¹Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada
²Lynde Institute for Dermatology (Private Practice), Markham, ON, Canada
³Division of Dermatology, University of Toronto, ON, Canada

Funding Sources: None

Conflict of interest:
Cindy Kang and Monica Shah have no conflicts of interest to disclose. Charles Lynde has acted as a principal investigator, speaker and/or consultant and/or advisory board member for AbbVie, Amgen, AnaptysBio, Arcutis, Avillon, Bristol-Myers Squibb, Celgene, Cipher, Eli Lilly, Galderma, Genentech, GlenMark, Incyte, Janssen, Kyowa, Leo Pharma, L’Oréal, Merck, Novartis, Pfizer, Sanofi and Valeant. Patrick Fleming has received honorarium and/or consulting and/or advisory boards and/or speaking fees for AbbVie, Altius, Amgen, Aralez, Bausch Health, Cipher, Eli Lilly, Galderma, Janssen, Leo Pharma, L’Oréal, Novartis, Pfizer, Sanofi-Genzyme and UCB.

Abstract:
Hair removal practices have evolved from adhering to social, cultural, and religious traditions to meeting aesthetic standards. Hair removal methods can be divided into two categories: 1) depilation, which involves removing the hair shaft and includes shaving and chemical depilatories, and 2) epilation, which involves removing the hair shaft, follicle, and bulb, and includes plucking, threading, waxing, sugaring, lasers, intense pulsed light system, electrolysis, and photodynamic therapy. Furthermore, an eflornithine hydrochloride 13.9% cream (Vaniqa®, neither an epilatory or depilatory technique), has been US FDA- and Health Canada-approved to slow the rate of facial hair growth and to be used in combination with other hair removal methods. Most methods are temporary except for electrolysis and laser therapy for some individuals, and each technique has advantages and disadvantages in terms of efficacy and adverse events. Importantly, most studies examining the efficacy of hair removal techniques are limited to darker hair and fairer skin, and further research is required especially for those with light-colored hair.

Key Words:
chemical depilatories, depilation, electrolysis, epilation, hair removal, laser hair removal, photodynamic therapy, plucking, shaving, sugaring, threading, Vaniqa, waxing

Introduction

Hair removal methods fall under two categories of depilation and epilation, each with distinctive advantages, disadvantages, and adverse events (Table 1).¹ Depilation removes the hair shaft and includes techniques such as shaving and chemical depilatories. Epilation removes the hair shaft, follicle, and bulb, and includes techniques such as plucking, threading, waxing, sugaring, lasers, intense pulsed light system (IPL), electrolysis, and photodynamic therapy (PDT).¹ In the 2000s, eflornithine hydrochloride cream 13.9% (Vaniqa®) was US FDA and Health Canada approved. Topical eflornithine is not considered an epilatory or depilatory technique but slows the rate of facial hair growth when used in conjunction with other methods.²

Table 1: Hair removal methods – advantages, disadvantages, adverse events, and permanency

Hair Removal Methods

Depilation

Shaving

Shaving is a cost-efficient and popular technique for male facial hair and female underarm and leg hair removal.^1,3 The two methods include: 1) wet shaving with a safety razor and 2) dry shaving with an electric razor.^1,3 The first razors used in the 17th century had straight, fixed blades made of tempered steel which were dangerous to use and required regular maintenance (honing and stropping). In 1903, the revolutionary King Camp Gillette T-shape razor was introduced with the first double-edged disposable blade which did not require honing and stropping, but still needed direct handling for blade replacement. In the 1920s, the disposable injector blade was introduced, a safer and more convenient method without direct handling. In 1931, the razor blade was again revolutionized by the electric razor blade, which was costlier, but provided enhanced safety (the blade never directly touched the skin) and convenience (long-lasting and eliminated the need for shaving cream).^3,4 Finally, in 1970, hoe-shaped safety razors with disposable cartridges were launched, and in 1975, the disposable razor was introduced. Both were safe to use, inexpensive, and convenient, with the disposable razor the most convenient of all models.⁵

