Drugs (2014) 74:1457–1465 DOI 10.1007/s40265-014-0281-x
LEADING ARTICLE
Rosacea: New and Emerging Treatments Farah A. Moustafa • Laura F. Sandoval Steven R. Feldman
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Published online: 26 August 2014 Ó Springer International Publishing Switzerland 2014
Abstract Rosacea is a chronic inflammatory skin condition that negatively impacts patients’ quality of life. We sought to review important aspects of the pathogenesis of rosacea and the role of new treatment options in its management. New, emerging treatments show promise; however, quality randomized controlled trials for many of these drugs are lacking. Brimonidine tartrate is an effective newly approved treatment for erythematotelangiectatic rosacea. Topical oxymetazoline has potential for the treatment of erythematotelangiectatic rosacea, with efficacy described in case reports and randomized controlled trials currently underway. Both oral and topical ivermectin have been studied for the treatment of papulopustular rosacea, both showing benefit; however, only topical ivermectin 1 % cream has been studied in randomized controlled trials. As our understanding of the etiology of rosacea continues to evolve, so will our options for therapeutic interventions. Further studies need to be performed to assess the long-term safety and efficacy of these treatments.
F. A. Moustafa L. F. Sandoval S. R. Feldman (&) Department of Dermatology, Center for Dermatology Research, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157-1071, USA e-mail: [email protected]; [email protected] S. R. Feldman Department of Pathology, Wake Forest School of Medicine, Winston-Salem, NC, USA S. R. Feldman Department of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, NC, USA
Key Points Rosacea is a chronic inflammatory skin condition that remains difficult to treat. New, emerging treatments such as brimonidine tartrate, oxymetazoline, and ivermectin have been studied and show promise; however, evidence is limited at this time. Further studies are needed to assess the long-term safety and efficacy of these treatments.
1 Introduction Rosacea is a chronic inflammatory skin disease and is one of the most common conditions that dermatologists treat. The reported prevalence of rosacea is between 1 and 22 % [1]. This wide discrepancy in data largely stems from various methodologies used to capture prevalence and therefore cannot be reliably compared. The National Rosacea Society recently reported that rosacea now affects 16 million Americans [2]. There are four well-known manifestations of disease: erythematotelangiectatic (ET), papulopustular (PP), phymatous (PH), and ocular [3]. It is more common in middle-age individuals, women, Caucasians, and those with Fitzpatrick skin type I and II. Because it typically localizes on the central face, and can be disfiguring in some cases, many patients experience a decreased quality of life [4]. The pathogenesis of this disease is complex and poorly understood. Many theories have been proposed and include dysregulation of innate immunity, dysregulation of the neurovascular system, and overgrowth of commensal organisms (e.g., Demodex).
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Treatment recommendations vary based on subtype of rosacea or on the signs and symptom present; however, effective treatment can prove difficult [5]. Therapies primarily focus on symptom suppression, in general targeting inflammation. A better understanding of the pathogenesis of rosacea is necessary to ensure better treatment outcomes. In this paper, we review the recent developments in the pathogenesis of rosacea and discuss the role of new treatments and their relationship to the pathophysiology of rosacea.
2 Pathogenesis of Rosacea The pathogenesis of rosacea is complex and thought to involve dysregulation of the immune, vascular, and nervous systems. While not caused by microorganisms, another evolving theory of the pathophysiology of rosacea is the involvement of overgrowth of commensal mites on the skin (Demodex folliculorum and Demodex brevis) in some patients with rosacea. Evolving theories on the pathophysiology of rosacea appreciate the complex interplay of dysregulation from these systems culminating in the clinical picture of rosacea [6]. There is also a strong suggestion of a genetic component, as transcriptome analysis has verified distinct gene profiles of rosacea subtypes [7].
Fig. 1 The role of innate immune system dysregulation in rosacea pathogenesis. CAP18 cathelicidin-related antimicrobial peptide 18, KLK5 kallikrein-related peptidase 5, TLR2 Toll-like receptor 2, UV ultraviolet
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2.1 Dysregulation of the Innate Immune System Dysregulation of the innate immune system may contribute to chronic inflammation and vascular abnormalities in patients with rosacea [8]. One pathway that may be relevant involves Toll receptor activation. Initially, Toll-like receptor 2 (TLR2) (a component of the innate system) is triggered by inciting factors. Numerous environmental stimuli can trigger TLR2, such as physical or chemical trauma, UV light, and microorganisms. This results in release of a processing enzyme, Kallikrein 5 (KLK5), from epidermal keratinocytes. This enzyme is responsible for processing the antimicrobial peptide cathelicidin into active its active form, LL-37. In rosacea-prone skin, the proteolytically processed forms of cathelicidin peptides are also different from normal individuals and are more pro-inflammatory. It is unclear how the abnormal form of cathelicidin is developed, but it is hypothesized to be the result of post-translational processing abnormalities associated with an increase in KLK5, also known as stratum corneum tryptic enzyme (SCTE), in the epidermis [8]. There is also higher expression of TLR2 in keratinocytes of rosacea skin [9]. Increased levels of cathelicidin and KLK5 present in skin from rosacea patients support the hypothesis of their role in pathogenesis [8]. Downstream effects of these proteins result in increased inflammatory cytokine release and angiogenesis, contributing to the clinical picture of rosacea
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(Fig. 1). Mouse studies involving the injection of cathelicidin peptides from patients with rosacea led to inflammation and vascular dilation, further supporting the role of cathelicidin in rosacea pathogenesis [8]. 2.2 Dysregulation of the Vascular and Neurovascular System Facial erythema is a central component of rosacea and is required for diagnosis. Worsening of disease is associated with persistence and intensity of facial erythema. Skin blood flow is increased in some patients, raising questions regarding the role of vascular dysregulation in the pathogenesis of rosacea and a potential factor to facial erythema in rosacea patients [10–14]. Facial erythema in rosacea can be divided into two major groups with different etiologies: (1) central facial erythema; and (2) perilesional erythema (surrounding papules and pustules in PP rosacea) [3, 15, 16]. Distinguishing between these types of erythema is important for treatment selection. Persistant facial erythema is a result of abnormal vasculature that results from chronic inflammation present in rosacea-prone skin. This is a multifactorial process, but one component involves LL-37 (the active form of cathelicidin) promotion of inflammation and angiogenesis through its downstream effects on endothelial growth factor receptors (EGFRs) in keratinocytes [9]. Chronic inflammation also leads to the associated telangiectasias found in rosacea [15]. Increases in vascular endothelial growth factor (VEGF) and endothelial nitric oxide (eNO) leading to increased vascularization and vasodilation, respectively, are also implicated in the chronic facial erythema present in rosacea [8, 9]. Neurovascular dysregulation or increased ‘vasoactivity’ is also thought to play an important role [17]. The superficial cutaneous system is largely regulated by the sympathetic nervous system through action on adrenoreceptors. While their role in rosacea pathophysiology is currently poorly understood, they do seem to play an important role as evidenced by the ability of new medications targeting these adrenoreceptors to reduce erythema [14, 18]. 2.3 Overgrowth of Commensal Organisms D. brevis and D. folliculorum are two commensal mite species that colonize the pilosebaceous follicle of human skin. The role of the Demodex overgrowth in the pathogenesis of rosacea has been controversial. Because the presence of these mites on human skin is ubiquitous, developing a causal relationship is difficult. The presence of Demodex does not indicate rosacea; however, Demodex infestation (defined as C5 mites/cm2) is higher in some patients with ETR and PPR rosacea [17, 19].
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Key components of Demodex overgrowth on the skin and their interaction with an aberrant immune system makes it an important consideration to better understand the etiology of rosacea as well as therapeutic options. Demodicosis (Demodex infestation) closely resembles rosacea clinically; patients often experience erythema, telangiectasias, and itching [20–22]. It is difficult to differentiate patients as having Demodex infestation resembling rosacea or rosacea with greater than average density of Demodex. Perhaps it is not simply a Demodex infestation that triggers rosacea, but the interaction of Demodex mite products interacting with the already aberrant and sensitive innate immune system in rosacea-prone skin. As mentioned above, TLR2 is over-expressed and more sensitive to activation in rosacea prone skin. Recently, Bacillus oleronius bacterium has been cultured from Demodex mites and its role in the pathogenesis of rosacea is under investigation [23]. Antigens on the mite as well as the bacteria may could potentially be recognized by TLR2 and result in its activation and downstream inflammatory effects in the skin. In cases in which patients are found to have high Demodex counts, it may be worth considering anti-parasitic agents (ivermectin, permethrin) for the treatment of their rosacea.
