ImportanceInconsistent reporting of outcomes in clinical trials of rosacea is impeding and likely preventing accurate data pooling and meta-analyses. There is a need for standardization of outcomes assessed during intervention trials of rosacea.ObjectiveTo develop a rosacea core outcome set (COS) based on key domains that are globally relevant and applicable to all demographic groups to be used as a minimum list of outcomes for reporting by rosacea clinical trials, and when appropriate, in clinical practice.Evidence ReviewA systematic literature review of rosacea clinical trials was conducted. Discrete outcomes were extracted and augmented through discussions and focus groups with key stakeholders. The initial list of 192 outcomes was refined to identify 50 unique outcomes that were rated through the Delphi process Round 1 by 88 panelists (63 physicians from 17 countries and 25 patients with rosacea in the US) on 9-point Likert scale. Based on feedback, an additional 11 outcomes were added in Round 2. Outcomes deemed to be critical for inclusion (rated 7-9 by ≥70% of both groups) were discussed in consensus meetings. The outcomes deemed to be most important for inclusion by at least 85% of the participants were incorporated into the final core domain set.FindingsThe Delphi process and consensus-building meetings identified a final core set of 8 domains for rosacea clinical trials: ocular signs and symptoms; skin signs of disease; skin symptoms; overall severity; patient satisfaction; quality of life; degree of improvement; and presence and severity of treatment-related adverse events. Recommendations were also made for application in the clinical setting.Conclusions and RelevanceThis core domain set for rosacea research is now available; its adoption by researchers may improve the usefulness of future trials of rosacea therapies by enabling meta-analyses and other comparisons across studies. This core domain set may also be useful in clinical practice.

This phase 2a trial investigated the efficacy of NFX-179 Topical Gel, a metabolically labile MEK inhibitor, in the treatment of cutaneous neurofibromas (cNFs) in neurofibromatosis type 1. Forty-eight participants were randomized to four treatment arms: NFX-179 Topical Gel 0.05%, 0.15%, and 0.5% or vehicle applied once daily to five target cNFs for 28 days. Treatment with NFX-179 Topical Gel resulted in a dose-dependent reduction in p-ERK levels in cNFs at day 28, with a 47% decrease in the 0.5% NFX-179 group compared to the vehicle ( P = 0.0001). No local or systemic toxicities were observed during the treatment period, and systemic concentrations of NFX-179 remained below 1 ng/ml. In addition, 20% of cNFs treated with 0.5% NFX-179 Topical Gel showed a ≥50% reduction in volume compared to 6% in the vehicle group by ruler measurement with calculated volume ( P = 0.021). Thus, NFX-179 Topical Gel demonstrated significant inhibition of MEK in cNF with excellent safety and potential therapeutic benefit.

Topical tretinoin has historically been limited by poor tolerability and molecular instability. Research advances have enhanced its efficacy and tolerability, along with reducing oxidation and photodegradation. By overcoming historical limitations, tretinoin use can be extended to patient populations and clinical situations previously not suitable. This review discusses historical limitations of tretinoin, methods employed to overcome those limitations, use within clinical practice, and new formulations of tretinoin for the treatment of acne. J Drugs Dermatol. 2023;22(1):35-40. doi:10.36849/JDD.7146.

Background: Introduction: Historically, tretinoin use within acne has been limited by its tolerability and molecular stability. Tretinoin 0.1% has a higher rate of irritant adverse events (AEs) than lower concentrations. When used concurrently with benzoyl peroxide (BPO), the tretinoin molecule is unstable and oxidizes the BPO. New technology enables BPO and tretinoin to be combined in one cream, improving the stability of tretinoin and tolerability of the combined product.

