Topical Tretinoin Therapy and All-Cause Mortality, Treating Hereditary Angioedema with Danazol, and Atopic Dermatitis Disease Control

This online-only bonus feature is an ongoing review of past peer reveiw journal articles with significant impact on dermatology.

Katarina Kesty, MD, MBA

Topical Tretinoin Therapy and All-Cause Mortality

A study in 1998 launched called the Veterans Affairs Topical Tretinoin Chemoprevention (VATTC) Trial. This was initiated to investigate the role of topical retinoids in the prevention of basal cell carcinoma and squamous cell carcinoma. The initial study was deigned to determine whether high-dose topical tretinoin 0.1% would have a chemopreventive effect. This trial was halted 6 months before its scheduled end date because mortality in the tretinoin-treated group was significantly higher than in the vehicle group. Patients included in the trial included those who had had at least 2 keratinocyte carcinomas in the previous 5 years prior to randomization. These patients also got a skin exam at the time of randomization to exclude any patients with current basal or squamous cell carcinomas. Patients were recruited from 6 VA Health Centers across the country.

The study cream was applied up to twice daily as tolerated by the patient. The primary endpoints for the initial study was time to development of basal cell carcinoma or squamous cell carcinoma. The Charlson Index of comorbidities was calculated for was patient. This is a weighted sum of 19 indicator variables scored as 0 or 1 which all correlate to a medical condition. Age and smoking status was also collected at time of study initiation.

A total of 1131 veterans were randomized; 566 to receive tretinoin and 565 to receive the vehicle control. The average age was 71 and 97% were men. Before the end of the study 122 patients had died in the tretinoin group and 90 had died in the vehicle group. This association was analyzed using multivariate Cox regression which adjusted for the Charlson index, age, and smoking status. Using this analysis, the use of tretinoin therapy remained statistically significant. The confidence interval lower boundary approached 1.0, however, and was only marginally decreased in magnitude.

It is difficult now and for the study investigators to come up with biologically plausible explanations for the difference in mortality between the two groups. It has been shown that only a small amount of topical tretinoin is systemically absorbed. This is unlikely to have significant systemic effects. Unfortunately studying the aged populations puts one at risk for confounding variables due to their higher mortality risk. Overall, this study does not provide substantial data for not prescribing tretinoin to this population.

Weinstock et al, Arch Dermatol, Jan 2009

Treating Hereditary Angioedema with Danazol

This study was conducted in the 1970’s. Hereditary angioedema clinically presents as episodes of swelling of the face, arms, legs, abdominal viscera, or airway. Factors associated with attacks include trauma, anxiety, and emotional stress. Many attacks occur without any known inciting factors. It is believed that this disease is due to low levels of the inhibitor of the activated first component of complement (C1 esterase).  Mortality is mostly due to airway obstruction.

In the study, 5 women and 4 men who all had attacks at least once per month were enrolled. The study was a controlled double-blind trial; either danazol 200 mg or placebo was taken three times daily. If the patient had an attack, then the medicine was stopped and a new “course” was started with either placebo or danazol. If no attack occurred, the “course” lasted 28 days. The 9 patients completed 93 courses, of which 47 were placebo and 46 were danazol. Attacks occurred in 44 of the 47 placebo courses and in only 1 of the danazol courses. This was highly statistically significant. No virilization was noted in the women and no changes in potency were reported by the men, although every study patient gained weight.

The levels of C1 esterase inhibitor increased significantly over the course of treatment with danazol compared to the patient’s own control.  The levels of C4 also increased on drug therapy. At the time of this study, danazol had a much more desirable side effects profile than other androgens on the market. Interestingly, after the study ended all 9 patients chose to remain on danazol. They also noted that the patients could tell whether they were on danazol vs. placebo by the end of the trial due to absence of symptoms.

Gelfand et al, NEJM, Dec 1976

Atopic Dermatitis Disease Control and Age

This study was an observational cohort study regarding atopic dermatitis (AD). They examined data from the Pediatric Eczema Elective Registry. This examined patients who used pimecrolimus 1% topically and had AD diagnosed by a physician. The scale of disease control was based on self-reported control and was classified as: complete, good, limited, or poor. Treatment use was also recorded.

Patients who reported complete control were categorized further into 1 groups: those who had complete control with treatment and those who had complete control without treatment. A total of 5,798 patients aged 2-26 years returned 49,840 surveys. The patients were 47% male, 44% white, mean age was 7.2 years, and mean follow up was 4.2 years. 8% of surveys were completed under the category of complete control without treatment. Good or limited disease control was reported 80% of the time.  The odds of complete control of the patient’s AD increased with each additional year of age. Of note,  although overall AD improves with age, only a minority of patients reported “outgrowing” their disease according to this registry. Interestingly, the frequency of visits to a dermatologist decreased with age. This finding was consistent regardless of the reported severity of their AD. This may explain why many dermatologists perceive that the severity of AD decreases with age.

Overall, age is predictive of disease control. This is independent of other factors including sex, race, income, and history of atopic disease. AD may be a disease with a heterogeneous chronic course with periods of patients’ lives without disease activity.

Abuabara et al. J Allergy Clin Immunol, 2015 July

Katarina Kesty is currently a Dermatology PGY-3 resident at Wake Forest University School of Medicine in Winston-Salem, North Carolina. She grew up in North Bay, Ontario, and attended Wake Forest for her undergraduate studies, medical school, and business school.