Systemic Immunomodulatory Treatments for Atopic Dermatitis: Living Systematic Review and Network Meta-Analysis Update.

Importance: There are multiple approved systemic treatments for atopic dermatitis. Lebrikizumab is a newly licensed biologic medication that has been compared to placebo in clinical trials but not to other systemic treatments. Objective: To compare reported measures of efficacy and safety of lebrikizumab to other systemic treatments for atopic dermatitis in a living systematic review and network meta-analysis. Data Sources: The Cochrane Central Register of Controlled Trials, MEDLINE, Embase, the Latin American and Caribbean Health Science Information database, the Global Resource of Eczema Trials database, and trial registries were searched from inception through November 3, 2023. Study Selection: Randomized clinical trials evaluating 8 or more weeks of treatment with systemic immunomodulatory medications for moderate to severe atopic dermatitis. Titles, abstracts, and full texts were screened in duplicate. Data Extraction and Synthesis: Data were abstracted in duplicate and random-effects bayesian network meta-analyses were performed. Minimal important differences were used to define important differences between medications. Certainty of evidence was assessed using the GRADE approach (Grading of Recommendations Assessment, Development and Evaluation). The updated analysis was completed from December 13, 2023, to February 20, 2024. Main Outcome Measures: Efficacy outcomes were the Eczema Area and Severity Index (EASI), the Patient Oriented Eczema Measure (POEM) Dermatology Life Quality Index (DLQI), and Peak Pruritus Numeric Rating Scales (PP-NRS) and were compared using mean difference (MD) with 95% credible intervals (CrI). Safety outcomes were serious adverse events and withdrawal due to adverse events. Other outcomes included the proportion of participants with 50%, 75%, and 90% improvement in EASI (EASI-50, -75, -90) and the proportion with success on the Investigator Global Assessment compared using odds ratios with 95% CrI. Results: The study sample included 98 eligible trials, with a total of 24 707 patients. Lebrikizumab was associated with no important difference in change in EASI (MD, -2.0; 95% CrI, -4.5 to 0.3; moderate certainty), POEM (MD, -1.1; 95% CrI -2.5 to 0.2; moderate certainty), DLQI (MD, -0.2; 95% CrI -2.1 to 1.6; moderate certainty), or PP-NRS (MD, 0.1; 95% CrI -0.4, 0.6; high certainty) compared to dupilumab among adults with atopic dermatitis who were treated for up to 16 weeks. Dupilumab was associated with higher odds of efficacy in binary outcomes compared with lebrikizumab. The relative efficacy of other approved systemic medications was similar to that found by previous updates of this living study, with high-dose upadacitinib and abrocitinib demonstrating numerically highest relative efficacy. For safety outcomes, low event rates limited useful comparisons. Conclusions and Relevance: In this living systematic review and network meta-analysis, lebrikizumab was similarly effective to dupilumab for the short-term treatment of atopic dermatitis in adults. Clinicians and patients can use these comparative data to inform treatment decisions.

Comparing binary efficacy outcomes for systemic immunomodulatory treatments for atopic dermatitis in a living systematic review and network meta-analysis.