Shaving (wet or dry) does not interrupt the anagen phase and, therefore, is a temporary hair removal method that necessitates frequent treatment.^1,6 Shaving is convenient and inexpensive, but may cause irritation, skin abrasions, and pseudofolliculitis.^1,7 Moreover, shaving does not change hair thickness or growth rate and leaves a blunt tip that appears to be thicker than uncut hair;³ thus, it is uncommon for facial hair removal in females.¹

Chemical Depilatories

Chemical depilatories are made as powders, pastes, creams, or lotions,^1,6,8 and used for the legs, bikini area, and face.³ Examples include detergents, hair-shaft-swelling agents, adhesives, pH adjusters, and bond-breaking agents, which disrupt disulfide bonds within keratin and provide temporary hair removal.³ The most common chemical depilatories are substituted mercaptans, 2% to 10% thioglycolates, mixed with 2% to 6% of sodium hydroxide or calcium hydroxide to increase pH.^3,6,8 Sulfide depilatories and sodium hydroxide depilatories are unpopular as they cause greater irritant dermatitis and skin damage.³ Depilatories are applied to hairs for 3 to 15 minutes to dissolve the hair shaft, and are then washed off with soap and water.^6,8

While chemical depilatories are easy to use, painless, have a slower regrowth than shaving, and do not result in stiffness of hairs post-treatment,³ they have unpleasant odors and may cause irritant contact dermatitis due to the alkalinity and allergic contact dermatitis due to fragrances.^3,7 Thus, less than 1% of patients find facial application tolerable.⁷ Moreover, chemical depilatories are less effective in removing darkly pigmented and coarse hair.³

Epilation

Plucking

Plucking with tweezers temporarily removes hairs in small areas, and is most effective at removing terminal as opposed to vellus hairs, with the latter tending to break near the skin surface.^1,3 Plucking is simple, inexpensive, causes minimal skin damage, and affords a longer regrowth period (2 to 12 weeks).³ However, plucking does not alter hair growth rate unless hairs are in the anagen phase, and can be a tedious process, making it impractical for use over larger areas.¹ Plucking can cause discomfort or pain, and its efficacy is dependent on user tolerance and technique.¹ Other drawbacks include folliculitis, follicular distortion, hyperpigmentation, erythema, and scarring.^6-8

Threading

Threading involves the use of a twisted loop of cotton thread, with ends held by hand and teeth,³ that is pressed against the skin to trap and pull hairs.^1,6 Threading is used in men to remove cheek, ear, and forehead hairs, and in women to remove facial hair.^1,3, Threading is a temporary hair removal technique widely practiced in the Middle East and dates back to antiquity, also known as fatlah in Egypt, that has gained popularity in Western cultures due to its precision in shaping eyebrows.¹ Threading, however, can be painful, tedious, and typically requires an esthetician with expertise.¹

Waxing

Waxing is a popular, temporary hair removal method resulting in hair-free skin for 2 to 6 weeks depending on the individual’s hair growth rate and body site.^1,3,7 Waxing is commonly used for larger areas.⁹ Wax is composed of beeswax and rosin with additives, essential oils, chemicals, and preservatives. Hot wax is preferred over cold wax especially in beauty salons⁹ as the heat dilates the follicular opening to facilitate hair removal.^1,3,7 Once the wax cools and hardens, the strip is removed quickly in the direction opposite of hair growth.^1,9

Waxing removes both vellus and terminal hairs in large areas, and is longer-lasting than shaving or chemical depilatories as hairs are removed from the bulb.^1,3 Repeated waxing can cause follicular trauma and reduce hair regrowth over time.^7,9 Other adverse events include folliculitis, thermal injury, skin irritation, scars,^7,9 and allergic reactions to the additives.^1,7 Patients using systemic retinoids are advised not to wax due to increased risk of scarring.

