Safety and efficacy of subcutaneous iscalimab (CFZ533) in two distinct populations of patients with Sjögren's disease (TWINSS): week 24 results of a randomised, double-blind, placebo-controlled, phase 2b dose-ranging study.

BACKGROUND: Sjögren's disease is a chronic autoimmune disease with an unmet need for targeted therapies. The aim of the TWINSS study is to evaluate the safety and efficacy of iscalimab, a monoclonal antibody against CD40, in patients with active Sjögren's disease. METHODS: This randomised, double-blind, placebo-controlled, phase 2b study, conducted at 71 sites in 23 countries, enrolled patients aged 18 years or older fulfilling the American College of Rheumatology/European Alliance of Associations for Rheumatology (EULAR) 2016 criteria. In the dose-ranging cohort 1, patients with a EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI) score of 5 or higher and a EULAR Sjögren's Syndrome Patient Reported Index (ESSPRI) score of 5 or higher were randomly assigned (1:1:1:1) to subcutaneous iscalimab 150 mg, 300 mg, 600 mg, or placebo. In the proof-of-concept cohort 2, patients with an ESSDAI score of less than 5, ESSPRI (dryness or fatigue) score of 5 or higher, and Impact of Dry Eye on Everyday Life score of 30 or higher were randomly assigned (1:1) to iscalimab 600 mg or placebo. The sponsor, investigator, site personnel, and patients were masked to the treatment assignment. The primary objectives were to demonstrate a dose-response relationship of iscalimab based on the change in ESSDAI from baseline to week 24 in cohort 1 by Multiple Comparison Procedure-Modelling (MCP-Mod), and to assess the effect of iscalimab 600 mg on ESSPRI at week 24 in cohort 2. All the efficacy analyses included all patients who were randomly assigned, and safety analysis included all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov (NCT03905525), and is complete. FINDINGS: Between Oct 1, 2019, and Feb 28, 2022, 460 patients were screened; 173 patients were assigned to cohort 1 (44 to iscalimab 150 mg, 43 to 300 mg, 43 to 600 mg, and 43 to placebo) and 100 to cohort 2 (50 to each group). In cohort 1, the MCP step showed a significant dose-response relationship for placebo-adjusted ESSDAI change from baseline in one of four models (Linlog model, one-sided p=0·0041). ESSDAI decreased from baseline to week 24 with all three doses of iscalimab; 150 mg and 600 mg doses showed statistically significant improvement (placebo-adjusted least squares [LS] mean difference -3·0 [95% CI -4·9 to -1·1]; p=0·0025 for 150 mg and -2·9 [-4·9 to -1·0]; p=0·0037 for 600 mg). In cohort 2, ESSPRI showed a trend towards improvement with iscalimab 600 mg (placebo-adjusted LS mean change from baseline -0·57 points [95% CI -1·30 to 0·15]; p=0·12). Serious adverse events were reported in nine patients in cohort 1 (one [2%] of 43 in the placebo group, one [2%] of 44 in the iscalimab 150 mg group, three [7%] of 42 in the 300 mg group, four [9%] of 44 in the 600 mg group) and four patients in cohort 2 (two [4%] of 50 in each group). No deaths occurred over the 24-week period. INTERPRETATION: The study met the primary objective of demonstrating a significant dose-response relationship with iscalimab in terms of disease activity at week 24. Iscalimab was well tolerated and showed initial clinical benefit over placebo in two distinct populations of patients with Sjögren's disease, to be confirmed in larger trials. FUNDING: Novartis Pharma.

CD40 ligand antagonist dazodalibep in Sjögren's disease: a randomized, double-blinded, placebo-controlled, phase 2 trial.

Sjögren's disease (SjD) is a chronic, systemic autoimmune disease with no approved disease-modifying therapies. Dazodalibep (DAZ), a novel nonantibody fusion protein, is a CD40 ligand antagonist that blocks costimulatory signals between T and B cells and antigen-presenting cells, and therefore may suppress the wide spectrum of cellular and humoral responses that drive autoimmunity in SjD. This study was a phase 2, randomized, double-blinded, placebo (PBO)-controlled trial of DAZ with a crossover stage in two distinct populations of participants with SjD. Population 1 had moderate-to-severe systemic disease activity and population 2 had an unacceptable symptom burden and limited systemic organ involvement. All participants had a diagnosis of SjD, with 21.6% and 10.1% having an associated connective tissue disease (rheumatoid arthritis or systemic lupus erythematosus) in populations 1 and 2, respectively. The remaining participants would be considered as having primary Sjögren's syndrome. The primary endpoint for population 1 (n = 74) was the change from baseline in the European League Against Rheumatism Sjögren's Syndrome Disease Activity Index at day 169. The primary endpoint for population 2 (n = 109) was the change from baseline in the European League Against Rheumatism Sjögren's Syndrome Patient Reported Index at day 169. The primary endpoints (least squares mean ± standard error) were achieved with statistical significance for both population 1 (DAZ, -6.3 ± 0.6; PBO, -4.1 ± 0.6; P = 0.0167) and population 2 (DAZ, -1.8 ± 0.2; PBO, -0.5 ± 0.2; P = 0.0002). DAZ was generally safe and well tolerated. Among the most frequently reported adverse events were COVID-19, diarrhea, headache, nasopharyngitis, upper respiratory tract infection, arthralgia, constipation and urinary tract infection. In summary, DAZ appears to be a potential new therapy for SjD and its efficacy implies an important role for the CD40/CD40 ligand pathway in its pathogenesis. ClinicalTrials.gov identifier: NCT04129164 .

