One of Sjögren’s syndrome (SS) commonest features is persistent salivary gland hypofunction which typically leads to chronic dry mouth (xerostomia) intra‐oral discomfort, difficulty with speaking (dysarthria), swallowing (dysphagia) and altered taste (dysgeusia). There may also be an increased risk of dental disease and infection with an impact on oral health and general quality of life. A range of systemic and topical have been used to either restore, stimulate or replace saliva to minimise the impact of xerostomia.

The aim of this review was to summarise and estimate the effectiveness of available treatment options for xerostomia, hyposalivation and quality of life in individuals with SS.

Methods

Searches were conducted in the Medline, Embase and Cochrane Central Register of Controlled Trials (CENTRAL) Randomised controlled trials of treatments designed to stimulate saliva production and/or to reduce the symptoms of xerostomia in patients with a diagnosis of SS were considered. The primary outcome was the mean change in xerostomia symptoms. The secondary outcomes included changes in salivary flow and quality of life.

Two reviewers independently selected studies, abstracted data and assessed risk of bias using the Cochrane tool. Mean difference (MD) and 95% confidence intervals (CI) were calculated for continuous data and with odds ratios (OR) and 95%CI of improvement for categorical data. The GRADE approach was used to assess quality of evidence for each outcome.

Results

• 36 studies involving a total of 3274 patients were included.
• Interventions included topical saliva substitutes (3 studies), topical saliva stimulants (2studies), systemic cholinergic agonists (7 trials), electrostimulation (2studies), acupuncture/laser acupuncture (2 studies), biologic response modifier biological agents (9 studies), disease‐modifying antirheumatic drugs (5 studies) and dehydroepiandrosterone (2 studies). There was one study on gamma‐linolenic acid, nizatidine, omega‐3 supplements and traditional Chinese medicine
• 17 studies were considered to be at low risk of bias.
• 14 studies contributed to a meta-analysis with two comparison being sufficiently clinically homogenous to perform pooling: systemic cevimeline versus placebo and systemic pilocarpine versus placebo.
  • Patients using pilocarpine were significantly more likely to have a 25 mm or higher reduction (probably short‐term) in xerostomia VAS score compared to placebo; OR= 3.79 (95%CI; 2.63–5.47) [ 3 studies,517 patients]
  • Use of cevimeline was associated with a higher short‐term reduction in dry mouth symptoms than placebo; MD = 9.85 (95%CI; 1.76–17.94) [ 2 studies,180 patients].
  • In relation to the secondary outcome of salivary function increase,
  • 2 studies (92 patients) showed a mean difference in short‐term unstimulated salivary flow change of 0.16ml/min (95% CI 0.09–0.22; p < 0.00001) between the participants taking one tablet of cevimeline versus placebo.
  • 2 studies (298 patients) indicated a mean difference in short‐term unstimulated salivary flow change of 0.15 ml/min (95% CI 0.08–0.22; p < 0.0001) between the group taking one tablet of pilocarpine versus placebo.
  • 2 studies (100 patients) comparing a first-generation electrostimulating device and sham stimulation showed a mean difference in short‐term unstimulated salivary flow change between groups of 0.17 ml/min (95%CI; 0.11–0.23; p < 0.00001).
  • 3 studies (283 patients) comparing rituximab and placebo showed a mean difference in long‐term unstimulated salivary flow change of 0.04 ml/ min between the arm (95%CI; 0.01–0.06; p = 0.002).
  • 3 studies (553 patients) of interferon‐α versus placebo showed a mean difference in short‐term unstimulated salivary flow change of 0.01 ml/min (95%CI; 0.01– 0.02; p < 0.00001).
• Adverse events including nausea, sweating, headache and palpitations were observed in up to 64% and 36% of patients taking pilocarpine and cevimeline, respectively.
• No adverse events were associated with salivary electrostimulation. Infections, serum sickness and infusion reactions were observed in up to 52% of patients taking rituximab.
• interferon‐α was associated with gastrointestinal adverse events in up to 34% of patients.
• Withdrawal from the experimental intervention compared to control was observed in up to 30% versus 16% (pilocarpine), 22% versus 22% (interferon‐alpha), 21% versus 15% (cevimeline), 20% versus 10% (rituximab) and 7% versus 26% (electrostimulation) of participants.

Conclusions

The authors concluded: –

Clinicians should be very confident in the beneficial effects of pilocarpine upon dry mouth symptoms of SS. However, adverse events are common and contributing to the reported 30% withdrawal from treatment. Similar convincing evidence with regard to cevimeline is lacking. With respect to increasing salivary flow of individuals with SS, there remains limited confidence in the beneficial effects of cevimeline and electrostimulation. Clinicians should be moderately confident that pilocarpine, rituximab and interferon‐alpha might have beneficial effects upon salivary flow, although the effect size seems large for pilocarpine and much smaller for rituximab and interferon‐alpha. Indeed, the two latter agents failed to show a significant reduction in dry mouth symptoms. Adverse events are common with these agents, contributing to the reported 30%, 20% and 22% withdrawal from treatment, respectively. The use of other treatment modalities cannot be sup‐ ported on the basis of current evidence.

Comments

It is a few years since two Cochrane reviews were published on treatments for the management of dry mouth (Dental Elf – 3^rd Sep 2013 &– 14^th Dec 2011). While a number of studies are now available the wide range of interventions and assessment methods means that many of them could not be combined in a meta-analysis. Where combinations were possible they only involved a small number of studies. The reviews provide a good narrative summary of the treatments that could not be combine qualitatively.  As the reviewers noted while there were good positive outcomes with the use of pilocarpine adverse effects were very common and high rates of treatment withdrawal were seen.   The limited number of studies available, their short term nature and the level of adverse effects need to be taken into account and further high quality studies using common outcome are needed in relation to  treatments for dry mouth.

Links

Primary Paper

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. 2018 Aug 7. doi: 10.1111/odi.12952. [Epub ahead ofprint] Review. PubMed PMID: 30086205.

Other references

Dental Elf – 3^rd Sep 2013

Insufficient evidence for effects of non-pharmacological interventions for the relief of dry mouth

 

Dental Elf – 14^th  Dec 2011

No strong evidence that any topical treatment is effective for relieving the sensation of dry mouth