Association of Apremilast With Vascular Inflammation and Cardiometabolic Function in Patients With Psoriasis: The VIP-A Phase 4, Open-label, Nonrandomized Clinical Trial.

Importance: Psoriasis is an inflammatory condition associated with metabolic and cardiovascular disease. Apremilast, a phosphodiesterase 4 inhibitor, is commonly used for psoriasis and can cause weight loss. Objective: To determine the association between apremilast and aortic vascular inflammation as assessed by 18F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT), cardiometabolic markers (primary outcomes at week 16), and abdominal fat composition. Design, Setting, and Participants: A single-arm, open-label, interventional, nonrandomized clinical trial in which the imaging and laboratory outcomes were measured by an investigator who was blinded to time was conducted between April 11, 2017, and August 17, 2021, at 7 dermatology sites in the United States. A total of 101 patients with moderate to severe psoriasis were screened, 70 enrolled, 60 completed week 16, and 39 completed week 52. Intervention: Apremilast, 30 mg, twice daily. Main Outcomes and Measures: Aortic vascular inflammation (measured by FDG-PET/CT), 68 cardiometabolic biomarkers, and abdominal fat composition (measured by CT) at week 16 and week 52 compared with baseline. Results: The mean (SD) age of the 70 patients was 47.5 (14.6) years, 54 were male (77.1%), 4 were Black (5.7%), and 58 were White (82.9%). There was no change in aortic vascular inflammation at week 16 (target to background ratio, -0.02; 95% CI, -0.08 to 0.05; P = .61) or week 52 (target to background ratio, -0.07; 95% CI, -0.15 to 0.01; P = .09) compared with baseline. At week 16, potentially beneficial decreases in interleukin 1b, valine, leucine, isoleucine, fetuin A, and branched-chain amino acids were observed. At week 52 compared with baseline, potentially beneficial decreases in ferritin, ß-hydroxybutyrate, acetone, and ketone bodies, with an increase in apolipoprotein A-1, were observed, but there was a reduction in cholesterol efflux. There was an approximately 5% to 6% reduction in subcutaneous and visceral adiposity at week 16 that was maintained at week 52. Conclusions and Relevance: The findings of this nonrandomized clinical trial suggest that apremilast has a neutral association with aortic vascular inflammation, variable but generally beneficial associations with a subset of cardiometabolic biomarkers, and associations with reductions in visceral and subcutaneous fat, indicating that the drug may have an overall benefit for patients with cardiometabolic disease and psoriasis. Trial Registration: ClinicalTrials.gov Identifier: NCT03082729.

A Phase IV, Randomized, Double-Blind, Placebo-Controlled Crossover Study of the Effects of Ustekinumab on Vascular Inflammation in Psoriasis (the VIP-U Trial).

Psoriasis is a T helper type 17 autoimmune disease associated with an increased risk cardiovascular events and mortality. Ustekinumab, an antibody to p40, blocks cytokines IL-12 and IL-23, and is a highly effective and safe treatment for psoriasis. We conducted a randomized double-blinded placebo-controlled trial to determine the effect of ustekinumab on aortic vascular inflammation (AVI) measured by imaging, and key biomarkers of inflammation, lipid, and glucose metabolism in the blood of patients with moderate-to-severe psoriasis. A total of 43 patients were randomized, and at week 12, ustekinumab-treated patients had a -18.65% (95% confidence interval = -29.45% to -7.85%) reduction in AVI, a reduction in inflammatory biomarkers, and an increase in apolipoprotein B lipoproteins compared with placebo. At week 12, placebo patients were crossed over such that all patients received ustekinumab for 52 weeks. At the end of 52 weeks of ustekinumab treatment, there was no change in AVI compared with baseline, inflammatory markers were reduced, and there were increases in selected measures of lipids and leptin. These results show that blockade of IL-12 and/or IL-23 may transiently reduce AVI, with more durable reduction in inflammatory cytokines associated with cardiovascular disease.

Prevalence of clinically significant incidental findings by whole-body fludeoxyglucose F 18 positron emission tomography/computed tomography scanning in moderate-to-severe psoriasis patients participating in clinical trials.

