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.

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.

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.

Isotretinoin: Mechanism of Action and Patient Selection.

Oral isotretinoin is a highly effective treatment for appropriately selected patients with acne. This medication is the only treatment that targets all four of the identified factors underlying acne pathogenesis. In addition to the approved indication of resistant nodular scarring acne, clinical studies and experience have shown that other categories of patients benefit from isotretinoin therapy, including those with resistant scarring papular acne, those with resistant acne that interferes with normal living, those who have severe acne-related psychological sequelae, and those with acne who have a skin picking habit or compulsion. Semin Cutan Med Surg 34(supp5):S86-S88© 2015 published by Frontline Medical Communications.

Failure of lichen planopilaris to respond to ustekinumab.

Lichen planopilaris failed to respond to ustekinumab after 10 months of treatment.

Cutaneous tolerability to tretinoin shows little variation with Fitzpatrick skin type.

Determinants of skin irritability are poorly understood. This study aims to assess differences in cutaneous safety/irritation based on Fitzpatrick skin type among patients with acne treated with tretinoin gel microsphere (TGM). This was a phase 4, 12-week, prospective, nonrandomized, open-label, multicenter study. Approximately 500 patients with mild to moderate acne were treated with TGM 0.04% or 0.1% and assessed for cutaneous irritation at baseline and weeks 3, 6, and 12. In this post hoc analysis of patients with Fitzpatrick skin type I-III vs Fitzpatrick skin type IV-VI, there was a general trend toward initial worsening of cutaneous adverse events (AEs) by week 3 across all variables and groups. This was followed by a trend toward improvement and resolution of skin-related AEs from week 3 to week 12 regardless of Fitzpatrick skin type, with a few exceptions. Erythema was the only cutaneous AE that consistently decreased among patients with darker skin. Results from a subsequent 3-group analysis (Fitzpatrick I-II vs Fitzpatrick III-IV vs Fitzpatrick V-VI) generally mirrored those from the 2-group study. Study limitations include patient nonadherence, lack of a placebo arm, and lack of data regarding the impact of concurrent medications on outcomes. There was no correlation between irritation and Fitzpatrick skin type. ABBREVIATIONS USED: adverse event (AE), analysis of variance (ANOVA), benzoyl peroxide (BP), case report form (CRF), modified Global Acne Grading Score (mGAGS), tretinoin gel microsphere (TGM).

Results of a Phase III, double-blind, randomized, parallel-group, non-inferiority study evaluating the safety and efficacy of isotretinoin-Lidose in patients with severe recalcitrant nodular acne.

BACKGROUND: Isotretinoin-Lidose, the first new formulation of isotretinoin in 30 years, differs from previously approved isotretinoin formulations in that it is less dependent on the presence of fat in the gut for absorption. OBJECTIVE: Evaluate the safety profiles of isotretinoin-Lidose and food-dependent generic isotretinoin in the largest clinical study with isotretinoin-925 randomized patients from 49 study sites. Determine if the efficacy of this new formulation is noninferior to an existing isotretinoin. METHODS: Multicenter, double-blind, randomized, parallel-group, noninferiority trial. Study medication was taken with meals twice daily for 20 weeks. Patients were followed for 4 weeks after the last dose. Safety evaluations included recordings of adverse events, assessments for depression, anxiety, emergent psychotic symptoms, and suicidal ideation/behavior, as well as DEXA and X-ray evaluations and changes in bone age. Two co-primary efficacy outcomes were measured to assess noninferiority: a) change in total nodular facial and truncal lesion count at from baseline to week 20 and b) percentage of patients who experienced at least 90% reduction in nodular facial and truncal lesion count from baseline to week 20. LIMITATIONS: Although isotretinoin-Lidose can be taken without meals, it was given with food because the absorption of both formulations in the study had to be similar to detect noninferiority. RESULTS: The safety profile of the 2 formulations was comparable. Criteria for noninferiority for both co-primary efficacy outcomes were met based on predetermined margins. CONCLUSION: Safety and efficacy of isotretinoin-Lidose is similar and noninferior to food-dependent generic isotretinoin, respectively.

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.

Ocular rosacea: a dermatologic perspective.

As many as 50% of patients given the diagnosis of cutaneous rosacea also have ocular rosacea. Conservative figures indicate that approximately 10 million patients are affected by ocular rosacea in the United States alone. Despite this prevalence, ocular symptoms of rosacea are often improperly diagnosed, particularly when they occur in the absence of skin involvement.

