Recommendations for rosacea diagnosis, classification and management: update from the global ROSacea COnsensus 2019 panel.

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.

Long-term safety and efficacy of trifarotene 50 µg/g cream, a first-in-class RAR-γ selective topical retinoid, in patients with moderate facial and truncal acne.

BACKGROUND: Treatment for both facial and truncal acne has not sufficiently been studied. OBJECTIVES: To evaluate the long-term safety and efficacy of trifarotene in both facial and truncal acne. METHODS: In a multicentre, open-label, 52-week study, patients with moderate facial and truncal acne received trifarotene 50 µg/g cream (trifarotene). Assessments included local tolerability, safety, investigator and physician's global assessments (IGA, PGA) and quality of life (QOL). A validated QOL questionnaire was completed by the patient at Baseline, Week 12, 26 and 52/ET. RESULTS: Of 453 patients enrolled, 342 (75.5%) completed the study. Trifarotene-related treatment-emergent adverse events (TEAEs) were reported in 12.6% of patients, and none was serious. Most related TEAEs were cutaneous and occurred during the first 3 months. Signs and symptoms of local tolerability were mostly mild or moderate and severe signs, and symptoms were reported for 2.2% to 7.1% of patients for the face and 2.5% to 5.4% for the trunk. Local irritation increased during the first week of treatment on the face and up to Weeks 2 to 4 on the trunk with both decreasing thereafter. At Week 12, IGA and PGA success rates were 26.6% and 38.6%, respectively. Success rates increased to 65.1% and 66.9%, respectively at Week 52. Overall success (both IGA and PGA success in the same patient) was 57.9% at Week 52. At Week 52 visit, 92/171 (53.8%) patients who had completed their assessments had scores from 0 to 1 (i.e. no effect of acne on their QOL) vs. 47/208 (22.6%) patients at Baseline visit. CONCLUSION: In this 52-week study, trifarotene was safe, well tolerated and effective in moderate facial and truncal acne.

The noncompliant patient with acne.

Clinical studies with topical and systemic agents for acne show remarkable improvement over a 3 month period of time, with continued progress in long-term use. However, in clinical practice it is uncommon to see these favorable results. Clinical experience and recent published data suggest that compliance, perhaps better referred to as adherence, is a major obstacle in achieving these outcomes. This article will review this problem and offer a number of suggestions, including dosing considerations and the use of laser/light devices, to better treat the nonadherent patient.

alphavbeta3 integrin mediates the cell-adhesive capacity and biological activity of basic fibroblast growth factor (FGF-2) in cultured endothelial cells.

Fibroblast growth factor-2 (FGF-2) immobilized on non-tissue culture plastic promotes adhesion and spreading of bovine and human endothelial cells that are inhibited by anti-FGF-2 antibody. Heat-inactivated FGF-2 retains its cell-adhesive activity despite its incapacity to bind to tyrosine-kinase FGF receptors or to cell-surface heparan sulfate proteoglycans. Recombinant glutathione-S-transferase-FGF-2 chimeras and synthetic FGF-2 fragments identify two cell-adhesive domains in FGF-2 corresponding to amino acid sequences 38-61 and 82-101. Both regions are distinct from the FGF-receptor-binding domain of FGF-2 and contain a DGR sequence that is the inverse of the RGD cell-recognition sequence. Calcium deprivation, RGD-containing eptapeptides, soluble vitronectin (VN), but not fibronectin (FN), inhibit cell adhesion to FGF-2. Conversely, soluble FGF-2 prevents cell adhesion to VN but not FN, thus implicating VN receptor in the cell-adhesive activity of FGF-2. Accordingly, monoclonal and polyclonal anti-alphavbeta3 antibodies prevent cell adhesion to FGF-2. Also, purified human alphavbeta3 binds to immobilized FGF-2 in a cation-dependent manner, and this interaction is competed by soluble VN but not by soluble FN. Finally, anti-alphavbeta3 monoclonal and polyclonal antibodies specifically inhibit mitogenesis and urokinase-type plasminogen activator (uPA) up-regulation induced by free FGF-2 in endothelial cells adherent to tissue culture plastic. These data demonstrate that FGF-2 interacts with alphavbeta3 integrin and that this interaction mediates the capacity of the angiogenic growth factor to induce cell adhesion, mitogenesis, and uPA up-regulation in endothelial cells.