3 Overview of Treatment 3.1 Current Treatment In general, adjunct measures including high-factor sunscreens, cosmetic camouflage, cooling, and avoidance of irritants and triggers (extremes of temperatures, sunlight, diet, alcohol, exercise, acute psychological stressors, medications, menopausal hot flashes) are recommended for all patients with rosacea [5]. The use of photoprotection is particularly important in that it may prevent a flare triggered by UV exposure, as well as help avert photodamage skin changes such as erythema and telangiectasias that only contribute to vascular changes of rosacea [24]. When conservative measures fail to control disease, patients may benefit from medical interventions, including pharmacologic and light-based therapies (Table 1). A treatment algorithm based on signs and symptoms, with consideration to severity, has been proposed by the Rosacea International Expert Group [5]. For episodic erythema or flushing, only experimental treatments are suggested such as oxymetazoline, nadolol, and clonidine. In patients with persistent erythema, topical treatment with azelaic acid or sulfacetamide should be considered. However, since the publication of guidelines, brimonidine tartrate (BT) has recently been approved in the USA specifically for treatment of persistent facial erythema. Oxymetazoline, which works by a similar mechanism as brimonidine,
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stimulating a-adrenergic receptors resulting in vasoconstriction, could potentially also fall under the category for treatment of persistent erythema. When topical therapies fail to control disease or the rosacea is more severe, shortterm oral antibacterials including tetracyclines and macrolides can be added. Topical agents, including brimonidine, do not target telangiectasias; however, electrosurgery can be used to treat these small vessels and laser can be used to treat both telangiectasias and PH changes. Support for the use of lasers is limited, but a Cochrane review by van Zuuren et al. [25] did find some evidence for the use of pulsed dye laser (PDL) and intense pulse light (IPL) therapy for reducing erythema and telangiectasias. The American Acne and Rosacea Society current consensus recommendations for the use of physical modalities for the treatment of rosacea include the use of IPL, PDL, and neodymium-doped yttrium aluminium garnet (Nd:YAG) lasers to target telangiectasias [26]. The recommendations encourage appropriate patient selection and setting of patient expectations; while improvement of 50–75 % in telangiectasias over one to two sessions can be achieved, improvement is of a much lesser extent in persistent erythema, and complete resolution should not be anticipated. The treatment of acne rosacea with papules and pustules involves the use of topical agents for mild disease and combination topical and oral therapy for more severe disease. Topical treatments including the topical antibacterials metronidazole, clindamycin, and sulfacetamide-sulfur as well as topical azelaic acid and retinoids are recommended. A Cochrane systematic review of rosacea therapies provided support for the use of topical metronidazole and azelaic acid, which were both more effective than placebo [25]. There was some evidence that azelaic acid was more effective than metronidazole in the treatment of PP rosacea, but metronidazole may be better tolerated. When oral therapy is warranted, low-dose doxycycline (40 mg/day) is recommended for less severe disease, and for severe disease, high-dose antibacterials or low-dose oral isotretinoin
(10 mg/day) should be considered [5]. The anti-inflammatory properties of the tetracyclines, rather than their antibacterial properties, are a primary rationale for their use in rosacea [27, 28]. It is noteworthy that in a comparison study doxycycline 40 and 100 mg/day were equally effective, with the lower-dose regimen having few adverse effects, specifically gastrointestinal symptoms [29]. In addition, of all the systemic drugs used for rosacea, only the modified-release doxycycline 40 mg/day formulation is US Food and Drug Administration (FDA) approved. This specific formulation was designed to exert anti-inflammatory properties, with no antibacterial effects [30]. In rosacea with nodules and plaques, systemic treatment with high-dose tetracyclines and macrolides or isotretinoin (0.5–1 mg/kg/day) is recommended, combined with topical therapy. The use of isotretinoin is considered off-label for the treatment for rosacea; however, studies support its use in recalcitrant PP rosacea [31]. Unlike in the treatment of acne, the use of isotretinoin is not likely to result in remission of rosacea. 3.2 New and Emerging Treatments 3.2.1 Brimonidine Tartrate Brimonidine 0.33 % gel (which contains 0.5 % BT salt) was approved by the FDA in August 2013 for treatment of persistent facial erythema. BT is an a2-adrenergic receptor agonist, with vasoconstriction its primary mechanism of action. To a lesser degree, it may also exert anti-inflammatory effects [32]. It has historically been used in the treatment of open-angle glaucoma. Phase II Clinical Trial (Table 2) The phase II clinical trial consisted of two studies [33]. In Study A, BT gel was effective in a dose-dependent fashion in reduction of erythema for up to 12 h after a single application. The percentage of subjects who achieved a one-grade improvement in Clinician’s Erythema Assessment (CEA)
Table 1 Current and emerging treatment options for rosacea Rosacea presentation
Current and emerging drug treatment options
Episodic erythema or flushing
Topicals (oxymetazoline)
Persistent erythema
Topical a-adrenoreceptor agonists (brimonidine tartrate and oxymetazoline) Topical azelaic acid or sulfacetamide
Papulopustular
Mild: topical antimicrobials (metronidazole, clindamycin, and sulfacetamide-sulfur, and ivermectin), azelaic acid, or retinoids
Oral (nadolol and clonidine)
Moderate: topicals plus oral antimicrobials [tetracyclines (low-dose doxycycline 40 mg/day), macrolides, or ivermectin] Severe: topicals plus high-dose tetracyclines or low-dose isotretinoin Recommendations based on the Rosacea International Expert Group, the Consensus Recommendations from the American Acne and Rosacea Society on the management of rosacea, and the current literature [5, 14, 18, 20, 21, 33, 34, 41–43, 46, 47]
122
269
254
283
Phase II(a)
Phase II(b)
Phase III(a)
Phase III(b)
Same as phase IIIa
Patients were randomized in a 1:1 fashion to apply BT gel 0.5 %:vehicle for 4 weeks. Six visits (screening visit, days 1, 15, 29 of treatment phase, and weeks 6 and 8 of the follow-up phase). During the treatment phase (days 1, 15, 29), subjects remained in the clinic for 12 h and were assessed prior to study drug application, then again at 30 min, and 1, 3, 6, 9, and 12 h after application
Patients were randomized in a 1:1:1:1:1 to receive BT 0.5 % once daily:BT 0.18 % once daily:vehicle once daily:BT 0.18 % twice daily:vehicle twice daily for 4 weeks
Subjects were randomized in a 1:1:1:1 to receive BT 0.5 %:BT 0.18 %:BT 0.07 %:vehicle
Methods
One-grade improvement in CEA and PSA (secondary)
Two-grade improvement in CEA and PSA
One-grade improvement in CEA and PSA (secondary)
Two-grade improvement in CEA and PSA
One-grade improvement in CEA and PSA (secondary)
Two-grade improvement in CEA and PSA (primary)
One-grade improvement in CEA and PSA scores
Outcome measures
BT brimonidine tartrate, CEA Clinician’s Erythema Assessment, PSA Patient’s Self-Assessment
No. of subjects
Study
Percentage of subjects using BT 0.5 % gel who had a one-grade improvement on CEA and PSA scores on day 29 at hours 3, 6, 9, and 12 after application was 71.1, 64.8, 66.9, and 53.5 %, respectively (vs. 40.1, 43.0, 29.4, and 40.1 % for vehicle) (p \ 0.001)
Percentage of subjects using BT 0.5 % gel who had a two-grade improvement on CEA and PSA scores on day 29 at hours 3,6, 9, and 12 after application was 25.4, 25.4, 17.6, and 21.1 %, respectively (vs. 9.2, 9.2, 10.6, and 9.9 % for vehicle once daily) (p \ 0.05)
Percentage of subjects using BT 0.5 % gel who had a one-grade improvement on CEA and PSA scores on day 29 at hours 3, 6, 9, and 12 after application was 70.9, 69.3, 63.8, and 56.7 %, respectively (vs. 32.8, 32.0, 29.7, and 30.5 % for vehicle) (p \ 0.001)
Percentage of subjects using BT 0.5 % gel who had a two-grade improvement on CEA and PSA scores on day 29 at hours 3, 6, 9, and 12 after application was 31.5, 30.7, 26.0, and 22.8 %, respectively (vs. 10.9, 9.4, 10.2, and 8.6 % for vehicle once daily) (p \ 0.05)
Percentage of subjects using BT 0.5 % gel who had a one-grade improvement on CEA and PSA scores on day 29 at hours 3, 6, 9, and 12 after application ranged from 60 to 76 % (vs. 31–42 % for vehicle once daily) (p \ 0.001)
Percentage of subjects using BT 0.5 % gel who had a two-grade improvement on CEA and PSA scores on day 29 at hours 3, 6, 9, and 12 after application was 30, 28, 32, and 19 %, respectively (vs. 4, 7, 4, and 4 % for vehicle once daily) (p \ 0.001)
Largest effect was observed in the BT 0.5 % group
Percentage of subjects with one-grade improvement in CEA and PSA was 84, 81, 75, and 28 % (BT 0.5, 0.18, 0.07 %, vehicle, respectively)
BT topical gel was effective in a dose-dependent fashion in reduction of erythema for up to 12 h after one application
Results
Table 2 Summary of Fowler et al. [33, 34]: phase II and III clinical trials of brimonidine tartrate in rosacea erythema treatment