Sugaring

Sugaring is an ancient hair removal technique used in the Middle East and Egypt¹ involving a paste composed of sugar, lemon juice, and water¹⁰ applied to skin in the direction of hair growth, then removed in the opposite direction with cloth.¹⁰ Sugaring has a similar application to waxing, but may remove shorter hairs (1/16 inch versus ¼ inch) as water-based pastes can more easily penetrate follicles.¹⁰ Moreover, sugaring is safe (utilizes natural ingredients), cost-effective, hydrating, painless, and can be used for larger areas,⁷ and reduces the risk of skin redness, trauma, and scarring compared to shaving or hot waxing.¹⁰ However, sugaring may cause skin irritation and allergic reactions¹ and can only remove hairs of sufficient length.

Lasers

Laser hair removal can be permanent for some individuals,¹¹ and involves selective photothermolysis that emits a light at a specific wavelength (nm), pulse duration, and fluence, causing thermal injury without damaging the skin.^1,12 Light is either directly absorbed by melanin within the hair bulb and shaft⁶ or by an exogenous chromophore applied topically then absorbed by the follicle.^1,6,12 Lasers are more effective when the pigmented hair shaft is intact; thus, plucking and waxing are discouraged, whereas depilation (e.g., shaving) is recommended pretreatment.^1,12

Laser types include the ruby laser (694 nm),^1,6,13 diode laser (800 nm),^1,6,13-21 alexandrite laser (795 nm),^1,18,22,23 and neodymium:yttrium-aluminum-garnet (Nd:YAG) laser (1064 nm),^6,12,24,25 and efficacy depends on laser fluence, spot size, number of treatments and individual factors (e.g., skin type, hair type and hormonal status).26 Lasers work best for dark, thick terminal hairs, light/fair skin, and a normal hormonal status, but are ineffective for thin vellus hairs, and white, grey, or red hairs.²⁶ Longer wavelengths reduce epidermal damage due to poor absorption and are therefore safe and effective in darker skin types. Cooling devices should also be used to reduce skin damage.¹⁶ Adverse events include immediate erythema,¹³edema, first- and second- degree burns,^19,20 folliculitis,^22,23 skin damage, pigmentation changes, blisters, and crust formation, and are more likely to occur in darker skin types [Fitzpatrick skin type (FST) III to VI].^6,24

Intense Pulsed Light (IPL) System

The IPL system is a non-laser source of polychromatic light (550 nm to 1200 nm)⁶ tailored to individual skin type and hair color.^1,6,24 Multiple treatments are typically required,¹ however, results (60% hair reduction) may last up to 12 weeks after one session.²⁷ For optimal results, individuals should avoid tanning but should shave prior to treatment to prevent conducting thermal energy to adjacent epidermis.¹ IPL is most effective in individuals with the combination of darker hair and lighter skin.¹

IPL has several advantages, including lower cost compared to laser hair removal and the ability to treat large surface areas (back, chest, and legs). However, IPL is generally less effective than laser hair removal, requires more treatment sessions,²⁸ and the IPL device is bulky, heavy, and difficult to maneuver as it houses a lamp and cooling device.¹⁸ Adverse events include pain, edema, erythema, hypopigmentation, and hyperpigmentation.^1,18,24 IPL devices can emit inconsistent fluence and wavelengths from pulse to pulse, making it difficult to predict efficacy.¹⁸

Electrolysis

Electrolysis is a permanent method of hair removal,^1,6,8 but patients with hirsutism will experience conversion of vellus to terminal hairs in treatment areas. The three types of electrolysis [1) galvanic (direct current) electrolysis, 2) thermolysis (alternating current), and 3) combination/blend method] all involve inserting a probe to deliver electric currents that destroy and prevent regrowth of hair follicles.¹

Galvanic electrolysis treatment is slow (15 seconds to 3 minute application per hair) with multiple treatments required; however, it can reduce the number of active hair follicles by 80% to 90%.¹ This technique is tedious, time-consuming, painful, and can cause post-inflammatory hyperpigmentation and scarring, and is not recommended for larger areas requiring hair removal.⁸ In contrast, thermolysis is faster than galvanic electrolysis due to a shorter skin contact time, but generally less effective – hair has been found to regrow in 20% to 40% of follicles post-treatment.¹ The blend method (combination of galvanic electrolysis and thermolysis) is considered the most effective form, as it is as fast as thermolysis and less painful than galvanic electrolysis.¹