A distinct basic fibroblast growth factor (FGF-2)/FGF receptor interaction distinguishes urokinase-type plasminogen activator induction from mitogenicity in endothelial cells.

Basic fibroblast growth factor (FGF-2) induces cell proliferation and urokinase-type plasminogen activator (uPA) production in fetal bovine aortic endothelial GM 7373 cells. In the present paper we investigated the role of the interaction of FGF-2 with tyrosine-kinase (TK) FGF receptors (FGFRs) in mediating uPA up-regulation in these cells. The results show that FGF-2 antagonists suramin, protamine, heparin, the synthetic peptide FGF-2(112-155), and a soluble form of FGFR-1 do not inhibit FGF-2-mediated uPA up-regulation at concentrations that affect growth factor binding to cell surface receptors and mitogenic activity. In contrast, tyrosine phosphorylation inhibitors and overexpression of a dominant negative TK- mutant of FGFR-1 abolish the uPA-inducing activity of FGF-2, indicating that FGFR and its TK activity are essential in mediating uPA induction. Accordingly, FGF-2 induces uPA up-regulation in Chinese hamster ovary cells transfected with wild-type FGFR-1, -2, -3, or -4 but not with TK- FGFR-1 mutant. Small unilamellar phosphatidyl choline:cholesterol vesicles loaded with FGF-2 increased uPA production in GM 7373 cells in the absence of a mitogenic response. Liposome-encapsulated FGF-2 showed a limited but significant capacity, relative to free FGF-2, to interact with FGFR both at 4 degrees C and 37 degrees C and to be internalized within the cell. uPA up-regulation by liposome-encapsulated FGF-2 was quenched by neutralizing anti-FGF-2 antibodies, indicating that the activity of liposome-delivered FGF-2 is mediated by an extracellular action of the growth factor. Taken together, the data indicate that a distinct interaction of FGF-2 with FGFR, quantitatively and/or qualitatively different from the one that leads to mitogenicity, is responsible for the uPA-inducing activity of the growth factor.

Interaction of fibroblast growth factor-2 (FGF-2) with free gangliosides: biochemical characterization and biological consequences in endothelial cell cultures.

