Treatment of dry mouth and other non-ocular sicca symptoms in Sjögren’s disease

INTRODUCTION — Sjögren’s disease (SjD) is a chronic multisystem inflammatory disorder characterized by lymphocytic infiltration of the lacrimal and salivary glands and resultant dry eyes and mouth. A variety of other disease manifestations may also be present, including additional issues with sicca, such as dryness of the skin, nasal passages, and vagina; extraglandular involvement; and systemic symptoms, such as fever and malaise. Both local and systemic medical therapies are used in the treatment of the different manifestations of SjD [1-4].

The treatment of dry mouth, including topical therapy, mechanical/gustatory stimulants, and the use of systemic cholinergic agents and other systemic therapies, along with other therapies for the management of other non-ocular sicca symptoms of SjD, will be reviewed here. Other issues in SjD, including the clinical manifestations, the diagnosis, the treatment of dry eye, and the role of systemic therapy in extraglandular manifestations of SjD, are discussed separately. (See "Clinical manifestations of Sjögren's disease: Exocrine gland disease" and "Clinical manifestations of Sjögren’s disease: Extraglandular disease" and "Diagnosis and classification of Sjögren’s disease" and "Treatment of dry eye in Sjögren’s disease: General principles and initial therapy" and "Overview of the management and prognosis of Sjögren's disease" and "Treatment of Sjögren's disease: Constitutional and non-sicca organ-based manifestations".)

TREATMENT OF DRY MOUTH — Treatment of dry mouth due to salivary gland hypofunction aims to alleviate symptoms and prevent complications such as dental caries, gingivitis, halitosis, salivary gland calculi, dysphagia, and oral candidiasis.

Various strategies are employed to compensate for the loss of normal salivary functions; these functions include lubricating the mucosa, helping to clear food residue that may lead to dental plaque and bacterial growth, buffering acids that favor demineralization of teeth, and providing antimicrobial effects [5]. Thus, stimulating residual salivary flow, providing lubrication, and treating fungal infection, along with close attention to dental care, are the major aspects of treatment [5-7].

Our treatment approach is consistent with expert opinion and is supported by the evidence reviewed here [6-9]. Briefly, this approach includes the following:

●Basic self-care measures to stimulate oral secretions and prevent oral dryness and dental caries, as well as regular preventive dental care. (See 'Basic measures for all patients' below.)

●Use of artificial saliva in patients who receive insufficient benefit from mechanical stimulation of salivary flow or water or who have maximized water intake (eg, resulting in nocturia). (See 'Inadequate benefit from salivary stimulation and water' below.)

●Use of muscarinic agonists (eg, pilocarpine or cevimeline) in patients with an inadequate response to mechanical stimulation and artificial saliva. (See 'Mechanical and gustatory stimulation of salivary flow' below and 'Inadequate response to salivary stimulation and substitutes' below.)

●Specialized interventions by a dentist with expertise in dry mouth dentistry in patients with dental caries or with very low salivary production. (See 'Basic dental care and oral hygiene' below and 'Dental professional care' below.)

●A high level of suspicion for oral candidiasis, which is a common complication in patients with Sjögren’s disease (SjD). Such patients may describe symptoms such as burning, mouth pain, or sensitivity and may exhibit apparent resistance to treatment for symptoms of oral dryness. (See 'Oral candidiasis' below.)

Basic measures for all patients — The following measures should be used in all patients with dry mouth due to SjD, regardless of symptom severity:

●Prevention of dryness (see 'Prevention of dryness' below)

●Stimulation of secretions (see 'Mechanical and gustatory stimulation of salivary flow' below)

●Dental prophylaxis (see 'Basic dental care and oral hygiene' below)

Prevention and management of potential complications of dry mouth are an important component of patient education. Patients should be instructed regarding signs and symptoms of oral candidiasis, which may mimic or exacerbate dry mouth symptoms and require prompt intervention. Additionally, they should be cautioned regarding the risks of cosmetic dental procedures in the setting of severe salivary hypofunction. (See 'Oral candidiasis' below and 'Restorative and cosmetic dentistry' below.)

The published evidence supporting these measures is limited, largely consisting of small trials, case series, and clinical experience [5-8,10,11].

Prevention of dryness — Preventive measures against dry mouth include:

●Maintenance of good hydration by taking regular sips of water, drinking sugar-free liquids, and avoidance of oral irritants (eg, coffee, alcohol, and nicotine).

●Avoidance of oral desiccants (eg, coffee, alcohol, tobacco and cannabis smoke).

●Avoidance of medications that may worsen oral dryness, especially those with anticholinergic side effects. Medications for urinary incontinence and depression have the strongest association with this side effect [12]. Over-the-counter cold and sleep remedies may be overlooked as potential contributors. (See "Treatment of dry eye in Sjögren’s disease: General principles and initial therapy", section on 'Avoidance of medications causing dryness'.)

●Maintenance of open nasal passages to avoid mouth breathing. (See 'Nasal dryness' below.)

●Avoidance of low-humidity environments, such as air-conditioned stores, centrally heated houses, and airplanes; and implementing the use of humidifiers to maintain adequate humidity, particularly at night.

Various solutions can be used to replace oral secretions, ranging from water to forms of artificial saliva. We suggest frequent sips of water because of convenience, cost, and efficacy. Sufficient water is needed to maintain adequate hydration. However, water used for moistening does not have to be swallowed; it can be rinsed around the mouth and then expectorated. Sucking on ice may be preferred by some patients. The addition of a small amount of liquid omega-3 oil to the water (¼ to ½ teaspoon per 16 oz) may enhance the wetting effect [11].

Although water provides temporary moisture, it does not provide the lubricating properties that are characteristic of the mucin and water mixtures that constitute normal saliva.

Patients should be advised that sipping water too often may be counter-productive, reducing the mucus film in the mouth and possibly worsening symptoms. In this case, it is better to drink the water in a large bolus (ie, one cup at a time) to maintain adequate hydration. If water consumption is excessive, especially in the evening, nocturia can occur, resulting in sleep disturbance that may worsen fatigue, cognitive difficulties, and pain that some patients experience.