Comparative pharmacokinetic profiles of a novel isotretinoin formulation (isotretinoin-Lidose) and the innovator isotretinoin formulation: a randomized, 4-treatment, crossover study.

BACKGROUND: A high-fat meal is needed for optimal absorption of isotretinoin. A new formulation of isotretinoin, which enhances absorption of isotretinoin in the absence of dietary fat, has recently been approved by the Food and Drug Administration (FDA). OBJECTIVE: We sought to compare the pharmacokinetic profiles of a new formulation of isotretinoin (isotretinoin-Lidose) with the innovator isotretinoin formulation. METHODS: This study was an open-label, single-dose, randomized, 4-treatment, crossover comparative trial between a new and innovator formulation of isotretinoin in the fasting and fed states. RESULTS: Both formulations were bioequivalent under fed conditions. As expected in a fasting state, absorption of both formulations was reduced. A considerable difference between the 2 drugs occurred under fasted conditions-there was a marked improvement in overall bioavailability of the isotretinoin-Lidose formulation. Mean plasma levels of the isotretinoin-Lidose formulation during fasting reached 66.8% of that observed with a fatty meal, and those of the isotretinoin formulation only reached 39.6% of that observed with a fatty meal. LIMITATIONS: Only the FDA-stipulated standard high-fat, high-calorie meal of 50-g fat was studied in the fed state. CONCLUSION: Isotretinoin-Lidose formulation is bioequivalent to the innovator formulation under fed conditions with regard to its pharmacokinetic profile but delivers twice as much isotretinoin and 4-oxo-isotretinoin when administered after an overnight fast.

A phase IV, open-label study evaluating the use of triple-combination therapy with minocycline HCl extended-release tablets, a topical antibiotic/retinoid preparation and benzoyl peroxide in patients with moderate to severe acne vulgaris.

BACKGROUND: Moderate to severe acne vulgaris is often treated with a combination of an oral antibiotic, topical antibiotic/retinoid, and benzoyl peroxide (BP), but data are limited on the efficacy of this and other combination regimens that incorporate both oral and topical therapies.
METHODS: Patients were required to be aged 12-30 years with moderate to severe acne (grades 3-4 acne on the Investigator's Global Assessment [IGA]) and deemed potential candidates for treatment with isotretinoin. Enrolled patients were given triple-combination therapy, defined in this study as oral minocycline HCl extended release 1 mg/kg QD, 6% BP foaming cloths used QD, and clindamycin phosphate 1.2%/tretinoin 0.025% gel applied QD, and were evaluated at baseline and weeks 2, 4, 8, and 12.
RESULTS: A total of 97 patients were enrolled in the study. At week 12, 89% of patients had at least a one-grade improvement from baseline IGA and 96% had at least a one-grade improvement from baseline Global Aesthetic Improvement Scale score. Mean ± SD in- flammatory, non-inflammatory, and total lesion counts decreased from baseline by 61.8% ± 38.3%, 48.8% ± 34.5%, and 56.5% ± 29.9%, respectively. The percentage of patients evaluated as candidates for isotretinoin by independent photographic review was 77% (69/90) at baseline and only 16% (14/90) at week 12. Treatment-related adverse events (AEs) occurred in eight of 97 (8%) patients. Triplecombination therapy was not associated with any serious AEs or AEs leading to discontinuation.
CONCLUSION: Triple-combination therapy was well tolerated and substantially reduced facial acne lesion counts, with 84% of patients judged to no longer be candidates for isotretinoin therapy by study end. These data support the clinical observation that a triple-combination regimen incorporating oral minocycline (dosed by patient weight), BP foaming cloths 6% QD, and clindamycin phosphate 1.2%/ tretinoin 0.025% gel QD can substantially improve moderate to severe acne vulgaris.

An evaluation of potential correlations between pathophysiologic mechanisms, clinical manifestations, and management of rosacea.

This article discusses rosacea, a common facial dermatosis of uncertain etiology and recent investigations that have begun to shed considerable light on the sequence of events leading to clinical manifestations of rosacea. The article content is based on a dedicated meeting about rosacea sanctioned by the American Acne & Rosacea Society (AARS) and represents the consensus of the authors and AARS Board of Directors.

