Efficacy of Cevimeline on Xerostomia in Sjögren's Syndrome Patients: A Systematic Review and Meta-Analysis of Randomized Clinical Trials
Sjögren's syndrome is a chronic autoimmune disorder that largely affects the body's exocrine glands, causing widespread dryness, particularly in the eyes and mouth. Xerostomia, or dry mouth, is a common and debilitating symptom of Sjögren's syndrome that has a significant impact on patients’ quality of life. , It causes difficulty speaking, eating, and swallowing, as well as increasing the risk of dental decay, mouth infections, and general discomfort. , The root cause of xerostomia in Sjögren's syndrome is immune-mediated destruction of the salivary glands, which lowers their ability to generate saliva, compromising oral function and health. Individuals with Sjögren's syndrome require effective xerostomia care to improve their daily comfort and overall well-being. Several pharmaceutical therapies have been investigated to ameliorate xerostomia in Sjögren's syndrome, including secretagogues like pilocarpine and cevimeline, which enhance salivary flow. Cevimeline, a selective muscarinic M1 and M3 receptor agonist has gained popularity as a potential therapeutic approach. It acts by stimulating muscarinic receptors in the salivary glands, which causes greater saliva output. , In addition to increasing salivary flow, cevimeline is thought to increase the secretion of digesting and defensive components such as mucins and enzymes, all of which contribute to oral health and pathogen defense. While cevimeline has been licensed for the treatment of dry mouth in Sjögren's syndrome, the extent of its efficacy, particularly in comparison to other medications, is still being investigated. Despite numerous studies investigating the use of cevimeline for xerostomia, results have been inconsistent, with some showing significant improvement in symptoms while others report minimal effects. , , , , Additionally, the optimal dosage and treatment duration have not been fully established. Given these uncertainties, a meta-analysis is necessary to consolidate the available evidence and provide a clearer understanding of the therapeutic benefits of cevimeline in managing xerostomia in Sjögren's syndrome patients. This meta-analysis evaluates the efficacy of cevimeline in reducing xerostomia by assessing salivary flow and mouth dryness in patients with Sjögren's syndrome. 

This systematic review and meta-analysis aimed to assess the efficacy of Cevimeline in treating xerostomia (dry mouth) in patients with Sjögren's Syndrome. The methodology followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Literature search A comprehensive literature search was conducted in the PubMed, Scopus, Cochrane, and Web of Science databases up to January 3, 2024, to identify relevant studies for this systematic review and meta-analysis. The search strategy followed the PICO framework, utilizing a combination of keywords and Medical Subject Headings for “Cevimeline,” “Sjogren's Syndrome,” “xerostomia,” and “dry mouth,” applied to the Title/Abstract fields. The terms were organized into subgroups and combined using the “AND” operator to capture studies addressing all aspects of the research question. No restrictions were placed on date, publication type, or language to ensure the broadest possible inclusion of studies. Two independent reviewers (M.K. and F.A.) conducted all search steps, with discrepancies resolved through discussion or by consulting a third reviewer when necessary ( ). Criteria for selecting studies The inclusion criteria for this systematic review and meta-analysis focused on clinical trials that evaluated the effects of orally administered Cevimeline on xerostomia in adult patients diagnosed with Sjögren's Syndrome. Only studies involving human subjects reporting outcomes related to the xerostomia symptoms (through subjective assessments or objective measures such as salivary flow rate) were considered. Exclusion criteria included nonclinical studies conducted on animal models or in vitro, review articles, editorials, letters, case reports, and conference abstracts without full data. Studies that evaluated other treatments or lacked xerostomia-related outcomes were excluded. Additionally, studies with duplicate or overlapping data were excluded, with preference given to the most comprehensive or recent study. Data extraction Two independent reviewers (M.K. and F.A.) meticulously evaluated the titles and abstracts of each study to assess their eligibility for inclusion in the current meta-analysis. Studies that did not meet the predefined inclusion criteria were excluded from further consideration. The full texts of the remaining studies were then thoroughly screened to ensure compliance with the criteria. Qualified studies advanced to the data extraction phase, where relevant information was systematically collected and categorized into several key domains: study characteristics (including authors, study type, year of publication, and geographical location), participant demographics, study design, and reported outcomes. Any discrepancies between the reviewers were addressed through consultation with the third reviewer (N.D.), ensuring consensus and enhancing the reliability of the findings. Statistical analysis The data analysis was conducted using STATA 13.1 software. Results were presented as pooled odds ratios accompanied by a 95% confidence interval, visualized in a forest plot. Assessment of heterogeneity among eligible studies was performed using the I 2 statistic, with the random effects model employed in instances of significant heterogeneity ( I 2 > 50%). Additionally, a sensitivity analysis was conducted, systematically excluding one study at a time and repeating the meta-analysis to assess the robustness of the findings. Both visual inspection of funnel plot symmetry and Egger's regression analysis were employed to evaluate the potential for publication bias. 