We advise patients to avoid sipping highly acidic beverages, particularly between meals, since a sustained lowering of intraoral pH may adversely affect dental enamel [13]. Examples of common beverages and their relative acidity include:

●Cola drinks – pH 2.6

●Coffee – pH 5.0

●Tea (herbal) – pH 3.2

●Tea (black) – pH 5.7 to 7.0

●Water from tap – pH 7.0 (but flavored waters are often acidic)

●Energy drinks – Usually acidic

The maintenance of a stable neutral pH in the oral cavity is highly important since this serves to decrease dental demineralization. The buffering systems responsible for the human saliva buffering capacity include bicarbonate, phosphate, and protein. Even a minor drop in pH can promote dental caries or can damage the teeth by erosion [14]. The pH and buffering capacity of the parotid saliva of individuals with SjD are much lower than those in healthy individuals.

Mechanical and gustatory stimulation of salivary flow — All patients with dry mouth should use mechanical and gustatory stimulants, in addition to the basic measures described for prevention of dryness and dental care (see 'Prevention of dryness' above and 'Basic dental care and oral hygiene' below). Salivary flow may be stimulated in patients with residual salivary function by sucking on sugar-free candies and lozenges and by using sugar-free chewing gums [5,7]. Particular care must be taken not to increase the risk of dental caries by the prolonged use of sugar-containing products and by avoidance of acidic drinks (eg, carbonated beverages and citrus juices). (See 'Prevention of dryness' above.)

The choice of stimulatory agent largely depends upon patient preference. A clear advantage of one product over another has not been rigorously shown, and a variety of products should be tried to determine which is most acceptable and effective in a given patient. Although the use of highly acidic products is usually not advised, drops of lemon juice in a glass of water may be used to stimulate saliva production without dropping the pH sufficiently to damage dental enamel.

Products identified as "sugarless" should be distinguished from those that are "sugar-free," as items identified in the United States as "sugarless" may contain significant amounts of fructose, thus being potentially cariogenic. These and similar terms may be defined differently based upon regulations regarding food labeling in different countries.

Examples of salivary stimulants include:

●Sugar-free hard candies or lozenges.

●Sugar-free chewing gums containing various sweeteners such as aspartame, saccharin, and sorbitol, which can increase saliva production in patients with residual secretory capacity. Excessive sorbitol can lead to gastrointestinal side effects such as cramps and diarrhea [10].

●Xylitol-containing gum or candy, which may also reduce the cariogenicity of the oral bacterial flora [5]. Xylitol can also cause diarrhea and flatulence if used in excess [15].

●Topically applied oral inserts (eg, Xylimelt, Salese lozenges) that adhere to the mucosa [16,17].

●Citrus-flavored sugarless tablets or oral drops, which may also contain malic acid. This acid, which is normally found in fruits such as apples or pears, stimulates salivary flow.

●Dried fruit slices, such as peaches or nectarines, which stimulate salivary flow.

A systematic review of topical therapies for xerostomia found 36 small trials (average size of 44 patients), with a wide range of interventions, comparisons, and outcome measures, and a resultant lack of strong evidence for efficacy of any specific topical therapy [10]. Additionally, most of the products were not tested in patients with SjD. However, some evidence suggested a patient preference for chewing gums, which may increase saliva production in patients with residual secretory capacity, although there was no evidence that gum was more or less effective than use of saliva substitutes. Additionally, chewing gums have the benefit that they enhance the patient's own saliva production so that taste and consistency are not an obstacle. The use of these interventions is also supported by extensive clinical experience.

Basic dental care and oral hygiene — Particular attention to basic dental care is important for all patients with dry mouth; the development of dental caries is a major problem in such patients, who are especially prone to rapidly progressing root and incisal caries [5,18-20]. To help avoid these complications, we suggest aggressive application of the same general dental hygiene principles as in individuals without dry mouth, including meticulous self-care, frequent visits to the dentist (at least every six months for patients with mild disease), and fluoride supplementation (table 1).

Patients should also avoid eating preprocessed "sticky" foods (caramels, taffy, etc), which may be high in sugar content and hard to remove [6,20]. If they drink a sugar-containing beverage, it is best to do so in one sitting (over several minutes) rather than sipping on it throughout the day; this helps to avoid repeated exposure of the teeth to sugar and a drop in oral pH with each exposure. They should remember to perform oral hygiene (brushing/flossing) after each exposure to sugary substances. If this is difficult to achieve, they should at a minimum rinse their mouth vigorously with water after use.

We suggest that patients do the following under the supervision of their dentist:

●Use dental hygiene techniques regularly to remove trapped food debris and plaque. These include the use of dental floss and dental appliances such as interdental brushes (for cleaning between teeth) and electric toothbrushes. Use dental floss or another interdental cleaner after each meal. Toothbrushing should be done at least twice daily. We advise patients to carry a toothbrush and toothpaste to use when they will not be at home following meals.

●Use topical fluoride, which is highly effective in reducing caries in dry mouth patients. Topical fluorides are available in many different strengths and formulations. The choice of formulation depends in part upon caries risk stratification and changes as caries susceptibility increases. A caries risk assessment by a dental professional involves weighing multiple factors, including the baseline presence of frank caries, erosions of the enamel without penetration into the dentin, or recent (<3 years) dental restoration; the presence of predisposing factors, such as high oral colony counts of cariogenic bacteria, poor dietary habits, absence of saliva, heavy dental plaque, exposed roots, and orthodontic appliances; and protective factors already in place, such as regular access to fluoridated water and use of fluoride toothpastes, varnishes, or rinses [21].

We take the following approach (table 1):

•Patients with symptomatic dry mouth but without clinical signs of dry mouth and without recent caries can be treated with over-the-counter fluoride-containing mouth rinses. Patients should be advised to carefully check the labels as not all mouth rinses contain fluoride.

