Effect of NFX-179 MEK inhibitor on cutaneous neurofibromas in persons with neurofibromatosis type 1.

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.

Rosacea Core Domain Set for Clinical Trials and Practice: A Consensus Statement.

Importance: Inconsistent 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. Objective: To 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 Review: A 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. Findings: The 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 Relevance: This 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.

Tretinoin Review With Newer Formulations: Providing Effective and Tolerable Solutions in Clinical Practice.

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.

How to Optimize Rosacea Treatment for Better Patient Outcomes: An Opinion Piece.

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.

Isotretinoin Laboratory Monitoring in Acne Treatment: A Delphi Consensus Study.

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.

Nonantibiotic Properties of Tetracyclines in Rosacea and Their Clinical Implications.

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.

50 Years of Topical Retinoids for Acne: Evolution of Treatment.

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.

Update on the Management of Rosacea from the American Acne & Rosacea Society (AARS).

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.

Susceptibility of Cutibacterium acnes to topical minocycline foam.

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.

Microencapsulated Benzoyl Peroxide and Tretinoin for the Treatment of Acne Vulgaris: Results from a Phase 2 Multicenter, Double-Blind, Randomized, Vehicle-Controlled Study.

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.

Update on the Management of Rosacea from the American Acne & Rosacea Society (AARS).

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.

Tumour Seeding in the Tract of Percutaneous Renal Tumour Biopsy: A Report on Seven Cases from a UK Tertiary Referral Centre.

The role of percutaneous renal tumour biopsy (RTB) in the management of radiological indeterminate renal masses is long established. Patients with small renal masses who have biopsy-proven renal cell carcinoma (RCC) may be offered surgery, ablative therapy, or active surveillance, and RTB can provide diagnostic tissue from patients with metastatic disease who might benefit from systemic therapy. Current guidelines suggest that tumour seeding along the needle tract is anecdotal, but several cases have been reported recently, although some have been associated with lack of a coaxial sheath. We report on seven patients who underwent surgical resection of RCC in our tertiary referral institution following diagnostic RTB between 2014 and 2017 for whom RTB tract seeding by tumour was identified on histological examination of the resection specimen. One of these patients subsequently developed local tumour recurrence at the site of the previous biopsy.

Defining treatment success in rosacea as 'clear' may provide multiple patient benefits: results of a pooled analysis.

BACKGROUND: Rosacea treatment success is usually defined as a score of 1 ('almost clear') or 0 ('clear') on the 5-point Investigator Global Assessment (IGA) scale. OBJECTIVE: To evaluate whether, after successful treatment, 'clear' subjects had better outcomes than 'almost clear' subjects. METHODS: A pooled analysis was performed on 1366 rosacea subjects from four randomized controlled trials with IGA before and after treatment (ivermectin, metronidazole or vehicle). Assessments included the Dermatology Life Quality Index (DLQI) questionnaire and subject assessment of rosacea improvement. In one trial, patients were followed after the treatment period to measure time to relapse (IGA score ≥2). RESULTS: At end of treatment, more 'clear' than 'almost clear' subjects had a clinically meaningful difference in DLQI (59% vs. 44%; p < .001) and a final DLQI score of 0-1 indicating no effect on quality of life (84% vs. 66%; p < .001). More 'clear' subjects reported an 'excellent' improvement in their rosacea (77% vs. 42%; p < .001). The median time to relapse was more than 8 months for 'clear' vs. 3 months for 'almost clear' subjects (p < .0001). CONCLUSIONS: Achieving an endpoint of 'clear' (IGA 0) vs. 'almost clear' (IGA 1) is associated with multiple positive patient outcomes, including delayed time to relapse.

Evidence-based recommendations for the management of acne fulminans and its variants.

BACKGROUND: Acne fulminans (AF) is a severe variant of inflammatory acne. It typically manifests as an explosive worsening and ulceration of skin lesions, and can be associated with systemic symptoms. However, there is a paucity of evidence-based information and no clear guidelines concerning the classification and treatment of AF. OBJECTIVE: To better define the spectrum of AF and its variants, devise optimal therapeutic approaches, and identify areas of future research. METHODS: A panel of physicians with expertise in severe acne vulgaris was convened after a comprehensive literature review of severe acne variants. Priority topics were reviewed and presented by each panelist at a 5-hour conference. Following review of the audiotape and scribed notes from the conference, surveys were utilized to address points of controversy and to clarify consensus recommendations. RESULTS: Appropriate clinical case presentations and consensus survey questions were utilized to create final recommendations based on both the literature and the expert consensus. LIMITATIONS: Limited evidenced-based data and prospective studies in the literature concerning the treatment of AF is available. CONCLUSION: These guidelines better characterize AF and provide health care practitioners approaches to the classification, treatment, and prevention of AF and its variants.

Laboratory tests in patients treated with isotretinoin: occurrence of liver and muscle abnormalities and failure of AST and ALT to predict liver abnormality.

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.

Multiplex assessment of serum cytokine and chemokine levels in idiopathic morphea and vitamin K1-induced morphea.

The levels of 63 cytokines, chemokines, and growth factors were measured in the serum of four patients with idiopathic morphea and of one patient with vitamin K1-induced morphea employing a multiplex assay to identify the role of inflammatory/immunologic events in their pathogenesis. Full-thickness skin biopsies of affected skin were analyzed by histopathology. Luminex assays for 63 cytokines, chemokines, and growth factors were performed in the sera from four patients with idiopathic morphea and in two different samples of serum obtained in two separate occasions from one patient with vitamin K1-induced morphea. The serum values of numerous inflammatory cytokines and growth factors including IL-2, IL-4, IL-6, and IFNß were markedly increased in the serum of patients with idiopathic morphea, whereas, these values were normal in the serum of the patient with vitamin K1-induced morphea. In contrast, serum eotaxin levels were greater than threefold higher in the patient with vitamin K1-induced morphea compared to patients with idiopathic morphea. The results demonstrated remarkable increases in the levels of numerous cytokines and chemokines in the serum samples of all patients with idiopathic morphea indicative of a prominent role of inflammatory/immunologic events in its pathogenesis. The results also showed statistically significant differences between idiopathic morphea and vitamin K1-induced morphea suggesting that their development involves different pathogenetic mechanisms.