A comprehensive literature search was conducted in the PubMed, Scopus, Cochrane, and Web of Science databases up to January 3, 2024, to identify relevant studies for this systematic review and meta-analysis. The search strategy followed the PICO framework, utilizing a combination of keywords and Medical Subject Headings for “Cevimeline,” “Sjogren's Syndrome,” “xerostomia,” and “dry mouth,” applied to the Title/Abstract fields. The terms were organized into subgroups and combined using the “AND” operator to capture studies addressing all aspects of the research question. No restrictions were placed on date, publication type, or language to ensure the broadest possible inclusion of studies. Two independent reviewers (M.K. and F.A.) conducted all search steps, with discrepancies resolved through discussion or by consulting a third reviewer when necessary ( ). 

The inclusion criteria for this systematic review and meta-analysis focused on clinical trials that evaluated the effects of orally administered Cevimeline on xerostomia in adult patients diagnosed with Sjögren's Syndrome. Only studies involving human subjects reporting outcomes related to the xerostomia symptoms (through subjective assessments or objective measures such as salivary flow rate) were considered. Exclusion criteria included nonclinical studies conducted on animal models or in vitro, review articles, editorials, letters, case reports, and conference abstracts without full data. Studies that evaluated other treatments or lacked xerostomia-related outcomes were excluded. Additionally, studies with duplicate or overlapping data were excluded, with preference given to the most comprehensive or recent study. 

Two independent reviewers (M.K. and F.A.) meticulously evaluated the titles and abstracts of each study to assess their eligibility for inclusion in the current meta-analysis. Studies that did not meet the predefined inclusion criteria were excluded from further consideration. The full texts of the remaining studies were then thoroughly screened to ensure compliance with the criteria. Qualified studies advanced to the data extraction phase, where relevant information was systematically collected and categorized into several key domains: study characteristics (including authors, study type, year of publication, and geographical location), participant demographics, study design, and reported outcomes. Any discrepancies between the reviewers were addressed through consultation with the third reviewer (N.D.), ensuring consensus and enhancing the reliability of the findings. 

The data analysis was conducted using STATA 13.1 software. Results were presented as pooled odds ratios accompanied by a 95% confidence interval, visualized in a forest plot. Assessment of heterogeneity among eligible studies was performed using the I 2 statistic, with the random effects model employed in instances of significant heterogeneity ( I 2 > 50%). Additionally, a sensitivity analysis was conducted, systematically excluding one study at a time and repeating the meta-analysis to assess the robustness of the findings. Both visual inspection of funnel plot symmetry and Egger's regression analysis were employed to evaluate the potential for publication bias. 

Study selection A systematic search was conducted across four databases, including PubMed/Medline ( n = 47), Cochrane ( n = 12), Web of Science ( n = 60), and Scopus ( n = 170), yielding a total of 289 records. After removing 22 duplicate records, 267 unique records were screened for relevance. Of these, 220 records were excluded after the initial screening due to not meeting the inclusion criteria. The remaining 47 reports were assessed for eligibility, with 44 reports subsequently excluded due to irrelevant outcomes. Ultimately, three randomized clinical trials (RCTs) were included in the final meta-analysis ( ). Baseline characteristics of patients Three double-blind, randomized placebo-controlled (RCTs), with a combined total of 302 patients with Sjögren's syndrome (187 in the case group and 115 in the control or placebo group), were included in this analysis to assess the effect of Cevimeline on xerostomia in patients with Sjögren's syndrome. Two RCTs were conducted in the USA , and one in China, that were published between 2002 and 2008. Patients ranged in age from 23 to 86, with an average age between 47 and 62. One RCT included only female patients, the two others included both male and female patients, though the majority were female overall. Cevimeline doses of 15 mg, 30 mg, and 60 mg were used, with 30 mg being the most common dose. The follow-up duration varied from 1 day to 24 weeks across the studies. Detailed characteristics of patients are presented in . Results of meta-analysis The analysis revealed that cevimeline significantly decreased xerostomia (regarded as salivary flow, mouth dryness) (pooled effect = –5.79, 95% CI = [–10.55, –1.03], I 2 = 39.6%) ( ). Risk of bias of included studies The sensitivity analysis results revealed that any single study or cluster of studies with shared characteristics had minimal influence on the RR and its corresponding CI, indicating the stability of our findings. Additionally, we performed Egger's regression test, Begg's test, and funnel plot analysis to identify any publication bias. Results from Begg's test showed no publication bias ( P > 0.05) ( and Supplementary Figure 1). 