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and the Patient’s Self-Assessment (PSA) was 84, 81, 75, and 28 % (BT 0.5, 0.18, 0.07 %, and vehicle, respectively). In Study B, the outcome measure was defined as a twograde improvement in the CEA and PSA scores over 12 h [33]. The percentage of subjects using BT 0.5 % gel who had a two-grade improvement on CEA and PSA scores on day 29 at hours 3, 6, 9, and 12 after application was 30, 28, 32, and 19 %, respectively, compared with 4, 7, 4, and 4 % for vehicle once daily (p \ 0.001). Phase III Clinical Trial (Table 2) The phase III clinical trial comprised of two identical studies, with a total of 537 subjects randomized in a 1:1 fashion to apply BT gel 0.5 % or vehicle daily for 4 weeks, followed by a 4-week followup phase [34]. CEA and PSA were assessed during the treatment phase before drug application as well as 30 min, 3, 6, 9, and 12 h after study drug application. The primary outcome measure or defined ‘treatment success’ was a twograde improvement on both CEA and PSA scores over 12 h. In Study A, the percentage of subjects using BT gel 0.5 % who had a two-grade improvement on CEA and PSA scores on day 29 at hours 3, 6, 9, and 12 after application was 31.5, 30.7, 26.0, and 22.8 %, respectively (vs. 10.9, 9.4, 10.2, and 8.6 % for vehicle once daily; p \ 0.05). In Study B, the percentage of subjects using BT gel 0.5 % who had a two-grade improvement on CEA and PSA scores on day 29 at hours 3,6, 9, and 12 after application was 25.4, 25.4, 17.6, and 21.1 %, respectively (vs. 9.2, 9.2, 10.6, and 9.9 % for vehicle once daily; p \ 0.05). One-grade improvement was a secondary outcome measure in phase II and III clinical trials. Although there were modest two-grade improvements in CEA and PSA in these studies, one-grade improvements were significant (Table 2) and represented clinically relevant effects. All doses of topical BT gel were safe and well-tolerated during the studies. The majority of related adverse events were dermatological (skin irritation, erythema, skin burning sensation, dry skin, and pruritus). Most of these cases were transient and mild. In B10 % of cases, the following adverse effects occur: flushing, skin burning sensation, and contact dermatitis. No clinically significant rebound (worsening of erythema compared with baseline after stopping treatment) was observed. In practice, however, rebound has been an issue for select patients. A case report describes rebound erythema in three patients using an FDA-approved dosage of brimonidine gel 0.33 % for treatment of rosacea [35]. All three patients reported reduced erythema from baseline 1–6 h after application, followed by severe erythema and burning sensation lasting for approximately 12 h. Signs of hypersensitivity such as urticaria and edema were not present. In our clinical practice, we have seen a handful of patients who cannot tolerate the medication due to rebound erythema. It is also important to remind patients to avoid trigger factors while
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using brimonidine, as the use of brimonidine does not override flares as a result of exposure to a trigger. An open-label study assessing the long-term safety and efficacy of once-daily topical BT 0.5 % gel for 1 year reported that efficacy of BT gel was maintained over the time period with no observed tachyphylaxis (mean CEA score prior to application of BT gel reduced gradually from 3.1 on day 1 to 2.4 at month 3 and remained stable until month 12) [36]. PSA results were similarly maintained. Drug-related adverse events were highest during the first 90 days of the study, and decreased after continued use. The most frequently observed adverse events were flushing (9.1 %), worsening of erythema (6.5 %), worsening of rosacea (3.6 %), skin burning sensation (3.3 %), skin irritation (3.1 %), contact dermatitis (2.2 %), and pruritus (2.0 %). The efficacy of brimonidine on PP lesions of rosacea has not been studied. It appears not to aggravate inflammatory lesions of rosacea in randomized trials evaluating its efficacy for facial erythema, including when patients used concomitant topical medications for PP rosacea [36]. However, due to the vasoconstrictive effects of the drug and reduction of erythema, PP lesions may be more noticeable. Brimonidine does not have effects on fixed changes such as telangiectasia, and these lesions too may become more visible when erythema is reduced. Patients should be educated on expectations of treatment with brimonidine prior to use. 3.2.2 Oxymetazoline Oxymetazoline, a derivative of xylometazoline, is a selective adrenoreceptor agonist (a1 and partial a2) and is present in over-the-counter decongestants. It is also indicated for the treatment of epistaxis, allergic rhinitis, and conjunctivitis [37]. Although there is a much more complex action than previously understood, topical application reduces erythema through vasoconstrictive effects on the a1-adrenoreceptors on smooth muscle surrounding blood vessels that maintain vascular tone. Because of its action on the a-receptors present on smooth muscle of larger blood vessels, it has no effect on smaller blood vessels, capillaries, and telangiectasias that are not surrounded by smooth muscle (and are therefore not regulated by the sympathetic nervous system). Activation of a-receptors has also demonstrated anti-inflammatory effects [32, 38]. Oxymetazoline and xylometazoline have been shown to inhibit neutrophilic phagocytosis and to decrease the generation of proinflammatory cytokines, which could contribute to the inflammation in rosacea [38]. Oxymetazoline and xylometazoline work through a similar mechanism as BT (a2-agonist), and therefore have potential indications for the treatment of persistent facial erythema. Compared
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to brimonidine, oxymetazoline was a less potent vasoconstrictor of the small subcutaneous vessels (less than 200 lm in diameter) that are thought to be the most important in rosacea [32]. Concerns regarding long-term use of these medications include tachyphylaxis and rebound phenomenon. Several case reports have described the off-label topical use of oxymetazoline and xylometazoline in rosacea. In two patients with recalcitrant ETR, once-daily application of OTC nasal decongestant containing oxymetazoline hydrocholoride 0.05 % resulted in significant improvement of facial erythema after application [18]. At long-term followup (8 and 17 months), both patients reported continued satisfaction with their treatment and had discontinued all other medications for rosacea control except for the oxymetazoline nasal spray, with no reported tachyphylaxis or rebound erythema. One patient with ETR treated topically with xylometazoline 0.05 % solution experienced improvement in erythema as well as in subjective symptoms (flushing, itching). Improvement in symptoms lasted hours after application and long-term follow-up (8 months) showed that daily topical application of the solution controlled facial erythema with no reported adverse effects [14]. Erythema is universal in patients with rosacea, yet it remains the most difficult feature to treat. Given the reported efficacy and safety of oxymetazoline and xylometazoline in the treatment of persistent erythema, formal randomized control trials are underway to assess its longterm safety and efficacy [39]. 3.2.3 Ivermectin Both oral and topical ivermectin have been used to treat rosacea and rosacea-like dermatitides. Ivermectin is a macrocyclic lactone disaccharide antiparasitic agent typically used to treat parasitic infestations such as onchocerciasis, strongyloidiasis, and filariasis, among others. In dermatology, it is also used for the treatment of scabies, an ectoparasitic infection. Ivermectin also targets the overgrowth of Demodex mites. As support for the role of D. folliculorum and D. brevis in the pathophysiology of rosacea grows, more interest is taken in investigation of anti-parasitic agents that can control overpopulation of these commensal mites on the skin. Ivermectin also has anti-inflammatory properties that may contribute to mitigating rosacea symptoms. Ivermectin exerts its antiinflammatory effect by down-regulating the nuclear transcription factor jB activation pathway that leads to downstream production of pro-inflammatory cytokines such as tumor necrosis factor (TNF)-a [40]. Two case reports of immunocompetent patients describe the use of single doses of oral ivermectin (200
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and 250 lg/kg) and topical permethrin resulting in complete resolution of rosacea-like demodicidosis [20, 21]. Both patients had many Demodex mites on biopsy. Another patient with recalcitrant PP rosacea with many Demodex organisms on histologic examination was treated with oral ivermectin (3 mg daily for a total dose of 24 mg) with complete resolution [41]. Oral ivermectin was also safe and effective in three cases of demodicidosis in patients with HIV infection [42]. Although there are no formal randomized control trials to date that assess oral ivermectin for treatment of rosacea, these cases suggest that it can be a valuable treatment consideration in patients who have recalcitrant rosacea and are found to have excess Demodex infestation. The efficacy and safety of topical ivermectin 1 % cream has recently been investigated in PP rosacea with promising results. Two phase III multicenter, randomized, double-blinded, parallel-group, vehicle-controlled trials of identical design assessed use of ivermectin 1 % cream or vehicle daily in patients to moderate to severe PP rosacea [43]. At 12 weeks, significantly more patients in the ivermectin 1 % group achieved ‘clear’ or ‘almost clear’ on the Investigator’s Global Assessment of Rosacea Severity in both Study 1 (38.4 %) and Study 2 (40.1 %) compared with vehicle (11.6 and 18.8 %, respectively). Inflammatory lesion counts were also reduced with a mean difference of -8.13 lesions (Study 1) and -8.22 (Study 2) between ivermectin 1 % and vehicle (p \ 0.001 for both studies). No serious related adverse effects were reported and the ivermectin group reported less related adverse effects than the vehicle group in both studies (4.2 and 2.6 % vs. 7.8 and 6.5 %, respectively). In a related extension study, patients used vehicle used azaleic acid 15 % twice daily for 40 weeks instead of vehicle, with less treatment-related adverse effects in the ivermectin group than in azaleic acid group: 1.3 vs. 5.3 %, respectively [44]. A 16-week study comparing the efficacy and safety of ivermectin 1 % cream and metronidazole 0.75 % cream has also been completed with results yet to be published. 3.2.4 Other Antiparasitics Other scabicidal treatments such as permethrin and crotamatin cream have been used for treatment of Demodex dermatitis [20, 41, 45]. A retrospective chart review of 63 patients with resistant rosacea-like dermatitis treated twice daily with topical crotamatin showed that 90.6 % of patients experienced C50 % reduction in erythema, dryness, scaling, roughness, and/or papules/pustules at the first follow-up visit (range 13–55 days) compared with baseline [45]. Improvements in symptoms were sustained over the second follow-up visit (13–59 days after the first followup).
