Cindy Na-Young Kang, BMSc1, Monica Shah, BSc1, Jerry Tan, MD, FRCPC2,3

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

Cutaneous Rosacea FeaturesDescription
Diagnostic features
Phymatous changesFacial skin thickening due to fibrosis and/or sebaceous glandular hyperplasia. Most commonly affects the nose, where it can impart a bulbous appearance.
Persistent erythemaBackground ongoing centrofacial redness. May periodically intensify in response to variable triggers. In darker skin phototypes (V and VI), erythema may be difficult to detect visually.
Major features
Flushing/transient erythemaTemporary increase in centrofacial redness, which may include sensations of warmth, heat, burning and/or pain.
Papules and pustulesRed papules and pustules, usually in the centrofacial area. Some may be larger and deeper.
TelangiectasesVisible vessels in the centrofacial region but not only in the alar area.
Minor features
Burning sensation of the skinAn uncomfortable or painful feeling of heat, typically in the centrofacial region.
Stinging sensation of the skinAn uncomfortable or painful sharp, pricking sensation, typically in the centrofacial region.
Dry sensation of the skinSkin that feels rough. May be tight, scaly and/or itchy.
EdemaLocalized facial swelling. Can be soft or firm (nonpitting) and may be self-limited in duration or persistent.

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


 

Ocular Rosacea FeaturesDescription
Lid margin telangiectasiaVisible vessels around the eyelid margins. May be difficult to detect visually in darker skin phototypes (V and VI).
BlepharitisInflammation of the eyelid margin, most commonly arising from Meibomian gland dysfunction.
KeratitisInflammation of the cornea that can lead to defects and, in the most severe cases, vision loss.
ConjunctivitisInflammation of the mucous membranes lining the inner surface of the eyelids and bulbar conjunctiva. Typically associated with injection or vascular congestion and conjunctival oedema.
Anterior uveitisInflammation of the iris and/or ciliary body.

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.

Distinguishing Clinical FeatureDifferential DiagnosisOther Clinical Features
Facial erythemaContact dermatitisItching, eczematous features
PhotodermatitisTender erythema in photo-distribution
Seborrheic dermatitisScaly erythema at frontal hairline, scalp, eyebrows, and nasolabial folds
Systemic lupus erythematosus (SLE)Cheilitis and other manifestations of SLE
FlushingPerimenopausal flushingTransient episodes of intense heat sensation
Flushing of chest, head, and neck
Profuse drenching sweats
Episodes lasts 3-5 minutes up to 20 times a day and are frequently followed by chills accompanied by palpitations and sense of anxiety
Emotional flushingEpisodes of flushing are correlated with emotional upset or feelings of embarrassment
Carcinoid syndromeAssociated diarrhea, wheezing, and abdominal pain
MastocytosisAssociated diarrhea, abdominal pain, and musculoskeletal pain
Papules and pustulesAcne vulgarisPresence of comedones
FolliculitisMonomorphous lesions, no centrofacial erythema

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

 

Associated ComorbidityOR95% CIP-ValueReference
Metabolic
Type 1 diabetes2.591.41-4.73<0.002Egeberg et al., 201657
Dyslipidemia1.411.36-1.46<0.008Hua et al., 201558
Cardiovascular
Hypertension1.171.12-1.21<0.008Hua et al., 201558
Coronary artery disease1.351.29-1.41<0.008Hua et al., 201558
Gastrointestinal
Ulcerative colitis1.651.43-1.90N/ASpoendlin et al., 201659
Crohn’s disease1.491.25-1.77N/AHolmes et al., 201818
Inflammatory bowel disease2.171.59-2.97<0.001Kim et al., 201760
Celiac disease2.031.35-3.08<0.001Egeberg et al., 201657
Gastroesophageal reflux disease4.21.70-10.20<0.002Rainer et al., 201561
Neurologic/psychiatric
DepressionN/AN/AN/AWu et al., 201862
Migraine1.181.13-1.24N/ASpoendlin et al., 201363

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

 

