Histologic evaluation of the long term effects of tretinoin on photodamaged skin.

Sustained improvement with prolonged topical tretinoin for photodamaged skin has been well documented for up to 22 months of continuous treatment. We now report long-term (4 years) histologic effects of topical tretinoin in photodamaged skin of 27 patients, the longest study to date. The observed decreases in dermal elastin content and perivascular inflammation and increase in epidermal mucin in facial biopsies obtained after up to 4 years of treatment may be partly responsible for the continued clinical improvement. Furthermore, the study shows that there are no untoward effects on keratinocytes or melanocytes during long-term use of topical tretinoin.

An ultrastructural study of the effects of topical tretinoin on microcomedones.

It has been hypothesized that topical tretinoin prevents inflammatory acne lesions by loosening follicular impactions (microcomedones) and clearing the follicular canal of retained keratin. To lend support to this hypothesis, 15 volunteers applied 0.1% tretinoin cream once daily for 12 weeks to one side of the face and an emollient cream to the other side. During the 12-week treatment period, samples of microcomedones were obtained using the follicular biopsy technique. By 6 weeks, the number of microcomedones was reduced approximately 50% from baseline on the side treated with tretinoin and approximately 80% at the end of the study. Only a minimal reduction in the number of microcomedones was seen on the emollient side, even after 12 weeks of application. Morphologic examination showed a progressive loss of the cohesiveness of the microcomedones and ultrastructural alterations in the epithelial cells treated with tretinoin. The microcomedones changed from well-developed keratinous plugs containing many bacteria to a few wispy layers of keratin containing few bacteria. This study confirms the microcomedolytic activity of tretinoin and provides evidence that this activity is associated with changes in the differentiation of the follicular epithelial cells.

Lifetime topical application of tretinoin to hairless mice.

The discovery that topical tretinoin can reverse some of the effects of photodamage may lead to its chronic application. Examination of long-term effects was of interest. Three groups of hairless mice (age 6-8 weeks) were treated dorsally with 1) tretinoin (0.025%), 2) cream vehicle, 3) sham treatment. Applications were 3 times weekly and continued for up to 2 years until all mice were sacrificed or had died. Biweekly examinations showed no sign of retinoid toxicity, with growth and longevity similar in all groups. Tretinoin-treated skin was smooth and pink, resembling that of younger mice. Controls had yellowed, irregularly thickened skin. Histologically, tretinoin-treated skin had a hyperplastic epidermis consisting of plump, cytologically normal cells. Control skin had 3-4 compressed cell layers. Foci of new normally staining collagen were present in the subepidermal dermis of tretinoin-treated skin; fibroblasts were large and abundant in these areas. These foci were absent in controls. Mice treated with tretinoin also appeared to have increased amounts of elastic fibers and glycosaminoglycans.

Long-term clinical experience with a topical retinoid.

Topical tretinoin is a well-established treatment for acne, with a low incidence of reported adverse effects, most of which are local skin reactions. The retinoid has limited absorption through the skin, so that even with repeated applications plasma concentrations do not exceed normal endogenous levels. In mice, lifetime treatment with topical tretinoin improved skin texture and did not have any tumorigenic effects. Data from multicentre clinical trials have shown that 0.05% tretinoin emollient cream reduced fine wrinkling, surface roughness and mottled hyperpigmentation caused by photodamage. Improvement of these clinical signs was maintained after 12 months of daily tretinoin therapy, and regressed slowly after cessation of therapy. However, maintenance of the visible effects of topical tretinoin was reported after continued therapy with once or three times weekly applications of tretinoin emollient cream. Data from multicentre studies suggested that 0.1% tretinoin cream has a potential role in the treatment of solar keratoses. It is concluded that the application of tretinoin to photodamaged skin used in conjunction with sunscreens and judicious sun exposure is an effective regimen to treat the damaging cutaneous effects of chronic sun exposure.

Tretinoin emollient cream: a new therapy for photodamaged skin.

