Trifarotene Reduces Risk for Atrophic Acne Scars: Results from A Phase 4 Controlled Study.

BACKGROUND: Atrophic acne scarring often accompanies acne vulgaris. The efficacy of topical retinoids for treatment of acne is well documented; however, evidence for use in atrophic acne scars is limited. METHODS: In this randomized, split-face, double-blind study, subjects (age: 17-34 years, N = 121) with moderate-to-severe facial acne, with acne scars present, were treated with either trifarotene 50 µg/g or vehicle once daily for 24 weeks. Efficacy was assessed by absolute and percent change from baseline in atrophic acne scar counts, Scar Global assessment (SGA), and IGA success rates as well as acne lesion counts. RESULTS: At week 24, a statistically significantly greater reduction in the mean absolute change from baseline in the total atrophic scar count was noted in the trifarotene- vs vehicle-treated area (- 5.9 vs - 2.7; p < 0.0001) with differences between sides noted as early as week 2 (- 1.5 vs - 0.7; p = 0.0072). The SGA success rate was higher in the trifarotene side at week 12 (14.9% vs 5.0%, P < 0.05) and improved through week 24 (31.3% vs 8.1%, P < 0.001). Similarly, at week 24, the IGA success rate was higher with trifarotene (63.6% vs 31.3%, P < 0.0001) along with reductions in total (70% vs 45%) and inflammatory (76% vs 48%) lesion counts. The incidence of treatment-emergent adverse events was 5.8% (trifarotene) and 2.5% (vehicle); most common (> 1%) was skin tightness (1.7% vs 0.8%), and all events were mild to moderate in severity. CONCLUSIONS: Trifarotene was effective and well tolerated in treating moderate-to-severe facial acne and reducing atrophic acne scars, with reduction of total atrophic scar count as early as week 2. TRIAL REGISTRATION: Clinicaltrials.gov NCT04856904.

Enhanced Effectiveness of Adalimumab Compared to Topical/Traditional Systemic Agents in the Treatment of Moderate to Severe Plaque Psoriasis: Results from a Canadian Observational Epidemiologic Study (COMPLETE-PS).

INTRODUCTION: Real-world evidence is important for post-marketing evaluation. Data comparing adalimumab's effectiveness and safety with traditional therapies in clinical settings are currently lacking. The aim of this study was to compare real-world effectiveness of adalimumab versus topical/traditional systemic agents for management of moderate to severe plaque psoriasis METHODS: Patients requiring change in treatment were enrolled between 2011 and 2016 and followed per routine care for up to 24 months. Achievement of Physician Global Assessment (PGA) ≤ 1.0 at 6 months was assessed with logistic regression; time to achievement was assessed using Cox regression. Additional outcomes were assessed using repeated measures mixed models. RESULTS: Patients receiving adalimumab (n = 293) versus topical/traditional systemic agents (n = 302) were more likely to achieve PGA ≤ 1.0 at 6 months (odds ratio 2.37, 95% confidence interval [CI] 1.31-4.30) in a shorter time (hazard ratio 2.14, 95% CI 1.53-3.00), reporting both lower body surface area and improved quality of life and work productivity. CONCLUSION: In this real-world study, adalimumab was more effective than topical/traditional systemic agents at reducing disease activity and improving quality of life outcomes among Canadians with moderate to severe plaque psoriasis. (NCT00799877).

Long-Term Effectiveness and Safety of Up to 48 Weeks' Treatment with Topical Adapalene 0.3%/Benzoyl Peroxide 2.5% Gel in the Prevention and Reduction of Atrophic Acne Scars in Moderate and Severe Facial Acne.

