IMPORTANCE Most patients with tuberous sclerosis complex (TSC), an autosomal-dominant disorder that is caused by the constitutive activation of mammalian target of rapamycin, experience disfigurement caused by skin lesions involving facial angiofibromas. Many have been left untreated because of a lack of therapeutic options that are less invasive than surgery or laser treatment. OBJECTIVE To confirm the efficacy and safety of sirolimus gel, 0.2%, for treatment of patients with angiofibromas and/or skin lesions. DESIGN, SETTING, AND PATIENTS Multicenter, randomized clinical trial at 9 centers in Japan from December 2015 to October 2016 including 62 children and adults with TSC. INTERVENTIONS Patients who developed angiofibromas were randomly assigned, in a 1:1 ratio, to receive sirolimus gel, 0.2%, or placebo, each applied topically twice daily for 12 weeks. MAIN OUTCOMES AND MEASURES The primary end point was composite improvement in the size and color of angiofibromas in photographs at week 12 of treatment. It was assessed by an independent review committee comprising 3 blinded dermatologists who categorized patient results into the following 6 categories: "markedly improved," "improved," "slightly improved," "unchanged," "slightly aggravated," and "aggravated." RESULTS Sixty-two patients (27 pediatric and 35 adult; 34 [55%] female; mean [SD] age, 22.5 [11.9] years) were enrolled and randomly assigned to receive sirolimus gel, 0.2% (30 patients), or placebo (32 patients). The response rates of angiofibromas at weeks 4, 8, and 12 of treatment were 0 each in the placebo group in contrast to 20% (95% CI, 8%-39%; P = .01), 43% (95% CI, 26%-63%; P < .001), and 60% (95% CI, 41%-77%; P < .001), respectively, in the sirolimus group. None of the 31 assessable patients in the placebo group were rated improved or better, and 26 of them (84%) were rated unchanged. In contrast, 5 (17%) and 13 (43%) patients in the sirolimus group were rated markedly improved and improved, respectively. Adverse events were mild to moderate and were observed in 27 (90%) and 22 (69%) patients in the sirolimus and placebo groups, respectively; however, none of the trial participants discontinued treatment. Acute pancreatitis developed as a serious adverse event in 1 patient in the sirolimus group, and the patient recovered soon after hospitalization without discontinuing treatment. CONCLUSIONS AND RELEVANCE Sirolimus gel, 0.2%, demonstrated a significant clinical benefit for patients with TSC involving angiofibromas, thus providing a promising therapeutic modality.
Introduction Our previous clinical studies have demonstrated the short-term efficacy and safety of the sirolimus gel for patients with tuberous sclerosis complex (TSC). However, long-term clinical evidence is lacking. Our objective was to assess the safety and efficacy of long-term treatment with the sirolimus gel for the skin lesions of TSC patients. Methods We conducted a multicenter, open-label, uncontrolled clinical trial in 94 Japanese patients with TSC. Patients applied the 0.2% sirolimus gel on their face or head twice daily for > 52 weeks (maximum 136 weeks for safety). The safety endpoints were the rate of adverse event (AE)-caused discontinuation (primary endpoint) and the incidence of AEs. The efficacy endpoint was the response rate of angiofibromas, cephalic plaques, and hypomelanotic macules. Results Among 94 enrolled patients (mean age, 21 years; range 3–53 years), the rate of AE-caused discontinuation was 2.1% (2/94 patients). Although application site irritation and dry skin occurred relatively frequently, none of the drug-related AEs were serious; most of the drug-related AEs resolved rapidly. The major drug-related AEs (≥ 5% in incidence) were application site irritation (30.9%), dry skin (27.7%), acne (20.2%), eye irritation (8.5%), pruritus (8.5%), erythema (7.4%), dermatitis acneiform (6.4%), and dermatitis contact (5.3%). The response rates of angiofibromas, cephalic plaques, and hypomelanotic macules were 78.2% [95% confidence interval (CI) 68.0–86.3%], 66.7% (95% CI 51.1–80.0%), and 72.2% (95% CI 46.5–90.3%), respectively. Conclusions The gel was well tolerated for a long time by patients with TSC involving facial skin lesions and continued to be effective. Trial Registration ClinicalTrials.gov identifier: NCT02634931.
Dermatologists should consider Achenbach syndrome in the differential diagnosis for patients with purpura on the fingers. The patient should be monitored following appropriate examination and invasive tests, such as skin biopsy or angiography, should be avoided unless necessary.
There is not enough evidence available to guide wound care management in patients with Stevens-Johnson Syndrome (SJS)/ Toxic Epidermal Necrolysis (TEN). Current guidelines are based on expert opinion and mimic burn wound treatments, including the use of silverimpregnated dressings. Silver-containing dressings reduce the risk of invasive infection by minimizing the bacterial colonization of wounds. Evidence from small clinical trials in burn patients and a retrospective study in SJS/TEN patients indicate that they offer the advantage of not requiring daily dressing changes, which may damage the healing epidermis, and minimize patient discomfort. However, cytotoxic effects of silver have been demonstrated in human cell lines, including leukocytes. Studies investigating silver absorption from silvercoated dressings in burn patients have yielded conflicting results, with only a few case reports warning against the use of silver due to its cytotoxic effects. Systemic silver absorption in patients with SJS/TEN treated with any type of silver-based dressing has not been addressed in previous studies. We performed a retrospective chart review to investigate silver absorption in SJS/TEN patients treated with silver-nylon and silver-foam dressings. Six patients met inclusion/exclusion criteria, with body surface area (BSA) involvement of 75 %-100% and 5 to 25 % denuded skin. Five patients had elevated serum silver levels in the range of 9.9 to 110 ug/l, and had a decrease in leukocyte counts compared to baseline. The patient with normal serum silver levels had normal leukocyte counts, but developed transaminitis. None of the patients developed argyria. Our study indicates that silver-nylon and silver-foam dressings used in patients with SJS/TEN lead to systemic silver absorption. Whether the observed leukopenia and transaminitis are a result of either silver toxicity, the underlying hematological malignancy (3 patients), or SJS/TEN itself, our observations support the need to further investigate the safety of silver-based dressings in patients with SJS/TEN.
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