The Sjögren's Working Group: The 2023 OMERACT meeting and provisional domain generation.

Sjögren's disease (SjD) is a systemic autoimmune exocrinopathy with key features of dryness, pain, and fatigue. SjD can affect any organ system with a variety of presentations across individuals. This heterogeneity is one of the major barriers for developing effective disease modifying treatments. Defining core disease domains comprising both specific clinical features and incorporating the patient experience is a critical first step to define this complex disease. The OMERACT SjD Working Group held its first international collaborative hybrid meeting in 2023, applying the OMERACT 2.2 filter toward identification of core domains. We accomplished our first goal, a scoping literature review that was presented at the Special Interest Group held in May 2023. Building on the domains identified in the scoping review, we uniquely deployed multidisciplinary experts as part of our collaborative team to generate a provisional domain list that captures SjD heterogeneity.

Efficacy and safety of remibrutinib, a selective potent oral BTK inhibitor, in Sjögren's syndrome: results from a randomised, double-blind, placebo-controlled phase 2 trial.

OBJECTIVES: To evaluate the safety and efficacy of remibrutinib in patients with moderate-to-severe Sjögren's syndrome (SjS) in a phase 2 randomised, double-blind trial (NCT04035668; LOUiSSE (LOU064 in Sjögren's Syndrome) study). METHODS: Eligible patients fulfilling 2016 American College of Rheumatology/European League Against Rheumatism (EULAR) criteria for SjS, positive for anti-Ro/Sjögren's syndrome-related antigen A antibodies, with moderate-to-severe disease activity (EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI) (based on weighted score) ≥ 5, EULAR Sjögren's Syndrome Patient Reported Index (ESSPRI) ≥ 5) received remibrutinib (100 mg) either one or two times a day, or placebo for the 24-week study treatment period. The primary endpoint was change from baseline in ESSDAI at week 24. Key secondary endpoints included change from baseline in ESSDAI over time, change from baseline in ESSPRI over time and safety of remibrutinib in SjS. Key exploratory endpoints included changes to the salivary flow rate, soluble biomarkers, blood transcriptomic and serum proteomic profiles. RESULTS: Remibrutinib significantly improved ESSDAI score in patients with SjS over 24 weeks compared with placebo (ΔESSDAI -2.86, p=0.003). No treatment effect was observed in ESSPRI score (ΔESSPRI 0.17, p=0.663). There was a trend towards improvement of unstimulated salivary flow with remibrutinib compared with placebo over 24 weeks. Remibrutinib had a favourable safety profile in patients with SjS over 24 weeks. Remibrutinib induced significant changes in gene expression in blood, and serum protein abundance compared with placebo. CONCLUSIONS: These data show preliminary efficacy and favourable safety of remibrutinib in a phase 2 trial for SjS.

Identification of Salivary Metabolic Signatures Associated with Primary Sjögren's Disease.

Sjögren's disease (SjD) is the second most prevalent autoimmune disorder that involves chronic inflammation of exocrine glands. Correct diagnosis of primary SjD (pSjD) can span over many years since disease symptoms manifest only in advanced stages of salivary and lachrymal glandular destruction, and consensus diagnostic methods have critical sensitivity and selectivity limitations. Using nuclear magnetic resonance (NMR) spectroscopy, we determined the composition of metabolites in unstimulated saliva samples from 30 pSjD subjects and 30 participants who do not have Sjögren's disease (non-Sjögren's control group, NS-C). Thirty-four metabolites were quantified in each sample, and analysis was conducted on both non-normalized (concentration) and normalized metabolomics data from all study participants (ages 23-78) and on an age-restricted subset of the data (ages 30-70) while applying false discovery rate correction in determining data significance. The normalized data of saliva samples from all study participants, and of the age-restricted subset, indicated significant increases in the levels of glucose, glycerol, taurine, and lactate, as well as significant decreases in the levels of 5-aminopentanoate, acetate, butyrate and propionate, in subjects with pSjD compared to subjects in the NS-C group. Additionally, a significant increase in choline was found only in the age-restricted subset, and a significant decrease in fucose was found only in the whole study population in normalized data of saliva samples from the pSjD group compared to the NS-C group. Metabolite concentration data of saliva samples from all study participants, but not from the age-restricted subset, indicated significant increases in the levels of glucose, glycerol, taurine, and lactate in subjects with pSjD compared to controls. The study showed that NMR metabolomics can be implemented in defining salivary metabolic signatures that are associated with disease status, and can contribute to differential analysis between subjects with pSjD and those who are not affected with this disease, in the clinic.