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4 Conclusion As our understanding of the etiology of rosacea continues to evolve, so will our options for therapeutic interventions. The emergence of BT and oxymetazoline/xylometazoline for ET rosacea, as well as ivermectin for PP rosacea show promise for the future of rosacea treatment and more targeted therapy. These drugs need further investigations assessing longterm safety and efficacy in the treatment of rosacea. Rosacea is a common skin condition that affects many people, and can negatively impact quality of life. Interventions aimed at controlling this chronic inflammatory condition and delaying disease progression can positively affect the quality of life of the many people affected by rosacea. Acknowledgments The Center for Dermatology Research is supported by an unrestricted educational grant from Galderma Laboratories, L.P. Dr. Feldman is a consultant and speaker for Galderma, Connetics, Abbott Labs, Warner Chilcott, Centocor, Amgen, Photomedex, Genentech, BiogenIdec, and Bristol Myers Squibb. Dr. Feldman has received grants from Galderma, Connetics, Astellas, Abbott Labs, Warner Chilcott, Centocor, Amgen, Photomedex, Genentech, BiogenIdec, Coria, Pharmaderm, Ortho Pharmaceuticals, Aventis Pharmaceuticals, Roche Dermatology, 3M, Bristol Myers Squibb, Stiefel, GlaxoSmithKline, and Novartis and has received stock options from Photomedex. Farah Moustafa and Dr. Sandoval have no conflicts to disclose.
References 1. Tan J, Berg M. Rosacea: current state of epidemiology. J Am Acad Dermatol. 2013;69(6 Suppl 1):S27–35. 2. National Rosacea Society. If you have rosacea, you’re not alone. 2014. http://www.rosacea.org/patients/index.php. Accessed 28 Apr 2014. 3. Wilkin J, Dahl M, Detmar M, Drake L, Feinstein A, Odom R, et al. Standard classification of rosacea: report of the National Rosacea Society Expert Committee on the classification and staging of rosacea. J Am Acad Dermatol. 2002;46(4):584–7. 4. Salamon M, Chodkiewicz J, Sysa-Jedrzejowska A, Wozniacka A. Quality of life in patients with rosacea [in Polish]. Przegl Lek. 2008;65(9):385–9. 5. Elewski BE, Draelos Z, Dreno B, Jansen T, Layton A, Picardo M. Rosacea—global diversity and optimized outcome: proposed international consensus from the Rosacea International Expert Group. J Eur Acad Dermatol Venereol. 2011;25(2):188–200. 6. Steinhoff M, Schauber J, Leyden JJ. New insights into rosacea pathophysiology: a review of recent findings. J Am Acad Dermatol. 2013;69(6 Suppl 1):S15–26. 7. Steinhoff M, Buddenkotte J, Aubert J, Sulk M, Novak P, Schwab VD, et al. Clinical, cellular, and molecular aspects in the pathophysiology of rosacea. J Investig Dermatol Symp Proc. 2011;15(1):2–11. 8. Yamasaki K, Di NA, Bardan A, Murakami M, Ohtake T, Coda A, et al. Increased serine protease activity and cathelicidin promotes skin inflammation in rosacea. Nat Med. 2007;13(8):975–80. 9. Yamasaki K, Kanada K, Macleod DT, Borkowski AW, Morizane S, Nakatsuji T, et al. TLR2 expression is increased in rosacea and stimulates enhanced serine protease production by keratinocytes. J Invest Dermatol. 2011;131(3):688–97.
F. A. Moustafa et al. 10. Crawford GH, Pelle MT, James WD. Rosacea: I. Etiology, pathogenesis, and subtype classification. J Am Acad Dermatol. 2004;51(3):327–41. 11. Sibenge S, Gawkrodger DJ. Rosacea: a study of clinical patterns, blood flow, and the role of Demodex folliculorum. J Am Acad Dermatol. 1992;26(4):590–3. 12. Guzman-Sanchez DA, Ishiuji Y, Patel T, Fountain J, Chan YH, Yosipovitch G. Enhanced skin blood flow and sensitivity to noxious heat stimuli in papulopustular rosacea. J Am Acad Dermatol. 2007;57(5):800–5. 13. Yamasaki K, Gallo RL. The molecular pathology of rosacea. J Dermatol Sci. 2009;55(2):77–81. 14. Kim JH, Oh YS, Ji JH, Bak H, Ahn SK. Rosacea (erythematotelangiectatic type) effectively improved by topical xylometazoline. J Dermatol. 2011;38(5):510–3. 15. Del Rosso JQ. Advances in understanding and managing rosacea: part 2: the central role, evaluation, and medical management of diffuse and persistent facial erythema of rosacea. J Clin Aesthet Dermatol. 2012;5(3):26–36. 16. Del Rosso JQ. Management of facial erythema of rosacea: what is the role of topical alpha-adrenergic receptor agonist therapy? J Am Acad Dermatol. 2013;69(6 Suppl 1):S44–56. 17. Schwab VD, Sulk M, Seeliger S, Nowak P, Aubert J, Mess C, et al. Neurovascular and neuroimmune aspects in the pathophysiology of rosacea. J Investig Dermatol Symp Proc. 2011;15(1):53–62. 18. Shanler SD, Ondo AL. Successful treatment of the erythema and flushing of rosacea using a topically applied selective alpha1adrenergic receptor agonist, oxymetazoline. Arch Dermatol. 2007;143(11):1369–71. 19. Forton F, Seys B. Density of Demodex folliculorum in rosacea: a case-control study using standardized skin-surface biopsy. Br J Dermatol. 1993;128(6):650–9. 20. Forstinger C, Kittler H, Binder M. Treatment of rosacea-like demodicidosis with oral ivermectin and topical permethrin cream. J Am Acad Dermatol. 1999;41(5 Pt 1):775–7. 21. Brown M, Hernandez-Martin A, Clement A, Colmenero I, Torrelo A. Severe demodexfolliculorum-associated oculocutaneous rosacea in a girl successfully treated with ivermectin. JAMA Dermatol. 2014;150(1):61–3. 22. Forton F, Germaux MA, Brasseur T, De LA, Laporte M, Mathys C, et al. Demodicosis and rosacea: epidemiology and significance in daily dermatologic practice. J Am Acad Dermatol. 2005;52(1):74–87. 23. Lacey N, Delaney S, Kavanagh K, Powell FC. Mite-related bacterial antigens stimulate inflammatory cells in rosacea. Br J Dermatol. 2007;157(3):474–81. 24. Del Rosso JQ, Thiboutot D, Gallo R, Webster G, Tanghetti E, Eichenfield L, et al. Consensus recommendations from the American Acne & Rosacea Society on the management of rosacea, part 1: a status report on the disease state, general measures, and adjunctive skin care. Cutis. 2013;92(5):234–40. 25. van Zuuren EJ, Kramer SF, Carter BR, Graber MA, Fedorowicz Z. Effective and evidence-based management strategies for rosacea: summary of a Cochrane systematic review. Br J Dermatol. 2011;165(4):760–81. 26. Tanghetti E, Del Rosso JQ, Thiboutot D, Gallo R, Webster G, Eichenfield LF, et al. Consensus recommendations from the American Acne & Rosacea Society on the management of rosacea, part 4: a status report on physical modalities and devices. Cutis. 2014;93(2):71–6. 27. Sapadin AN, Fleischmajer R. Tetracyclines: nonantibiotic properties and their clinical implications. J Am Acad Dermatol. 2006;54(2):258–65. 28. Monk E, Shalita A, Siegel DM. Clinical applications of nonantimicrobial tetracyclines in dermatology. Pharmacol Res. 2011;63(2):130–45.