Acne severity grading: determining essential clinical components and features using a Delphi consensus.

BACKGROUND: There are multiple global scales for acne severity grading but no singular standard. OBJECTIVE: Our objective was to determine the essential clinical components (content items) and features (property-related items) for an acne global grading scale for use in research and clinical practice using an iterative method, the Delphi process. METHODS: Ten acne experts were invited to participate in a Web-based Delphi survey comprising 3 iterative rounds of questions. RESULTS: In round 1, the experts identified the following clinical components (primary acne lesions, number of lesions, extent, regional involvement, secondary lesions, and patient experiences) and features (clinimetric properties, ease of use, categorization of severity based on photographs or text, and acceptance by all stakeholders). In round 2, consensus for inclusion in the scale was established for primary lesions, number, sites, and extent; as well as clinimetric properties and ease of use. In round 3, consensus for inclusion was further established for categorization and acceptance. Patient experiences were excluded and no consensus was achieved for secondary lesions. LIMITATIONS: The Delphi panel consisted solely of the United States (U.S.)-based acne experts. CONCLUSION: Using an established method for achieving consensus, experts in acne vulgaris concluded that an ideal acne global grading scale would comprise the essential clinical components of primary acne lesions, their quantity, extent, and facial and extrafacial sites of involvement; with features of clinimetric properties, categorization, efficiency, and acceptance.

Effectiveness and safety of once-daily doxycycline capsules as monotherapy in patients with rosacea: an analysis by Fitzpatrick skin type.

Rosacea is often under-recognized or misdiagnosed in patients with skin of color (Fitzpatrick Skin Types [FST] IV-VI). Subtle clinical features and a low index of suspicion likely contribute to less frequent diagnosis in this population. Clinical trials of therapeutic agents for rosacea generally include few patients from nonwhite racial/ethnic groups and therefore, potential differences in treatment outcomes have not been previously studied. The objective of this prospective analysis was to fill the gap in knowledge of the effectiveness and safety of treatment for rosacea in patients with skin of color. We analyzed data from 826 adults aged ≥ 18 years with papulopustular (subtype 2) rosacea (663 FST I-III; 163 FST IV-VI). All patients received doxycycline 40 mg capsules (30 mg immediate release and 10 mg delayed release beads) once daily as monotherapy for 12 weeks in this open-label, multicenter, community-based study. Investigators assessed disease severity with the Investigator's Global Assessment (IGA) and erythema with the Clinician's Erythema Assessment (CEA). Significant improvement in disease severity and erythema was obtained in patients with FST I-III and IV-VI at week 12 (P<.001). Treatment success, defined as an IGA score of 0 or 1 was achieved in 74.6% and 74.3% of patients with FST I-III and IV-VI, respectively. Approximately 12% of patients experienced adverse events with no difference between the two skin type groups. The results of this prospective subgroup analysis of data from a large community-based trial suggest that doxycycline produced similar effectiveness and safety profiles in patients with FST I-III and IV-VI.

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.

Evidence-based review: fixed-combination therapy and topical retinoids in the treatment of acne.

Topical fixed-combination products and topical retinoid monotherapy are established first-line treatments for mild-to-moderate acne vulgaris, yet adequate comparative data are lacking. The following evidence-based review addresses the question: "In patients with mild-to-moderate acne, are topical fixed-combination products or topical retinoids a more efficacious choice in reducing noninflammatory, inflammatory and total lesions after 12 weeks of treatment?" To identify relevant studies, a PubMed search was performed using "acne" and search terms for adapalene, tretinoin, tazarotene, benzoyl peroxide, clindamycin, or erythromycin. Forty-two studies from January 1991 to November 2009 were included. The studies were evaluated using the Strength of Recommendation Taxonomy, and all but seven received the highest level of evidence grade. To evaluate efficacy, a side-by-side comparison was made using reduction in acne lesion counts at week 12 for study groups treated with fixed-combination therapy or retinoid monotherapy. Twenty-nine studies containing relevant efficacy data for fixed-combination therapy and retinoid monotherapy are summarized here. Nine studies compared fixed-combination therapy with retinoid monotherapy; in eight of these studies, fixed-combination therapy was significantly more efficacious in reducing acne lesion counts. This evidence-based review analyzes clinical evidence to date for these therapies to provide guidance in determining appropriate treatment for patients with mild-to-moderate acne.