mouth and inside the cheeks. The correlations of the scores between these four regions can be considered strong, whereas the other regions have a moderate correlation according to the standards described by Mukaka and co-workers and Akoglu and co-workers [31, 32]. 2

36 Chapter 2 Table 1 The unstimulated whole saliva (UWS), chewing-stimulated whole saliva (CH-SWS), and acidstimulated whole saliva secretion rates of the study sample. Data are expressed as the median with the corresponding interquartile range (IQR), and mean with standard deviation (SD). Median IQR Mean SD N UWS (mL/min) 0.18 0.08–0.34 0.27 0.33 264 CH-SWS (mL/min) 0.70 0.34–1.18 0.89 0.84 313 A-SWS (mL/min) 1.80 1.05–2.78 2.00 1.23 321 Table 2 Perceived oral dryness in nine different intra-oral regions as determined with the Regional Oral Dryness Inventory (RODI) in patients visiting a saliva clinic. Data are presented as median with corresponding interquartile range (IQR) and mean with standard deviation (SD). Median IQR Mean SD N Upper lip 3.0 2.0–4.0 2.80 1.26 303 Anterior palate 3.0 1.0–4.0 2.82 1.40 302 Inside cheeksa,b 3.0 1.0–4.0 2.68 1.34 302 Posterior palatea,b, c 3.0 2.0–4.0 3.09 1.35 302 Lower lipd 3.0 2.0–4.0 2.70 1.26 299 Floor of the moutha,b,c,d,e 2.0 1.0–4.0 2.54 1.34 297 Posterior tonguea,b,c,e,f 3.0 2.0–4.0 3.03 1.32 297 Anterior tonguea,c,d,e,f 3.0 2.0–4.0 2.94 1.40 297 Pharynxa,b,c,d,e,f 3.0 2.0–4.0 2.96 1.36 297 Wilcoxon signed-rank tests: a p < 0.05 vs upper lip, b p < 0.05 vs anterior palate, c p < 0.05 vs inside cheeks, d p < 0.05 vs posterior palate, e p < 0.05 vs lower lip, f p < 0.05 vs floor of mouth, g p < 0.05 vs posterior tongue, and h p < 0.05 vs anterior tongue

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