BACKGROUND: Systemic treatments for atopic dermatitis (AD) are evaluated primarily in placebo-controlled trials with binary efficacy outcomes. In a living systematic review and network meta-analysis (NMA), we previously analysed continuous efficacy measures. OBJECTIVES: To compare binary efficacy outcomes of systemic treatments for AD. METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, Latin American and Caribbean Health Science Information (LILACS) database, Global Resource for Eczema Trials (GREAT) database and trial registries up to 1 March 2023. We included randomized trials examining ≥ 8 weeks of treatment with systemic immunomodulatory medications for moderate-to-severe AD. We screened titles, abstracts and full texts and abstracted data independently, in duplicate. Outcomes included the proportion of patients achieving at least 50%, 75% and 90% improvements in Eczema Area and Severity Index (EASI 50, EASI 75 and EASI 90, respectively) and Investigator Global Assessment (IGA) success. We performed random-effects Bayesian NMAs to calculate odds ratios (OR) and 95% credible intervals (CrIs) between each intervention for each outcome. RESULTS: Eighty-three trials with 22 122 participants were included in the systematic review. In analyses limited to trials of 8-16 weeks' duration with predominantly adult populations, abrocitinib 200 mg daily (OR 1.5, 95% CrI 1.1-2.2) and upadacitinib 15 mg daily (OR 1.7, 95% CrI 0.9-3.3) and 30 mg daily (OR 2.5, 95% CrI 1.3-5.0) were associated with higher odds of achieving EASI 50 vs. dupilumab. Abrocitinib 100 mg daily (OR 0.7, 95% CrI 0.5-1.0), baricitinib 2 mg daily (OR 0.4, 95% CrI 0.3-0.5) and 4 mg daily (OR 0.5, 95% CrI 0.3-0.7), and tralokinumab (OR 0.4, 95% CrI 0.3-0.6) were associated with lower odds of achieving EASI 50 vs. dupilumab. Results were similar for EASI 75, EASI 90 and IGA success. CONCLUSIONS: Supporting results for continuous outcome measures, upadacitinib 30 mg daily and abrocitinib 200 mg daily are the most efficacious with regard to binary efficacy endpoints up to 16 weeks in adults with moderate-to-severe AD, followed by upadacitinib 15 mg daily, dupilumab and abrocitinib 100 mg daily. Dupilumab and both doses of upadacitinib and abrocitinib are more efficacious than baricitinib 4 and 2 mg daily and tralokinumab.

Exploring the emotional impact of axial Spondyloarthritis: a systematic review and thematic synthesis of qualitative studies and a review of social media.

BACKGROUND: The psychological burden in people with inflammatory arthritis is substantial, yet little is known about the disease-related affect experienced by individuals with axial Spondyloarthritis (axial SpA). The aim of this study was to conduct a qualitative evidence synthesis and a review of social media to explore the emotional impact of living with axial SpA. METHODS: We searched nine databases for studies reporting qualitative data about participants' emotional experience of living with axial SpA. In addition, we searched social media platforms for posts from people with axial SpA based in the UK that offered insights into emotional responses to living with the condition. We employed a thematic approach to synthesise the data. RESULTS: We included 27 studies (1314 participants; 72% men) in our qualitative evidence synthesis and developed seven descriptive themes from the data: 1) delayed diagnosis: a barrier to emotional wellbeing; 2) disruptive symptoms: a source of mood swings; 3) work disability: a loss of self-esteem; 4) obstacles in interpersonal relationships: a trigger of distress; 5) taking up exercise: personal pride or unwelcomed reminders; 6) anti-TNF therapy: hope reignited despite concerns and 7) a journey of acceptance: worry mixed with hope. Posts extracted from social media fora (537; 48% from women) for the most part supported the seven themes. One additional theme-COVID-19, uncertainty and anxiety during the pandemic, was developed, reflecting common emotions expressed during the UK's first wave of the coronavirus pandemic. CONCLUSION: This study highlights a preponderance of negative affect experienced by people living with axial SpA, conditioned through existing and anticipated symptoms, failed expectations, and lost sense of self. Given the bidirectional relationships between negative emotions and inflammation, negative emotions and perceptions of pain, and the influence of affect in self-care behaviours, this finding has important implications for treatment and management of people with axial SpA.

A Systematic Review and Meta-Analysis of the Role of Sugar-Free Chewing Gum on Plaque Quantity in the Oral Cavity.

Background: The aim of this systematic review of published literature was to answer the research question, "What is the difference in the level of plaque quantity, in adults and children who chew sugar-free gum (SFG), compared with those who do not chew SFG, who do not chew gum, or who use alternatives such as probiotics or fluoride varnish?". Methods: The systematic review [registered on PROSPERO 2018 (CRD42018094676)] included studies on adults and children with chewing of SFG as the main intervention, where "sugar" referred to monosaccharides and disaccharides. Included studies were in English and corresponded to primary research published between 1946 and 2020. The search conducted spanned all relevant databases using both Medical Subject Headings (MESH) and free text with combinations of "chewing gum," "sugar-free," "caries," "xerostomia," "periodontal disease." Results: Eight articles included plaque quantity as part of their outcomes. Meta-analysis showed that SFG significantly reduced plaque quantity (effect size-0.778; 95% CI-1.167 to-0.39). The correlation between the baseline and the end of study data was assumed to be 0.95 for the control and 0.65 for the SFG group. A sensitivity analysis was conducted with the pre- to post-test correlation, set at 0.95 for the SFG group. This gave an effect size of-1.098 (95% CI-1.539 to-0.656) with I 2 = 89.73%. When looking more specifically at xylitol gum, the results of the meta-analysis showed that it significantly reduced plaque quantity (effect size-0.743; 95% CI-1.148 to-0.338). There was a high degree of heterogeneity between studies with I 2 = 86.0%. Conclusion: There is some evidence that chewing sugar-free gum, in particular xylitol SFG, reduces the quantity of plaque in the oral cavity in comparison to non SFG chewing or no chewing controls. Further research with improved design, lengthier timeframes and higher number of participants should be considered. Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=94676.