•In patients with clinical signs of dry mouth but no new carious lesions and no other risk factors, we advise daily use of 1.1% sodium fluoride gel (5000 parts per million [ppm]) once a day (preferably at bedtime) in addition to an over-the-counter toothpaste with fluoride (1000 to 1200 ppm) for their daytime brushing.

Topical fluoride is also beneficial for patients with dental crowns and veneers, preventing caries formation at the margin of the crown and tooth, an area particularly susceptible to such decay.

•We consider any SjD patient with clinical signs of dry mouth (see 'Evaluation of response to therapy' below) and/or salivary hypofunction (eg, whole unstimulated saliva flow <0.1 mL/minute) who has developed new incisal or root caries to be at high risk for further caries and in need of an intensive caries prevention program, including quarterly dental examinations and the use of fluoride supplementation (ie, daily use of 1.1% sodium fluoride gel or fluoride gel in dental trays and professionally applied fluoride varnishes every three to six months). The patient's dentist should determine if fluoride gel in a custom-fitted tray once daily (1.1% neutral sodium fluoride) is indicated [5,6,22]. These treatments should be coupled with the professional application of a fluoride varnish every three to six months [6]. (See 'Dental professional care' below.)

•Toothpastes containing 5000 ppm fluoride have been shown to be more effective for promoting remineralization and/or inhibiting demineralization than over-the-counter fluoride toothpastes (containing 1000 to 1200 ppm fluoride), particularly in children [23].

●Use of toothpastes specifically designed for dry mouth if indicated based on an assessment by the patient's dentist. Factors considered in this assessment include the rate of development of caries, the patient's carbohydrate exposure, and the degree of salivary hypofunction. Lack of lubrication in most over-the-counter toothpastes may contribute to irritation to the tongue and cheeks. Dry mouth toothpastes lack detergents, such as sodium lauryl sulfate, which is the foaming agent in most toothpastes and which can irritate the mucosa; however, they do not contain prescription-strength concentrations of fluoride [24]. Additionally, while infrequent, we caution patients that some of the prescription-strength fluoride-containing toothpastes may lead to brown discoloration of the teeth, particularly in younger patients [25].

The use of topical fluoride is supported by strong recommendations of a 2016 guidelines panel of experts on SjD [8]. Most of the evidence in the panel's systematic literature review was from trials involving patients with dry mouth due to radiotherapy for head and neck cancer but also included more limited evidence from several other conditions and one trial that included patients with SjD but lacked a placebo control [8,26]. Since the publication of these 2016 guidelines, the results of a 24-month, randomized trial of quarterly applications of fluoride varnish in 78 SjD patients were published [27]. The fluoride-treated patients had 33 percent less coronal dentin caries compared with placebo, but this difference did not reach statistical significance.

Evaluation of response to therapy — The response to therapy may be evaluated by ongoing assessment for common clinical signs of dry mouth [6,28]. In addition to patient-reported dryness, these include:

●Difficulty with swallowing or speech due to dryness

●Absence of a pool of saliva on the floor of the mouth

●"Lipstick sign" (spreading of the patient's lipstick onto teeth)

●Mucosal adherence (ie, "sticking") of a gloved finger, dental mirror, or wooden tongue depressor to the mucosa

●Frequent occurrence of erythematous oral candidiasis

●Burning mouth symptoms

●Atrophic glossitis (or lack of papilla) on the tongue

●Atypical dental caries at the gingival margin and/or incisal regions

Insufficient response to basic measures — In patients who do not respond adequately to the basic measures described above and who continue to have signs or symptoms of dry mouth (see 'Evaluation of response to therapy' above), further measures may include:

●Saliva substitutes ("artificial saliva") (see 'Inadequate benefit from salivary stimulation and water' below)

●Muscarinic agonists, including pilocarpine and cevimeline (see 'Inadequate response to salivary stimulation and substitutes' below)

●Systemic antiinflammatory and immunosuppressive medications, such as hydroxychloroquine and rituximab, for which the evidence for benefit is weak [29] (see 'Systemic antiinflammatory and immunosuppressive therapy' below)

Inadequate benefit from salivary stimulation and water

Artificial saliva: Role, selection, and use — We suggest the use of artificial saliva in patients who do not receive sufficient symptomatic benefit from mechanical stimulation, topical stimulants of salivary flow, and water, or who have excessive water intake (eg, resulting in nocturia). A number of artificial saliva preparations that provide more viscosity and lubrication than water are available, generally without prescription. Formulations include sprays, liquid rinses, and gels. These compounds typically contain a unique mix of multiple components in each preparation, such as carboxymethylcellulose, polyethylene glycol, sorbitol, and electrolytes [7,10]. A product containing animal mucin (AS Saliva Orthana) is available in some countries, but not the United States, and may be superior to saliva substitutes with carboxymethylcellulose and hydroxyethyl cellulose in terms of symptom relief [30,31].

Individual preferences and degree of improvement can differ between patients and between products; therefore, several different products should be tried if a particular substitute is not acceptable due to viscosity, texture, flavor, and other characteristics [32]. The product should be applied to the inner lips, buccal mucosa, tongue, and hard palate. We advise patients to mix and match a variety of these agents in their daily or nightly schedule. For example, a patient may use a mouth spray before speaking to a group, an oral solution before eating to help with dysphagia, and an oral gel before bedtime. Sprays may be more difficult to use for patients with arthritis.

Saliva substitutes may be most useful during telephone conversations, during social and workplace interactions, and in patients with dentures. If patients eat, drink, or maintain a high degree of salivary flow, these agents will be washed away rapidly and patients will have to reapply the agents frequently. Patients should be informed of the normal diurnal variation in saliva flow, which decreases and has altered composition at night; therefore, saliva substitutes may be most useful before sleep and after waking at night with dry mouth symptoms [33].

Efficacy of artificial saliva — The use of artificial saliva preparations is supported by several randomized trials and by additional studies that show benefit compared with placebo in relieving symptoms of dry mouth, including burning mouth and tongue, and difficulties with chewing and swallowing [10,32,34-37]. They have not been shown in randomized trials to improve salivary flow, although observations in one open-label study suggested improvement both in symptoms of dryness and in salivary flow with the use of an oral spray containing hydroxymethylcellulose [10,37].