ImportanceAlthough isotretinoin may rarely be associated with laboratory abnormalities such as hypertriglyceridemia, the optimal approach to laboratory monitoring is uncertain, and there is wide variation in clinical practice.ObjectiveTo establish a consensus for isotretinoin laboratory monitoring among a diverse, international cohort of clinical and research experts in acne.Design, Setting, and ParticipantsUsing a modified electronic Delphi process, 4 rounds of anonymous electronic surveys were administered from 2021 to 2022. For laboratory tests reaching consensus (≥70% agreement) for inclusion, questions regarding more time-specific monitoring throughout isotretinoin therapy were asked in subsequent rounds. The participants were international board-certified dermatologist acne experts who were selected on a voluntary basis based on involvement in acne-related professional organizations and research.Main Outcomes and MeasuresThe primary outcome measured was whether participants could reach consensus on key isotretinoin laboratory monitoring parameters.ResultsThe 22 participants from 5 continents had a mean (SD) time in practice of 23.7 (11.6) years and represented a variety of practice settings. Throughout the 4-round study, participation rates ranged from 90% to 100%. Consensus was achieved for the following: check alanine aminotransferase within a month prior to initiation (89.5%) and at peak dose (89.5%) but not monthly (76.2%) or after treatment completion (73.7%); check triglycerides within a month prior to initiation (89.5%) and at peak dose (78.9%) but not monthly (84.2%) or after treatment completion (73.7%); do not check complete blood cell count or basic metabolic panel parameters at any point during isotretinoin treatment (all >70%); do not check gamma-glutamyl transferase (78.9%), bilirubin (81.0%), albumin (72.7%), total protein (72.7%), low-density lipoprotein (73.7%), high-density lipoprotein (73.7%), or C-reactive protein (77.3%).Conclusions and RelevanceThis Delphi study identified a core set of laboratory tests that should be evaluated prior to and during treatment with isotretinoin. These results provide valuable data to guide clinical practice and clinical guideline development to optimize laboratory monitoring in patients treated with isotretinoin.

Rosacea is a chronic disease requiring long-term management. However, it is often treated according to package label instructions, which reflect the conditions of a Phase III study rather than a chronic disease. Furthermore, due to a lack of clinical data or guidelines on long-term treatment, many clinicians choose to discontinue treatment once success has been reached, rather than continuing with maintenance therapy. As experienced practicing dermatologists and investigators in the field, in this article we address the current evidence gaps in rosacea management and provide practical advice to clinicians on how optimal outcomes can be achieved and maintained in patients with rosacea in real-world practice, based on our own experience and the available clinical data.

Importance:Although isotretinoin may rarely be associated with laboratory abnormalities such as hypertriglyceridemia, the optimal approach to laboratory monitoring is uncertain, and there is wide variation in clinical practice.Objective:To establish a consensus for isotretinoin laboratory monitoring among a diverse, international cohort of clinical and research experts in acne.Design, Setting, and Participants:Using a modified electronic Delphi process, 4 rounds of anonymous electronic surveys were administered from 2021 to 2022. For laboratory tests reaching consensus (≥70% agreement) for inclusion, questions regarding more time-specific monitoring throughout isotretinoin therapy were asked in subsequent rounds. The participants were international board-certified dermatologist acne experts who were selected on a voluntary basis based on involvement in acne-related professional organizations and research.Main Outcomes and Measures:The primary outcome measured was whether participants could reach consensus on key isotretinoin laboratory monitoring parameters.Results:The 22 participants from 5 continents had a mean (SD) time in practice of 23.7 (11.6) years and represented a variety of practice settings. Throughout the 4-round study, participation rates ranged from 90% to 100%. Consensus was achieved for the following: check alanine aminotransferase within a month prior to initiation (89.5%) and at peak dose (89.5%) but not monthly (76.2%) or after treatment completion (73.7%); check triglycerides within a month prior to initiation (89.5%) and at peak dose (78.9%) but not monthly (84.2%) or after treatment completion (73.7%); do not check complete blood cell count or basic metabolic panel parameters at any point during isotretinoin treatment (all >70%); do not check gamma-glutamyl transferase (78.9%), bilirubin (81.0%), albumin (72.7%), total protein (72.7%), low-density lipoprotein (73.7%), high-density lipoprotein (73.7%), or C-reactive protein (77.3%).Conclusions and Relevance:This Delphi study identified a core set of laboratory tests that should be evaluated prior to and during treatment with isotretinoin. These results provide valuable data to guide clinical practice and clinical guideline development to optimize laboratory monitoring in patients treated with isotretinoin.