Safety and efficacy of subcutaneous ianalumab (VAY736) in patients with primary Sjögren's syndrome: a randomised, double-blind, placebo-controlled, phase 2b dose-finding trial.

BACKGROUND: Sjögren's syndrome is an autoimmune disease characterised by dry eyes and mouth, systemic features, and reduced quality of life. There are no disease-modifying treatments. A new biologic, ianalumab (VAY736), with two modes of suppressing B cells, has previously shown preliminary efficacy. This dose-finding trial aimed to assess the safety and efficacy of different subcutaneous doses of ianalumab in patients with moderate to severe primary Sjögren's syndrome. METHODS: VAY736A2201 was a randomised, parallel, double-blind, placebo-controlled, phase 2b dose-finding study done in 56 centres in 19 countries. Patients aged 18-75 years with primary Sjögren's syndrome with moderate to severe disease activity (European Alliance of Associations for Rheumatology [EULAR] Sjögren's Syndrome Disease Activity Index [ESSDAI] score ≥6) and symptom severity (EULAR Sjögren's Syndrome Patient Reported Index score ≥5) were eligible. Participants were randomly assigned (1:1:1:1) to receive subcutaneous placebo or ianalumab (5 mg, 50 mg, or 300 mg) every 4 weeks for 24 weeks using a secure, online randomisation system. Randomisation was stratified by the ESSDAI score at baseline (≥10 or <10). Study personnel and patients were masked to treatment assignment. The primary outcome was the change in ESSDAI score from baseline to 24 weeks in all randomly assigned patients. Dose-related change in disease activity (ESSDAI) from baseline at week 24 was assessed by multiple comparison procedure with modelling analysis. Safety was measured in all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, NCT02962895. FINDINGS: Between June 27, 2017, and Dec 06, 2018, 293 patients were screened, 190 of whom were randomly assigned (placebo n=49, ianalumab 5 mg n=47, ianalumab 50 mg n=47, ianalumab 300 mg n=47). Statistically significant dose-responses were seen for overall disease activity (ESSDAI score) in four of the five dose-response models tested (p<0·025 in four models, p=0·060 in one model). The ESSDAI score decreased from baseline in all ianalumab groups, with the maximal ESSDAI score change from baseline observed in the ianalumab 300 mg group: placebo-adjusted least-squares mean change from baseline -1·92 points (95% CI -4·15 to 0·32; p=0·092). There were four serious adverse events in three patients considered treatment-related (pneumonia [n=1] and gastroenteritis [n=1] in the placebo group; appendicitis plus tubo-ovarian abscess in the same patient in the ianalumab 50 mg group). INTERPRETATION: The study met its primary objective, showing a dose-related decrease in disease activity as measured by ESSDAI at week 24. Overall, ianalumab was well tolerated and safe, with no increase in infections. To our knowledge, this is the first large, randomised, controlled trial in primary Sjögren's syndrome that met its primary endpoint, and its results mean there is potential for more studies of this mechanism in the future. FUNDING: Novartis.

Efficacy and safety of a novel mucoadhesive clobetasol patch for treatment of erosive oral lichen planus: A phase 2 randomized clinical trial.

BACKGROUND: Oral lichen planus (OLP) is a chronic inflammatory disorder of the oral mucosa. Currently there is no approved treatment for OLP. We report on the efficacy and safety of a novel mucoadhesive clobetasol patch (Rivelin® -CLO) for the treatment of OLP. METHODS: Patients with confirmed OLP and measurable symptomatic ulcer(s) participated in a randomized, double-blind, placebo-controlled, multicenter clinical trial testing a novel mucoadhesive clobetasol patch (Rivelin® -CLO) in OLP across Europe, Canada, and the United States. Patients were randomized to placebo (nonmedicated), 1, 5, 20 µg Clobetasol/patch, twice daily, for 4 weeks. The primary endpoint was change in total ulcer area compared to baseline. Secondary endpoints included improvement from baseline in pain, disease activity, and quality of life. RESULTS: Data were analyzed and expressed as mean [SD]. One hundred thirty-eight patients were included in the study; 99 females and 39 males, mean age was 61.1 [11.6] years. Statistical analyses revealed that treatment with 20-µg Rivelin® -CLO patches demonstrated significant improvement with ulcer area (p = 0.047), symptom severity (p = 0.001), disease activity (p = 0.022), pain (p = 0.012), and quality of life (p = 0.003) as compared with placebo. Improvement in OLP symptoms from beginning to the end of the study was reported as very much better (best rating) in the 20-µg group (25/32) patients compared to the placebo group (11/30), (p = 0.012). Adverse events were mild/moderate. Candidiasis incidence was low (2%). CONCLUSIONS: Rivelin® -CLO patches were superior to placebo demonstrating statistically significant, clinically relevant efficacy in objective and subjective improvement and, with a favorable safety profile.