Inadequate response to salivary stimulation and substitutes

Indications for sialagogues — We suggest the use of a muscarinic agonist such as pilocarpine or cevimeline in patients with salivary hypofunction and xerostomia who do not achieve sufficient salivary secretion or symptomatic relief with topical stimulants or saliva substitute.

The benefits of pilocarpine and cevimeline have been shown in several randomized trials of each drug; these include increased salivary flow and improvement in symptoms of dry mouth in comparison with placebo [38-46]. However, pilocarpine and cevimeline have not been compared directly with each other in patients with SjD. (See 'Pilocarpine efficacy' below and 'Cevimeline efficacy' below.)

These agents are most useful early in the course of SjD, while the patient still has baseline saliva and greater residual excretory capacity upon stimulation [40,41,47-51]. For SjD patients with residual salivary gland function, it is hoped that stimulation of saliva flow with a secretagogue may aid in preventing long-term oral complications.

Choice of sialagogue — The choice between pilocarpine and cevimeline, which appear equally efficacious compared with placebo, is largely determined by individual factors; these include cost to the patient, individual clinical response, convenience, and regulatory or insurance limitations on drug availability. The following factors may differentiate the drugs:

●Cevimeline, which has a longer half-life and receptor occupancy time than pilocarpine, is better tolerated by some patients and usually requires dosing only three, rather than four, times daily [40,41,52].

●Cevimeline may result in less diaphoresis or flushing than pilocarpine but causes gastrointestinal side effects (eg, nausea, diarrhea) more often [39,41-43]. In a retrospective chart review of 110 patients in an oral medicine clinic, the use of pilocarpine was associated with a higher proportion of adverse events compared with cevimeline, and the adherence rate was higher with cevimeline [53].

●Patients using pilocarpine, generally dosed four times daily, typically experience a brief spurt of saliva due to the relatively short serum half-life of this drug [41].

●Some formularies require an initial trial of pilocarpine, which has been available longer, before approving use of cevimeline, and patients who have not responded to or who have not tolerated pilocarpine may benefit from cevimeline, as shown in trials of cevimeline including patients previously treated with pilocarpine.

Sialagogue dose — The usual dose of pilocarpine is 5 mg by mouth, up to four times daily, and the usual dose of cevimeline is 30 mg by mouth, up to three times daily taken approximately a half-hour before meals to allow time for the medication to enhance saliva flow for the meal. The dose of pilocarpine or cevimeline should be increased gradually when initiating therapy, starting with one dose daily for a week, which helps to prevent a sudden onset of sweating. Taking the medication with food may alleviate the side effects of dyspepsia and gastric bloating (although this may reduce drug absorption). We suggest a trial of at least three months' duration if the medication is tolerated since the response is frequently delayed.

An increase in pilocarpine dose from 5 to 7.5 mg every six hours has been effective in some patients who have not responded to the usual dose. In some patients with unacceptable levels of side effects at the full dose, a reduced dose of 2.5 to 3.75 mg three times daily or 5 mg twice daily may still provide benefit [5,45].

Cevimeline can be taken in a fourth dose at bedtime if needed for nocturnal dryness. Use of lower doses in patients with poor tolerance of the full dose has been reported [5]. A lower dose is prepared by dissolving the desired fraction of a 30 mg capsule's contents in water. The desired fraction can be taken to achieve the desired reduced dose, or the solution can be used in a "rinse-and-spit" regimen to minimize systemic absorption [5,11].

Pilocarpine oral rinse has been shown to increase salivary flow and relieve dry mouth symptoms in a small study of 19 older adult patients [54]. Systemic side effects were less prevalent than in a clinical trial of oral pilocarpine tablets (5 mg three times daily). It is compounded by dissolving three 5 mg tablets in 150 mL of water. Patients held the rinse in their mouth for two minutes before spitting it out and were allowed to use up to 150 mL of the rinse per day. Similarly, the application of topical ocular pilocarpine drops to the oral cavity (2 to 3 drops of a 4% ocular pilocarpine solution is equivalent to 4 to 6 mg) may facilitate dose titration in an effort to avoid the systemic side effects of oral pilocarpine tablets [55].

Pilocarpine efficacy — Pilocarpine, a muscarinic agonist that stimulates all muscarinic receptors (M1, M2, and M3), can increase aqueous secretions in patients with residual salivary gland function [42-45,56]. In addition to effects upon xerostomia, pilocarpine may improve symptoms of ocular dryness, although without any objective change in tear production [45]. Improvement in symptoms of nasal, vaginal, and skin dryness has also been reported [42,43]. (See "Treatment of dry eye in Sjögren’s disease: General principles and initial therapy".)

In the largest randomized trial that demonstrated the benefit of pilocarpine, 357 patients were randomly assigned to receive either pilocarpine (5 or 2.5 mg every six hours) or placebo for 12 weeks [42]. A greater proportion of patients receiving pilocarpine (5 mg), compared with those who received placebo, experienced improvement in global assessments of symptoms of both dry mouth and dry eye (61 versus 31 percent and 42 versus 26 percent, respectively). There was no difference in benefit found between pilocarpine 2.5 mg every six hours and placebo, and the overall withdrawal rate did not differ between the three groups (6 to 7 percent).

No published studies have examined the long-term efficacy of pilocarpine as a sialogogue in patients with SjD. In a prospective cohort study using national health insurance databases in Taiwan, the use of pilocarpine in 1014 new-onset SjD patients was not associated with a reduction in caries when compared with 2028 SjD patients not using pilocarpine [57].

Cevimeline efficacy — Cevimeline, an effective sialagogue, is a derivative of acetylcholine with a higher affinity for muscarinic M1 and M3 receptors on the lacrimal and salivary epithelium than for receptors on cardiac tissue [47]. In randomized trials, cevimeline increases salivary flow and patient "oral quality of life" compared with placebo [39,41,46,51,58,59].