Since the US Food and Drug Administration (FDA) approved tretinoin in 1971, retinoids alone or combined with other agents have become the mainstay of acne treatment. Retinoids act through binding to retinoic acid receptors, altering expression levels of hundreds of cellular proteins affecting multiple pathways involved in acne pathogenesis. Retinoids have evolved from first-generation agents, such as tretinoin, through chemical modifications resulting in a second generation (etretinate and acitretin for psoriasis), a third generation (adapalene and tazarotene) and, most recently, a fourth (trifarotene). For all topical retinoids, local irritation has been associated with poor tolerability and suboptimal adherence. Efforts to improve tolerability have utilized novel delivery systems and/or novel agents. This qualitative literature review summarizes the evolution of the four topical single-agent retinoids available for the treatment of acne in the US today and their various formulations, presenting the rationale behind their development and data from key studies.

Rosacea is one of the most common inflammatory skin diseases in the United States, with a complex pathophysiology. One of the major components of the pathophysiology of rosacea is an abnormal immune detection and response to stimuli. Tetracyclines and their derivatives, including minocycline and doxycycline, have anti-inflammatory properties independent of their antibacterial activity that correlate with certain aspects of the pathophysiology, and these drugs are often used by dermatologists to treat rosacea. Biological actions of tetracyclines correlating with rosacea include anti-inflammatory and antioxidative activities, inhibitory effects on angiogenesis, and proteolysis. The objective of this review is to re-establish the current understanding of tetracyclines and their mechanism of action as they relate to the pathophysiology and treatment of rosacea for clinicians. This includes reviewing the inflammatory aspects of rosacea that correlate with the known nonantibiotic properties of tetracyclines and providing the most up-to-date clinical evidence supporting the use of tetracyclines to treat rosacea. Given the evolving and multifactorial nature of pathophysiology, this review offers clinicians a unified picture that includes research on the links between rosacea pathophysiology and clinical presentation, the nonantibiotic properties of tetracyclines that relate to pathophysiologic pathways in rosacea, and the potential for clinical application of tetracyclines in rosacea therapy.

Rosacea is a skin disease that mainly affects facial skin and eyes. It has a number of different visible signs and symptoms, or ‘features’. Doctors are currently switching from a subtype approach, which specifies groups of disease features, to a phenotype approach that treats each patient as an individual with their own particular set of features. The 2019 ROSCO panel (a panel of experts) aimed to make recommendations and produce methods that help doctors use the phenotype approach with their rosacea patients. The panel was formed of 19 skin specialists and two eye specialists from around the world. They used a process to vote how far they agreed with statements on rosacea diagnosis and management. Statements with 75% agreement were recorded as recommendations. The panel recommended that doctors should discuss disease burden with patients during appointments and offered questions to help them do this. The main treatment goal should be clear skin, because it can improve many aspects of patients’ lives. New descriptions of how rosacea affects the skin and eyes are provided, to help recognition of this disease. Recent research has been used to update recommendations for treating rosacea, including ways to combine treatments. The panel also developed the Rosacea Tracker tool, which doctors can use with patients to keep an ongoing record of their rosacea and its treatment, and a patient case study library to help doctors recognise common rosacea features. Altogether, these recommendations should continue supporting improvements in the care of patients with rosacea. This is a summary of the study: Recommendations for rosacea diagnosis, classification and management: update from the global ROSacea COnsensus 2019 panel.

