New trends in botulinum toxin use in dermatology

Background Recent studies have highlighted new botulinum neurotoxin (BoNT) applications in the field of dermatology. Objective To review current knowledge of BoNT use in dermatology. Methods The literature of the last 5 five years has been reviewed. Results We describe interesting protocols of BoNT treatment for hyperhidrosis (HH), hypertrophic scars and keloids, Raynaud phenomenon, facial flushing, oily skin, psoriasis, Hailey-Hailey disease, and cutaneous lesions like painful lesions and periorbital syringomas. Conclusions Several skin conditions eligible for BoNT treatment have been described. After the wide application for HH treatment, scars as well as vascular and inflammatory skin disorders, oily skin and cutaneous lesions represent fields of application of BoNT.

Specifically, BoNT-B seems to be the treatment of choice in patients with multifocal HH since it can be used to treat multiple sites in the same session, thus improving QoL [4].
In pediatric patients, HH affects 1.6% of adolescents and 0.6% of prepubertal children [20], and it remains widely undertreated. However, BoNT has been demonstrated to be effective and safe [21]. A multicenter, nonrandomized, open-label study of onabotulinumtoxinA treatment (50 IU per axilla) of bilaterally primary axillary HH in adolescents from 12 to 17 years old showed an improvement of 75% in 79.4-93.2% patients [22]. The efficacy of BoNT treatment has been proven for axillary HH by several randomized trials in the past. Therefore, BoNT for HH of the axillae is FDA-approved, but it has also been reported effective for the treatment of other sites. Palmar HH, for instance, is usually treated with 100 -200 IU. Pain can limit this treatment; thus several strategies have been evaluated to increase the compliance. Among these, ice with pressure, ice <20 or >20 seconds associated or not with topical anesthesia [23,24], general anesthesia, nerve blocks, vibration, pressure [21], and needle-free injections (Med-Jet MBX, Medical International Technologies, Montreal, QC, Canada) [25]. However, an open-label prospective study involving 20 patients with palmar HH, treated with needle injection on the right hand and with a needle-free device, has proven the efficacy of the device to be lower as compared to the classic needle injection [25].
Repeated injection protocols have been proposed for both axillary and palmar treatment, in 3 different retrospective studies [26][27][28]. Repeated injections have been demonstrated to increase the duration of the effect from 5.5 to 8.5 months with 125 IU of abobotulinumtoxinA per underarm while it passed from 4 to 5 months when 50 U of onabotulinumtox-inA per axilla were employed [26,27]. The median duration of efficacy for palmar repetitive treatment was 7 months for the first injection and 9.5 months for the last with 250 IU of abobotulinumtoxinA per palm [28]. Palmar treatment should be performed carefully on the thenar eminence, as there is a risk of inducing weakness of the hand. On the other hand, repeated injections can be related to the development of neutralizing antibodies. Nevertheless, a 3-month interval between each injection has not been related to the presence of these antibodies [26,28].
Data concerning plantar treatment with BoNT are scarce [29]. Doses employed vary from 50 to 250 IU of onabotu-linumtoxinA per plantar area with effects lasting 3 -6 months [30]. 279 highlight the improvement in terms of both Raynaud's score (for 16 weeks after treatment) and the number of digital ulcers in patients treated with 1,000 and 2,000 IU of BoNT-B, as compared to the other 2 groups [45]. Furthermore, BoNT-A and B treatments have been proven to improve pulp temperature in patients with Raynaud, with or without systemic sclerosis [44,45].