TreatmentDoseEfficacyCertainty of Evidence for EfficacyRate of Adverse EventsCertainty of Evidence for Adverse EventsReference
Persistent erythema
Topical brimonidine0.33% gelCompared to vehicle/placebo; RR 2.11, 95% CI 1.60-2.78, P < 0.001, I2 = 0%; NNTB 5, 95% CI 3-7HighEqual to vehicle/placebo; RR 1.29, 95% CI 0.98-1.69, I2 = 0%ModerateFowler et al., 201322
Topical oxymetazoline1% creamCompared to vehicle/placebo; RR 1.65, 95% CI 1.23–2.21, P < 0.001, I2 = 0%; NNTB 11, 95% CI 7-27ModerateEqual to vehicle/placebo; RR 1.32, 95% CI 0.97-1.78, I2 = 13ModerateBaumann et al., 201823
Kircik et al., 201824
Papules and pustules
Dicarboxylic acids
Topical azelaic acid15% foamCompared to vehicle/placebo; RR 1.40, 95% CI 1.28-1.53, P < 0.001, I2 = 0%; NNTB 6, 95% CI 5-8HighEqual to vehicle/ placebo; RR 1.29, 95% CI 0.92-1.81, I2 = 46%ModerateDraelos et al., 201327
Draelos et al., 201528
Topical azelaic acid is superior to topical metronidazole15% gel azelaic acid, 0.5% gel metronidazoleMean nominal lesion count reduction –12.9 vs. –10.7, P = 0.003Moderate; non-reproducible by other RCTsN/AModerateElewski et al., 200329
Antiparasitics
Topical ivermectin1% creamCompared to vehicle/placebo; RR 1.84, 95% CI 1.62-2.09, P < 0.001, I2 = 0%; NNTB 3, 95% CI 3-4HighEqual to vehicle/placebo; RR 0.83, 95% CI 0.54-1.28, I2 = 26%ModerateStein et al., 201432
Topical ivermectin is superior to topical metronidazole1% cream ivermectin, 0.75% cream metronidazoleTopical ivermectin compared to topical metronidazole; RR 1.14, 95% CI 1.07-1.22, P <0.001; NNTB 10, 95% CI 7-17ModerateN/AN/ATaieb et al., 201533
Retinoids
Oral isotretinoin0.25 mg/kg, 0.30 mg/kgCompared to vehicle/placebo; RR 5.51, 95% CI 2.37-12.83, P < 0.001; NNTB 2, 95% CI 2-3HighHigher than vehicle/placebo; RR 1.59, 95% CI 1.12-2.24, P = 0.009, NNTH 4, 95% CI 2-11ModerateSbidian et al., 201634
Antibiotics
Topical metronidazole1% creamCompared to vehicle/placebo; RR 1.98, 95% CI 1.29-3.02, P = 0.002ModerateEqual to vehicle/placebo; RR 1.19, 95% CI 0.94-1.51, I2 = 0%ModerateBjerke et al., 198936
Breneman et al., 199837
Nielsen, 198338
Topical minocycline1.5% or 3% foamCompared to vehicle/placebo; MD – 13.30, 95% CI -15.82 to -10.78, P < 0.001ModerateHigher than vehicle/placebo; RR 1.47, 95% CI 1.05-2.04, P = 0.02; NNTH 5, 95% CI 3-32ModerateMrowietz et al., 201839
Oral doxycycline40 mg MRCompared to vehicle/placebo; RR 1.69, 95% CI 1.26-2.28, P < 0.001, I2 = 0; NNTB 9, 95% CI 6-20ModerateEqual to vehicle/placebo; RR 1.27, 95% CI 1.08-1.49ModerateDi Nardo et al., 201640
Oral tetracycline250 mgN/ALowN/AModerateMarks, 197141
Sneddon, 196642
Oral doxycycline is just as effective as oral minocycline40 mg doxycycline, 100 mg minocyclineOral doxycycline compared to oral minocycline; RR 1.10, 95% CI 0.72-1.67ModerateEqual to minocycline; RR 1.17, 95% CI 0.83-1.65Lowvan der Linden et al., 201744
Oral doxycycline is similar to oral azithromycin100 mg doxycycline, 500 mg three times a week then tapered azithromycinMean nominal lesion count reduction N/A, 95% CI –30.1 to –32.4, P = 0.771Very lowN/AN/AAkhyani et al., 200845
Oral doxycycline (low dose) is similar to oral doxycycline (high dose)40 mg, 100 mg doxycyclineN/ALowN/AN/ADel Rosso et al., 200846
Telangiectasias
PDL, Nd:YAG, IPLN/AN/ALow-to-moderateN/AN/Avan Zuuren et al., 201921
Clinically non-inflamed phyma
Ablative laser surgery, Er:YAG modalities, electrosurgery, cryosurgeryN/AN/ANo RCTs but recommended by expertsN/AN/AOgé et al., 201519
Clinically inflamed phyma
Oral doxycyclineN/AN/ANo RCTs but recommended by expertsN/AN/AOgé et al., 201519
Oral isotretinoinN/AN/ANo RCTs but recommended by expertsN/AN/AOgé et al., 201519
Ocular rosacea
Omega-3 fatty acids180 mg eicosapentaenoic acid and 120 mg docosahexaenoic acidN/AModerateN/AN/ABhargava et al., 201647
Cyclosporine ophthalmic emulsion is superior to artificial tears0.05% cyclosporine ophthalmic emulsionN/ALowSimilar to artificial tears; N/ALowSchechter et al., 200948
Cyclosporine ophthalmic emulsion is superior to artificial tears0.05% cyclosporine ophthalmic emulsionN/ALowSimilar to artificial tears; N/ALowSchechter et al., 200948
Cyclosporine ophthalmic emulsion is superior to oral doxycycline0.05% cyclosporine ophthalmic emulsion, 100 mg doxycyclineN/ALowN/AN/AArman et al., 201549
Combination therapies
Topical brimonidine with topical ivermectin0.33% gel brimonidine, 1% topical ivermectinRR 1.84, 95% CI 1.38-2.46, P < 0.001; NNTB 3, 95% CI 2-5N/AN/AN/AGold et al., 201750
Topical metronidazole with oral doxycycline is superior to topical metronidazole alone1% gel metronidazole, 40 mg MR doxycyclineN/AN/AN/AN/AFowler, 200751
Oral minocycline with topical azelaic acid is just as effective as oral
minocycline without azelaic acid
45 mg minocycline, 15% gel azelaic acidN/AModerateN/AN/AJackson et al., 201352
Topical clindamycin phosphate with tretinoin1.2% clindamycin phosphate, 0.025% gel tretinoinN/AModerateHigher than vehicle/placebo; N/AModerateChang et al., 201253
Maintenance therapies
Topical metronidazole 0.75% gel for papules and pustules0.75% gelN/AN/AN/AN/AStein Gold et al., 201454
Topical ivermectin for papules and pustules1% creamN/AN/AN/AN/AStein Gold et al., 201454
Topical azelaic acid for papules and pustules15% gelN/AN/AN/AN/AStein Gold et al., 201454

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 oxymetazoline23,24 (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 pustules27,28 (high-certainty evidence)21 with an adverse event frequency similar to vehicle27,28 (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 daily41,42 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 metronidazole36-38 (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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