Systemic Immunomodulatory Treatments for Atopic Dermatitis: Update of a Living Systematic Review and Network Meta-analysis.

Importance: Systemic treatments for atopic dermatitis are being evaluated primarily in placebo-controlled trials; network meta-analysis can provide relative efficacy and safety estimates for treatments that have not been compared head to head. Objective: To compare reported measures of efficacy and assessments of safety in clinical trials of systemic treatments for atopic dermatitis in a living systematic review and network meta-analysis. Data Sources: The Cochrane Central Register of Controlled Trials, MEDLINE, Embase, Latin American and Caribbean Health Science Information database, Global Resource of EczemA Trials database, and trial registries were searched through June 15, 2021. Study Selection: Randomized clinical trials examining 8 or more weeks of treatment with systemic immunomodulatory medications for moderate-to-severe atopic dermatitis were included after screening titles, abstracts, and papers in duplicate. Data Extraction and Synthesis: Data were abstracted in duplicate. Bayesian network meta-analyses and assessed Grading of Recommendations Assessment, Development and Evaluation certainty of evidence were performed. The updated analysis was completed from June to December 2021. Main Outcomes and Measures: Outcomes include change in Eczema Area and Severity Index (EASI), Patient Oriented Eczema Measure (POEM), Dermatology Life Quality Index (DLQI), and Peak Pruritus Numeric Rating Scales (PP-NRS). Results: Since October 2019, 21 new studies were added, for a total of 60 trials with 16 579 patients. Up to 16 weeks of treatment in adults, abrocitinib, 200 mg daily (mean difference [MD], 2.2; 95% credible interval [CrI], 0.2-4.0; high certainty) and upadacitinib, 30 mg daily (MD, 2.7; 95% CrI, 0.6-4.7; high certainty) were associated with reduced EASI slightly more than dupilumab, 600 mg then 300 mg every 2 weeks. Abrocitinib, 100 mg daily (MD, -2.1; 95% CrI, -4.1 to -0.3; high certainty), baricitinib, 4 mg daily (MD, -3.2; 95% CrI, -5.7 to -0.8; high certainty), baricitinib, 2 mg daily (MD, -5.2; 95% CrI, -7.5 to -2.9; high certainty) and tralokinumab, 600 mg then 300 mg every 2 weeks (MD, -3.5; 95% CrI, -5.8 to -1.3; high certainty) were associated with reduced EASI slightly less than dupilumab. There was little or no difference between upadacitinib, 15 mg daily, and dupilumab (MD, 0.2; 95% CrI, -1.9 to 2.2; high certainty). The pattern of results was similar for POEM, DLQI, and PP-NRS. Conclusions and Relevance: In this systematic review and meta-analysis, abrocitinib, 200 mg; and upadacitinib, 30 mg daily, were associated with slightly better scores than dupilumab, and upadacitinib, 15 mg daily, was associated with similar scores to dupilumab. Abrocitinib, 100 mg daily, baricitinib, 4 mg and 2 mg daily, and tralokinumab, 300 mg, every 2 weeks were associated with slightly worse scores.

A systematic review and meta-analysis of the role of sugar-free chewing gum on Streptococcus mutans.