Adverse events of electrolysis depend on current type, duration, and intensity, but include pain, scarring/keloid formation in susceptible patients, and post-inflammatory hypo- or hyperpigmentation. Topical anesthetics can be offered before treatment, however maintaining sensation is preferred as pain is related to skin damage.⁶ Erythema and edema are common but transient, and crusting or follicular nodules may form with repeated insertion of a needle into the same follicle. There is also risk of local infection if instruments are not cleaned properly; operators should wear gloves at all times and apply antibacterial ointment to the area post-treatment.⁶ The efficacy of electrolysis depends largely on the operator’s skills, and unfortunately there is no standardization of licensure to practice this technique.^1,6

Photodynamic Therapy (PDT)

PDT involves the application of a topical photosensitizer⁶ and subsequent exposure to nonionizing radiation of red light (635 nm) through a projector, broadband light device, or laser.²⁹ Light is absorbed by a photosensitizer, subsequently forming singlet oxygen that causes lipid peroxidation of follicular cell membranes and protein damage,^6,8 resulting in phototoxic effects on hairs.³⁰ The most common topical agents used for PDT are 10% or 20% topical 5-aminolevulinic acid (5-ALA) and methyl aminolevulinate – prodrugs that lead to the formation of a photosensitizer, protoporphyrin IX (PPIX). PDT treatment duration is dependent on the incubation time of 5-ALA, which should be sufficient to allow for its conversion to PPIX. The incubation period for 5-ALA is typically 3 hours²⁹ followed by brief light exposure.³¹ PDT can be used in all skin and hair types as its mechanism of action is independent of melanin concentration and has minimal side-effects.³⁰ Uebelhoer et al. described a 40% hair reduction at 6 months of wax epilated areas after ALA application for 3 hours with one treatment of irradiation with continuous wave 630 nm red light.³² Moreover, in a recent study by Comacchi et al. on the use of PDT in idiopathic hirsutism and hypertrichosis, two to five treatments (with a 1 month period between treatments) led to a 75% hair reduction at 12 months.³⁰ Since PDT is primarily used to treat cutaneous malignancy, its use in hair removal is limited and further investigations are required.^8,12

Other

Topical Eflornithine Hydrochloride

Eflornithine hydrochloride 13.9% cream (Vaniqa®), is a topical prescription medication that is not meant to be used alone and should be combined with another hair removal technique. Topical eflornithine does not fall under epilation or depilation as it does not remove hair but rather slows facial hair growth, and inhibition of ornithine decarboxylase is the postulated mechanism of action. If applied twice daily at least 8 hours apart, results may be seen as early as 4 to 8 weeks. Adverse event rates include acne, folliculitis, stinging or burning, dry skin, itching, tingling, redness or irritation, indigestion, rash, and dizziness. Patients should consult their physician before using eflornithine if pregnant, planning pregnancy, or breastfeeding.²

Conclusion

This article is a general overview of hair removal practices, which have evolved from utilizing waxes and blades, to advanced lasers and electrolysis, with further advancements still being studied.¹ Residual, unwanted hair is a common problem for many individuals and traditional methods of hair removal (e.g., shaving and waxing) have provided temporary solutions and unsatisfactory results. Laser therapy is a safe modality that can produce permanent results in some individuals.^11,12 Electrolysis is a permanent hair removal method but can be tedious and associated with several adverse events. A relatively recent FDA and Health Canada approved treatment, eflornithine hydrochloride 13.9% cream, can be used in combination with another hair removal technique to slow the rate of facial hair growth. Importantly, studies examining hair removal efficacy are limited to individuals with darker hair and fairer skin, whereby precautionary measures such as cooling devices are recommended for safe treatment. Further research is required to develop safe and effective treatments for those with lighter-colored hair.¹²

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¹Faculty of Medicine, University of Toronto, Toronto, ON, Canada
²Windsor Clinical Research, Windsor, ON, Canada
³Western University, Schulich School of Medicine, Windsor, ON, Canada

Conflict of interest:
Cindy Kang and Monica Shah have no conflicts of interest to disclose. Jerry Tan has been a consultant, investigator and/or speaker for Almirall, Bausch, Boots/Walgreens, Cipher, Galderma, L’Oréal, Promius, Sun and Vichy. Disclaimers: This manuscript is an original submission. Views expressed in the submitted article are our own and not official positions of our institutions.