FMX101 4% minocycline foam (FMX101 4%) is a novel, topical minocycline formulation for treatment of acne vulgaris. We report that FMX101 4% had an MIC90 of 0.25 μg/ml and was ≥4-fold more active than comparator antimicrobials against a panel of 98 clinical Cutibacterium acnes isolates. The panel was diverse by clonal complex and sequence type, having 20 novel multi-locus sequence types including clonal complexes and sequence types associated with acne (CC1, CC3, and CC4; ST1 and ST3). Some isolates were phenotypically resistant to clindamycin (6.1%), erythromycin (14.3%), and tetracycline (2.0% intermediate resistance). Six isolates (6.4%) carried a mutation in the quinolone resistance-determining region of gyrA. With C. acnes, spontaneous resistance to FMX101 4% occurred at frequencies ranging from ≤5 × 10-9 to <1 × 10-8; mutations were identified in rpsJ, a gene encoding 30S ribosomal protein S10. No mutant exhibited a minocycline MIC above 0.5 μg/ml. No second-step mutation in previously isolated mutants or strains containing rpsJ ± 16S rRNA mutations was detected following minocycline challenge. Minocycline retained antibacterial activity against C. acnes over 15 multiple passages; thus, no selective growth advantage for minocycline-resistant mutants occurred under the experimental conditions. FMX101 4% has the potential to retain the favorable resistance profile of minocycline in diverse C. acnes isolates while providing the benefits of a topical formulation for treatment of acne vulgaris.

This phase 2, 12-week, multicenter, randomized, double-blind, active- and vehicle-controlled (VC), parallel-group trial assessed the efficacy and safety of silica encapsulated benzoyl peroxide BP (E-BP), two concentrations of silica encapsulated tretinoin (E-ATRA) and their combinations (TWIN high and low) vs VC in 726 males and females ≥9 years of age with moderate-to-severe inflammatory facial acne. The co-primary efficacy endpoints were Investigators Global Assessment (IGA) success rate ("clear" or "almost clear") and changes from baseline in inflammatory and non-inflammatory lesion counts. TWIN high and low were each significantly superior vs VC for IGA success at 12 weeks (39.7% and 27.4%, respectively, vs 12.3%, P < 0.001 and P < 0.01). TWIN high and low resulted in mean reductions in inflammatory lesions of -16.9 (64%) and -17.0 (60.8%) vs -11.5 (42%) for VC. Reductions in non-inflammatory lesions were -23.7 for TWIN low (54.9%) and -23.6 for TWIN high (53.3%) vs -13.7 (32.4%) for VC (all P < 0.001 vs VC). Results for TWIN were also numerically superior to E-BP and E-ATRA. All treatments were safe with comparable skin tolerability. The significant superiority of both combinations over VC and numerical superiority over E-BP and E-ATRA were achieved without an increase in adverse events or reduced skin tolerability.

Importance: Previous consensus articles on rosacea from the American Acne and Rosacea Society (AARS) have focused on pathophysiology, clinical assessment based on phenotypic expressions of rosacea, management guidelines, discussions of individual medical therapies, and reviews of physical modalities. Pathophysiologic mechanisms believed to be operative in rosacea have been covered extensively in the literature. Objective: This article updates the previously published consensus recommendations from the AARS on the management of rosacea, including systematic literature and evidence-based reviews of available therapeutic agents and physical modalities. Observations: This article includes discussions of available published data on topical ivermectin, topical oxymetazoline, combination therapy approaches, and physical devices for the management of rosacea. Consistent with what many publications on rosacea currently emphasize, clinicians are encouraged to define the clinical manifestations present in the patient and to select therapies that correlate with the optimal treatment of those manifestations. There are less data available on how to optimally integrate therapies; however, it appears that rationally selected medical therapies can be utilized concurrently. Conclusion: Due to the multifactorial pathogenesis of rosacea, its clinical presentation is heterogeneous. Rosacea is a chronic and recurrent inflammatory disorder, and clinical manifestations often vary in nature and severity over time, which might necessitate an adjustment in treatment. As new data become available, rosacea management approaches should be updated.

