Amy S. Paller

Perceptions of Physicians and Pediatric Patients About Atopic Dermatitis, Its Impact, and Its Treatment:

The National Eczema Association for Science and Education surveyed 429 patients with atopic dermatitis or their parents and 303 physicians about atopic dermatitis, its effect on quality of life (QOL), and the adequacy of available treatments. The physician survey focused on disease severity and management; the patient survey, on disease severity, impact on QOL, and treatment preferences. Physician and patient/parent respondents generally agreed about their assessments of disease severity, poor effectiveness of over-the-counter products, and the need for more patient support groups and toll-free phone information. Atopic dermatitis significantly impacts QOL in children, particularly in those with moderate-to-severe disease. New treatments should offer enhanced efficacy, less frequent application, and fewer adverse effects.

Effects of a low-potency corticosteroid lotion plus a moisturizing regimen in the treatment of atopic dermatitis

Treatment goals for atopic dermatitis consist of attempting to eliminate inflammation and infection, hydrating the skin, controlling pruritus, and avoiding exacerbative factors. The aim of this study was to evaluate the effects of adding a moisturizing regimen to a low-potency topical corticosteroid lotion regimen in the treatment of atopic dermatitis. This controlled, randomized, investigator-masked 3-week study was undertaken to compare twice-daily applications of desonide lotion 0.05% alone with twice-daily applications of desonide lotion 0.05% plus three-times-daily applications of a moisturizing cream. The efficacy variables assessed included erythema, dryness or scaling, pruritus, excoriations, lichenification, oozing or crusting, and induration or papules. Administration of desonide lotion alone created statistically significant improvement in total sign and symptom scores. The addition of a moisturizer to the treatment regimen produced additional statistically significant improvement in total sign and symptom scores, physicians global assessments of improvement, and most of the individual efficacy variables. Results of this study suggest that the addition of a moisturizer to a low-potency corticosteroid lotion in separate regimens was effective in treating the signs and symptoms of mild-to-moderate atopic dermatitis.

Expression of eotaxin, an eosinophil‐selective chemokine, parallels eosinophil accumulation in the vesiculobullous stage of incontinentia pigmenti

Incontinentia pigmenti (IP) is an X‐linked dominant genodermatosis primarily affecting female children. The initial vesiculobullous stage of IP is characterized clinically by inflammatory papules, blisters, and pustules, and histopathologically by acanthosis, keratinocyte necrosis, epidermal spongiosis and massive epidermal eosinophil infiltration. The cause of this multisystem disease is attributed to the mutations of an X‐linked regulatory gene, termed nuclear factor‐κB essential modulator (NEMO). The exact mechanism of epidermal eosinophil accumulation has not yet been determined. We explored the possible role of an eosinophil‐selective, nuclear factor‐κB‐activated chemokine, eotaxin, in the accumulation of eosinophils in the initial stage of the disease. Monoclonal antibody (6H9) specific for human eotaxin strongly labelled the suprabasal epidermis of IP skin, paralleling the upper epidermal accumulation of eosinophils, but did not label the epidermis of normal skin or lesional skin from patients with other inflammatory skin diseases not characterized by prominent eosinophil accumulation, namely dermatitis herpetiformis and selected cases of atopic dermatitis lacking significant numbers of eosinophils. In addition, endothelial cells in lesional skin of IP also exhibited strong expression of eotaxin, which correlated with perivascular and intravascular eosinophil infiltration. We also examined the in vitro effects on epidermally derived eotaxin of several cytokines that were nuclear factor‐κB‐activated and/or known to induce eotaxin expression. In normal human keratinocytes, proinflammatory cytokines either independently (IL‐1α) or synergistically (tumour necrosis factor‐alpha (TNF‐α)/ interferon‐gamma (IFN‐γ) and TNF‐α/IL‐4) up‐regulated eotaxin expression. These studies suggest that release of cytokines during the initial inflammatory stage of IP induces epidermal expression of eotaxin, which may play a role in the epidermal accumulation of eosinophils.