Abstract:
The diagnosis and classification of rosacea has been modified to reflect presenting features. On exclusion of differentials, the diagnosis of rosacea is based on the presence of either (1) phymatous changes, or (2) centrofacial persistent erythema. In their absence, diagnosis can be established by presence of any two of: flushing/transient erythema, papules and pustules, telangiectases, or ocular manifestations. Management of rosacea depends on presenting feature(s), their severity, and impact. General management includes gentle skin care, sun protection, and trigger avoidance. Evidence-based treatment recommendations include topical brimonidine and oxymetazoline for persistent erythema; topical azelaic acid, ivermectin, metronidazole, minocycline and oral doxycycline, tetracycline and isotretinoin for papules and pustules; vascular lasers and light devices for telangiectases; and omega-3 fatty acids and cyclosporine ophthalmic emulsion for ocular rosacea. While surgical or laser therapy can be considered for clinically noninflamed phyma, there are no trials on their utility. Combination therapies include topical brimonidine with topical ivermectin, or topical metronidazole with oral doxycycline. Topical metronidazole, topical ivermectin, and topical azelaic acid are appropriate for maintenance therapy. In conclusion, the updated phenotype approach, based on presenting clinical features, is the foundation for current diagnosis, classification, and treatment of rosacea.

Key Words:
alpha-adrenergic agonist, anti-parasitic, antibiotic, diagnosis, dicarboxylic acid, erythema, laser therapy, management, phenotype approach, phyma, retinoids, rosacea, telangiectasia

Table of Content:

1. Introduction
2. Quality of Evidence
3. Diagnosis
4. Evaluation and Differential Diagnosis
5. Associated Comorbidities
6. Management
7. Conclusion

Introduction

Rosacea is a chronic inflammatory dermatosis affecting the centrofacial region (cheeks, chin, nose, and central forehead), with a prevalence of 5.5% of the adult population.¹ While rosacea has been considered to primarily affect fair-skinned individuals, this may be due to difficulty in detecting facial redness in darker skin types. Nevertheless, rosacea patients of Asian, Hispanic, or African ancestry have been described in literature.² Women are more likely to develop rosacea, however, when present in men, the disease tends to be more severe.³ The typical age of onset is after 30 years old;^4,5 however, ocular rosacea can occur as early as 22 months of age.⁶ Pediatric rosacea is rare and is usually associated with a family history of the condition.^6,7 Ocular manifestations of rosacea occur in more than 50% of rosacea patients.⁸

There are several flare triggers in patients with rosacea including temperature changes, heat, cold, exercise, ultraviolet radiation, spicy food, and alcoholic beverages.⁹ Microbes have also been implicated in the pathophysiology of rosacea, including Demodex species, Bacillus oleronius, Staphylococcus epidermidis, Helicobacter pylori, and Bartonella quintana.¹⁰ The immune system, neurogenic inflammation, and vascular hyperreactivity are central to the pathophysiology of rosacea. Specifically, innate immune system activation via toll-like receptor 2 (TLR2), transient receptor potential (TRP) ion channels, and proinflammatory cytokines contribute to clinical manifestations of rosacea.¹¹

Rosacea has a significant impact on the emotional, social, and occupational wellbeing of affected individuals. Due to the altered facial features characterising this disease, patients with rosacea frequently experience stigmatization. Consequently, they can suffer from depression and anxiety and tend to avoid social situations.¹²

The phenotype approach establishes diagnosis and management based on the presenting features of the individual.¹³ While previously classified according to subtypes, each potentially comprising multiple signs and symptoms, this nomenclature should be abandoned as it limits the ability to study, evaluate, and treat individual features.¹³ The phenotype approach more accurately addresses patient features and can facilitate focused treatment on those of greatest severity and impact.¹³ Thus, this review provides an overview of the updated phenotype approach in the diagnosis and management of rosacea.