Rosacea: New and Emerging Treatments 29. Del Rosso JQ, Schlessinger J, Werschler P. Comparison of antiinflammatory dose doxycycline versus doxycycline 100 mg in the treatment of rosacea. J Drugs Dermatol. 2008;7(6):573–6. 30. Del Rosso JQ, Webster GF, Jackson M, Rendon M, Rich P, Torok H, et al. Two randomized phase III clinical trials evaluating antiinflammatory dose doxycycline (40-mg doxycycline, USP capsules) administered once daily for treatment of rosacea. J Am Acad Dermatol. 2007;56(5):791–802. 31. Park H, Del Rosso JQ. Use of oral isotretinoin in the management of rosacea. J Clin Aesthet Dermatol. 2011;4(9):54–61. 32. Piwnica D, Rosignoli C, de Menonville ST, Alvarez T, Schuppli NM, Roye O, et al. Vasoconstriction and anti-inflammatory properties of the selective alpha-adrenergic receptor agonist brimonidine. J Dermatol Sci. 2014;75(1):49–54. 33. Fowler J, Jarratt M, Moore A, Meadows K, Pollack A, Steinhoff M, et al. Once-daily topical brimonidine tartrate gel 0.5 % is a novel treatment for moderate to severe facial erythema of rosacea: results of two multicentre, randomized and vehicle-controlled studies. Br J Dermatol. 2012;166(3):633–41. 34. Fowler J Jr, Jackson M, Moore A, Jarratt M, Jones T, Meadows K, et al. Efficacy and safety of once-daily topical brimonidine tartrate gel 0.5 % for the treatment of moderate to severe facial erythema of rosacea: results of two randomized, double-blind, and vehicle-controlled pivotal studies. J Drugs Dermatol. 2013;12(6):650–6. 35. Routt ET, Levitt JO. Rebound erythema and burning sensation from a new topical brimonidine tartrate gel 0.33 %. J Am Acad Dermatol. 2014;70(2):e37–8. 36. Moore A, Kempers S, Murakawa G, Weiss J, Tauscher A, Swinyer L, et al. Long-term safety and efficacy of once-daily topical brimonidine tartrate gel 0.5 % for the treatment of moderate to severe facial erythema of rosacea: results of a 1-year open-label study. J Drugs Dermatol. 2014;13(1):56–61. 37. National Institutes of Health. Oxymetazoline drug information. 2014. http://dailymed.nlm.nih.gov/dailymed/search.cfm?startswith= oxymetazoline&x=0&y=0. Accessed 28 Apr 2014. 38. Bjerknes R, Steinsvag SK. Inhibition of human neutrophil actin polymerization, phagocytosis and oxidative burst by components of decongestive nosedrops. Pharmacol Toxicol. 1993;73(1):41–5.
1465 39. Pascoe D. Allergan dose finding trials for AGN-199201 oxymetazoline. 2012. http://rosacea-support.org/allergan-dose-findingtrials-for-agn-199201-oxymetazoline.html. Accessed 1 May 2014. 40. Ci X, Li H, Yu Q, Zhang X, Yu L, Chen N, et al. Avermectin exerts anti-inflammatory effect by downregulating the nuclear transcription factor kappa-B and mitogen-activated protein kinase activation pathway. Fundam Clin Pharmacol. 2009;23(4):449–55. 41. Allen KJ, Davis CL, Billings SD, Mousdicas N. Recalcitrant papulopustular rosacea in an immunocompetent patient responding to combination therapy with oral ivermectin and topical permethrin. Cutis. 2007;80(2):149–51. 42. Clyti E, Nacher M, Sainte-Marie D, Pradinaud R, Couppie P. Ivermectin treatment of three cases of demodecidosis during human immunodeficiency virus infection. Int J Dermatol. 2006;45(9):1066–8. 43. Stein L, Kircik L, Fowler J, Tan J, Draelos Z, Fleischer A, et al. Efficacy and safety of ivermectin 1 % cream in treatment of papulopustular rosacea: results of two randomized, double-blind, vehicle-controlled pivotal studies. J Drugs Dermatol. 2014;13(3): 316–23. 44. Jancin B. Novel topical rosacea drug sails through phase III: expert analysis from SDEF Hawaii Dermatology Seminar. Skin and Allergy News. 2-19-2014. http://www.skinandallergynews. com/index.php?id=372&cHash=071010&tx_ttnews[tt_news]= 237841. Accessed 20 Jul 2014. 45. Bikowski JB, Del Rosso JQ. Demodex dermatitis: a retrospective analysis of clinical diagnosis and successful treatment with topical crotamiton. J Clin Aesthet Dermatol. 2009;2(1):20–5. 46. Del Rosso JQ, Thiboutot D, Gallo R, Webster G, Tanghetti E, Eichenfield L, et al. Consensus recommendations from the American Acne & Rosacea Society on the management of rosacea, part 2: a status report on topical agents. Cutis. 2013;92(6):277–84. 47. Del Rosso JQ, Thiboutot D, Gallo R, Webster G, Tanghetti E, Eichenfield LF, et al. Consensus recommendations from the American Acne & Rosacea Society on the management of rosacea, part 3: a status report on systemic therapies. Cutis. 2014;93(1):18–28.
LEADING ARTICLE
Rosacea: New and Emerging Treatments Farah A. Moustafa • Laura F. Sandoval Steven R. Feldman
•
Published online: 26 August 2014 Ó Springer International Publishing Switzerland 2014
Abstract Rosacea is a chronic inflammatory skin condition that negatively impacts patients’ quality of life. We sought to review important aspects of the pathogenesis of rosacea and the role of new treatment options in its management. New, emerging treatments show promise; however, quality randomized controlled trials for many of these drugs are lacking. Brimonidine tartrate is an effective newly approved treatment for erythematotelangiectatic rosacea. Topical oxymetazoline has potential for the treatment of erythematotelangiectatic rosacea, with efficacy described in case reports and randomized controlled trials currently underway. Both oral and topical ivermectin have been studied for the treatment of papulopustular rosacea, both showing benefit; however, only topical ivermectin 1 % cream has been studied in randomized controlled trials. As our understanding of the etiology of rosacea continues to evolve, so will our options for therapeutic interventions. Further studies need to be performed to assess the long-term safety and efficacy of these treatments.
F. A. Moustafa L. F. Sandoval S. R. Feldman (&) Department of Dermatology, Center for Dermatology Research, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157-1071, USA e-mail: [email protected]; [email protected] S. R. Feldman Department of Pathology, Wake Forest School of Medicine, Winston-Salem, NC, USA S. R. Feldman Department of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, NC, USA
Key Points Rosacea is a chronic inflammatory skin condition that remains difficult to treat. New, emerging treatments such as brimonidine tartrate, oxymetazoline, and ivermectin have been studied and show promise; however, evidence is limited at this time. Further studies are needed to assess the long-term safety and efficacy of these treatments.
1 Introduction Rosacea is a chronic inflammatory skin disease and is one of the most common conditions that dermatologists treat. The reported prevalence of rosacea is between 1 and 22 % [1]. This wide discrepancy in data largely stems from various methodologies used to capture prevalence and therefore cannot be reliably compared. The National Rosacea Society recently reported that rosacea now affects 16 million Americans [2]. There are four well-known manifestations of disease: erythematotelangiectatic (ET), papulopustular (PP), phymatous (PH), and ocular [3]. It is more common in middle-age individuals, women, Caucasians, and those with Fitzpatrick skin type I and II. Because it typically localizes on the central face, and can be disfiguring in some cases, many patients experience a decreased quality of life [4]. The pathogenesis of this disease is complex and poorly understood. Many theories have been proposed and include dysregulation of innate immunity, dysregulation of the neurovascular system, and overgrowth of commensal organisms (e.g., Demodex).
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Treatment recommendations vary based on subtype of rosacea or on the signs and symptom present; however, effective treatment can prove difficult [5]. Therapies primarily focus on symptom suppression, in general targeting inflammation. A better understanding of the pathogenesis of rosacea is necessary to ensure better treatment outcomes. In this paper, we review the recent developments in the pathogenesis of rosacea and discuss the role of new treatments and their relationship to the pathophysiology of rosacea.