Salivary glands ultrasonography as a diagnostic aid in Sjögren syndrome: A prospective pilot investigation.

OBJECTIVE: The aims of this pilot investigation were to calculate the levels of sensitivity and specificity of salivary glands ultrasonography (SGUS) in diagnosing Sjögren syndrome (SS) and to assess the ultrasonographic findings of parotid and submandibular glands. STUDY DESIGN: Patients diagnosed with SS or dry mouth and healthy controls were enrolled. Bilateral parotid and submandibular glands were assessed for (1) parenchymal inhomogeneity (PIH), (2) median size of the glands, (3) visibility of glandular posterior borders, and (4) size of sialolith, if present. RESULTS: This study included 34 female patients, of whom 12 had SS (35.3%), 12 had dry mouth (35.3%), and 10 were healthy controls (29.4%). Patients with SS showed higher PIH scores in all glands with the median differences being statistically higher in the right and left parotids and left submandibular glands (P < .001, P = .012, and P < .001, respectively). SGUS, with a PIH cutoff ≥2, showed a sensitivity of 100% and a specificity of 81.6% for detecting SS. The majority of SS had invisible glandular posterior borders (P < .001). Median size of the glands and size of the sialolith did not show any statistically significant differences between groups. CONCLUSIONS: SGUS is a noninvasive imaging modality with good sensitivity and specificity that might be valuable as a diagnostic aid for SS.

Conservative Management of Chronic Suppurative Parotitis in Patients with Sjögren Syndrome: A Case Series.

BACKGROUND Parotitis is an inflammation of the parotid gland, which can be caused by factors including infection, radiation, and hyposalivation secondary to systemic conditions, such as Sjögren syndrome, rheumatoid arthritis, or medication. Bacterial parotitis is a rare complication that can be observed in patients with hyposalivation. However, it is also observed in elderly and immunocompromised patients. Lack of continuous flushing of salivary glands and their ducts due to decreased salivary flow renders the glands prone to retrograde colonization with oral microflora. Several microorganisms have been associated with bacterial infections of the parotid glands; Staphylococcus aureus is the most common, accounting for 80% of cases, followed by mixed bacterial communities, including streptococci, anaerobes, and gram-negative bacilli. Bacterial parotitis presents as tenderness, swelling, and purulent sialorrhea from the salivary gland's duct. Immediate administration of broad-spectrum antibiotics, based on the results of the patient's culture and sensitivity test, has shown success in treating these cases. CASE REPORT We report 3 cases of chronic suppurative parotitis secondary to dry mouth and due to Sjögren syndrome that did not respond to oral or intravenous antibiotics and was successfully managed using conservative methods, such as the local application of superficial moist heat and periodic pus drainage by manipulating the parotid glands at dental clinics. CONCLUSIONS We concluded that conservative approaches, such as massaging the glands, local application of superficial moist heat, and periodic pus drainage without using antibiotics, should be considered as the first-line management of bacterial infection of the parotid glands.

Repeated delivery of chlorhexidine chips for the treatment of peri-implantitis: A multicenter, randomized, comparative clinical trial.

BACKGROUND: Peri-implantitis is a challenging condition to manage and is frequently treated using non-surgical debridement. The local delivery of antimicrobial agents has demonstrated benefit in mild to moderate cases of peri-implantitis. This study compared the safety and efficacy of chlorhexidine gluconate 2.5 mg chip (CHX chips) as an adjunctive treatment to subgingival debridement in patients afflicted with peri-implantitis. METHODS: A multicenter, randomized, single-blind, two-arm, parallel Phase-3 study was conducted. Peri-implantitis patients with implant pocket depths (IPD) of 5-8 mm underwent subgingival implant surface debridement followed by repeated bi-weekly supragingival plaque removal and chlorhexidine chips application (ChxC group) for 12 weeks, or similar therapy but without application of ChxC (control group). All patients were followed for 24 weeks. Plaque and gingival indices were measured at every visit whereas IPD, recession, and bleeding on probing were assessed at 8, 12, 16, 24 week. RESULTS: A total of 290 patients were included: 146 in the ChxC group and 144 in the control. At 24 weeks, a significant reduction in IPD (P = 0.01) was measured in the ChxC group (1.76 ± 1.13 mm) compared with the control group (1.54 ± 1.13 mm). IPD reduction of ≥2 mm was found in 59% and 47.2% of the implants in the ChxC and control groups, respectively (P = 0.03). Changes in gingival recession (0.29 ± 0.68 mm versus 0.15 ± 0.55 mm, P = 0.015) and relative attachment gain (1.47 ± 1.32 mm and 1.39 ± 1.27 mm, P = 0.0017) were significantly larger in the ChxC group. Patients in the ChxC group that were < 65 years exhibited significantly better responses (P < 0.02); likewise, non-smokers had similarly better response (P < 0.02). Both protocols were well tolerated, and no severe treatment-related adverse events were recorded throughout the study. CONCLUSIONS: Patients with peri-implantitis that were treated with an intensive treatment protocol of bi-weekly supragingival plaque removal and local application of chlorhexidine chips had greater mean IPD reduction and greater percentile of sites with IPD reduction of ≥2 mm as compared with bi-weekly supra-gingival plaque removal.