Full-thickness surgical excision for the treatment of inflammatory linear verrucous epidermal nevus

Inflammatory linear verrucous epidermal nevus (ILVEN) is a benign cutaneous hamartoma characterized by intensely erythematous, pruritic, inflammatory papules that occur as linear bands along the lines of Blaschko. Because of its chronic and unremitting symptomatology, patients with ILVEN seek medical treatment for relief of discomfort as well as concerns regarding cosmetic appearance. Reported therapeutic approaches include topical agents, dermabrasion, cryotherapy, laser therapy, and partial-thickness excision. Unfortunately, no one therapy has been successful consistently. Medical management is often unsatisfactory, because improvement tends to be temporary. Surgical modalities have met with better success in relief of symptoms but at the risk of marked scarring and a high rate of recurrence. Furthermore, the occurrence of extensive ILVEN or localization to certain anatomic regions has been considered previously a relative contraindication to excision. The authors report 4 patients with extensive ILVEN treated successfully with full-thickness surgical excision. Our report underscores the effectiveness of this surgical modality for the definitive treatment of ILVEN.

Ganglioside Modulation Regulates Epithelial Cell Adhesion and Spreading via Ganglioside-specific Effects on Signaling

Gangliosides are implicated in regulating cell adhesion and migration on fibronectin by binding with the α5 subunit of α5β1integrin. However, the effects of gangliosides on cell spreading and related signaling pathways are unknown. Increases in gangliosides GT1b and GD3 inhibited spreading on fibronectin, concurrent with inhibition of Src and focal adhesion kinase. Although antibody blockade of GT1b or GD3 function and gene-modulated ganglioside depletion stimulated spreading and activated Src and focal adhesion kinase, the augmented spreading by disruption of GT1b function, but not by disruption of GD3 function, was inhibited by blockade of Src and focal adhesion kinase activation. In contrast, inhibitors of protein kinase C prevented the stimulation of spreading by GD3 functional inhibition, but not by GT1b functional blockade. Modulation of either GT1b or GD3 content affected phosphoinositol 3-kinase activation, and inhibition of this activation reversed the stimulation of cell spreading by anti-GD3 antibody, anti-GT1b antibody, and ganglioside depletion, suggesting that phosphoinositol 3-kinase is an intermediate in both the FAK/Src and protein kinase C pathways that lead to cell spreading. These studies demonstrate that epithelial cell ganglioside GT1b modulates cell spreading through α5β1/FAK and phosphoinositol 3-kinase signaling, whereas GD3-modulated spreading appears to involve phosphoinositol 3-kinase-dependent protein kinase C signaling.

Raised limb bands developing in infancy

Congenital cutaneous constriction bands are rare and often occur with other abnormalities, including the presence of rudimentary digits. This diverse syndrome lacks a precise definition and a satisfactory explanation. We describe two unusual cases with features previously undescribed, in which predominantly raised, annular limb bands became apparent postnatally. One infant was also born with foreshortened digits and a constricting limb band, suggesting a shared aetiology with other congenital cases. The development of raised bands during infancy would be difficult to reconcile with the widely held amniotic band hypothesis, and would be more in keeping with a multifocal developmental abnormality in limb growth.

Safe treatment of head/neck AD with tacrolimus ointment

BACKGROUNDnAtopic dermatitis(AD) with head and neck involvement is common and therapeutically challenging.nnnMETHODSnEfficacy and safety data specific to treatment of head/neck regions with tacrolimus ointment (Protopic) from three double-blind, randomized, vehicle-controlled studies are reported. A total of 631 adult and 352 pediatric patients with moderate to severe atopic dermatitis applied the vehicle, 0.03% or 0.1% tacrolimus ointment twice daily to affected areas for up to 12 weeks.nnnRESULTSnSignificant improvements from baseline to end of treatment for signs of atopic dermatitis (erythema, edema, excoriation, oozing, scaling, and lichenification) were noted for head/neck and non-head/neck areas treated with either 0.03% or 0.1% tacrolimus ointment (p<0.001). Within each treatment group, the overall 12-week adjusted incidence rate of application site adverse events was similar for both head/neck and non-head/neck areas. The incidence of common adverse events such as pruritus, skin burning, erythema, infection, and skin tingling in head/neck areas was comparable to that observed in non-head/neck areas within each treatment group. The overall prevalence of application site adverse events decreased rapidly during the first few days of treatment.nnnCONCLUSIONnTacrolimus ointment is a safe and effective treatment for atopic dermatitis on the head and neck.

