A New Treatment Regimen for Rosacea: OnabotulinumtoxinA

most consistent finding in all rosacea patients. Facial flushing, vasodilation, and increase in blood flow, whether pathological or not, are a result of both humoral and neural stimuli. Neuropeptides such as substance P (SP), vasoactive intestinal polypeptide (VIP), and acetylcholine (ACh) have all been implicated in increased vascular flow. Moreover, increased microvascular flow secondary to stress, heat, or irritants is common to the ETR and PPR rosacea subtypes. Over the past few years, a neurogenic component to rosacea is becoming increasingly clear. Although supporting evidence for SP seems to be waning,^5,6 the morphological and molecular evaluation using immunohistochemistry studies and gene array analysis have shown marked upregulation of the neuropeptide genes for VIP, pituitary adenylate cyclase-activating polypeptide (PACAP), 5-hydroxytryptamine (serotonin) 3A receptors, nerve growth factor beta, alpha1D-adrenergic receptors, adrenomedullin 2, and cathelicidin antimicrobial peptide in rosacea patients.⁷ This all suggests that there is an important neurogenic component to vascular dysfunction in rosacea.

Chronic poor vascular hemostasis leads to leaky vessels, pooling, delayed removal of inflammatory mediators, and a prolonged perivascular inflammation. Inflammation is a common denominator in rosacea and, when prolonged, leads to tissue hypertrophy and fibroplasias, the likely mechanism behind rhinophyma. There is debate over the origin of the inflammation in rosacea, and controversy surrounds the theory of a perifollicular inflammatory process that is aggravated by microbial organisms. The bacteria Propionibacterium acnes and Demodex mites have been causatively linked to rosacea, with evidence that antibiotics targeting these organisms are helpful in treating the symptoms of rosacea; but these organisms are also found in high concentration in people without rosacea.³ However, a neurogenic component to the inflammation in rosacea is strongly supported by histochemical evidence. Mast cells, a potent contributor to the release of inflammatory mediators, including histamine, are identified in increased quantity in rosacea patients, and receptors for histamine and serotonin, leading to vasodilatory effects, are upregulated in all forms of rosacea. Additionally, the neuropeptides VIP and PACAP are known activators of mast cells and may be important connectors from nerve to mast cell to histamine release, all affecting inflammation in rosacea. A neurogenic origin to the inflammatory component of rosacea, as well as the vascular component, can be well supported. Therefore, as eluded to by Schwab et al, drugs that affect neurovascular and neuroimmune communication may be advantageous in the treatment of rosacea.⁷

Botulinum toxin type A, as an inhibitor of ACh and VIP release, supports a mechanism of action which explains its benefits in reducing facial and neck flushing. When body temperature rises, cutaneous blood flow and vasodilatory effects are partially dependent on post ganglionic cholinergic ACh and VIP release.^8,9 OnabotulinumtoxinA as a potential modality for treating flushing

was described by Yuraitis and Jacob, who noted a decrease in facial flushing and extremely satisfying results two weeks after 10 units (2 U/0.1 cc) of onabotulinumtoxinA had been placed at 1 cm intervals into one cheek of a 26-year-old male.¹⁰ Flushing is also common to gustatory sweating (Frey syndrome), a well-described sequelae following parotid surgery in which parasympathetic fibers intended for the parotid gland regenerate and reinnervate sweat glands. Upon eating, neurosignaling intended to stimulate parotid gland salivation instead triggers regional sweating. Tugnoli et al reported that 25 U to 55 U of onabotulinumtoxinA (100 U/5 cc) in 2 U increments and 100 U to 180 U of abobotulinumtoxinA (300 U/5 cc) in 6 U increments effectively reduced gustatory sweating, cutaneous blood flow, and flushing on the treated side for up to 18 months.¹¹

Although botulinum toxin's potent effects on ACh release inhibition suggest it is the signaling neuropeptide behind the flushing, another peptide must also be involved because atropine blockade of ACh action in patients with Frey syndrome stops the sweating, but not the flushing.^12,13 Vasoactive intestinal peptide has been suggested as another parasympathetically released neuropeptide likely responsible for the flushing.¹⁴ Sterodimas and colleagues in 2003 reported on treating a patient with neck flushing with a diluted version of onabotulinumtoxinA.¹⁵ Three hundred units of onabotulinumtoxinA (1 U/0.1 cc) was injected into the anterior chest in three subsequent 100 U doses; each dose was separated by two weeks. Four weeks after the third treatment, the patient had complete abolition of her symptoms and no adverse events. Using the same concentrated version of onabotulinumtoxinA (4 U/ 0.1 cc) as Yuraitis and Jacobs,¹⁰ Kranendonk et al injected eight units in four sites over the central cheek. They noted no reduction in erythema but were concerned at an alteration in mimetic activity of the cheek and upper lip during smiling one week after the injection.¹⁶ However, others have been unable to duplicate the onabotulinumtoxinA antiflushing effects.¹⁷ Alexandroff and colleagues, using 2 U/0.1 cc dilution, injected 10 units at 1 cm intervals to one cheek of two separate patients with a history of facial flushing, and they noted no improvement after six weeks. Although injection protocols may be similar in the few existing case reports, the dilution and dosing of the toxin seem to differ,