The efficacy of cevimeline was illustrated in a trial that randomly assigned 197 patients with either primary or secondary SjD to cevimeline or placebo [39]. At 12 weeks, the patients' global assessments of dryness were improved more often by cevimeline 30 mg three times daily than by doses of 15 mg three times daily or by placebo (66 versus 32 and 36 percent, respectively). Patients reported improvement in dry mouth symptoms more often with cevimeline (30 or 15 mg) than with placebo (66 and 45 versus 37 percent, respectively); salivary flow rate was increased in patients on the 30 mg dose compared with placebo but not with the 15 mg dose. In addition, patients reported improvement in dry eye symptoms more often with cevimeline (30 or 15 mg) than with placebo (39 and 31 versus 24 percent, respectively); lacrimal flow was greater with the higher dose of cevimeline than with the lower dose and with either dose of active drug compared with placebo.

Drugs that inhibit cytochrome CYP2D6 and CYP3A3 also inhibit the metabolism of cevimeline. Individuals who are known to be deficient in these cytochrome isoenzymes should use cevimeline with caution. More detailed information on drug interactions and a list of medications in each group are available using the drug interactions program included with UpToDate.

Adverse effects and precautions — The use of these medications (pilocarpine and cevimeline) may be limited by poor tolerance, largely due to cholinergic side effects including undesirable levels of increased or excessive sweating, increased urinary frequency, flushing, chills, rhinitis, nausea, and diarrhea [38,39,42-44]. They are contraindicated in patients with uncontrolled asthma and obstructive pulmonary disease. Other infrequent adverse effects of either medication include bradycardia and hypotension [60]. They should be thus used with caution in patients with cardiovascular disease and in those taking beta blockers.

Patients using these medications should be cautioned about driving at night or performing hazardous activities in reduced lighting because of the very uncommon adverse effects of decreased visual acuity (particularly at night and in patients with central lens changes) and impaired depth perception.

Some patients do not respond sufficiently enough to the muscarinic agonists to justify continued use, especially when cholinergic side effects are present.

Inadequate response to sialagogues — In patients with an inadequate response to sialagogues, the degree of adherence to the treatment regimen, particularly with dosing four times daily, should be ascertained. Some patients may tolerate a fourth daily dose of cevimeline or an increase in the dose of pilocarpine if needed. Patients should be instructed to begin with once daily dosing and gradually increase the number of doses if they are able to tolerate the adverse effects (see 'Adverse effects and precautions' above). They should also be advised that it may take several weeks to months before they experience a beneficial response so they should not give up too soon. Patients who maintain sufficient saliva flow during meals but find their oral dryness most problematic between meals may try taking the sialagogue 30 minutes after meals instead of prior to meals.

Systemic antiinflammatory and immunosuppressive therapy — We generally do not use systemic antiinflammatory or immunosuppressive therapies for the treatment of sicca symptoms alone, such as dry eye and mouth, although some of these agents have beneficial effects in patients with systemic and extraglandular disease, and a few have shown some efficacy for sicca symptoms, including dry mouth, when used in patients with systemic disease [61,62].

The use of these agents in patients with systemic and extraglandular manifestations of SjD and the evidence describing their efficacy and safety in SjD are described in detail separately. (See "Treatment of Sjögren's disease: Constitutional and non-sicca organ-based manifestations", section on 'Therapeutic rationale and evidence overview' and "Treatment of Sjögren's disease: Constitutional and non-sicca organ-based manifestations", section on 'Efficacy of specific therapeutic agents'.)

Investigational and other approaches — Several other medications and interventions have been evaluated for use for xerostomia in SjD or in other conditions, but they have significant disadvantages compared with available therapies or have not been adequately studied to justify routine clinical use for patients with SjD. These include:

●Several devices (eg, Salitron, Saliwell) that utilize electrical stimulation to increase saliva production have been approved by the US Food and Drug Administration (FDA). These are designed as mouthpieces, handheld stimulators, or dental implants [63]. These may be a therapeutic option for patients who develop intolerable side effects from systemic sialogogues [64].

●Acupuncture, which has shown mixed results in a small number of trials for xerostomia resulting from radiation therapy for cancer and which has also been studied in patients with SjD with uncertain benefit [65-71].

●Continuous delivery of water to the mouth with a micropump and ultrafine tubing (eg, Voutia system).

Dental professional care

Preventive care and treatment — Treatment administered by a dental professional is required for patients with SjD. At a minimum, patients should receive annual dental examinations with twice-yearly dental cleanings in addition to basic dental care (see 'Basic dental care and oral hygiene' above). More frequent visits may be necessary depending upon the severity of oral involvement, even in patients who floss and brush regularly with toothpaste containing fluoride [14]. Whenever possible, we suggest that patients be seen by a dentist familiar with the care of patients with SjD.

An alternative resource is those dentists with expertise in dry mouth who may be working collaboratively with radiation oncologists to care for patients with head and neck malignancies; such patients may experience severe sicca symptoms due to radiotherapy.

Professional dental care includes:

●Frequent cleanings and use of minimally invasive dental techniques to treat caries and other lesions early and to prevent the need for restorative care [5].

●Guidance regarding home self-care and oral hygiene, as well as prescription fluoride or calcium phosphate preparations when indicated. There are several different topical fluoride preparations available, including toothpastes, gels, mouthwashes, and varnishes. Varnishes need to be applied in the dental office while more potent pastes and gels (eg, PreviDent 5000, Pro-DenRx) require prescriptions. (See 'Basic dental care and oral hygiene' above.)

●Use of fluoride varnishes after each professional cleaning or topical fluoride gel or foam application (brushed onto tooth surfaces or applied to fluoride delivery trays for more intensive treatment) [8,22]. In most cases, the gels and foams contain either 1.23% acidulated phosphate fluoride or 2% sodium fluoride. Fluoride gel/foam delivery in trays has the advantage of a lengthened contact time with the tooth surface. The varnishes offer ease of application and longer adhesion time to the tooth surface, resulting in a decreased caries rate.