2 Pathogenesis of Rosacea The pathogenesis of rosacea is complex and thought to involve dysregulation of the immune, vascular, and nervous systems. While not caused by microorganisms, another evolving theory of the pathophysiology of rosacea is the involvement of overgrowth of commensal mites on the skin (Demodex folliculorum and Demodex brevis) in some patients with rosacea. Evolving theories on the pathophysiology of rosacea appreciate the complex interplay of dysregulation from these systems culminating in the clinical picture of rosacea [6]. There is also a strong suggestion of a genetic component, as transcriptome analysis has verified distinct gene profiles of rosacea subtypes [7].
Fig. 1 The role of innate immune system dysregulation in rosacea pathogenesis. CAP18 cathelicidin-related antimicrobial peptide 18, KLK5 kallikrein-related peptidase 5, TLR2 Toll-like receptor 2, UV ultraviolet
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2.1 Dysregulation of the Innate Immune System Dysregulation of the innate immune system may contribute to chronic inflammation and vascular abnormalities in patients with rosacea [8]. One pathway that may be relevant involves Toll receptor activation. Initially, Toll-like receptor 2 (TLR2) (a component of the innate system) is triggered by inciting factors. Numerous environmental stimuli can trigger TLR2, such as physical or chemical trauma, UV light, and microorganisms. This results in release of a processing enzyme, Kallikrein 5 (KLK5), from epidermal keratinocytes. This enzyme is responsible for processing the antimicrobial peptide cathelicidin into active its active form, LL-37. In rosacea-prone skin, the proteolytically processed forms of cathelicidin peptides are also different from normal individuals and are more pro-inflammatory. It is unclear how the abnormal form of cathelicidin is developed, but it is hypothesized to be the result of post-translational processing abnormalities associated with an increase in KLK5, also known as stratum corneum tryptic enzyme (SCTE), in the epidermis [8]. There is also higher expression of TLR2 in keratinocytes of rosacea skin [9]. Increased levels of cathelicidin and KLK5 present in skin from rosacea patients support the hypothesis of their role in pathogenesis [8]. Downstream effects of these proteins result in increased inflammatory cytokine release and angiogenesis, contributing to the clinical picture of rosacea
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(Fig. 1). Mouse studies involving the injection of cathelicidin peptides from patients with rosacea led to inflammation and vascular dilation, further supporting the role of cathelicidin in rosacea pathogenesis [8]. 2.2 Dysregulation of the Vascular and Neurovascular System Facial erythema is a central component of rosacea and is required for diagnosis. Worsening of disease is associated with persistence and intensity of facial erythema. Skin blood flow is increased in some patients, raising questions regarding the role of vascular dysregulation in the pathogenesis of rosacea and a potential factor to facial erythema in rosacea patients [10–14]. Facial erythema in rosacea can be divided into two major groups with different etiologies: (1) central facial erythema; and (2) perilesional erythema (surrounding papules and pustules in PP rosacea) [3, 15, 16]. Distinguishing between these types of erythema is important for treatment selection. Persistant facial erythema is a result of abnormal vasculature that results from chronic inflammation present in rosacea-prone skin. This is a multifactorial process, but one component involves LL-37 (the active form of cathelicidin) promotion of inflammation and angiogenesis through its downstream effects on endothelial growth factor receptors (EGFRs) in keratinocytes [9]. Chronic inflammation also leads to the associated telangiectasias found in rosacea [15]. Increases in vascular endothelial growth factor (VEGF) and endothelial nitric oxide (eNO) leading to increased vascularization and vasodilation, respectively, are also implicated in the chronic facial erythema present in rosacea [8, 9]. Neurovascular dysregulation or increased ‘vasoactivity’ is also thought to play an important role [17]. The superficial cutaneous system is largely regulated by the sympathetic nervous system through action on adrenoreceptors. While their role in rosacea pathophysiology is currently poorly understood, they do seem to play an important role as evidenced by the ability of new medications targeting these adrenoreceptors to reduce erythema [14, 18]. 2.3 Overgrowth of Commensal Organisms D. brevis and D. folliculorum are two commensal mite species that colonize the pilosebaceous follicle of human skin. The role of the Demodex overgrowth in the pathogenesis of rosacea has been controversial. Because the presence of these mites on human skin is ubiquitous, developing a causal relationship is difficult. The presence of Demodex does not indicate rosacea; however, Demodex infestation (defined as C5 mites/cm2) is higher in some patients with ETR and PPR rosacea [17, 19].
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Key components of Demodex overgrowth on the skin and their interaction with an aberrant immune system makes it an important consideration to better understand the etiology of rosacea as well as therapeutic options. Demodicosis (Demodex infestation) closely resembles rosacea clinically; patients often experience erythema, telangiectasias, and itching [20–22]. It is difficult to differentiate patients as having Demodex infestation resembling rosacea or rosacea with greater than average density of Demodex. Perhaps it is not simply a Demodex infestation that triggers rosacea, but the interaction of Demodex mite products interacting with the already aberrant and sensitive innate immune system in rosacea-prone skin. As mentioned above, TLR2 is over-expressed and more sensitive to activation in rosacea prone skin. Recently, Bacillus oleronius bacterium has been cultured from Demodex mites and its role in the pathogenesis of rosacea is under investigation [23]. Antigens on the mite as well as the bacteria may could potentially be recognized by TLR2 and result in its activation and downstream inflammatory effects in the skin. In cases in which patients are found to have high Demodex counts, it may be worth considering anti-parasitic agents (ivermectin, permethrin) for the treatment of their rosacea.
3 Overview of Treatment 3.1 Current Treatment In general, adjunct measures including high-factor sunscreens, cosmetic camouflage, cooling, and avoidance of irritants and triggers (extremes of temperatures, sunlight, diet, alcohol, exercise, acute psychological stressors, medications, menopausal hot flashes) are recommended for all patients with rosacea [5]. The use of photoprotection is particularly important in that it may prevent a flare triggered by UV exposure, as well as help avert photodamage skin changes such as erythema and telangiectasias that only contribute to vascular changes of rosacea [24]. When conservative measures fail to control disease, patients may benefit from medical interventions, including pharmacologic and light-based therapies (Table 1). A treatment algorithm based on signs and symptoms, with consideration to severity, has been proposed by the Rosacea International Expert Group [5]. For episodic erythema or flushing, only experimental treatments are suggested such as oxymetazoline, nadolol, and clonidine. In patients with persistent erythema, topical treatment with azelaic acid or sulfacetamide should be considered. However, since the publication of guidelines, brimonidine tartrate (BT) has recently been approved in the USA specifically for treatment of persistent facial erythema. Oxymetazoline, which works by a similar mechanism as brimonidine,
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stimulating a-adrenergic receptors resulting in vasoconstriction, could potentially also fall under the category for treatment of persistent erythema. When topical therapies fail to control disease or the rosacea is more severe, shortterm oral antibacterials including tetracyclines and macrolides can be added. Topical agents, including brimonidine, do not target telangiectasias; however, electrosurgery can be used to treat these small vessels and laser can be used to treat both telangiectasias and PH changes. Support for the use of lasers is limited, but a Cochrane review by van Zuuren et al. [25] did find some evidence for the use of pulsed dye laser (PDL) and intense pulse light (IPL) therapy for reducing erythema and telangiectasias. The American Acne and Rosacea Society current consensus recommendations for the use of physical modalities for the treatment of rosacea include the use of IPL, PDL, and neodymium-doped yttrium aluminium garnet (Nd:YAG) lasers to target telangiectasias [26]. The recommendations encourage appropriate patient selection and setting of patient expectations; while improvement of 50–75 % in telangiectasias over one to two sessions can be achieved, improvement is of a much lesser extent in persistent erythema, and complete resolution should not be anticipated. The treatment of acne rosacea with papules and pustules involves the use of topical agents for mild disease and combination topical and oral therapy for more severe disease. Topical treatments including the topical antibacterials metronidazole, clindamycin, and sulfacetamide-sulfur as well as topical azelaic acid and retinoids are recommended. A Cochrane systematic review of rosacea therapies provided support for the use of topical metronidazole and azelaic acid, which were both more effective than placebo [25]. There was some evidence that azelaic acid was more effective than metronidazole in the treatment of PP rosacea, but metronidazole may be better tolerated. When oral therapy is warranted, low-dose doxycycline (40 mg/day) is recommended for less severe disease, and for severe disease, high-dose antibacterials or low-dose oral isotretinoin