Exogenous gangliosides affect the angiogenic activity of fibroblast growth factor-2 (FGF-2), but their mechanism of action has not been elucidated. Here, a possible direct interaction of sialo-glycolipids with FGF-2 has been investigated. Size exclusion chromatography demonstrates that native, but not heat-denatured, 125I-FGF-2 binds to micelles formed by gangliosides GT1b, GD1b, or GM1. Also, gangliosides protect native FGF-2 from trypsin digestion at micromolar concentrations, the order of relative potency being GT1b > GD1b > GM1 = GM2 = sulfatide > GM3 = galactosyl-ceramide, whereas asialo-GM1, neuraminic acid, and N-acetylneuramin-lactose were ineffective. Scatchard plot analysis of the binding data of fluorochrome-labeled GM1 to immobilized FGF-2 indicates that FGF-2/GM1 interaction occurs with a Kd equal to 6 microM. This interaction is inhibited by the sialic acid-binding peptide mastoparan and by the synthetic fragments FGF-2(112-129) and, to a lesser extent, FGF-2(130-155), whereas peptides FGF-2(10-33), FGF-2(39-59), FGF-2(86-96), and the basic peptide HIV-1 Tat(41-60) were ineffective. These data identify the COOH terminus of FGF-2 as a putative ganglioside-binding region. Exogenous gangliosides inhibit the binding of 125I-FGF-2 to high-affinity tyrosine-kinase FGF-receptors (FGFRs) of endothelial GM 7373 cells at micromolar concentrations. The order of relative potency was GT1b > GD1b > GM1 > sulfatide a = sialo-GM1. Accordingly, GT1b,GD1b, GM1, and GM2, but not GM3 and asialo-GM1, prevent the binding of 125I-FGF-2 to a soluble, recombinant form of extracellular FGFR-1. Conversely, the soluble receptor and free heparin inhibit the interaction of fluorochrome-labeled GM1 to immobilized FGF-2. In agreement with their FGFR antagonist activity, free gangliosides inhibit the mitogenic activity exerted by FGF-2 on endothelial cells in the same range of concentrations. Also in this case, GT1b was the most effective among the gangliosides tested while asialo-GM1, neuraminic acid, N-acetylneuramin-lactose, galactosyl-ceramide, and sulfatide were ineffective. In conclusion, the data demonstrate the capacity of exogenous gangliosides to interact with FGF-2. This interaction involves the COOH terminus of the FGF-2 molecule and depends on the structure of the oligosaccharide chain and on the presence of sialic acid residue(s) in the ganglioside molecule. Exogenous gangliosides act as FGF-2 antagonists when added to endothelial cell cultures. Since gangliosides are extensively shed by tumor cells and reach elevated levels in the serum of tumor-bearing patients, our data suggest that exogenous gangliosides may affect endothelial cell function by a direct interaction with FGF-2, thus modulating tumor neovascularization.

Inhibition of angiogenesis and tumor growth by SCH221153, a dual alpha(v)beta3 and alpha(v)beta5 integrin receptor antagonist.

New blood vessel formation is essential for tumor growth and metastatic spread. Integrins alpha(v)beta3 and alpha(v)beta5 are arginine-glycine-aspartic acid-dependent adhesion receptors that play a critical role in angiogenesis. Hence, selective dual alpha(v)beta3 and alpha(v)beta5 antagonists may represent a novel class of angiogenesis and tumor-growth inhibitors. Here, an arginine-glycine-aspartic acid-based peptidomimetic library was screened to identify alpha(v)beta3 antagonists. Selected compounds were then modified to generate potent and selective dual inhibitors of alpha(v)beta3 and alpha(v)beta5 receptors. One of these compounds, SCH 221153, inhibited the binding of echistatin to alpha(v)beta3 (IC50 = 3.2 nM) and alpha(v)beta5 (IC50 = 1.7 nM) with similar potency. Its IC50 values for related alpha(IIb)beta3 and alpha5beta1 receptors were 1294 nM and 421 nM, respectively, indicating that SCH 221153 is highly selective for alpha(v)beta3 and alpha(v)beta5 receptors. In cell-based assays, SCH 221153 inhibited the binding of echistatin to alpha(v)beta3- and alpha(v)beta5-expressing 293 cells and blocked the adhesion of endothelial cells to immobilized vitronectin and fibroblast growth factor 2 (FGF2). SCH 221153, but not the inactive analogue SCH 216687, was effective in inhibiting FGF2 and vascular endothelial growth factor-induced endothelial cell proliferation in vitro with an IC50 equal to 3-10 microM. Angiogenesis induced by FGF2 in the chick chorioallantoic membrane assay was also inhibited by SCH 221153. Finally, SCH 221153 exerted a significant inhibition on tumor growth induced by intradermal or s.c. injection of human melanoma LOX cells in severe combined immunodeficient mice.

alpha(v)beta(3) integrin engagement modulates cell adhesion, proliferation, and protease secretion in human lymphoid tumor cells.