A systematic search was conducted across four databases, including PubMed/Medline ( n = 47), Cochrane ( n = 12), Web of Science ( n = 60), and Scopus ( n = 170), yielding a total of 289 records. After removing 22 duplicate records, 267 unique records were screened for relevance. Of these, 220 records were excluded after the initial screening due to not meeting the inclusion criteria. The remaining 47 reports were assessed for eligibility, with 44 reports subsequently excluded due to irrelevant outcomes. Ultimately, three randomized clinical trials (RCTs) were included in the final meta-analysis ( ). 

Three double-blind, randomized placebo-controlled (RCTs), with a combined total of 302 patients with Sjögren's syndrome (187 in the case group and 115 in the control or placebo group), were included in this analysis to assess the effect of Cevimeline on xerostomia in patients with Sjögren's syndrome. Two RCTs were conducted in the USA , and one in China, that were published between 2002 and 2008. Patients ranged in age from 23 to 86, with an average age between 47 and 62. One RCT included only female patients, the two others included both male and female patients, though the majority were female overall. Cevimeline doses of 15 mg, 30 mg, and 60 mg were used, with 30 mg being the most common dose. The follow-up duration varied from 1 day to 24 weeks across the studies. Detailed characteristics of patients are presented in . 

The analysis revealed that cevimeline significantly decreased xerostomia (regarded as salivary flow, mouth dryness) (pooled effect = –5.79, 95% CI = [–10.55, –1.03], I 2 = 39.6%) ( ). 

The sensitivity analysis results revealed that any single study or cluster of studies with shared characteristics had minimal influence on the RR and its corresponding CI, indicating the stability of our findings. Additionally, we performed Egger's regression test, Begg's test, and funnel plot analysis to identify any publication bias. Results from Begg's test showed no publication bias ( P > 0.05) ( and Supplementary Figure 1). 