(10 mg/day) should be considered [5]. The anti-inflammatory properties of the tetracyclines, rather than their antibacterial properties, are a primary rationale for their use in rosacea [27, 28]. It is noteworthy that in a comparison study doxycycline 40 and 100 mg/day were equally effective, with the lower-dose regimen having few adverse effects, specifically gastrointestinal symptoms [29]. In addition, of all the systemic drugs used for rosacea, only the modified-release doxycycline 40 mg/day formulation is US Food and Drug Administration (FDA) approved. This specific formulation was designed to exert anti-inflammatory properties, with no antibacterial effects [30]. In rosacea with nodules and plaques, systemic treatment with high-dose tetracyclines and macrolides or isotretinoin (0.5–1 mg/kg/day) is recommended, combined with topical therapy. The use of isotretinoin is considered off-label for the treatment for rosacea; however, studies support its use in recalcitrant PP rosacea [31]. Unlike in the treatment of acne, the use of isotretinoin is not likely to result in remission of rosacea. 3.2 New and Emerging Treatments 3.2.1 Brimonidine Tartrate Brimonidine 0.33 % gel (which contains 0.5 % BT salt) was approved by the FDA in August 2013 for treatment of persistent facial erythema. BT is an a2-adrenergic receptor agonist, with vasoconstriction its primary mechanism of action. To a lesser degree, it may also exert anti-inflammatory effects [32]. It has historically been used in the treatment of open-angle glaucoma. Phase II Clinical Trial (Table 2) The phase II clinical trial consisted of two studies [33]. In Study A, BT gel was effective in a dose-dependent fashion in reduction of erythema for up to 12 h after a single application. The percentage of subjects who achieved a one-grade improvement in Clinician’s Erythema Assessment (CEA)
Table 1 Current and emerging treatment options for rosacea Rosacea presentation
Current and emerging drug treatment options
Episodic erythema or flushing
Topicals (oxymetazoline)
Persistent erythema
Topical a-adrenoreceptor agonists (brimonidine tartrate and oxymetazoline) Topical azelaic acid or sulfacetamide
Papulopustular
Mild: topical antimicrobials (metronidazole, clindamycin, and sulfacetamide-sulfur, and ivermectin), azelaic acid, or retinoids
Oral (nadolol and clonidine)
Moderate: topicals plus oral antimicrobials [tetracyclines (low-dose doxycycline 40 mg/day), macrolides, or ivermectin] Severe: topicals plus high-dose tetracyclines or low-dose isotretinoin Recommendations based on the Rosacea International Expert Group, the Consensus Recommendations from the American Acne and Rosacea Society on the management of rosacea, and the current literature [5, 14, 18, 20, 21, 33, 34, 41–43, 46, 47]
122
269
254
283
Phase II(a)
Phase II(b)
Phase III(a)
Phase III(b)
Same as phase IIIa
Patients were randomized in a 1:1 fashion to apply BT gel 0.5 %:vehicle for 4 weeks. Six visits (screening visit, days 1, 15, 29 of treatment phase, and weeks 6 and 8 of the follow-up phase). During the treatment phase (days 1, 15, 29), subjects remained in the clinic for 12 h and were assessed prior to study drug application, then again at 30 min, and 1, 3, 6, 9, and 12 h after application
Patients were randomized in a 1:1:1:1:1 to receive BT 0.5 % once daily:BT 0.18 % once daily:vehicle once daily:BT 0.18 % twice daily:vehicle twice daily for 4 weeks
Subjects were randomized in a 1:1:1:1 to receive BT 0.5 %:BT 0.18 %:BT 0.07 %:vehicle
Methods
One-grade improvement in CEA and PSA (secondary)
Two-grade improvement in CEA and PSA
One-grade improvement in CEA and PSA (secondary)
Two-grade improvement in CEA and PSA
One-grade improvement in CEA and PSA (secondary)
Two-grade improvement in CEA and PSA (primary)
One-grade improvement in CEA and PSA scores
Outcome measures
BT brimonidine tartrate, CEA Clinician’s Erythema Assessment, PSA Patient’s Self-Assessment
No. of subjects
Study
Percentage of subjects using BT 0.5 % gel who had a one-grade improvement on CEA and PSA scores on day 29 at hours 3, 6, 9, and 12 after application was 71.1, 64.8, 66.9, and 53.5 %, respectively (vs. 40.1, 43.0, 29.4, and 40.1 % for vehicle) (p \ 0.001)
Percentage of subjects using BT 0.5 % gel who had a two-grade improvement on CEA and PSA scores on day 29 at hours 3,6, 9, and 12 after application was 25.4, 25.4, 17.6, and 21.1 %, respectively (vs. 9.2, 9.2, 10.6, and 9.9 % for vehicle once daily) (p \ 0.05)
Percentage of subjects using BT 0.5 % gel who had a one-grade improvement on CEA and PSA scores on day 29 at hours 3, 6, 9, and 12 after application was 70.9, 69.3, 63.8, and 56.7 %, respectively (vs. 32.8, 32.0, 29.7, and 30.5 % for vehicle) (p \ 0.001)
Percentage of subjects using BT 0.5 % gel who had a two-grade improvement on CEA and PSA scores on day 29 at hours 3, 6, 9, and 12 after application was 31.5, 30.7, 26.0, and 22.8 %, respectively (vs. 10.9, 9.4, 10.2, and 8.6 % for vehicle once daily) (p \ 0.05)
Percentage of subjects using BT 0.5 % gel who had a one-grade improvement on CEA and PSA scores on day 29 at hours 3, 6, 9, and 12 after application ranged from 60 to 76 % (vs. 31–42 % for vehicle once daily) (p \ 0.001)
Percentage of subjects using BT 0.5 % gel who had a two-grade improvement on CEA and PSA scores on day 29 at hours 3, 6, 9, and 12 after application was 30, 28, 32, and 19 %, respectively (vs. 4, 7, 4, and 4 % for vehicle once daily) (p \ 0.001)
Largest effect was observed in the BT 0.5 % group
Percentage of subjects with one-grade improvement in CEA and PSA was 84, 81, 75, and 28 % (BT 0.5, 0.18, 0.07 %, vehicle, respectively)
BT topical gel was effective in a dose-dependent fashion in reduction of erythema for up to 12 h after one application
Results
Table 2 Summary of Fowler et al. [33, 34]: phase II and III clinical trials of brimonidine tartrate in rosacea erythema treatment
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and the Patient’s Self-Assessment (PSA) was 84, 81, 75, and 28 % (BT 0.5, 0.18, 0.07 %, and vehicle, respectively). In Study B, the outcome measure was defined as a twograde improvement in the CEA and PSA scores over 12 h [33]. The percentage of subjects using BT 0.5 % gel who had a two-grade improvement on CEA and PSA scores on day 29 at hours 3, 6, 9, and 12 after application was 30, 28, 32, and 19 %, respectively, compared with 4, 7, 4, and 4 % for vehicle once daily (p \ 0.001). Phase III Clinical Trial (Table 2) The phase III clinical trial comprised of two identical studies, with a total of 537 subjects randomized in a 1:1 fashion to apply BT gel 0.5 % or vehicle daily for 4 weeks, followed by a 4-week followup phase [34]. CEA and PSA were assessed during the treatment phase before drug application as well as 30 min, 3, 6, 9, and 12 h after study drug application. The primary outcome measure or defined ‘treatment success’ was a twograde improvement on both CEA and PSA scores over 12 h. In Study A, the percentage of subjects using BT gel 0.5 % who had a two-grade improvement on CEA and PSA scores on day 29 at hours 3, 6, 9, and 12 after application was 31.5, 30.7, 26.0, and 22.8 %, respectively (vs. 10.9, 9.4, 10.2, and 8.6 % for vehicle once daily; p \ 0.05). In Study B, the percentage of subjects using BT gel 0.5 % who had a two-grade improvement on CEA and PSA scores on day 29 at hours 3,6, 9, and 12 after application was 25.4, 25.4, 17.6, and 21.1 %, respectively (vs. 9.2, 9.2, 10.6, and 9.9 % for vehicle once daily; p \ 0.05). One-grade improvement was a secondary outcome measure in phase II and III clinical trials. Although there were modest two-grade improvements in CEA and PSA in these studies, one-grade improvements were significant (Table 2) and represented clinically relevant effects. All doses of topical BT gel were safe and well-tolerated during the studies. The majority of related adverse events were dermatological (skin irritation, erythema, skin burning sensation, dry skin, and pruritus). Most of these cases were transient and mild. In B10 % of cases, the following adverse effects occur: flushing, skin burning sensation, and contact dermatitis. No clinically significant rebound (worsening of erythema compared with baseline after stopping treatment) was observed. In practice, however, rebound has been an issue for select patients. A case report describes rebound erythema in three patients using an FDA-approved dosage of brimonidine gel 0.33 % for treatment of rosacea [35]. All three patients reported reduced erythema from baseline 1–6 h after application, followed by severe erythema and burning sensation lasting for approximately 12 h. Signs of hypersensitivity such as urticaria and edema were not present. In our clinical practice, we have seen a handful of patients who cannot tolerate the medication due to rebound erythema. It is also important to remind patients to avoid trigger factors while