OBJECTIVE: The mechanisms used by human lymphoproliferative diseases to invade locally and metastasize are thought to be similar to those developed by solid tumors, including cell proliferation and secretion of extracellular matrix-degrading enzymes following adhesion to extracellular matrix proteins. Hence, the ability of Namalwa (Burkitt's lymphoma), U266 (multiple myeloma), and CEM (T-cell lymphoblastic leukemia) cells to interact with the extracellular matrix components vitronectin and fibronectin was determined. Fresh bone marrow plasma cells from patients with multiple myeloma also were studied. MATERIALS AND METHODS: Engagement of alpha(v)beta(3) integrin, formation and protein composition of focal adhesion contacts on the cell surface, phosphorylation of several signal transduction proteins in the contacts, cell proliferation, and enzyme secretion were studied following adhesion to vitronectin and fibronectin. RESULTS: All three lines adhered to immobilized vitronectin and fibronectin. Adhesion was fully prevented by neutralizing monoclonal anti-alpha(v)beta(3) integrin antibody. Integrin engagement caused the formation of phosphorylated pp60(src)/focal adhesion kinase complexes and the aggregation of focal adhesion plaques containing the beta(3) integrin subunit, the cytoskeletal proteins vinculin, cortactin, and paxillin, the tyrosine kinases focal adhesion kinase and pp60(src), the adapter protein Grb-2, and the mitogen-activated protein kinase ERK-2. Free and immobilized vitronectin and fibronectin stimulated the proliferation of cells under serum-free conditions and the production and release of urokinase-type plasminogen activator, and increased the release of the activated forms of matrix metalloproteinase-2 and matrix metalloproteinase-9 in an alpha(v)beta(3) integrin-dependent manner. Similar results were obtained in myeloma plasma cells. CONCLUSIONS: The demonstrated ability of lymphoid tumor cells to interact with the extracellular matrix components vitronectin and fibronectin via alpha(v)beta(3) integrin can be interpreted as evidence of a novel mechanism for their invasion and spreading. This interaction allows them to adhere to the substratum and enhances their proliferation and protease secretion.

Upregulation of urokinase-type plasminogen activator by endogenous and exogenous HIV-1 Tat protein in tumour cell lines derived from BK virus/tat-transgenic mice.

OBJECTIVE: To demonstrate that Tat modulates the plasminogen-dependent proteolytic activity of tumour cell lines derived from BK virus (BKV)/tat-transgenic mice by affecting the production of plasminogen activators (PA) and the PA inhibitor (PAI)-1 and to demonstrate that this occurs through mechanism(s) that are distinct from those responsible for transactivating activity of extracellular Tat. DESIGN AND METHODS: To assess whether endogenous Tat is responsible for PA activity in T53 adenocarcinoma cells, cell cultures were transfected with antisense Tat cDNA and evaluated for cell-associated PA activity by a plasmin chromogenic assay. The assay was also used to evaluate PA activity in T53 cells and T111 leiomyosarcoma cells stimulated by extracellular Tat. The type(s) of PA produced were identified by sodium dodecyl sulphate-polyacrylamide gel electrophoresis zymography. The levels of PAI-1 were evaluated by Western blotting. Tat transactivating activity was measured by a chloramphenicol acetyltransferase (CAT) enzyme-linked immunosorbent assay in HL3T1 cells containing integrated copies of an HIV-1 long terminal repeat (LTR)-CAT plasmid. RESULTS: Transfection of T53 cells with antisense Tat cDNA results in the decrease of Tat production and PA activity. Exogenously added Tat increases PA levels in T53 and in T111 cells. PA activity was identified as urokinase-type PA (uPA). Tat also increases the production of PAI-1 in T111 but not in T53 cells. Chloroquine and heparin have different affects on the LTR-CAT-transactivating and the PA-inducing activities of Tat. The fusion protein glutathione-S-transferase-Tat and the mutant Tat-1e, lacking the second Tat exon, cause LTR-CAT transactivation without stimulating uPA upregulation. CONCLUSIONS: Tat affects the fibrinolytic activity of tumour cell lines derived from BKV/tat-transgenic mice by modulating the production of both uPA and PAI-1 via autocrine and paracrine mechanisms of action. The capacity of Tat to modulate the plasminogen-dependent proteolytic activity of these tumour cell lines may contribute to their metastatic potential. The uPA-inducing activity of Tat depends upon specific biological and structural features of the Tat protein that are distinct from those responsible for its LTR-CAT-transactivating activity, suggesting distinct mechanisms of induction for the two biological responses.