Assessment of the anti-CD40 antibody iscalimab in patients with primary Sjögren's syndrome: a multicentre, randomised, double-blind, placebo-controlled, proof-of-concept study.

BACKGROUND: Primary Sjögren's syndrome is an autoimmune disease that presents as dryness of the mouth and eyes due to impairment of the exocrine glands. To our knowledge, no systemic therapies for primary Sjögren's syndrome have shown efficacy. CD40-CD154-mediated T cell-B cell interactions in primary Sjögren's syndrome contribute to aberrant lymphocyte activation in inflamed tissue, leading to sialadenitis and other tissue injury. Therefore, we investigated the safety and preliminary efficacy of iscalimab (CFZ533), a novel anti-CD40 monoclonal antibody, in patients with primary Sjögren's syndrome. METHODS: This multicentre, randomised, double-blind, placebo-controlled, proof-of-concept study took place at ten investigational sites across Europe (UK, n=4; Germany, Switzerland, and Hungary, n=1 each) and the USA (n=3). Eligible patients were aged 18-75 years and fulfilled the 2002 American European consensus group diagnostic classification criteria for primary Sjögren's syndrome. In the double-blind phase of the trial, patients were randomly assigned (2:1) via computer-generated unique randomisation numbers to receive subcutaneous iscalimab (3 mg/kg) or placebo at weeks 0, 2, 4, and 8 (cohort 1) or intravenous iscalimab (10 mg/kg) or placebo at weeks 0, 2, 4, and 8 (cohort 2). Randomisation was stratified according to baseline intake of oral corticosteroids. At week 12, patients in both cohorts received open-label iscalimab (same dose and route) for 12 weeks. The primary objectives of the study were to assess the safety, tolerability, and efficacy of multiple doses of iscalimab in the two sequential dose cohorts. Safety and tolerability were assessed by adverse events and efficacy of iscalimab versus placebo was assessed by clinical disease activity, as measured by the change in European League Against Rheumatism Sjögren's syndrome disease activity index (ESSDAI) score after 12 weeks of treatment. Analyses were done on a per-protocol basis. The trial was registered with ClinicalTrials.gov, NCT02291029. FINDINGS: Between Oct 22, 2014, and June 28, 2016, we assessed 82 patients for eligibility (25 for cohort 1 and 57 for cohort 2). 38 patients were excluded because of ineligibility. In cohort 1, 12 patients were randomly assigned to receive either 3 mg/kg doses of iscalimab (n=8) or placebo (n=4), and in cohort 2, 32 patients were randomly assigned to receive either intravenous 10 mg/kg doses of iscalimab (n=21) or placebo (n=11). Adverse events were similar between iscalimab treatment groups and placebo groups, with adverse events occurring in all patients in cohort 1, and in 52% and 64% of the iscalimab and placebo groups, respectively, in cohort 2. Two serious adverse events were reported (one case of bacterial conjunctivitis in cohort 1 and one case of atrial fibrillation in cohort 2), which were unrelated to treatment with iscalimab. Intravenous treatment with iscalimab resulted in a mean reduction of 5·21 points (95% CI 0·96-9·46; one-sided p=0·0090) in ESSDAI score compared with placebo. There was no signficiant difference in ESSDAI score between subcutaneous iscalimab and placebo. INTERPRETATION: To our knowledge, this is the first randomised, placebo-controlled proof-of-concept study of a new investigational drug for primary Sjögren's syndrome that indicates preliminary efficacy. Our data suggest a role of CD40-CD154 interactions in primary Sjögren's syndrome pathology and the therapeutic potential for CD40 blockade in this disease should be investigated further. FUNDING: Novartis Pharma.

Comparing the effectiveness and adverse effects of pilocarpine and cevimeline in patients with hyposalivation.