Non-fluoride remineralization techniques may benefit some patients. As an example, the remineralization process may be facilitated by the provision of calcium phosphate ions through toothpaste (eg, MI paste, Tom's Rapid Relief Sensitive toothpaste), specialized chewing gums (eg, BasicBites), or oral solutions (eg, Caphosol, NeutraSal, SalivaMAX). Supersaturated calcium phosphate rinses are being marketed to promote remineralization of the teeth and relieve symptoms of xerostomia. A candy containing arginine, bicarbonate, and calcium carbonate, designed to neutralize acids in dental plaque and promote tooth mineralization, has been shown to inhibit the development of dental caries in children and is being marketed for dry mouth patients [72]. No long-term clinical trials have been done to test the effectiveness of these agents [18,26,73]. Although there are limited data to support the efficacy of such non-fluoride remineralizing agents for caries prevention in SjD, an expert panel has suggested their use in this disease [8].

Oral antibacterial interventions are sometimes prescribed. Several approaches may reduce oral bacterial flora, including the use of chlorhexidine (CHX), a topical antimicrobial agent, and products containing baking soda, bicarbonate, or xylitol [5,74]. Evidence gathered from three systematic reviews supported the value of CHX (swish for 30 seconds and spit twice daily) and mouthwashes containing essential oils in reducing plaque and gingival inflammation [75]. CHX should be used after brushing and flossing since it may stain dental plaque and food residue. There may be a beneficial effect of CHX in preventing root caries, but the evidence is weak [8,76].

Polyol sweeteners such as xylitol and sorbitol, which are not fermentable by acid-producing bacteria, are of low cariogenic potential or are noncariogenic; they may prevent or limit demineralization and may promote the remineralization process [77-81]. Xylitol may be a useful adjunct to other anticaries treatments but should not be considered as a substitute for fluoride or other well-established interventions [5,77].

Given the importance of fluoride in the prevention of dental caries, patients at high risk of caries should undergo professional application of fluoride varnish every three to six months, in addition to self-administration of fluoride gels and mouth rinses (including gels applied at home in custom-fitted trays) [8,22] (see 'Basic dental care and oral hygiene' above). Patients living in homes or areas without fluoridated water are at particular risk. The increasing use of non-fluoridated bottled water in place of fluoridated tap water has also decreased fluoride exposure for some patients. Topical fluoride promotes remineralization of teeth by the development of a crystalline protective veneer at the site of demineralization and by the inhibition of bacterial metabolism and acid production.

Restorative and cosmetic dentistry — Patients with SjD may be at greater risk of poor outcomes or adverse effects with certain common procedures used for restorative or cosmetic dental care, including the use of dentures, implants, and brightening products.

Dentures and implants — Patients with SjD may have more difficulty wearing dentures because of the decreased moisture in the mouth and inability to create an adequate suction/seal between the denture and the roof of the mouth. No adequately controlled clinical trials have addressed this question. In general, dentures cannot replicate the efficiency and comfort of natural teeth.

There are limited data regarding the ability of patients with SjD to tolerate implants [82,83]. However, it appears that adequate bone height and bone density are keys to the success and longevity of dental implants, as they are in individuals without dry mouth [84]. Favorable outcomes are reported in some series, but long-term follow-up data are very limited [85,86]. Decisions regarding use of implants in a patient with SjD should be made on an individual basis, and the limited evidence should be acknowledged. Experience with these techniques in SjD patients may improve the probability of success, given the particular challenges in this population [87,88].

Whitening products — We avoid the use of home products for whitening or brightening of teeth in patients with dry mouth and salivary gland dysfunction since there may be increased risk from the acidity of some over-the-counter products designed for use in patients with normal salivary flow and content and increased risk of tooth sensitivity. The safety of these home products has not been studied in patients with SjD, although whitening strips containing 10% hydrogen peroxide were well tolerated compared with placebo in a randomized trial in subjects with medication-induced xerostomia [89].

In patients in whom professionally applied whitening processes are undertaken, the use of a remineralizing solution containing calcium phosphate and a fluoride treatment may be beneficial in conjunction with a bleaching treatment. Such procedures should only be performed after consultation by the patients with their dry mouth dentist.

Oral candidiasis — The treatment of oral candidiasis in SjD is similar to that of other patients with oropharyngeal candidiasis [90] but requires consideration of several SjD-related factors that influence management decisions in these patients [5,91,92]. Recognition of the clinical manifestations of chronic erythematous candidiasis, typically oral pain or burning, is the first step in effective treatment; these manifestations are described in detail separately. (See "Clinical manifestations of Sjögren's disease: Exocrine gland disease", section on 'Oral candidiasis' and "Oropharyngeal candidiasis in adults".)

The SjD-related factors and strategies include the following:

●Treatment preferences vary among oral medicine specialists. Some prefer treatment with clotrimazole troches, 10 mg 5 times daily; miconazole mucoadhesive buccal 50 mg tablet, applied once daily; or nystatin suspension 500,000 units 4 times daily for 7 to 14 days. These recommendations mirror guidelines of the Infectious Diseases Society of America for patients without salivary hypofunction [90]. The high sugar content of nystatin suspension and clotrimazole troches may accelerate the development of dental caries in SjD patients with severe salivary hypofunction [93]. Accordingly, the sugar-free miconazole mucoadhesive buccal tablet would be the best topical product. However, high cost and limited availability of these tablets hinder their use in clinical practice. Additionally, patients with little to no salivary flow may have difficulty dissolving the clotrimazole troches, decreasing their effectiveness.

●For the reasons stated above, the authors prefer the use of fluconazole 100 mg tablets (2 tablets on the first day followed by 1 tablet daily for 14 to 21 days). We also recommend oral fluconazole for patients with recurrent oral candidiasis, in whom monthly courses of treatment or suppressive treatment may be necessary. For these patients, systemic treatment with fluconazole avoids exposure to the sugars in topical preparations, such as clotrimazole troches or nystatin suspension and enhances compliance compared with multiple daily dosing needed for the topical agents.