Examining new models for the study of autocrine and paracrine mechanisms of angiogenesis through FGF2-transfected endothelial and tumour cells.

Angiogenesis is the process of generating new capillary blood vessels. Uncontrolled endothelial cell proliferation is observed in tumour neovascularization. Several growth factors and cytokines have been shown to stimulate endothelial cell proliferation in vitro and in vivo and among them FGF2 was one of the first to be characterised. FGF2 is a Mr 18,000 heparin-binding cationic polypeptide that induces proliferation, migration, and protease production in endothelial cells in culture and neovascularization in vivo. FGF2 interacts with endothelial cells through two distinct classes of receptors, the high affinity tyrosine-kinase receptors (FGFRs) and low affinity heparan sulfate proteoglycans (HSPGs) present on the cell surface and in the extracellular matrix. Besides experimental evidence for paracrine mode of action for FGF2, some observations raise the hypothesis that FGF2 may also play an autocrine role in endothelial cells. FGF2 may therefore represent a target for anti-angiogenic therapies. In order to assess the angiostatic potential of different classes of compounds, novel experimental models have been developed based on the autocrine and/or the paracrine capacity of FGF2.

An observation study evaluating the efficacy of tazarotene plus corticosteroid in treating plaque psoriasis in patients switched from treatment with calcipotriene +/- corticosteroid.

The results of a multicenter, open-label observation study evaluating the use of tazarotene in 1393 patients being treated for plaque psoriasis have been reported recently. The analysis of data from a subset of 166 patients who were switched from calcipotriene therapy, with or without a topical corticosteroid, to receive tazarotene plus a corticosteroid is reported here. This subset of 166 patients showed substantial additional improvements in efficacy and patient satisfaction over and above those already achieved with calcipotriene +/- corticosteroid treatment. The mean scores for overall severity of plaque psoriasis, plaque elevation, scaling, pruritus, and overall discomfort were reduced by 35%, 41%, 44%, 45%, and 40%, respectively, compared with baseline levels at the time of switching therapy. The severity of each of these parameters was reduced from mild-to-moderate at baseline to trace-to-mild after a mean of 10 weeks' treatment with tazarotene plus a corticosteroid.

An observation study evaluating the treatment of plaque psoriasis with tazarotene gels, alone and with an emollient and/or corticosteroid.

A large-scale observation study has been performed to evaluate how tazarotene is used to treat plaque psoriasis in everyday clinical practice and to elucidate whether the efficacy and tolerability of tazarotene treatment can be optimized through the adjunctive use of an emollient and/or a topical corticosteroid. A total of 1393 patients with mild-to-moderate stable plaque psoriasis applied tazarotene 0.05% or 0.1% gel once daily for up to 12 weeks, either as monotherapy or in combination with other topical psoriasis therapies as deemed necessary by the investigator. The adjunctive use of an emollient and/or a corticosteroid enhanced the efficacy of tazarotene treatment and increased the percentage of patients who were satisfied with their treatment. Adjunctive steroid use also enhanced tolerability. The optimal treatment regimen was combination therapy of tazarotene and a corticosteroid.

Efficacy and tolerability of once-daily tazarotene 0.1% gel versus once-daily tretinoin 0.025% gel in the treatment of facial acne vulgaris: a randomized trial.