BACKGROUND: There has been an increase in the number of psoriasis treatments being investigated in clinical trials. Patients may have undiagnosed issues at the start of a study which may become identified during follow-up as incident medicinal conditions. The prevalence of incidental findings in patients with moderate-to-severe psoriasis presenting for clinical trials is unknown. OBJECTIVE: Determine the prevalence of incidentalomas and rate of malignancy identified by fludeoxyglucose F 18 (FDG) positron emission tomography/computed tomography (PET/CT) imaging in clinical trial patients with moderate-to-severe psoriasis. METHODS: A cross-sectional secondary analysis of patients with moderate-to-severe psoriasis who underwent FDG PET/CT scans at the baseline visit, before randomization, for 3 phase 4 clinical trials on vascular inflammation in psoriasis. Only patients without active infection, malignancy, or uncontrolled comorbidities were eligible for the clinical trials. RESULTS: A total of 259 healthy patients with moderate-to-severe psoriasis underwent an FDG PET/CT scan as part of the study procedures. In all, 31 patients (11.97%) (95% confidence interval [CI], 8.28-16.56) had clinically significant incidentalomas on the baseline FDG PET/CT scan. Univariate logistic regression demonstrated that with every increase of 10 years of age, there was an approximate 30% increased risk of discovery of an incidentaloma (odds ratio, 1.30; 95% CI, 1.01-1.68). Of those patients with findings suggestive of malignancy (n = 28), 6 were confirmed to have cancer, resulting in a 2.31% (95% CI, 0.9-5.0) prevalence of malignancy. The positive predictive value of a true cancer was 31.58% (range, 21%-54%). LIMITATIONS: Generalizability and lost to follow-up. CONCLUSION: Incidentalomas on FDG PET/CT imaging are common in otherwise healthy, asymptomatic patients with moderate-to-severe psoriasis in clinical trials. Our results can help inform interpretation of clinical trial safety data and emphasize the importance of compliance with cancer screening recommendations.

Association of HLA-DRB1 genetic variants with the persistence of atopic dermatitis.

Atopic dermatitis (AD) is a waxing and waning illness of childhood that is likely caused by interactions between an altered skin barrier and immune dysregulation. The goal of our study was to evaluate the association of DRB1 genetic variants and the persistence of AD using whole exome sequencing and high resolution typing. DRB1 was interrogated based on previous reports that utilized high throughput techniques. We evaluated an ongoing nation-wide long-term cohort of children with AD in which patients are asked every 6months about their medication use and their AD symptoms. In total, 87 African-American and 50 European-American children were evaluated. Genetic association analysis was performed using a software tool focusing on amino acid variable positions shared by HLA-DRB1 alleles covering the antigen presenting domain. Amino acid variations at position 9 (pocket 9), position 26, and position 78 (pocket 4) were marginally associated with the prevalence of AD. However, the odds ratio was 0.30 (0.14, 0.68; p=0.003) for residue 78, 0.27 (0.10, 0.69; p=0.006) for residue 26 and not significant for residue 9 with respect to the persistence of AD. In conclusion, amino acid variations at peptide-binding pockets of HLA-DRB1 were associated with the persistence of AD in African-American children.

Thymic stromal lymphopoietin variation, filaggrin loss of function, and the persistence of atopic dermatitis.

IMPORTANCE: Atopic dermatitis (AD) is a common chronic illness of childhood. OBJECTIVE: To evaluate the association between thymic stromal lymphopoietin (TSLP) variation and the persistence of skin symptoms of AD. DESIGN, SETTING, AND PARTICIPANTS: A prospective cohort study was conducted in the general community. Participants included 796 children enrolled in the Pediatric Eczema Elective Registry. EXPOSURE Evaluation of TSLP variation. MAIN OUTCOMES AND MEASURES: Self-reported outcome of whether a child's skin had no symptoms of AD and required no medications for 6 months at 6-month intervals. RESULTS: We evaluated 14 variants of TSLP. The variant rs1898671 was significantly associated with the outcome in white children (P = .01). As measured by overlapping CIs, similar odds ratios (ORs) were noted among whites (OR, 1.72; 95% CI, 1.11-2.66) and African Americans (1.33; 0.52-3.45). Further within the subcohort of individuals with a filaggrin protein (FLG) loss-of-function mutation, those with TSLP variation were more likely to have less-persistent disease (OR, 4.92; 95% CI, 2.04-11.86). CONCLUSIONS AND RELEVANCE: The TSLP variation is associated with less persistent AD. Therefore, TSLP may be a potential therapeutic target for the treatment of AD, especially in individuals with diminished barrier function due to FLG mutations. This is an attractive hypothesis that can be tested in clinical trials.

Filaggrin-2 variation is associated with more persistent atopic dermatitis in African American subjects.