An alternative approach is the once-daily use of an oral suspension of fluconazole, 10 mL of a 10 mg/mL solution. The patient rinses the mouth with the suspension for 2 to 3 minutes and then swallows it [94].

The pharmacokinetics of fluconazole in saliva and plasma were compared in 10 healthy subjects after either swishing an oral suspension in the mouth for two minutes and then swallowing it or ingesting the same dose as a capsule [95]. The former treatment regimen resulted in significantly higher peak saliva concentrations and mean area under the concentration-versus-time curves from 0 to 24 hours. Thus, fluconazole oral suspension, swished for two minutes and then swallowed, has theoretical pharmacokinetic advantages over swallowing a tablet in the treatment of oropharyngeal candidiasis.

●The advantages of oral fluconazole include once-daily dosing (leading to better patient adherence) and simultaneous treatment of esophageal and vaginal candidiasis, if present. (See "Oropharyngeal candidiasis in adults", section on 'Treatment'.)

●Other options include nystatin vaginal troches or vaginal tablets. These vaginal products do not contain sugar and can be used orally without concerns for accelerating dental caries. However, the latter are not available in the United States. An alternative approach is to prescribe troches containing 100,000 units of nystatin and flavored with artificial sweeteners from a compounding pharmacy.

These antifungal troches and vaginal tablets should be dissolved slowly in the mouth over 15 to 20 minutes. As with clotrimazole troches, the nystatin vaginal troches and dissolvable tablets may not be tolerated in patients with severe salivary hypofunction due to problems with solubilizing the medication. Therefore, frequent sips of water may aid tablet dissolution; however, care must be taken as frequent rinsing may wash the product away and reduce efficacy.

●For patients with observable saliva production but lack of adequate response, we increase the dose of fluconazole to 200 mg per day or treat with other azoles, such as itraconazole, posaconazole, or voriconazole if the candidal species is resistant to fluconazole. (See "Oropharyngeal candidiasis in adults" and "Esophageal candidiasis in adults".)

●Antifungal treatment should be continued for 7 to 10 days or until there is resolution of the mucosal erythema, restoration of filiform papillae on the dorsal tongue, and eradication of the oral symptoms (eg, burning, sensitivity to spicy foods, change in taste, and metallic taste). The endpoint of treatment should be relief of symptoms and resolution of the oral signs. With successful treatment, the tongue may regain its normal appearance. Treatment periods may sometimes need to be extended to three to four weeks.

●Recurrences are common and will require retreatment. Patients with more than one recurrence can be treated prophylactically with repeat courses every month or fluconazole 100 mg three times a week.

●In patients with partial or complete dentures, the topical oral antifungal treatment should be performed with the denture removed. Alternatively, if using nystatin powder, it can be sprinkled onto the tissue-contact surface of the removable denture prior to placing the denture in the mouth during the day.

The dentures can be soaked overnight in 0.2% chlorhexidine or a dilute bleach solution (1 part household bleach to 10 parts water) [5]; however, use of the dilute bleach solution should be avoided with partial dentures containing metal connectors or clasps, as they may get corroded or tarnished.

●A daily probiotic was shown to reduce oral candidal load significantly when compared with placebo capsules in a 5-week study involving 32 patients with SjD [96]. The use of probiotics may thus be an alternative approach to management of recurrent oral candidiasis in this disease.

TREATMENT OF OTHER SICCA SYMPTOMS — Patients should also be treated for other sicca symptoms in addition to dry eye and dry mouth; these include nasal dryness, laryngotracheal and genitourinary symptoms, and dry skin. These problems have not been the focus of randomized trials or other studies performed in patients with Sjögren’s disease (SjD), and their management is largely based upon the treatment of non-SjD patients and upon clinical experience.

Patients with these manifestations may also benefit from the use of muscarinic agonists, such as pilocarpine or cevimeline. Two randomized trials of pilocarpine for dry mouth and dry eye suggested that the drug may be more effective than placebo for symptoms of nasal, skin, and vaginal dryness and for the ability to expectorate mucus [38,42,43].

Nasal dryness — Treatment of nasal dryness may improve comfort and alleviate congestion that could increase mouth breathing and exacerbate oral dryness. Room humidifiers may also be helpful, and saline nasal sprays should be used as needed. Gentle nasal lavage can be used to remove encrusted secretions. Additional causes of nasal blockage, such as nasal polyps and sinus infection, should be identified and treated appropriately. (See "Etiologies of nasal obstruction: An overview" and "Chronic rhinosinusitis: Clinical manifestations, pathophysiology, and diagnosis".)

Laryngotracheal irritation — Patients with gastroesophageal reflux disease (GERD) should be treated appropriately; such symptoms may mimic those of recurrent sinusitis, burning mouth pain, or allergy, such as postnasal drip or frequent throat clearing with mucus, due to laryngotracheal irritation, which stimulates vagal responses [97]. Inappropriate treatment with antibiotics for presumed sinusitis can increase the risk of oral candidiasis. (See "Clinical manifestations and diagnosis of gastroesophageal reflux in adults" and "Medical management of gastroesophageal reflux disease in adults".)

Genitourinary symptoms — Women with SjD may experience symptoms from vaginal dryness related to SjD and/or from estrogen deficiency or an associated disorder such as interstitial cystitis. Additionally, women with SjD may be more susceptible to candida vulvovaginitis, which is discussed separately. (See "Clinical manifestations of Sjögren's disease: Exocrine gland disease" and "Candida vulvovaginitis: Clinical manifestations and diagnosis".)