Tazarotene 0.1% gel and tretinoin 0.025% gel are both effective in the treatment of acne vulgaris. Results of a multicenter, double-blind, randomized, parallel-group study that compared the efficacy and tolerability of these drugs are presented here. A total of 143 patients with mild-to-moderate facial acne vulgaris were randomized to receive tazarotene 0.1% gel or tretinoin 0.025% gel once daily for 12 weeks. Tazarotene 0.1% gel was more effective than tretinoin 0.025% gel in reducing the open comedo count (P < or = .05), the total noninflammatory lesion count (P < or = .05), and the total inflammatory lesion count (not statistically significant). At some time points, tazarotene was associated with increased irritation, but peeling, erythema, dryness, burning, and itching never exceeded trace levels. We conclude that tazarotene 0.1% gel is more effective than tretinoin 0.025% gel in reducing noninflammatory lesions and similarly effective in reducing inflammatory lesions.

Long pulse 532-nm laser treatment of facial telangiectasia.

BACKGROUND: Facial telangiectasias are a frequently observed cosmetic concern: Current therapeutic modalities have certain side effects and limitations. We treated a group of patients with facial telangiectasias with a new variable pulse width frequency-doubled neodymium: YAG laser at 532 nm. OBJECTIVE: This study evaluated the clinical response and side effects during the treatment of facial telangiectasias in 40 patients. METHODS: Forty patients with facial telangiectasias were treated with the VersaPulse laser. Fluences of between 9.5 and 12.0 J/cm2 at 3 or 4-mm spot size were used. A sapphire water-cooled chill tip was used to cool the cutaneous surface during treatment. RESULTS: Ninety percent of patients experienced between 75% and 100% clearance of their facial telangiectasias after single treatment. No significant side effects or complications were noted. CONCLUSION: The VersaPulse variable pulse width neodymium: YAG laser appears to be an effective treatment modality for facial telangiectasia.

The basic domain in HIV-1 Tat protein as a target for polysulfonated heparin-mimicking extracellular Tat antagonists.

Heparin binds extracellular HIV-1 Tat protein and modulates its HIV long terminal repeat (LTR)-transactivating activity (M. Rusnati, D. Coltrini, P. Oreste, G. Zoppetti, A. Albini, D. Noonan, F. d'Adda di Fagagna, M. Giacca, and M. Presta (1997) J. Biol. Chem. 272, 11313-11320). On this basis, the glutathione S-transferase (GST)-TatR49/52/53/55/56/57A mutant, in which six arginine residues within the basic domain of Tat were mutagenized to alanine residues, was compared with GST-Tat for its capacity to bind immobilized heparin. Dissociation of the GST-TatR49/52/53/55/56/57A.heparin complex occurred at ionic strength significantly lower than that required to dissociate the GST-Tat.heparin complex. Accordingly, heparin binds immobilized GST-Tat and GST-TatR49/52/53/55/56/57A with a dissociation constant equal to 0.3 and 1.0 microM, respectively. Also, the synthetic basic domain Tat-(41-60) competes with GST-Tat for heparin binding. Suramin inhibits [3H]heparin/Tat interaction, 125I-GST-Tat internalization, and the LTR-transactivating activity of extracellular Tat in HL3T1 cells and prevents 125I-GST-Tat binding and cell proliferation in Tat-overexpressing T53 cells. The suramin derivative 14C-PNU 145156E binds immobilized GST-Tat with a dissociation constant 5 times higher than heparin and is unable to bind GST-TatR49/52/53/55/56/57A. Although heparin was an antagonist more potent than suramin, modifications of the backbone structure in selected suramin derivatives originated Tat antagonists whose potency was close to that shown by heparin. In conclusion, suramin derivatives bind the basic domain of Tat, prevent Tat/heparin and Tat/cell surface interactions, and inhibit the biological activity of extracellular Tat. Our data demonstrate that tailored polysulfonated compounds represent potent extracellular Tat inhibitors of possible therapeutic value.