Background Papulopustular rosacea is characterized by chronic facial erythema and inflammatory facial lesions. Minocycline has anti-inflammatory properties which may be effective in the treatment of rosacea inflammatory lesions. Objectives To assess the safety and efficacy of once-daily topical minocycline gel 1% and 3% in patients with papulopustular rosacea. Methods This was a prospective, 12-week, double-blinded study conducted at 26 sites in the United States; 270 patients with papulopustular rosacea and 12-40 inflammatory lesions were randomized to minocycline 1%, minocycline 3% or vehicle. The primary endpoint was the mean change in inflammatory lesions at week 12. Key secondary endpoints included success on an Investigator's Global Assessment (IGA). Results Baseline mean lesion counts were 24 center dot 6, 25 center dot 1 and 24 center dot 3 in the minocycline 1%, minocycline 3% and vehicle groups, respectively; at week 12, the counts had decreased by 12 center dot 6, 13 center dot 1 and 7 center dot 9, respectively. Minocycline significantly decreased lesions, compared with the vehicle [P = 0 center dot 01, 95% confidence interval (CI) 7 center dot 9 to 0 center dot 9, for minocycline 1%; P = 0 center dot 007, 95% CI 8 center dot 3 to 1 center dot 3, for minocycline 3%]. The proportion of patients achieving IGA success was 39% in the minocycline 1% arm [P = 0 center dot 34, odds ratio (OR) 1 center dot 396 and OR 95% CI 0 center dot 71 to 2 center dot 75 vs. vehicle], 46% in the minocycline 3% arm (P = 0 center dot 04, OR 2 center dot 03 and OR 95% CI 1 center dot 04 to 3 center dot 95 vs. vehicle) and 31% in the vehicle arm. Conclusions Minocycline topical gel appears to be safe and tolerable at concentrations of 1% and 3%, and both concentrations significantly decreased inflammatory lesion counts, with a significantly larger proportion of patients achieving IGA success at week 12 in the minocycline 3% arm. These findings support further evaluation of minocycline gel for treating inflammatory lesions associated with papulopustular rosacea. What is already known about this topic? Papulopustular rosacea is characterized by inflammatory facial lesions and chronic erythema of the face. Oral minocycline has been reported to have efficacy in the treatment of inflammatory lesions of papulopustular rosacea. What does this study add? The study shows that a topical gel preparation of minocycline significantly decreased the number of inflammatory lesions and significantly improved the Investigator's Global Assessment score in patients with papulopustular rosacea. This may offer a topical therapeutic alternative to oral doxycycline or oral minocycline for the treatment of inflammatory lesions in papulopustular rosacea, with potentially fewer systemic side-effects, owing to lower systemic drug exposure.

酒渣鼻是一种主要影响面部皮肤和眼睛的皮肤病。它有许多不同的可见体征和症状,或“特征”。 医生目前正在从一种亚型方法(指定疾病特征分组)转换为一种表型方法,该方法将每个患者看为一个具有其自身特定特征的个体。 2019 ROSCO 小组(专家组)旨在提出建议和制定方法来帮助医生使用表型方法治疗酒渣鼻患者。 专家组由来自世界各地的 19 名皮肤科专家和 2 名眼科专家组成。他们通过流程来投票表达他们对酒渣鼻诊断和管理方面表述的同意程度。有 75% 同意的表述被记录为建议。 专家组建议医生应该在约诊期间与患者讨论疾病负担,并提出问题以帮助他们说明情况。主要治疗目标应该是洁净的皮肤,因为它可以改善患者生活的许多方面。 提供了酒渣鼻如何影响皮肤和眼睛的新描述,以帮助识别这种疾病。最近的研究已被用于更新治疗酒渣鼻的建议,包括联合治疗方法。专家组还开发了酒渣鼻追踪工具,医生可与患者一起使用以持续记录他们的酒渣鼻及其治疗,另外还开发了一个患者病例研究库,以帮助医生识别常见的酒渣鼻特征。 总之,这些建议应该会继续帮助改善酒渣鼻患者的护理。 本摘要涉及研究:酒渣鼻诊断、分类和管理建议:全球酒渣鼻共识 2019 小组(2019 ROSCO 小组)的更新。