Vaginal dryness and dyspareunia — A variety of preparations are available for the treatment of vaginal dryness, including topical moisturizers and lubricants; topical vaginal estrogens and hyaluronic acid vaginal creams may benefit patients with estrogen deficiency [98]. Patients with symptomatic vaginal dryness should be evaluated and treated in collaboration with an expert in gynecologic care. There are no randomized trials comparing the various available products in patients with SjD. Patients may need to try several different products as they differ in their viscosity, and scented products should be avoided [99,100]. In patients with dyspareunia due to vaginal dryness, use of a lubricant by the patient's male partner may also be of benefit. The treatments of vaginal dryness and dyspareunia are discussed in detail separately. (See "Genitourinary syndrome of menopause (vulvovaginal atrophy): Clinical manifestations and diagnosis" and "Genitourinary syndrome of menopause (vulvovaginal atrophy): Treatment" and "Female sexual pain: Differential diagnosis", section on 'Decreased lubrication'.)

Interstitial cystitis and pelvic pain — The treatments of vulvodynia (formerly vulvar vestibulitis) and interstitial cystitis are discussed in detail separately. These conditions may be exacerbated by dryness and candidiasis in patients with SjD. The use of tricyclic antidepressants, sometimes employed for treatment of these conditions, should be avoided in patients with SjD because of their anticholinergic side effects. (See "Interstitial cystitis/bladder pain syndrome: Clinical features and diagnosis" and "Interstitial cystitis/bladder pain syndrome: Management" and "Vulvar pain of unknown cause (vulvodynia): Clinical manifestations and diagnosis" and "Vulvar pain of unknown cause (vulvodynia): Treatment".)

Dry skin — Treatment of dry skin in patients with SjD is similar to the management of xerosis in other medical conditions and includes the use of mild cleansers, skin moisturizers, and/or occlusive agents; the avoidance of excessive skin washing; and the use of a humidifier. The management of xerosis and related pruritus is discussed in detail separately. (See "Pruritus: Therapies for generalized pruritus", section on 'Xerosis (dry skin)'.)

Fragranced moisturizers and heavily fragranced cleansers should be avoided, as should use of oral antihistamines, when possible, in patients with SjD and pruritus because of their irritative and anticholinergic effects, respectively. We also advise patients with SjD, regardless of whether it is associated with systemic lupus, to use sunblock, sunscreen, and sun-protective clothing for additional skin protection. (See "Overview of cutaneous photosensitivity: Photobiology, patient evaluation, and photoprotection".)

Other symptoms

●Perioral paresthesia and dry, cracking perioral skin or lips may be treated with frequent use of lip salves and/or petroleum jelly.

●Alterations in smell and taste may occur in SjD patients; they may respond to treatment of occult candidiasis or replacement of zinc deficiency [101]. Some studies and small trials in patients without SjD but with diminished taste associated with radiotherapy or other causes have also suggested that zinc supplementation might be of benefit in improving taste sensation [102-104].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Sjögren's disease".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Beyond the Basics topics (see "Patient education: Sjögren's disease (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●All patients with Sjögren’s disease (SjD) and dry mouth should be instructed in basic measures for self-care to stimulate oral secretions and prevent oral dryness and dental caries. These include maintaining good hydration; avoiding sucrose, carbonated beverages, juices, and water with additives; regularly sipping water; drinking sugar-free liquids; using sugar-free salivary stimulants; avoiding medications that may worsen dryness; and using a humidifier. (See 'Basic measures for all patients' above.)

●Patients with SjD should undergo regularly scheduled preventive dental care and be cared for by a dental hygienist and dentist with experience in dry mouth care whenever possible. Oral hygiene and dental self-care should include use of dental floss after meals, fluoride either as toothpaste or mouth rinse daily, and use of toothpastes specifically designed for dry mouth. Meticulous self-care, frequent visits to the dentist, and plaque control are necessary but are not always sufficient to completely prevent caries. (See 'Basic dental care and oral hygiene' above.)

●In patients with SjD who get inadequate benefit from mechanical or topical stimulants of salivary flow and sipping water, we suggest the use of artificial saliva for temporary symptomatic relief as the next step in therapy (Grade 2B). Several different preparations should be tried to find which is the most helpful. (See 'Inadequate benefit from salivary stimulation and water' above.)

●In patients with SjD with salivary dysfunction and dry mouth who receive inadequate benefit from mechanical stimulation and artificial saliva, we suggest the use of a muscarinic agonist, such as pilocarpine or cevimeline, as the next therapeutic option (Grade 2B). The usual dose of pilocarpine is 5 mg by mouth, up to four times/day, and the usual dose of cevimeline is 30 mg by mouth, up to three times/day taken approximately a half-hour before meals. The dose of medication should be increased gradually when initiating therapy to assess for ability to tolerate side effects. In many instances, it may take several weeks for patients to notice a therapeutic effect. (See 'Inadequate response to salivary stimulation and substitutes' above.)

●We generally do not use glucocorticoids or other systemic antiinflammatory or immunosuppressive therapies for the treatment of sicca symptoms alone, such as dry eye and mouth, although some of these agents have beneficial effects in patients with systemic and extraglandular disease and a few have shown some efficacy for sicca symptoms, including dry mouth. (See 'Systemic antiinflammatory and immunosuppressive therapy' above.)

●Patients with dental caries or very low salivary production should be evaluated by a dentist with expertise in dry mouth dentistry to determine if remineralizing mouth washes, special toothpastes, fluoride applications, or other measures are required and to direct such care. (See 'Dental professional care' above.)

●A high level of suspicion for oral candidiasis should be maintained in patients with SjD, especially in patients with mouth pain, burning, increased sensitivity, diffuse or patchy mucosal erythema, or white mucosal patches. Recurrent infections are common and patients benefit from early recognition and prompt treatment. (See 'Oral candidiasis' above.)

●Sicca symptoms other than dry mouth may also require treatment. In addition to dry eye, these include nasal dryness, laryngotracheal and genitourinary symptoms, and dry skin. Patients with these manifestations may benefit from various topical measures, as well as from the use of muscarinic agonists such as pilocarpine or cevimeline. (See "Treatment of dry eye in Sjögren’s disease: General principles and initial therapy" and 'Treatment of other sicca symptoms' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Paul Creamer, MD, who contributed to an earlier version of this topic review.