BACKGROUND: Preventive strategies targeting Streptococcus mutans may be effective in reducing the global burden of caries. The aim of the current systematic review of published literature was to determine the difference in level of Streptococcus mutans in adults and children who chew sugar-free gum (SFG), compared with those who did not chew gum, who chewed a control gum or received alternatives such as probiotics or fluoride varnish. METHODS: Systematic review (PROSPERO registration No. CRD42018094676) of controlled trials with adult and child participants where chewing of SFG was the main intervention. Databases searched (1 Jan 1946 to 31 August 2020): MEDLINE, EMBASE, PsycINFO, Scopus, Web of Science, Allied and Complimentary Medicine Database, Cochrane Central Register of Controlled Trials (CENTRAL), Open Grey, PROSPERO and the Cochrane library of systematic reviews. 'Search terms included Medical Subject Headings, and free text to cover the following range of constructs: chewing gum, sugar free, oral health, caries, xerostomia, periodontal disease. Data extraction and Risk of Bias assessment was undertaken by three researchers using a modified version of the Cochrane RoB tool (version 1). Data synthesis was conducted using meta-analysis in STATA. RESULTS: Thirteen studies of SFG with micro-organisms as outcomes were identified. The use of SFG significantly reduced the load of Streptococcus mutans (effect size - 0.42; 95% CI - 0.60 to - 0.25) compared to all controls. In seven of the 13 studies the confidence intervals of the effect size estimate included zero, suggesting no effect of the intervention. Twelve trials used xylitol gum only as the basis of the intervention; xylitol gum significantly reduced the load of Streptococcus mutans (effect size - 0.46; 95% CI - 0.64 to - 0.28) in comparison to all controls. There was a moderate level of heterogeneity across the included studies. No adverse effects were recorded. CONCLUSION: Chewing SFG reduces the load of Streptococcus mutans in the oral cavity in comparison to non-chewing controls. Considering the degree of variability in the effect and the moderate quality of the trials included, there is a need for future research exploring the use SFG as a preventive measure for reducing the cariogenic oral bacterial load.

Systemic Immunomodulatory Treatments for Patients With Atopic Dermatitis: A Systematic Review and Network Meta-analysis.

Importance: Most clinical trials assessing systemic immunomodulatory treatments for patients with atopic dermatitis are placebo-controlled. Objective: To compare the effectiveness and safety of systemic immunomodulatory treatments for patients with atopic dermatitis in a systematic review and network meta-analysis. Data Sources: The Cochrane Central Register of Controlled Trials, MEDLINE, Embase, Latin American and Caribbean Health Science Information database, Global Resource of Eczema Trials database, and clinical trial registries were searched from inception to October 28, 2019. Study Selection: English-language randomized clinical trials of 8 weeks or more of treatment with systemic immunomodulatory medications for moderate to severe atopic dermatitis were included. Titles, abstracts, and articles were screened in duplicate. Of 10 324 citations, 39 trials were included. Data Extraction and Synthesis: Data were extracted in duplicate, and the review adhered to Preferred Reporting Items for Systematic Reviews and Meta-analyses for Network Meta-Analyses guidelines. Random-effects bayesian network meta-analyses were performed and certainty of evidence was assessed using Grading of Recommendations Assessment, Development and Evaluation criteria. Main Outcomes and Measures: Prespecified outcomes were change in signs of disease, symptoms, quality of life, itch, withdrawals, and serious adverse events. Results: A total of 39 trials with 6360 patients examining 20 medications and placebo were included. Most trials were conducted for adults receiving up to 16 weeks of therapy. Dupilumab, 300 mg every 2 weeks, was associated with improvement in the Eczema Area and Severity Index score vs placebo (mean difference, 11.3-point reduction; 95% credible interval [CrI], 9.7-13.1 [high certainty]). Cyclosporine (standardized mean difference, -1.1; 95% CrI, -1.7 to -0.5 [low certainty]) and dupilumab (standardized mean difference, -0.9; 95% CrI, -1.0 to -0.8 [high certainty]) were similarly effective vs placebo in clearing clinical signs of atopic dermatitis and may be superior to methotrexate (standardized mean difference, -0.6; 95% CrI, -1.1 to 0.0 [low certainty]) and azathioprine (standardized mean difference, -0.4; 95% CrI, -0.8 to -0.1 [low certainty]). Several investigational medications for atopic dermatitis are promising, but data to date are limited to small early-phase trials. Safety analyses were limited by low event rates. Conclusions and Relevance: Dupilumab and cyclosporine may be more effective for up to 16 weeks of treatment than methotrexate and azathioprine for treating adult patients with atopic dermatitis. More studies directly comparing established and novel treatments beyond 16 weeks are needed and will be incorporated into future updates of this review.