F. A. Moustafa et al.
using brimonidine, as the use of brimonidine does not override flares as a result of exposure to a trigger. An open-label study assessing the long-term safety and efficacy of once-daily topical BT 0.5 % gel for 1 year reported that efficacy of BT gel was maintained over the time period with no observed tachyphylaxis (mean CEA score prior to application of BT gel reduced gradually from 3.1 on day 1 to 2.4 at month 3 and remained stable until month 12) [36]. PSA results were similarly maintained. Drug-related adverse events were highest during the first 90 days of the study, and decreased after continued use. The most frequently observed adverse events were flushing (9.1 %), worsening of erythema (6.5 %), worsening of rosacea (3.6 %), skin burning sensation (3.3 %), skin irritation (3.1 %), contact dermatitis (2.2 %), and pruritus (2.0 %). The efficacy of brimonidine on PP lesions of rosacea has not been studied. It appears not to aggravate inflammatory lesions of rosacea in randomized trials evaluating its efficacy for facial erythema, including when patients used concomitant topical medications for PP rosacea [36]. However, due to the vasoconstrictive effects of the drug and reduction of erythema, PP lesions may be more noticeable. Brimonidine does not have effects on fixed changes such as telangiectasia, and these lesions too may become more visible when erythema is reduced. Patients should be educated on expectations of treatment with brimonidine prior to use. 3.2.2 Oxymetazoline Oxymetazoline, a derivative of xylometazoline, is a selective adrenoreceptor agonist (a1 and partial a2) and is present in over-the-counter decongestants. It is also indicated for the treatment of epistaxis, allergic rhinitis, and conjunctivitis [37]. Although there is a much more complex action than previously understood, topical application reduces erythema through vasoconstrictive effects on the a1-adrenoreceptors on smooth muscle surrounding blood vessels that maintain vascular tone. Because of its action on the a-receptors present on smooth muscle of larger blood vessels, it has no effect on smaller blood vessels, capillaries, and telangiectasias that are not surrounded by smooth muscle (and are therefore not regulated by the sympathetic nervous system). Activation of a-receptors has also demonstrated anti-inflammatory effects [32, 38]. Oxymetazoline and xylometazoline have been shown to inhibit neutrophilic phagocytosis and to decrease the generation of proinflammatory cytokines, which could contribute to the inflammation in rosacea [38]. Oxymetazoline and xylometazoline work through a similar mechanism as BT (a2-agonist), and therefore have potential indications for the treatment of persistent facial erythema. Compared
Rosacea: New and Emerging Treatments
to brimonidine, oxymetazoline was a less potent vasoconstrictor of the small subcutaneous vessels (less than 200 lm in diameter) that are thought to be the most important in rosacea [32]. Concerns regarding long-term use of these medications include tachyphylaxis and rebound phenomenon. Several case reports have described the off-label topical use of oxymetazoline and xylometazoline in rosacea. In two patients with recalcitrant ETR, once-daily application of OTC nasal decongestant containing oxymetazoline hydrocholoride 0.05 % resulted in significant improvement of facial erythema after application [18]. At long-term followup (8 and 17 months), both patients reported continued satisfaction with their treatment and had discontinued all other medications for rosacea control except for the oxymetazoline nasal spray, with no reported tachyphylaxis or rebound erythema. One patient with ETR treated topically with xylometazoline 0.05 % solution experienced improvement in erythema as well as in subjective symptoms (flushing, itching). Improvement in symptoms lasted hours after application and long-term follow-up (8 months) showed that daily topical application of the solution controlled facial erythema with no reported adverse effects [14]. Erythema is universal in patients with rosacea, yet it remains the most difficult feature to treat. Given the reported efficacy and safety of oxymetazoline and xylometazoline in the treatment of persistent erythema, formal randomized control trials are underway to assess its longterm safety and efficacy [39]. 3.2.3 Ivermectin Both oral and topical ivermectin have been used to treat rosacea and rosacea-like dermatitides. Ivermectin is a macrocyclic lactone disaccharide antiparasitic agent typically used to treat parasitic infestations such as onchocerciasis, strongyloidiasis, and filariasis, among others. In dermatology, it is also used for the treatment of scabies, an ectoparasitic infection. Ivermectin also targets the overgrowth of Demodex mites. As support for the role of D. folliculorum and D. brevis in the pathophysiology of rosacea grows, more interest is taken in investigation of anti-parasitic agents that can control overpopulation of these commensal mites on the skin. Ivermectin also has anti-inflammatory properties that may contribute to mitigating rosacea symptoms. Ivermectin exerts its antiinflammatory effect by down-regulating the nuclear transcription factor jB activation pathway that leads to downstream production of pro-inflammatory cytokines such as tumor necrosis factor (TNF)-a [40]. Two case reports of immunocompetent patients describe the use of single doses of oral ivermectin (200
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and 250 lg/kg) and topical permethrin resulting in complete resolution of rosacea-like demodicidosis [20, 21]. Both patients had many Demodex mites on biopsy. Another patient with recalcitrant PP rosacea with many Demodex organisms on histologic examination was treated with oral ivermectin (3 mg daily for a total dose of 24 mg) with complete resolution [41]. Oral ivermectin was also safe and effective in three cases of demodicidosis in patients with HIV infection [42]. Although there are no formal randomized control trials to date that assess oral ivermectin for treatment of rosacea, these cases suggest that it can be a valuable treatment consideration in patients who have recalcitrant rosacea and are found to have excess Demodex infestation. The efficacy and safety of topical ivermectin 1 % cream has recently been investigated in PP rosacea with promising results. Two phase III multicenter, randomized, double-blinded, parallel-group, vehicle-controlled trials of identical design assessed use of ivermectin 1 % cream or vehicle daily in patients to moderate to severe PP rosacea [43]. At 12 weeks, significantly more patients in the ivermectin 1 % group achieved ‘clear’ or ‘almost clear’ on the Investigator’s Global Assessment of Rosacea Severity in both Study 1 (38.4 %) and Study 2 (40.1 %) compared with vehicle (11.6 and 18.8 %, respectively). Inflammatory lesion counts were also reduced with a mean difference of -8.13 lesions (Study 1) and -8.22 (Study 2) between ivermectin 1 % and vehicle (p \ 0.001 for both studies). No serious related adverse effects were reported and the ivermectin group reported less related adverse effects than the vehicle group in both studies (4.2 and 2.6 % vs. 7.8 and 6.5 %, respectively). In a related extension study, patients used vehicle used azaleic acid 15 % twice daily for 40 weeks instead of vehicle, with less treatment-related adverse effects in the ivermectin group than in azaleic acid group: 1.3 vs. 5.3 %, respectively [44]. A 16-week study comparing the efficacy and safety of ivermectin 1 % cream and metronidazole 0.75 % cream has also been completed with results yet to be published. 3.2.4 Other Antiparasitics Other scabicidal treatments such as permethrin and crotamatin cream have been used for treatment of Demodex dermatitis [20, 41, 45]. A retrospective chart review of 63 patients with resistant rosacea-like dermatitis treated twice daily with topical crotamatin showed that 90.6 % of patients experienced C50 % reduction in erythema, dryness, scaling, roughness, and/or papules/pustules at the first follow-up visit (range 13–55 days) compared with baseline [45]. Improvements in symptoms were sustained over the second follow-up visit (13–59 days after the first followup).
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4 Conclusion As our understanding of the etiology of rosacea continues to evolve, so will our options for therapeutic interventions. The emergence of BT and oxymetazoline/xylometazoline for ET rosacea, as well as ivermectin for PP rosacea show promise for the future of rosacea treatment and more targeted therapy. These drugs need further investigations assessing longterm safety and efficacy in the treatment of rosacea. Rosacea is a common skin condition that affects many people, and can negatively impact quality of life. Interventions aimed at controlling this chronic inflammatory condition and delaying disease progression can positively affect the quality of life of the many people affected by rosacea. Acknowledgments The Center for Dermatology Research is supported by an unrestricted educational grant from Galderma Laboratories, L.P. Dr. Feldman is a consultant and speaker for Galderma, Connetics, Abbott Labs, Warner Chilcott, Centocor, Amgen, Photomedex, Genentech, BiogenIdec, and Bristol Myers Squibb. Dr. Feldman has received grants from Galderma, Connetics, Astellas, Abbott Labs, Warner Chilcott, Centocor, Amgen, Photomedex, Genentech, BiogenIdec, Coria, Pharmaderm, Ortho Pharmaceuticals, Aventis Pharmaceuticals, Roche Dermatology, 3M, Bristol Myers Squibb, Stiefel, GlaxoSmithKline, and Novartis and has received stock options from Photomedex. Farah Moustafa and Dr. Sandoval have no conflicts to disclose.
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