Quality of Evidence

The PubMed database was searched for systematic reviews, meta-analyses, and guidelines on the diagnosis, classification, and management of rosacea, with a focus on phenotypes. Key words included “rosacea” and “diagnosis” or “classification” or “management” or “guidelines” or “treatment”. There were no limits on age, sex, or nationality or year of publication. Only studies published in English on human subjects were included.

Diagnosis

The diagnosis of rosacea is clinical and based on specific features according to the ROSacea COnsensus expert panel (ROSCO)¹³ and the National Rosacea Society (NRS).¹⁴ On clinical exclusion of other conditions with similar presenting features, the diagnosis of rosacea is established with either: (1) phymatous changes, or (2) centrofacial persistent erythema (Table 1).^13,15 In their absence, diagnosis can be established by the presence of any two of the following major features: flushing/transient erythema, papules and pustules, telangiectases (Table 1), or ocular rosacea (Table 2).^13,15 Minor features, such as burning, stinging, dry sensation of the skin, or edema are not diagnostic of rosacea (Table 1).¹⁵ The diagnosis of rosacea in darker skin types (Fitzpatrick phototypes V and VI) is difficult as erythema and telangiectasia may not be readily visible, and a high level of suspicion based on minor features is required. A less common variant of rosacea is granulomatous rosacea, with multiple brown, yellow, or red cutaneous papules of uniform size. Occasionally, skin biopsy may be useful for diagnostic support.¹³

Table 1: Descriptions of cutaneous rosacea features by consensus

Consensus of an expert panel of 19 dermatologists from Argentina (n = 1), Brazil (n = 1), Canada (n = 1), France (n = 1), Germany (n = 2), India (n = 1), Italy (n = 1), the Netherlands (n = 1), Qatar (n = 1), Singapore (n = 1), South Africa (n = 1), the U.K. (n = 1) and the U.S.A. (n = 6); and two ophthalmologists from Germany (n = 1) and the U.S.A (n = 1). Some panellists abstained when their clinical expertise did not extend to a particular subject.
Reprinted from Schaller M. et al., 2019, Br J Dermatol, 176, p. 1273.¹⁵

Table 2: Descriptions of ocular rosacea features

Note that these are recommendations rather than consensus due to n = 2. Both ophthalmologists voted ‘Agree’ or ‘Strongly agree’ to the descriptions.
Consensus of an expert panel of 19 dermatologists from Argentina (n = 1), Brazil (n = 1), Canada (n = 1), France (n = 1), Germany (n = 2), India (n = 1), Italy (n = 1), the Netherlands (n = 1), Qatar (n = 1), Singapore (n = 1), South Africa (n = 1), the U.K. (n = 1) and the U.S.A. (n = 6); and two ophthalmologists from Germany (n = 1) and the U.S.A (n = 1). Some panellists abstained when their clinical expertise did not extend to a particular subject.
Reprinted from Schaller M. et al., 2019, Br J Dermatol, 176, p. 1274.¹⁵

Evaluation and Differential Diagnosis

Differential diagnoses of rosacea depend on the clinical feature(s) present (Table 3). Examples include contact dermatitis, photodermatitis, seborrheic dermatitis, and systemic lupus erythromatous for facial erythema; perimenopausal flushing, emotional flushing, carcinoid syndrome, and mastocytosis for flushing; and acne vulgaris and folliculitis for papules and pustules.¹⁶ Exclusion of mimics can be established by taking an adequate history, performing a directed physical evaluation for distinguishing features, and further testing as required.