This meta-analysis aimed to evaluate the efficacy of Cevimeline in alleviating xerostomia, a common and distressing complication in individuals with Sjögren's Syndrome. Our findings demonstrate that Cevimeline significantly improves salivary flow and reduces symptoms of dry mouth, supporting its role as an effective therapeutic option for patients with Sjögren's syndrome. These results align with previous research, which has shown the efficacy of cevimeline as a viable treatment for alleviating the symptoms of xerostomia, a prevalent and distressing complication commonly observed in individuals with Sjögren's syndrome. , Cevimeline has emerged as a safe and effective therapeutic option for managing xerostomia, particularly in patients with mild to moderate salivary gland damage. , , , , Previous studies indicated that cevimeline enhances saliva production by targeting the M1 and M3 muscarinic receptors, and it remains in the bloodstream longer than other medications like pilocarpine. , In other studies, cevimeline was utilized as a therapeutic agent for rats diagnosed with Sjögren's syndrome. The authors observed that cevimeline produced beneficial effects on all major salivary glands. Additionally, it stimulated secretion in the labial glands, demonstrating a more physiological response compared to pan-muscarinic agonists. , Several studies have reported notable improvements in both subjective symptoms and objective measures of salivary and lacrimal flow rates following cevimeline treatment. However, while no reports of toxicity due to overdose have been documented, studies have highlighted potential side effects such as increased sweating, abdominal pain, dyspepsia, nausea, and diarrhea. , Our study corroborates these findings, demonstrating the ability of cevimeline to enhance salivary flow rate and alleviate dry mouth symptoms in patients with Sjögren's syndrome. Nevertheless, the efficacy of cevimeline may vary based on individual factors. Treatment with cevimeline at a dosage of 30 mg three times daily has been well-tolerated and significantly reduces xerostomia-related symptoms. Notably, increasing the dosage to 60 mg three times a day has been associated with a rise in adverse effects, particularly affecting the digestive system. Noteworthy clinical trials have further supported the efficacy of cevimeline in improving both subjective symptoms and objective measures of dry mouth and dry eyes. For instance, a research article published in the Journal of Oral Pathology & Medicine reported that cevimeline significantly enhanced salivary flow rates and ameliorated subjective symptoms of xerostomia in individuals diagnosed with Sjögren's syndrome. A study conducted by Fife et al evaluated the efficacy of cevimeline hydrochloride at dosages of 30 mg and 60 mg three times daily over 6 weeks, revealing significant improvements in dry mouth symptoms and salivary flow rates compared to placebo. Similarly, Petrone et al demonstrated significant improvements in dry eye and dry mouth symptoms with cevimeline treatment, particularly at a dosage of 30 mg three times daily. Furthermore, Suzuki et al reported a significant increase in salivary flow rate following the cevimeline administration. Leung et al conducted a randomized, double-blind, placebo-controlled study involving 44 female patients diagnosed with Sjögren's syndrome. Over a period of 10 weeks, participants were administered either Cevimeline (30 mg) or a placebo three times daily, following a 4-week washout period. Clinical assessments encompassed dental complications arising from xerostomia, sialometry, and evaluation of xerostomia severity. Surprisingly, contrary to previous findings, this study did not observe enhancements in salivary secretion or oral health status, despite a positive trend noted in the latter measures. Additionally, Papas et al demonstrated significant improvement in ocular symptoms with a dosage escalation to 30 mg/day, alongside notable relief in dry mouth symptoms at a dosage of 20 mg/day. Yamada et al revealed through parotid sialography that Sjögren's syndrome patients with sialectasis exhibited reduced sensitivity to cevimeline compared to those without this condition. Moreover, patients with severe periductal lymphocyte infiltration in the minor salivary glands exhibited lower cevimeline efficacy compared to those with minimal lymphocyte infiltration. Takagi et al investigated the effectiveness of cevimeline gargle as an alternative to oral administration in managing dry mouth among Sjögren's syndrome patients. Their study demonstrated favorable responses among most healthy participants, with a remarkable average increase in salivary flow rate by day five, reaching 81%. Notably, some subjects exhibited more than a twofold increase in salivary flow following cevimeline gargle, with no adverse outcomes observed. Furthermore, Komai et al suggested that cevimeline is particularly effective for Sjögren's syndrome patients with less severe disease activity. However, variations in treatment response have been observed based on disease severity and glandular involvement. Patients with less severe disease activity have shown better response rates to cevimeline treatment. Overall, while cevimeline holds promise as a therapeutic option for Sjögren's syndrome patients with xerostomia, further research is warranted to elucidate its optimal dosage, administration route, and long-term efficacy in managing dry mouth symptoms in this patient population. This meta-analysis represents the first systematic review to comprehensively assess the impact of cevimeline on xerostomia in patients with Sjögren's syndrome, thereby addressing a significant gap in the literature. The study's strength lies in its rigorous methodology, including an extensive literature search and careful adherence to PRISMA guidelines. However, the limited number of included studies and the geographical concentration of research, primarily in the USA, Japan, and China, may hinder the generalizability of the findings. Furthermore, the high heterogeneity observed among the studies indicates variability in treatment effects, underscoring the necessity for additional research involving larger and more diverse populations to validate these results. 

In conclusion, cevimeline significantly enhances salivary flow and alleviates xerostomia in patients with Sjögren's syndrome. Its favorable safety profile at recommended dosages makes it a promising therapeutic option, particularly for individuals with mild to moderate salivary gland damage. Further research involving diverse populations and varying disease severities is crucial to solidify cevimeline's role as a reliable treatment for xerostomia in Sjögren's syndrome. 

The manuscript does not contain clinical studies or patient data. 

The manuscript does not contain clinical studies or patient data. 

All authors have reviewed the final version of the manuscript and consent to its submission for publication in the journal. 

data is available upon request from corresponding authors. 

Niloofar Deravi conceptualized and designed the study. Mehdi Karimi conducted the literature search, study selection, and data extraction, and drafted, wrote, and supervised the manuscript. Anita Fatehi contributed to data extraction, while Mahdyieh Naziri performed data analysis. Mehdi Karimi, Fatemeh Ahmadi Hajikolaei, Fahime Hoseinpour, Seyed Ali Hashemi , and Seyed-Abbas Pakmehr were involved in writing the manuscript. All authors reviewed and approved the final version of the manuscript. 

During the preparation of this work, the authors used AI-assisted technologies in order to grammar review. After using this service, the authors reviewed and edited the content as needed and take(s) full responsibility for the content of the publication. 

The authors declare that they have no competing interests. 