OBJECTIVES: Pilocarpine (PILO) and cevimeline (CEV) are muscarinic acetylcholine receptor agonists that stimulate salivary gland function. The aim of this investigation was to retrospectively run a head-to-head comparison for their effectiveness and frequency of adverse effects in patients with hyposalivation. METHODS: A retrospective chart review was conducted for patients seen at the Oral Medicine Clinic at Tufts University School of Dental Medicine (TUSDM) and was prescribed PILO or CEV. Patients' demographics, medical history/medication, stimulated salivary (SS), and unstimulated salivary (US) flow recorded at the initial visit and at 3- and 6-month follow-ups were collected. Changes in dosage/frequency, side effects, and drug discontinuation were also reported. RESULTS: A total of 110 patients' charts were reviewed. The majority of subjects (91%) were females with an average age of 61. At 3-month follow-up, the use of CEV showed significant improvement in SS compared to PILO (p = .033) but not in US (p = .10). At 6-month follow-up, there was no significant difference in SS or US between the two groups (SS: p = .09; US: p = .71). The use of PILO was associated with a higher proportion of adverse effects compared to CEV (p = .04). The overall adherence rate was significantly higher in the CEV group (p = .0056). CONCLUSIONS: The effectiveness of CEV and PILO is comparable. However, PILO seems to be associated with more reporting of side effects.

Prevention of Opioid-Induced Nausea and Vomiting During Treatment of Moderate to Severe Acute Pain: A Randomized Placebo-Controlled Trial Comparing CL-108 (Hydrocodone 7.5 mg/Acetaminophen 325 mg/Rapid-Release, Low-Dose Promethazine 12.5 mg) with Conventional Hydrocodone 7.5 mg/Acetaminophen 325 mg.

OBJECTIVES: To evaluate the prevention of opioid-induced nausea and vomiting (OINV) and the relief of moderate to severe acute pain by CL-108, a novel drug combining a low-dose antiemetic (rapid-release promethazine 12.5 mg) with hydrocodone 7.5 mg/acetaminophen 325 mg (HC/APAP) was used. METHODS: This was a multicenter, randomized, double-blind, placebo- and active-controlled multidose study. After surgical extraction of two or more impacted third molar teeth (including at least one mandibular impaction), 466 patients with moderate to severe pain (measured on a categorical pain intensity scale [PI-CAT]) were randomized to CL-108, HC/APAP, or placebo. Over the next 24 hours, patients used the PI-CAT to assess pain at regular intervals whereas nausea, vomiting, and other opioid-related side effects were also assessed prospectively. Study medications were taken every four to six hours as needed; supplemental rescue analgesic and antiemetic medications were permitted. Co-primary end points were the incidence of OINV and the time-weighted sum of pain intensity differences over 24 hours (SPID24). RESULTS: Relative to HC/APAP treatment alone, CL-108 treatment reduced OINV by 64% (P < 0.001). Treatment with CL-108 significantly reduced pain intensity compared with placebo (SPID24 = 16.2 vs 3.5, P < 0.001). There were no unexpected or serious adverse events. CONCLUSIONS: CL-108 is a safe and effective combination analgesic/antiemetic for the prevention of OINV during treatment of moderate to severe acute pain.

Safety and effectiveness of a two-step dentifrice/gel sequence with medication-associated hyposalivation: A randomized controlled trial in a vulnerable population.

PURPOSE: A randomized controlled trial was conducted to evaluate the safety and effectiveness of a two-step dentifrice/gel oral hygiene sequence in a vulnerable population. METHODS: Prior to the research, institutional review was obtained for the protocol, consent and advertising. The study targeted adults with medication-associated xerostomia, because of the plaque accumulation and possible oral safety risks seen in this population. Eligible subjects with a medication history and measured hyposalivation were randomly assigned to one of two oral hygiene groups:(1) a two-step 0.454% SnF2 dentifrice and 3% H2O2 gel sequence or (2) a regular anticavity toothpaste control. Test products were dispensed with a regular manual brush in blinded over-labeled kits with usage instructions. Subjects were evaluated at baseline and after 2 and 6 weeks of test product use. Safety was assessed as adverse events from clinical examination and interview. Digital plaque image analysis of the anterior facial teeth measured fluorescein-disclosed daytime plaque levels, and unstimulated saliva was collected over a 5-minute period in pre-weighed vials. RESULTS: A total of 49 subjects ranging from 31-80 years of age (53% female) were enrolled, and 45 completed Week 6. Only the two-step dentifrice and gel sequence differed significantly (P< 0.005) from baseline on daytime plaque coverage, and salivary flow increased significantly (P= 0.033) in that group as well. Between-group comparisons for daytime plaque favored the two-step sequence with 41-46% improvements in plaque control. At Week 6, adjusted daytime plaque means (SE) were 5.9 (0.7) and 10.0 (1.1) for the two-step and control groups, respectively (P< 0.004). Adverse events were mild in severity, groups differed significantly (P= 0.02) on occurrence, and events did not contribute to dropout. CLINICAL SIGNIFICANCE: In a randomized controlled trial among a vulnerable population, use of an oral hygiene sequence comprised of stannous fluoride dentifrice and a hydrogen peroxide whitening gel improved daily plaque control without adversely impacting salivary flow or oral health.