Table 3: Differential diagnoses of rosacea

Information from Asai et al., 2016,¹⁶ Ogé et al., 2015,¹⁹ Scheinfeld et al., 2010,⁵⁵ and Izikson et al., 2006.⁵⁶

Associated Comorbidities

Associations between rosacea and metabolic, cardiovascular, gastrointestinal (GI), neurologic, and psychiatric diseases have been established (Table 4).¹⁷ Some of these share common innate inflammatory elements with rosacea, such as macrophage and macrophage-derived mediators, reactive oxygen species, matrix metalloproteinases, interleukin-1b (IL-1b), and tumor-necrosis-factor (TNF).¹⁸

Table 4: Rosacea and associated comorbidities

CI = confidence interval, N/A = not available, OR = odds ratio, P = probability

Management

The goals of rosacea treatment are to reduce the severity of features and the frequency and intensity of flares.¹³ General management includes routine skin care: gentle cleansers, moisturizers, sun protection, and avoidance of triggers.^16,19 Specific treatments should be targeted at clinical features (Table 5 on pages 7-8). If multiple features are present, combination treatment should be considered.¹⁶ The phenotype approach allows for such feature-based treatment according to the severity and impact of the presentation.²⁰ An updated systematic review of rosacea treatment based on the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) framework, is outlined below (Table 5).²¹

Table 5: Treatment recommendations and certainty of evidence

CI = confidence interval, Er:YAG = erbium-doped yttrium aluminium garnet, I2 = heterogeneity, IPL = intense pulsed light, MD = mean difference, MR = modified release, N/A = not available, Nd:YAG = neodymium-doped yttrium aluminum garnet, NNTB = number needed to benefit, NNTH = number needed to harm, PDL = pulsed dye laser, P = probability, RCT = randomized controlled trial, RR = relative risk
Information from van Zuuren et al., 2019.²¹

Flushing/Transient Erythema

No randomized controlled trials available.

Persistent Erythema

Evidence to support the efficacy and safety in transient reduction of persistent erythema was derived from two randomized vehicle-controlled trials for topical brimonidine 0.33% gel²² and topical oxymetazoline 1% cream.^23,24 Quality of evidence for efficacy was reported as high-certainty for brimonidine 0.33% gel and moderate-certainty for oxymetazoline 1% cream.²¹ Adverse event frequency was similar to vehicle for both brimonidine²² (moderate-certainty evidence)²¹ and for oxymetazoline^23,24 (moderate-certainty evidence).²¹ In both, there is ongoing concern about the potential risk of worsening erythema with repeated use.^25,26

Papules and Pustules

Dicarboxylic Acids

Topical azelaic acid 15% foam twice daily is a safe and effective treatment for papules and pustules^27,28 (high-certainty evidence)²¹ with an adverse event frequency similar to vehicle^27,28 (moderate-certainty evidence)²¹ according to two randomized vehicle-controlled trials.^27,28

Another randomized controlled trial showed that azelaic acid 15% gel may be more effective in reducing mean nominal lesion count than metronidazole 0.75% gel²⁹ (moderate-certainty evidence).²¹ These differences, however, were not reproducible and were considered to be unimportant.^30,31

Antiparasitics

Topical ivermectin 1% cream once daily is more effective in the treatment of papules and pustules compared to vehicle³² (high-certainty evidence),²¹ and compared to metronidazole 0.75% cream twice daily³³ (moderate-certainty evidence).²¹ Adverse event rates for topical ivermectin were similar compared to vehicle³² (moderate-certainty evidence)²¹ and topical metronidazole.³³

Retinoids

In two randomized controlled trials, low-dose oral isotretinoin 0.25 mg/kg and low-dose oral isotretinoin 0.30 mg/kg were more effective than placebo³⁴ (high-certainty evidence)²¹ and oral doxycycline (100 mg for 14 days, then tapered to 50 mg)³⁵ (moderate-certainty evidence),²¹ respectively. The frequency of adverse events was higher for isotretinoin compared to placebo³⁴ (moderate-certainty evidence),²¹ but similar to oral doxycycline³⁵ (moderate-certainty evidence).²¹