BACKGROUND: Scarring is a frequent consequence of acne. OBJECTIVES: Our objective was to evaluate the effect of up to 48 weeks' treatment with adapalene 0.3%/benzoyl peroxide 2.5% (A0.3/BPO2.5) gel on atrophic scars in moderate or severe acne vulgaris. METHODS: In Part 1 of this two-part study, A0.3/BPO2.5 gel or vehicle was applied on each half-face for 24 weeks in a randomized, investigator-blinded, split-face design. Part 2 was a 24-week, open-label extension phase during which A0.3/BPO2.5 gel was applied on both sides of the face. Assessments included investigator atrophic acne scar count, Scar Global Assessment (SGA), acne lesion count, local tolerability, and safety. RESULTS: Of the 45 subjects entering Part 2, 41 completed the 48-week study. At baseline (Part 1), most subjects had moderate acne (93.3%) with mild scars (62.2%). The scar count decrease from baseline was 21.7% at week 24 and 26.9% at week 48 on the half-face treated for 48 weeks with A0.3/BPO2.5. For the half-face treated with vehicle followed by 24 weeks' A0.3/BPO2.5, scar count increased by 16.7% at week 24 (under vehicle) and decreased by 22.7% between weeks 24 and 48. The half-face that received 48 weeks' A0.3/BPO2.5 had a lower final atrophic scar count (mean 8.4 vs. 9.9 for the half-face with 24 weeks' vehicle then 24 weeks' A0.3/BPO2.5) and a higher percentage of SGA clear/almost clear. High reductions in acne lesions between baseline and week 48 were observed for both sides of the face. Long-term treatment with A0.3/BPO2.5 was safe and well-tolerated. CONCLUSIONS: Reductions in atrophic acne scars and acne lesions observed after 24 weeks of treatment with A0.3/BPO2.5 gel were maintained with treatment up to 48 weeks. The additional improvement in atrophic scar count with 48 weeks' A0.3/BPO2.5 treatment, compared to delayed application at 24 weeks, highlights the importance of early initiation of effective acne treatment to prevent and reduce the formation of acne scars. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT02735421.

Prevention and Reduction of Atrophic Acne Scars with Adapalene 0.3%/Benzoyl Peroxide 2.5% Gel in Subjects with Moderate or Severe Facial Acne: Results of a 6-Month Randomized, Vehicle-Controlled Trial Using Intra-Individual Comparison.

BACKGROUND: Very few clinical trials have investigated the effect of topical acne treatment on scarring. OBJECTIVES: Our objective was to evaluate the efficacy of adapalene 0.3%/benzoyl peroxide 2.5% gel (A0.3/BPO2.5) in atrophic acne scar formation in patients with acne. METHODS: In this multicenter, randomized, investigator-blinded, vehicle-controlled study, subjects with moderate or severe facial acne (Investigator's Global Assessment [IGA] score 3 or 4; ≥ 25 inflammatory lesions; ten or more atrophic acne scars) applied A0.3/BPO2.5 or vehicle daily per half face for 24 weeks. Subjects with acne requiring systemic treatment were excluded. Assessments included investigator atrophic acne scar count, Scar Global Assessment (SGA), acne lesion count, IGA, skin roughness and skin texture, subject self-assessment of clinical acne-related scars and satisfaction questionnaire, tolerability, and safety. RESULTS: Included subjects (n = 67) had mainly moderate acne (92.5% IGA 3); mean scores at baseline were approximately 40 acne lesions and 12 scars per half face. By week 24, the change from baseline in total scar count was - 15.5% for A0.3/BPO2.5 versus + 14.4% for vehicle (approximately 30% difference), with a mean of 9.5 scars versus 13.3 per half face, respectively (p < 0.0001). For SGA at week 24, a total of 32.9% with A0.3/BPO2.5 versus 16.4% with vehicle (p < 0.01) were clear/almost clear. Inflammatory acne lesions decreased by 86.7% for A0.3/BPO2.5 versus 57.9% for vehicle (p < 0.0001), and 64.2 versus 19.4% of subjects, respectively, were IGA clear/almost clear (p < 0.0001) at week 24. Treatment-related AEs were reported by 20.9% for A0.3/BPO2.5 versus 9% for vehicle side, most commonly skin irritation (14.9 vs. 6%, respectively). CONCLUSIONS: Topical A0.3/BPO2.5 prevented and reduced atrophic scar formation. Scar count increased with vehicle (+ 14.4%) but decreased with A0.3/BPO2.5 (- 15.5%) over 24 weeks. TRIAL REGISTRY: ClinicalTrials.gov identifier NCT02735421.

C-C chemokine receptor-7 mediated endocytosis of antibody cargoes into intact cells.