Facial Flushing
Facial flushing consists of an episode of redness associated with a burning sensation. It can be primary or idiopathic and secondary to rosacea or hormonal stimuli like menopause. BoNT has been proven to provide symptomatic relief in patients with facial flushing through the inhibition of acetylcholine signaling pathway [46]. An open-label randomized controlled trial involving 24 patients with facial flushing showed an improvement within 2 to 3 weeks after the treatment. BoNT-A was injected, 1 IU per cm 2 , for a total amount of 30 IU in one session [47]. However, other protocols have also been described. The injection of 100 IU of onabotulinumtoxinA diluted in 7 mL of saline solution, distributed in microdroplets (0.05 mL), has been reported to be effective [48]. The assessment of clinical response followed a standardized grading system (0 = absent, 1 = mild erythema, 2 = moderate erythema, and 3 = severe erythema), revealing a significant improvement in erythema grade, as compared to baseline, at 1, 2, and 3 months after treatment (P < .05, P < .001, and P < .05, respectively) [49]. Although BoNT may cause headache, albeit rarely, it can be considered an option for reducing the severity of flushing [46,50]. However, studies with longterm follow-up are lacking [5].

Oily Skin
Oily skin is a common disorder, and treatment options often provide unsatisfactory results. The basis for BoNT-A treatment of oily skin, providing a reduction in sebum production, seems to lie in the expression of muscarinic acetylcholine receptors in sebaceous glands. These receptors control sebocyte differentiation and sebum production [3].
After preliminary data obtained on sebum reduction in a retrospective study, a prospective study involving 25 patients showing oily skin on the forehead was performed. Patients were treated with 10 intradermal injections of a total amount of 30-45 IU of abobotulinumtoxinA has been performed. A Sebumeter (Courage + Khazaka Electronic GmbH, Cologne, Germany) was used to assess baseline and post-treatment Indications for HH involving other cutaneous sites and osmidrosis treatment have also been described [31][32][33][34][35][36].

Hypertrophic Scars and Keloids
BoNT treatment has been proposed for the treatment of hypertrophic scars and keloids [37,38]. Tension due to motion is a well-known factor in determining scar tissue hypertrophy [39]. Thus, the ability of BoNT to reduce muscle contraction in the scar area can result in a decrease of skin tension, microtrauma, and subsequent inflammation [39]. Another underlying biological mechanism that has been hypothesized is the contribution in reducing the expression of transforming growth factor beta, the main regulator of hypertrophic scar formation [40]. Injection of BoNT may vary from 17.5-40 IU of onabotulinumtoxinA. BoNT can be employed either at the site of scar formation or suture removal [41]. sebum production. All 23 patients completing the study were satisfied after the treatment, with variable degrees of satisfaction (21 were satisfied, 1 was very satisfied, and 1 somewhat satisfied). However, Sebumeter readings revealed a significant sebum reduction in all patients at 1 week and 1, 2, and 3 months (P<0.001) [51]. Further studies are needed.

Psoriasis
The basis for BoNT-A use in psoriasis can be related to the inhibited release of substance P and CGRP. In particular, inverse psoriasis has been proven to benefit from BoNT, reducing both itch and pain. Intralesional BoNT-A has been employed for intertriginous psoriasis with the aim of reducing local sweating, skin maceration, and consequent infection.

Hailey-Hailey Disease
Similarly to what has been previously described for psoriasis, acanthosis and symptomatic relief seem to be the main effects of BoNT treatment in Hailey-Hailey disease. However, associated costs for achieving only temporary relief are a major issue [53]

Cutaneous Lesions
Pain relief has been evaluated in 18 patients with painful cutaneous leiomyomas who were randomized to obtain either onabotulinumtoxinA treatment versus placebo. BoNT-A was proven to be effective in pain improvement [54].
Periorbital syringomas are commonly treated with CO2 laser. However, the combined approach with ona-botulinumtoxinA has been found to give better results in 48 patients, as compared to 44 subjects treated with CO2 only [55].

Conclusions
In conclusion, we describe innovative protocols and applications for BoNT use in dermatology, reviewing the literature of the last 5 years. Although the action of this drug has a complex mechanism, the effect of BoNT on many cellular types has been highlighted. Based on these data, several applications of BoNT have emerged. After the wide application for HH treatment, scars, as well as vascular and inflammatory skin disorders, oily skin and cutaneous lesions seem to be interesting fields of application of BoNT. On the other hand, there are