A randomized controlled study to evaluate an experimental moisturizing mouthwash formulation in participants experiencing dry mouth symptoms.

OBJECTIVE: The aim of this study was to evaluate the efficacy and tolerability of an experimental moisturizing mouthwash versus water only in participants experiencing dry mouth symptoms, including those with Sjögren syndrome (n = 28). STUDY DESIGN: Participants were randomized to the experimental mouthwash group (n = 53) or the water-only group (n = 47). For 8 days, the mouthwash group used 1 to 2 doses/day at home; both groups could sip water, as needed. Supervised treatment occurred on days 1, 3, and 8, and during this treatment, before and after administration, participants completed the Product Performance and Attributes Questionnaire parts 1 through 4. RESULTS: Significant between-treatment differences on all Product Performance and Attributes Questionnaire questions were shown at most time points. On day 8, at 120 minutes, there was a significant difference on Product Performance and Attributes Questionnaire 3-Question 1 ("Relieves the discomfort of dry mouth"; the predefined primary efficacy variable) in favor of mouthwash versus water (0.63 [95% confidence interval 0.17-1.10]; P = .0084). Subgroup analysis found a significant difference that favored mouthwash in participants without Sjögren syndrome (0.67 [0.11,1.23]; P = .0203) but not with Sjögren syndrome (0.52 [-0.35,1.38; P = .2272). Eight, non-serious, oral treatment-related adverse events were reported by the mouthwash group. CONCLUSIONS: The findings of a subjective questionnaire showed that an experimental moisturizing mouthwash provided greater relief than water only from dry mouth symptoms over 8 days.

Meibomian Gland Dysfunction in Primary and Secondary Sjögren Syndrome.

PURPOSE: We hypothesized that women with primary (pSS) and secondary Sjögren syndrome (sSS; with systemic lupus erythematosus [SLE] or rheumatoid arthritis [RA]) have meibomian gland dysfunction (MGD). We sought to test our hypothesis. METHODS: Subjects with pSS, sSS + SLE, sSS + RA, and non-SS-related MGD were recruited from the Sjögren's Syndrome Foundation or outpatient clinics at Tufts University School of Dental Medicine or Brigham and Women's Hospital. The control population was recruited from the Greater Boston area. After providing written informed consent, the subjects underwent an eye examination and/or completed two questionnaires that assess symptoms of dry eye disease (DED). RESULTS: Our results demonstrate that pSS and sSS patients have MGD. These subjects had meibomian gland orifice metaplasia, an increased number of occluded meibomian gland orifices, and a reduced quality of meibomian gland secretions. Further, patients with pSS, sSS + SLE, sSS + RA, and MGD had significant alterations in their tear film, lid margin, cornea, and conjunctiva. Symptoms of DED were increased ∼10-fold in all pSS, sSS, and MGD groups relative to controls. CONCLUSIONS: Our findings support our hypothesis and show that individuals with pSS, sSS + SLE, and sSS + RA have MGD. In addition, our study indicates that patients with pSS and sSS have both aqueous-deficient and evaporative DED.

Management of dry mouth: assessment of oral symptoms after use of a polysaccharide-based oral rinse.

OBJECTIVE: Salivary dysfunction is associated with a range of oral/dental issues, and management of oral symptoms may improve oral function and overall quality of life. The purpose of this pilot study was to evaluate oral symptoms and function in a xerostomic population after use of a proprietary topical for dry mouth, Moisyn (Synedgen Inc., Claremont, CA), which is a polysaccharide-based product. STUDY DESIGN: A pre- and post-test survey was completed by 57 patients with xerostomia. Patients rated their common oral symptoms, based on the Vanderbilt Head and Neck Symptom Survey, before and after 1-week use of Moisyn rinse and spray. Saliva production under resting and chewing stimulation was also assessed. RESULTS: Most patients reported relief from dry mouth symptoms and thick saliva (81.7% and 76.0%, respectively) for more than 30 minutes after product use. Statistically significant reductions were found in 15 of 33 oral symptoms. Symptom improvement ranged from 10.7% to 28.4% for thick saliva, 8.4% to 30.6% for pain, 5.5% to 30.4% for dry mouth, and 12% to 21.3% for taste/diet change. Whole unstimulated/resting saliva improved by 100%, and whole stimulated saliva improved by 23.8%. CONCLUSIONS: These findings suggest that the product has utility in symptom control in patients with xerostomia and may lead to an increase in saliva production.