Inherited disorders of keratinization

Abstract The term inherited disorders of keratinization encompasses a number of genetic skin disorders linked by the common finding of abnormal epidermal differentiation, often with aberrant formation of the cornified envelope (cornification). These disorders, such as ichthyoses, palmoplantar keratodermas, and erythrokeratodermas, have been classified traditionally on the basis of clinical morphology and the presence or absence of extracutaneous manifestations. In many cases the features do not facilitate easy segregation into a single distinct and well-defined group (eg, palmoplantar keratoderma and ichthyosis coexist in a number of conditions). These inherited disorders of keratinization may also feature epidermal fragility. Clinical, histologic, and ultrastructural morphologic characteristics of these conditions have been used to further classify and subdivide them. As none of these diseases is common, the morphologic approach has great benefit to the practicing clinician and offers a logical pathway to diagnosis when confronted with a patient for the first time in the clinic. Advances in genetic technology during the past 10 years have led to an enormous increase in understanding the basic molecular defects responsible for inherited disorders of keratinization, and these advances have made possible a new, molecular mechanism-based approach to their classification that complements the morphologic system. In the great majority of cases recent molecular insights have confirmed the accuracy of the original clinical distinctions and stand as testimony to the skilled and detailed observations made by generations of clinicians. As knowledge increases, however, the association of mutations in one gene with a distinct phenotype has become more complex. For example, clinically distinct conditions have been attributed to different mutations in the KRT1 gene (clinical heterogeneity). A further example of clinical heterogeneity is the spectrum of phenotypes attributable to mutations in the gene that encodes desmoplakin 1; dominantly acting mutations cause a skin-limited phenotype, but recessively acting mutations may cause a dilated cardiomyopathy and hair phenotype in addition to epidermal changes. In others, identical clinical phenotypes have been attributed to mutations in several genes (genetic heterogeneity), for example, with lamellar ichthyosis, in which 4 gene loci in addition to that encoding transglutaminase 1 have been identified. A sound knowledge of these issues is vital to the clinician involved in the care of patients with inherited disorders of keratinization. The direct benefits to patients of this increased knowledge are improved diagnostic certainty, an understanding of the biology underlying the gene defect, and more accurate genetic counseling. It is likely that this increased understanding will lead to the development of more rational treatments for many of these distressing conditions in the near future. Attempts at gene therapy have been limited to date, but ex vivo gene correction has succeeded for both lamellar ichthyosis and recessive X-linked ichthyosis in mouse models. (Curr Probl Dermatol 2002;14:71-116)

DERMATOLOGIC CLUES TO INHERITED DISEASE

Genetic diseases often have cutaneous manifestations, which can be the first or most prominent signs of the underlying problem. Recognition of these dermatologic clues allows prompt diagnosis and intervention. In this article, the authors have attempted to outline several important examples of genodermatoses.

A colorimetric bead-binding assay for detection of intermolecular interactions

Abstract: We have developed a new technique that rapidly and reproducibly allows direct visualization of molecular interactions, including receptor‐ligand binding. The technique can be easily applied to examine binding between proteins and glycoproteins, or proteins and glycolipids, including gangliosides. In this novel bead‐binding assay, the suspected ‘ligand’ molecule is bound to 0.2‐ or 1.0‐µm colored FluoSphere beads. These coated beads are then mixed directly with 150‐µm Sepharose or 50‐ to 75‐µm agarose beads coated with the second ‘target’ molecule. Binding between molecules is easily detected by immunofluoresence microscopy as colored rosettes or aggregations formed by clustering of the smaller fluorescent beads around the larger non‐fluorescent bead. The validity of this technique for glycolipid binding to protein was verified through demonstration of the known interaction between the β subunit of cholera toxin with ganglioside GM1. The bead‐binding technique facilitated the novel observations of interaction between ganglioside GT1b with the α5 subunit of α5β1 integrin and the interaction of GM3 with the epidermal growth factor receptor. A modification of this technique, in which the coated beads are bound to protein fixed on plates, allows a quantifiable colorimetric assay of interaction. This versatile and rapid technique will have widespread applications for in vitro systems and may also be useful for in vivo analysis of binding to cell surface receptor molecules.