BACKGROUND: Atopic dermatitis (AD) is a common skin disease characterized by recurrent episodes of itching. Genetic variation associated with the persistence of AD has not been described for African American subjects. OBJECTIVE: We sought to evaluate genetic variation of filaggrin-2 (FLG2) in African American subjects with AD. METHODS: We evaluated a multiyear prospective cohort study of African American children with AD with respect to FLG2 variation based on whole-exome sequencing, followed by a targeted analysis. We ultimately evaluated the association of rs12568784 and rs16833974 with respect to the persistence of AD symptoms over time. RESULTS: Whole-exome analysis was conducted on 60 subjects, revealing a premature stop codon in exon 3 at S2377X (rs12568784) and X2392S (rs150529054) and a large exon 3 deletion mutation, Q2053del224. On the basis of a priori criteria, we then studied rs12568784, rs16833974 (H1249R), and Q2053del224. We noted that patients with S2377X (odds ratio [OR], 0.44; 95% CI, 0.25-0.46) and H1249R (OR, 0.23; 05% CI, 0.12-0.46) were significantly less likely to be free of symptoms of AD, and Q2053del224 (OR, 0.54; 95% CI, 0.16-1.80) trended toward this outcome. S2377X and H1249R were in high linkage disequilibrium (D' = 0.95). CONCLUSIONS: In an African American cohort with AD, FLG2 mutations were associated with more persistent AD. This is the first finding of genetic variation of a skin barrier protein in subjects of African ancestry with AD.

The persistence of atopic dermatitis and filaggrin (FLG) mutations in a US longitudinal cohort.

BACKGROUND: Atopic dermatitis (AD) is a common skin disease that is characterized by recurrent episodes of itching. Filaggrin (FLG) loss-of-function (FLG null) mutations have been associated with an increased risk of AD. OBJECTIVE: We sought to evaluate the effect of individual FLG null mutations on the persistence of AD over time. METHODS: We evaluated a multiyear prospective cohort study of children with AD with respect to FLG null mutations (R501X, 2282del4, R2447X, and S3247X). We evaluated the association of these mutations with the persistence of AD symptoms over time with respect to reports of no symptoms of AD and whether topical medication was needed for symptom resolution. RESULTS: Eight hundred fifty-seven subjects were followed for 3684 person-years. One or more FLG null mutations were noted in 16.3% of subjects and specifically in 27.5% of white subjects and 5.8% of African American subjects. Subjects with an FLG null mutation were less likely (odds ratio [OR], 0.54; 95% CI, 0.41-0.71) to report that their skin was symptom free at any time compared with those without an FLG null mutation. The effect of these mutations was similar in white subjects (OR, 0.42; 95% CI, 0.31-0.57) and African-American subjects (OR, 0.53; 95% CI, 0.25-1.12; P = .62). Children with the R501X mutation (OR, 0.44; 95% CI, 0.22-0.88) were the least responsive to therapy. CONCLUSIONS: In a US cohort with AD, FLG null mutations were common. Children with FLG null mutations were more likely to have persistent AD. Although these mutations were more common in those of European ancestry, their effect on persistence was similar in those of African ancestry. Response to therapy was not uniform among children with FLG null mutations.

Association of pharyngitis with oral antibiotic use for the treatment of acne: a cross-sectional and prospective cohort study.

OBJECTIVE: To prospectively evaluate the association between antibiotics used to treat acne and pharyngitis. DESIGN: Cross-sectional and 9-month prospective cohort. SETTING: Urban university setting. PARTICIPANTS: University students. INTERVENTION: Participants were asked to fill out a survey form, were swabbed for culture, and had a visual examination for acne. MAIN OUTCOME MEASURE: Report of pharyngitis. RESULTS: In the cross-sectional study, 10 of the 15 students receiving oral antibiotics for acne reported an episode of pharyngitis in the previous 30 days, whereas 47 of the 130 students not receiving oral antibiotics, but who had acne, reported an episode of pharyngitis in the prior month. The unadjusted odds ratio (OR) (95% CI) associating current oral antibiotic use in acne patients with a self-reported episode of pharyngitis was 3.53 (95% CI, 1.14-10.95). In the cohort study, there were 358 female and 218 male participants; 36 (6.2%) received oral antibiotics for acne during the study, and 96 (16.6%) received topical antibiotics for acne. Using mixed model logistic regression, the OR was 4.34 (95% CI, 1.51-12.47) associating oral antibiotic use with pharyngitis. Less than 1% of participants were colonized by group A streptococcus, which was not associated with pharyngitis. CONCLUSIONS: Our studies show that that the odds of reporting pharyngitis is more than 3 times baseline in patients receiving oral antibiotics for acne vs those who are not receiving oral antibiotics. The true clinical importance of these findings needs to be evaluated further by prospective studies, but this finding is not associated with group A streptococcus.

Phase I study of H5.020CMV.PDGF-beta to treat venous leg ulcer disease.

Venous leg ulcers are a prevalent nonhealing wound of the lower extremity. Although topically applied growth factors successfully improve wound repair in animal studies, similar studies on humans with venous leg ulcers have not been successful. This study was designed to evaluate the acute safety and biologic feasibility of peri-ulcer injection of a replication-incompetent adenoviral construct expressing platelet-derived growth factor-beta (PDGF-beta). In this phase I study, we demonstrate the initial safety, feasibility, and biologic plausibility of using H5.020CMV.PDGF-beta to treat venous leg ulcer disease.