BACKGROUND: Tretinoin administered topically in 0.1% concentration has been shown to improve the wrinkling and irregular pigmentation of photoaged skin. OBJECTIVE: The purpose of this study was to assess the safety and efficacy of various concentrations of tretinoin in a new emollient cream base in the treatment of photoaged skin. METHODS: Three concentrations of tretinoin (0.05%, 0.01%, and 0.001%) in a new emollient cream formulation were compared with vehicle in a 24-week, double-blind, randomized, multicenter study of 296 subjects with photodamaged facial skin. RESULTS: Tretinoin emollient cream 0.05% gave a significantly better global response to therapy than vehicle (p less than 0.001), with 68% of subjects exhibiting improvement at the end of therapy, compared with 43% of subjects in the vehicle group. An excellent or good response was found in 26% of subjects treated with tretinoin emollient cream 0.05% versus 11% of vehicle-treated subjects. Fine wrinkling, mottled hyperpigmentation, and roughness were more improved in subjects who received tretinoin emollient cream 0.05% than in vehicle-treated subjects (p less than 0.05). No significant difference was found between vehicle and tretinoin emollient cream 0.01% or 0.001%. Histologic examination showed increases in epidermal and granular layer thickness, decreased melanin content and compaction of the stratum corneum after therapy with tretinoin emollient cream 0.05% or 0.01%. Mild to moderate skin reactions, such as erythema, peeling, and burning, were the most common side effects and, although most prevalent in the group using the 0.05% concentration, generally did not limit tretinoin use. CONCLUSION: Tretinoin emollient cream 0.05% appears to be safe and effective in the treatment of photodamaged skin.

Skin replica analysis of photodamaged skin after therapy with tretinoin emollient cream.

Computerized image analysis of silicone replicas, a reproducible, objective technique for measuring skin topography, was used in addition to clinical measures in two multicenter, double-blind, randomized, controlled studies of tretinoin emollient cream, a new formulation for treating photodamaged skin. Previously, the skin replica technique had been successfully used in a pilot study of tretinoin 0.05% cream by one investigator. In the present studies, subjects treated for 24 weeks with tretinoin emollient 0.05% cream consistently showed more improvement in skin topography than did vehicle-treated patients. A 0.01% concentration of tretinoin emollient cream also improved skin topography to a greater extent than the vehicle, while the lowest concentration tested (0.001%) showed little difference from vehicle. These results, reflecting a smoothening of the skin surface in tretinoin emollient cream-treated subjects, were consistent with clinical data showing greater improvement in fine wrinkling and roughness after tretinoin emollient cream therapy than after vehicle therapy. Findings from these multicenter studies confirm the value of the skin replica technique and help establish the efficacy of tretinoin emollient 0.05% cream for photodamaged skin.

Topical tretinoin for treatment of photodamaged skin. A multicenter study.

The clinical and histologic effects of a new emollient cream formulation of topical tretinoin at concentrations of 0.05% and 0.01% were examined in 251 subjects with mild to moderate photodamaged facial skin in a randomized, double-blind, vehicle-controlled, multicenter study. Seventy-nine percent of the subjects who received 0.05% tretinoin for 24 weeks showed overall improvement in photodamaged skin compared with improvement in 48% of the vehicle-treated control subjects. Significant reductions were found in fine wrinkling, mottled hyperpigmentation, roughness, and laxity after 0.05% tretinoin therapy when compared with controls. In addition, histologic changes of increased epidermal thickness, decreased melanin content, and stratum corneum compaction provide independent evidence supporting clinical improvement. Side effects of erythema, peeling, and stinging were usually mild and well tolerated.

Effects of tretinoin on photodamaged skin. A histologic study.

The histologic effects of topical tretinoin therapy on photodamaged facial skin were investigated in two 24-week, double-blind, randomized, vehicle-controlled studies involving 533 subjects at eight US centers. Three concentrations of tretinoin (0.05%, 0.01%, and 0.001%) in a new emollient cream were studied. Pretherapy and posttherapy biopsy specimens from the periorbital (crow's foot) area were examined by conventional light microscopy and computerized image analysis. Four significant dose-dependent differences from vehicle were found in the tretinoin groups: increased epidermal thickness, increased granular layer thickness, decreased melanin content, and stratum corneum compaction. There was no significant difference between 0.001% tretinoin and the vehicle, and no obvious dermal changes were detected in any group. The four epidermal changes in tretinoin-treated skin establish the biologic activity of the new emollient cream formulation and may partially account for the clinical improvements in photodamage observed in the same group of subjects.

Topical tretinoin research: an historical perspective.