The C-C chemokine receptor-7 (CCR7) is a G protein coupled receptor that has a role in leukocyte homing, but that is also expressed in aggressive tumor cells. Preclinical research supports that CCR7 is a valid target in oncology. In view of the increasing availability of therapeutic monoclonal antibodies that carry cytotoxic cargoes, we studied the feasibility of forcing intact cells to internalize known monoclonal antibodies by exploiting the cycle of endocytosis and recycling triggered by the CCR7 agonist CCL19. Firstly, an anti-CCR7 antibody (CD197; clone 150503) labeled surface recombinant CCR7 expressed in intact HEK 293a cells and the fluorescent antibody was internalized following CCL19 treatment. Secondly, a recombinant myc-tagged CCL19 construction was exploited along the anti-myc monoclonal antibody 4A6. The myc-tagged ligand was produced as a conditioned medium of transfected HEK 293a cells that contained the equivalent of 430 ng/ml of immunoreactive CCL19 (average value, ELISA determination). CCL19-myc, but not authentic CCL19, carried the fluorophore-labeled antibody 4A6 into other recipient cells that expressed recombinant CCR7 (microscopy, cytofluorometry). The immune complexes were apparent in endosomal structures, co-localized well with the small GTPase Rab5 and progressed toward Rab7-positive endosomes. A dominant negative form of Rab5 (GDP-locked) inhibited this endocytosis. Further, endosomes in CCL19-myc- or CCL19-stimulated cells were positive for ß-arrestin2, but rarely for ß-arrestin1. Following treatment with CCL19-myc and the 4A6 antibody, the melanoma cell line A375 that expresses endogenous CCR7 was specifically stained using a secondary peroxidase-conjugated antibody. Agonist-stimulated CCR7 can transport antibody-based cargoes, with possible therapeutic applications in oncology.

Cation trapping by cellular acidic compartments: beyond the concept of lysosomotropic drugs.

"Lysosomotropic" cationic drugs are known to concentrate in acidic cell compartments due to low retro-diffusion of the protonated molecule (ion trapping); they draw water by an osmotic mechanism, leading to a vacuolar response. Several aspects of this phenomenon were recently reexamined. (1) The proton pump vacuolar (V)-ATPase is the driving force of cationic drug uptake and ensuing vacuolization. In quantitative transport experiments, V-ATPase inhibitors, such as bafilomycin A1, greatly reduced the uptake of cationic drugs and released them in preloaded cells. (2) Pigmented or fluorescent amines are effectively present in a concentrated form in the large vacuoles. (3) Consistent with V-ATPase expression in trans-Golgi, lysosomes and endosomes, a fraction of the vacuoles is consistently labeled with trans-Golgi markers and protein secretion and endocytosis are often inhibited in vacuolar cells. (4) Macroautophagic signaling (accumulation of lipidated and membrane-bound LC3 II) and labeling of the large vacuoles by the autophagy effector LC3 were consistently observed in cells, precisely at incubation periods and amine concentrations that cause vacuolization. Vacuoles also exhibit late endosome/lysosome markers, because they may originate from such organelles or because macroautophagosomes fuse with lysosomes. Autophagosome persistence is likely due to the lack of resolution of autophagy, rather than to nutritional deprivation. (5) Increased lipophilicity decreases the threshold concentration for the vacuolar and autophagic cytopathology, because simple diffusion into cells is limiting. (6) A still unexplained mitotic arrest is consistently observed in cells loaded with amines. An extended recognition of relevant clinical situations is proposed for local or systemic drug administration.

Unusual case of proximal calciphylaxis without renal failure.

BACKGROUND: Calciphylaxis is a rare syndrome of vascular calcification with subsequent cutaneous and tissue necrosis. It usually manifests as a complication of end-stage renal failure, affecting 1 to 4% of long-term dialysis patients. Very exceptionally, it can occur without chronic renal failure. OBJECTIVE: The goal of this study was to discuss an exceptional case of extensive calciphylaxis in the absence of chronic renal failure and its successful management. METHODS: We present a case of a 31-year-old woman with extensive proximal, ulcerated calciphylaxis without associated chronic renal failure. Our patient had quite a few risk factors associated with the pathogenesis of calciphylaxis, such as obesity, malnutrition, and a transient episode of acute renal failure. RESULTS: She was successfully treated with sodium thiosulfate, extensive wound débridement (more than 30% total body surface), and subsequent skin grafts. The patient has miraculously survived this often fatal condition. CONCLUSION: Calciphylaxis can occur even in the absence of chronic renal failure. This often fatal condition can be managed successfully with a combination of aggressive wound control and the fairly newly described sodium thiosulfate therapy.