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.

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.

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.

Status Report from the Scientific Panel on Antibiotic Use in Dermatology of the American Acne and Rosacea Society: Part 1: Antibiotic Prescribing Patterns, Sources of Antibiotic Exposure, Antibiotic Consumption and Emergence of Antibiotic Resistance, Impact of Alterations in Antibiotic Prescribing, and Clinical Sequelae of Antibiotic Use.

Oral and topical antibiotics are commonly prescribed in dermatologie practice, often for noninfectious disorders, such as acne vulgaris and rosacea. Concerns related to antibiotic exposure from both medical and nonmedical sources require that clinicians consider in each case why and how antibiotics are being used and to make appropriate adjustments to limit antibiotic exposure whenever possible. This first article of a three-part series discusses prescribing patterns in dermatology, provides an overview of sources of antibiotic exposure, reviews the relative correlations between the magnitude of antibiotic consumption and emergence of antibiotic resistance patterns, evaluates the impact of alterations in antibiotic prescribing, and discusses the potential relevance and clinical sequelae of antibiotic use, with emphasis on how antibiotics are used in dermatology.

Status Report from the Scientific Panel on Antibiotic Use in Dermatology of the American Acne and Rosacea Society: Part 3: Current Perspectives on Skin and Soft Tissue Infections with Emphasis on Methicillin-resistant Staphylococcus aureus, Commonly Encountered Scenarios when Antibiotic Use May Not Be Needed, and Concluding Remarks on Rational Use of Antibiotics in Dermatology.

In this third article of the three-part series, management of skin and soft tissue infections is reviewed with emphasis on new information on methicillin-resistant Staphylococcus aureus. Due to changes in the evolution of methicillin-resistant Staphylococcus aureus clones, previous distinctions between healthcare-acquired methicillin-resistant Staphylococcus aureus and community-acquired methicillin-resistant Staphylococcus aureus are currently much less clinically relevant. Many nosocomial cases of methicillin-resistant Staphylococcus aureus infection are now caused by community-acquired methicillin-resistant Staphylococcus aureus, with changing patterns of antibiotic susceptibility and resistance. Also reviewed are clinical scenarios where antibiotics may not be needed and suggestions for optimal use of antibiotic therapy for dermatologie conditions, including recommendations on perioperative antibiotic use.

Ocular rosacea, psoriasis, and lichen planus.

Although the number of dermatologic conditions with ocular manifestations is relatively limited, these entities have a high prevalence and represent a large proportion of clinic visits to both dermatologic and ophthalmic practices. This contribution will review oculocutaneous diseases that are not part of the allergic or autoantibody-mediated spectrum.

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.

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.

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).

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.

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.

Treatment of widespread granuloma annulare with adalimumab: a case report.

The authors report a case of widespread granuloma annulare that was resistant to multiple systemic therapies, but responded rapidly to a short course of adalimumab.

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.

Acne epidemiology and pathophysiology.

The demographic profile of facial acne vulgaris has changed during the past several decades; 12 years of age is no longer the low end of the "normal" range for onset of acne. The available epidemiologic evidence raises more questions than it answers regarding the etiology of this downward shift. More study is needed to clarify whether the trend toward an earlier onset of puberty in the United States has influenced the clinical picture of acne. Additional research will help advance understanding of the spectrum of pathophysiologic changes in acne in younger pediatric patients and whether it varies from that found in individuals in whom the onset of acne occurs at approximately 12 years of age or later.

Diagnosis and evaluation of acne.

The diagnosis of acne usually can be made on the basis of a history and physical examination. The differential diagnosis includes a variety of possible causes and differs according to age group (mid-childhood, 1-7 years of age; pre-, peri-, and early pubertal, 8-11 years of age; pubertal/postpubertal, >or=12 years of age). The presentation of acne in adolescents tends to include both noninflammatory and inflammatory lesions, whereas in younger patients noninflammatory comedones are typical. Keratosis pilaris affecting the cheeks sometimes may be confused with early acne vulgaris. Screening tests, particularly bone age, may be considered to support the clinical diagnosis in younger children. Further testing usually is not indicated unless patients show signs of virilization.