Summary Background Once-daily topical oxymetazoline cream 1·0% significantly reduced persistent facial erythema of rosacea in trials requiring live, static patient assessments. Objectives To evaluate critically the methodology of clinical trials that require live, static patient assessments by determining whether assessment of erythema is different when reference to the baseline photograph is allowed. Methods In two identically designed, randomized, phase III trials, adults with persistent facial erythema of rosacea applied oxymetazoline or vehicle once daily. This phase IV study evaluated standardized digital facial photographs from the phase III trials to record ≥ 1-grade Clinician Erythema Assessment (CEA) improvement at 1, 3, 6, 9 and 12 h postdose. Results Among 835 patients (oxymetazoline n =415, vehicle n =420), significantly greater proportions of patients treated with oxymetazoline vs. vehicle achieved ≥ 1-grade CEA improvement. For the comparison between phase IV study results and the original phase III analysis, when reference to baseline photographs was allowed while evaluating post-treatment photographs, the results for oxymetazoline were similar to results of the phase III trials (up to 85.7%), but a significantly lower proportion of vehicle recipients achieved ≥ 1-grade CEA improvement (up to 29.7% [phase 4] vs. 52.3% [phase 3]; P<0.001). In the phase IV study, up to 80·2% of patients treated with oxymetazoline achieved at least moderate erythema improvement vs. up to 22·9% of patients treated with vehicle. The association between patients’ satisfaction with facial skin redness and percentage of erythema improvement was statistically significant. Conclusions Assessment of study photographs, with comparison to baseline, confirmed significant erythema reduction with oxymetazoline on the first day of application. Compared with the phase III trial results, significantly fewer vehicle recipients attained ≥ 1-grade CEA improvement, suggesting a mitigated vehicle effect. This methodology may improve the accuracy of clinical trials evaluating erythema severity.

Background A transition from a subtyping to a phenotyping approach in rosacea is underway, allowing individual patient management according to presenting features instead of categorization by predefined subtypes. The ROSacea COnsensus (ROSCO) 2017 recommendations further support this transition and align with guidance from other working groups. Objectives To update and extend previous global ROSCO recommendations in line with the latest research and continue supporting uptake of the phenotype approach in rosacea through clinical tool development. Methods Nineteen dermatologists and two ophthalmologists used a modified Delphi approach to reach consensus on statements pertaining to critical aspects of rosacea diagnosis, classification and management. Voting was electronic and blinded. Results Delphi statements on which the panel achieved consensus of >= 75% voting 'Agree' or 'Strongly agree' are presented. The panel recommends discussing disease burden with patients during consultations, using four questions to assist conversations. The primary treatment objective should be achievement of complete clearance, owing to previously established clinical benefits for patients. Cutaneous and ocular features are defined. Treatments have been reassessed in line with recent evidence and the prior treatment algorithm updated. Combination therapy is recommended to benefit patients with multiple features. Ongoing monitoring and dialogue should take place between physician and patients, covering defined factors to maximize outcomes. A prototype clinical tool (Rosacea Tracker) and patient case studies have been developed from consensus statements. Conclusions The current survey updates previous recommendations as a basis for local guideline development and provides clinical tools to facilitate a phenotype approach in practice and improve rosacea patient management. What's already known about this topic? A transition to a phenotype approach in rosacea is underway and is being recommended by multiple working groups. New research has become available since the previous ROSCO consensus, necessitating an update and extension of recommendations. What does this study add? We offer updated global recommendations for clinical practice that account for recent research, to continue supporting the transition to a phenotype approach in rosacea. We present prototype clinical tools to facilitate use of the phenotype approach in practice and improve management of patients with rosacea.

Current laboratory monitoring may not be optimal. A retrospective chart review was performed on thelaboratory results of 246 patients who were treated with isotretinoin for acne over a 9-year period. Tests obtained were CBC, lipid panel, AST, ALT, CK, GGT,and C-reactive protein. Thirty-five patients had an elevated AST and 35 of these had an elevated CK; 32 had an elevated ALT and 11 of these had an elevated CK. Thirteen patients had an elevated GGT; in 5 this was the only abnormality, whereas 8 had a GGT elevation accompanied by an elevated AST or ALT. Two had an elevated GGT and an elevated CK with normal AST and ALT. Fifty-two patients had a single episode of elevated CK, of which 22 were female. However, 57 had multiple CK elevations and only one was female. Thirty-five patients had CK elevations <2 times normal; 38 had levels between 2 and 3 times normal, 18 had levels between 3 and 4 times normal, and 18 had levels greater than 4 times normal. We suggest that ALT and AST are not useful for monitoring isotretinoin therapy and that GGT and CK may be of greater value in managing patients.