Is there a relationship between periodontal conditions and number of medications among the elderly?

OBJECTIVE: To investigate possible correlations of clinical attachment level and pocket depth with number of medications in elderly individuals. METHODS: Intra-oral examinations for 139 patients visiting Tufts dental clinic were done. Periodontal assessments were performed with a manual UNC-15 periodontal probe to measure probing depth (PD) and clinical attachment level (CAL) at 6 sites. Complete lists of patients' medications were obtained during the examinations. Statistical analysis involved Kruskal-Wallis, chi square and multivariate logistic regression analyses. RESULTS: Age and health status attained statistical significance (p< 0.05), in contingency table analysis with number of medications. Number of medications had an effect on CAL: increased attachment loss was observed when 4 or more medications were being taken by the patient. Number of medications did not have any effect on periodontal PD. In multivariate logistic regression analysis, 6 or more medications had a higher risk of attachment loss (>3mm) when compared to the no-medication group, in crude OR (1.20, 95% CI:0.22-6.64), and age adjusted (OR=1.16, 95% CI:0.21-6.45), but not with the multivariate model (OR=0.71, 95% CI:0.11-4.39). CONCLUSION: CAL seems to be more sensitive to the number of medications taken, when compared to PD. However, it is not possible to discriminate at exactly what number of drug combinations the breakdown in CAL will happen. We need to do further analysis, including more subjects, to understand the possible synergistic mechanisms for different drug and periodontal responses.

Clinical practice guidelines for oral management of Sjögren disease: Dental caries prevention.

BACKGROUND: Salivary dysfunction in Sjögren disease can lead to serious and costly oral health complications. Clinical practice guidelines for caries prevention in Sjögren disease were developed to improve quality and consistency of care. METHODS: A national panel of experts devised clinical questions in a Population, Intervention, Comparison, Outcomes format and included use of fluoride, salivary stimulants, antimicrobial agents, and nonfluoride remineralizing agents. The panel conducted a systematic search of the literature according to pre-established parameters. At least 2 members extracted the data, and the panel rated the strength of the recommendations by using a variation of grading of recommendations, assessment, development, and evaluation. After a Delphi consensus panel was conducted, the experts finalized the recommendations, with a minimum of 75% agreement required. RESULTS: Final recommendations for patients with Sjögren disease with dry mouth were as follows: topical fluoride should be used in all patients (strong); although no study results link improved salivary flow to caries prevention, the oral health community generally accepts that increasing saliva may contribute to decreased caries incidence, so increasing saliva through gustatory, masticatory, or pharmaceutical stimulation may be considered (weak); chlorhexidine administered as varnish, gel, or rinse may be considered (weak); and nonfluoride remineralizing agents may be considered as an adjunct therapy (moderate). CONCLUSIONS AND PRACTICAL IMPLICATIONS: The incidence of caries in patients with Sjögren disease can be reduced with the use of topical fluoride and other preventive strategies.

Randomized Controlled Trial Evaluating Use of Two Different Oxalate Products in Adults with Recession-Associated Dentin Hypersensitivity.

A randomized positively controlled trial was conducted to evaluate the durable effects of 1.5% oxalate strips on dentin hypersensitivity. Informed consent and baseline measurements were obtained from adults with recession and air-related dentin hypersensitivity. Eligible subjects were randomized to one of two oxalate groups, either 1.5% oxalate gel strips (Crest® Sensi-Stop™ Strips, Procter and Gamble) or a professional oxalate-acid, potassium-salt solution (Super Seal® Dental Desensitizer Liner, Phoenix Dental). Test products were professionally administered at examiner-identified sensitive test sites following each manufacturer's instructions. Subjects received a blinded overwrapped anticavity paste and manual brush, two additional reapplication visits were scheduled over a 1-week period, and subjects returned 1 month later for evaluation. Sensitivity was evaluated using air and water stimuli measured by clinicians (Schiff Index) and subjects (visual analog scale), while safety was assessed by examination. The population (N = 80) was diverse with respect to gender, ethnicity, and age (22 to 82 years). At baseline, the overall mean (SD) air sensitivity was 1.34 (0.47), with individual subject means ranging from 1 to 2.5. Repeated treatment with both the commercial and professional oxalate treatments resulted in significant (P less than .05) reductions in sensitivity for all stimuli and methods. At the 1-month posttreatment recall, there were 84% to 86% reductions in clinically measured cool-air sensitivity for each oxalate group. Groups did not differ significantly (P > .57) on examiner or self-graded air or water sensitivity. In a clinical study, use of 1.5% oxalate gel strips yielded similar benefits as professionally applied oxalate treatments for adults with recession-based dentin hypersensitivity.