Antibiotics

Several randomized vehicle- or placebo-controlled trials demonstrated the efficacy of topical metronidazole 1% cream,^36-38 topical minocycline 1.5% and 3% foam,³⁹ oral doxycycline 40 mg modified-release (MR),⁴⁰ and oral tetracycline 250 mg twice daily^41,42 in the treatment of papules and pustules. The quality of evidence for efficacy was moderate-certainty for the first three treatments, but low-certainty for oral tetracycline.²¹ Adverse event frequency was similar to vehicle/placebo for topical metronidazole^36-38 (moderate-certainty evidence),²¹ oral doxycycline,⁴⁰ and oral tetracycline,^41,42 but higher than vehicle for topical minocycline39 (moderate-certainty evidence).²¹ Topical clindamycin 1% cream or gel was found to be no more effective than vehicle for any outcome⁴³ (low-to-moderate certainty evidence).²¹ Compared to oral doxycycline 40 mg MR, oral minocycline 100 mg is similarly effective⁴⁴ (moderate-certainty evidence)²¹ with no differences in the rate of adverse events⁴⁴ (low-certainty evidence).²¹ Compared to oral doxycycline 100 mg, oral azithromycin 500 mg three times a week then tapered is similarly effective in reducing lesion counts⁴⁵ (very low-certainty evidence).²¹ Finally, 40 mg MR doxycycline is as effective as 100 mg with fewer side effects.⁴⁶

Telangiectases

There is low-to-moderate certainty evidence that long pulsed dye laser (PDL), neodymium-doped yttrium aluminum garnet (Nd:YAG) laser, and intense pulsed light (IPL) therapy reduce telangiectasia.²¹

Clinically Non-inflamed Phyma

Physical modalities, such as ablative laser surgery using carbon dioxide or erbium-doped yttrium aluminium garnet (Er:YAG) modalities, electrosurgery, or cryosurgery, may improve clinically noninflamed phyma.¹⁶ However, it is difficult to determine their effectiveness due to the lack of evaluation by randomized controlled trials.^16,21

Clinically Inflamed Phyma

While there are no randomized controlled trials evaluating the efficacy of treatments for clinically inflamed phyma, oral doxycycline or oral isotretinoin are still recommended.^16,21

Ocular Rosacea

One randomized placebo-controlled trial supported omega-3 fatty acids (180 mg eicosapentaenoic acid and 120 mg docosahexaenoic acid) one capsule twice daily⁴⁷ (moderate-certainty evidence)²¹ in the treatment of ocular rosacea. Another randomized controlled trial supported cyclosporine ophthalmic emulsion 0.05% twice daily versus artificial tears⁴⁸ (low-certainty evidence)²¹ and versus oral doxycycline 100 mg twice daily for the first month followed by 2 months once daily⁴⁹ (low-certainty evidence).²¹ For the cyclosporine ophthalmic emulsion, there were no differences in the rate of adverse events compared to artificial tears (low-certainty evidence).²¹ For severe ocular rosacea or when there is diagnostic uncertainty, referral to an ophthalmologist should be arranged.²¹

Combination Therapies

Treatment combinations may address several different clinical features of rosacea. For example, compared to vehicle, topical brimonidine 0.33% gel with topical ivermectin 1% cream can effectively reduce both erythema and papules and pustules.⁵⁰ Compared to metronidazole 1% gel alone, metronidazole 1% gel with oral doxycycline 40 mg MR can reduce lesion counts to a greater extent.⁵¹

Finally, randomized controlled trials reported no difference in efficacy between oral minocycline 45 mg with or without topical azelaic acid 15% gel⁵² (moderate-certainty evidence)²¹ or between topical clindamycin phosphate 1.2% with tretinoin 0.025% gel compared to placebo⁵³ (moderate-certainty evidence).²¹ However, in the latter, there was a higher rate of adverse events in the topical clindamycin/tretinoin group compared to placebo (moderate-certainty evidence).²¹

Maintenance Therapies

Topical metronidazole 0.75% gel, ivermectin 1% cream, and azelaic acid 15% gel are reported as effective and safe for maintenance therapy of papules and pustules.^21,54

Conclusion

The diagnosis and classification of rosacea has evolved to a phenotype approach to accurately address the clinical features presenting in an individual and to advance epidemiological and clinical trials research.¹³ This review details the rosacea phenotype approach to diagnosis and classification, and summarizes current evidence-based treatment recommendations for individual features. There is no singularly effective treatment for all features of rosacea. There is an unmet need for high quality investigations for treatment of inflamed phyma, flushing/transient erythema, and ocular rosacea.

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