The topical tretinoin epoch began almost 30 years ago in the laboratories of Stüttgen where he first recognized that a vitamin A derivative, tretinoin, had the potential to be a truly significant form of dermatological therapy. His early clinical trials in a variety of skin disorders provided the first indication of topical activity for the retinoids. Kligman evaluated further the utility of topical tretinoin; focusing his attention on acne. Through these initial studies, topical tretinoin became a fundamental treatment modality for acne. Soon after topical tretinoin was made available, elderly patients using it to treat acne noted a general improvement in the quality of their skin. Kligman began open clinical trials to investigate the effects of topical tretinoin on treatment of photodamaged skin. Positive findings from these trials led to double-blind, vehicle-controlled pilot studies which supported the concept that topical tretinoin could improve the fine wrinkling, mottled hyperpigmentation and tactile roughness which are characteristic of photodamaged skin. These results were verified in two large double-blind, multicentre studies of approximately 700 patients that used not only clinical and patient evaluations but also biopsies and skin surface replicas.

Treatment of photodamaged facial skin with topical tretinoin.

A 6-month, randomized, double-blind, vehicle-controlled study was conducted with 0.05% tretinoin cream once daily in the treatment of photodamaged facial skin. Significant amelioration of many of the signs of photodamage were achieved with minimal side effects. Clinical grading showed significant improvement both in the assessments based on changes in clinical scores and in pre- and posttreatment comparisons of standardized photographs. Fine wrinkling, coarse wrinkling, sallowness, looseness, and hyperpigmentation were significantly improved with tretinoin therapy. Furthermore, a self-appraisal questionnaire indicated that tretinoin-treated patients, but not vehicle-treated patients, were able to perceive improvement in their facial appearance. An objective method based on digital image processing of silicone rubber casts obtained from the crow's-feet area also indicated that the skin surface topography was smoother and less wrinkled in the tretinoin-treated group compared with the vehicle-control group.

A new treatment for tinea versicolor using econazole nitrate 1.0 percent cream once a day.

Econazole nitrate 1.0 percent cream was compared with placebo for safety and efficacy in the treatment of 126 patients with tinea versicolor. Overall results showed that 97 percent of the patients who were treated with econazole nitrate 1.0 percent cream once a day achieved excellent or partial responses, while 62 percent of those patients applying the placebo cream attained similar responses. This difference is statistically significant (p = 0.001). The study results show that econazole nitrate cream is a valuable drug for the treatment of tinea versicolor.

Cicatricial pemphigoid in a patient with systemic lupus erythematosus.

Three years after the onset of lupus erythematosus, blisters, erosions, and erythema of the gingivae developed in a 31-year-old man. A diagnosis of cicatricial pemphigoid was established by routine and immunofluorescence microscopy studies. An association between cictricial pemphigoid and other autoimmune disorders seems to be rare. This case demonstrates the importance of performing immunofluorescence microscopy studies, as well as routine histologic assessments, of conditions that resemble desquamative gingivitis.

Cryoglobulinemia and decreased monocyte chemotaxis is malignant melanoma.

The sera fromm 13 patients with malignant melanoma were evaluated for immune complexes by cryoprecipitation and the 125I Clq binding assay. Cryoprecipitates were identified in 12/13 patients (92%) and cryoimmunoglobulins in 7/13 patients (54%). Either cryoimmunoglobulin or elevated Clq binding was identified in 8/13 patients (62%). Incubation of normal monocytes with the resuspended cryoimmunoglobulin of 7 melanoma patients produced greater than 50% reduction in the ability of th monocytes to respond to chemotactic stimuli (p < .01). Similar inhibition was seen with cryoimmunoglobulin from erythema multiforme patients, but not with 'medium alone, albumin, heat aggregated albumin or heat aggregated-IgG in similar concentrations. No soluble factors produced in vitro could be demonstrated to produce this inhibition. Inhibition of monocyte function by immune complexes may be an important component of impaired host response to malignant melanoma, or alternatively may represent an important mechanism for the accumulation of monocytes at sites of inflammation, analogous to migration inhibition factor.

Keratoacanthoma of the glans penis.

A patient with a solitary keratoacanthoma of the glans penis is presented. Since this area is devoid of hair, this keratoacanthoma could not have arisen from a hair follicle as has been suggested as the cause of keratoacanthoma. Keratoacanthoma should be included in the differential diagnosis of rapidly growing keratotic tumors of the glans penis. Correct diagnosis of this tumor may save patients from needless mutilating surgery of the penis.

Immune complex vasculitis, polymyositis, and hyperglobulinemic purpura.

This is the first description of a patient with both polymyositis and Waldenström hyperglobulinemic purpura. There was evidence of circulating immune complexes, and immune deposits were found in dermal and muscular vessels. Similar electron-dense deposits were seen ultrastructurally in the basement membrane of both normal and abnormal microvasculature. The findings suggest that the muscle and skin lesions may be associated with deposition of circulating immune complexes in and around blood vessels, followed by complement activation and subsequent inflammation.