Rosacea: An Update in Diagnosis, Classification and Management

Cindy Na-Young Kang, BMSc; Monica Shah, BSc; Jerry Tan, MD, FRCPC

Skin Therapy Letter. 2021;26(4):1-8.

Abstract and Introduction

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.

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.

Table 1. Descriptions of cutaneous rosacea features by consensus
Cutaneous Rosacea Features	Description
Diagnostic features
Phymatous changes	Facial skin thickening due to fibrosis and/or sebaceous glandular hyperplasia. Most commonly affects the nose, where it can impart a bulbous appearance.
Persistent erythema	Background 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 erythema	Temporary increase in centrofacial redness, which may include sensations of warmth, heat, burning and/or pain.
Papules and pustules	Red papules and pustules, usually in the centrofacial area. Some may be larger and deeper.
Telangiectases	Visible vessels in the centrofacial region but not only in the alar area.
Minor features
Burning sensation of the skin	An uncomfortable or painful feeling of heat, typically in the centrofacial region.
Stinging sensation of the skin	An uncomfortable or painful sharp, pricking sensation, typically in the centrofacial region.
Dry sensation of the skin	Skin that feels rough. May be tight, scaly and/or itchy.
Edema	Localized facial swelling. Can be soft or firm (nonpitting) and may be self-limited in duration or persistent.

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
Ocular Rosacea Features	Description
Lid margin telangiectasia	Visible vessels around the eyelid margins. May be difficult to detect visually in darker skin phototypes (V and VI).
Blepharitis	Inflammation of the eyelid margin, most commonly arising from Meibomian gland dysfunction.
Keratitis	Inflammation of the cornea that can lead to defects and, in the most severe cases, vision loss.
Conjunctivitis	Inflammation 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 uveitis	Inflammation of the iris and/or ciliary body.

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

Table 3. Differential diagnoses of rosacea
Distinguishing Clinical Feature	Differential Diagnosis	Other Clinical Features
Facial erythema	Contact dermatitis	Itching, eczematous features
	Photodermatitis	Tender erythema in photo-distribution
	Seborrheic dermatitis	Scaly erythema at frontal hairline, scalp, eyebrows, and nasolabial folds
	Systemic lupus erythematosus (SLE)	Cheilitis and other manifestations of SLE
Flushing	Perimenopausal flushing	Transient episodes of intense heat sensationFlushing of chest, head, and neckProfuse drenching sweatsEpisodes lasts 3–5 minutes up to 20 times a day and are frequently followed by chills accompanied by palpitations and sense of anxiety
	Emotional flushing	Episodes of flushing are correlated with emotional upset or feelings of embarrassment
	Carcinoid syndrome	Associated diarrhea, wheezing, and abdominal pain
	Mastocytosis	Associated diarrhea, abdominal pain, and musculoskeletal pain
Papules and pustules	Acne vulgaris	Presence of comedones
	Folliculitis	Monomorphous lesions, no centrofacial erythema

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

Table 4. Rosacea and associated comorbidities
Associated Comorbidity	OR	95% CI	P-Value	Reference
Metabolic
Type 1 diabetes	2.59	1.41–4.73	<0.002	Egeberg et al., 2016⁵⁷
Dyslipidemia	1.41	1.36–1.46	<0.008	Hua et al., 2015⁵⁸
Cardiovascular
Hypertension	1.17	1.12–1.21	<0.008	Hua et al., 2015⁵⁸
Coronary artery disease	1.35	1.29–1.41	<0.008	Hua et al., 2015⁵⁸
Gastrointestinal
Ulcerative colitis	1.65	1.43–1.90	N/A	Spoendlin et al., 2016⁵⁹
Crohn's disease	1.49	1.25–1.77	N/A	Holmes et al., 2018¹⁸
Inflammatory bowel disease	2.17	1.59–2.97	<0.001	Kim et al., 2017⁶⁰
Celiac disease	2.03	1.35–3.08	<0.001	Egeberg et al., 2016⁵⁷
Gastroesophageal reflux disease	4.2	1.70–10.20	<0.002	Rainer et al., 2015⁶¹
Neurologic/psychiatric
Depression	N/A	N/A	N/A	Wu et al., 2018⁶²
Migraine	1.18	1.13–1.24	N/A	Spoendlin et al., 2013⁶³

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

Table 5. Treatment recommendations and certainty of evidence
Treatment	Dose	Efficacy	Certainty of Evidence for Efficacy	Rate of Adverse Events	Certainty of Evidence for Adverse Events	Reference
Persistent erythema
Topical brimonidine	0.33% gel	Compared to vehicle/placebo; RR 2.11, 95% CI 1.60–2.78, P < 0.001, I2 = 0%; NNTB 5, 95% CI 3–7	High	Equal to vehicle/placebo; RR 1.29, 95% CI 0.98–1.69, I2 = 0%	Moderate	Fowler et al., 2013²²
Topical oxymetazoline	1% cream	Compared to vehicle/placebo; RR 1.65, 95% CI 1.23–2.21, P < 0.001, I2 = 0%; NNTB 11, 95% CI 7–27	Moderate	Equal to vehicle/placebo; RR 1.32, 95% CI 0.97–1.78, I2 = 13	Moderate	Baumann et al., 2018²³ Kircik et al., 2018²⁴
Papules and pustules
Dicarboxylic acids
Topical azelaic acid	15% foam	Compared to vehicle/placebo; RR 1.40, 95% CI 1.28–1.53, P < 0.001, I2 = 0%; NNTB 6, 95% CI 5–8	High	Equal to vehicle/placebo; RR 1.29, 95% CI 0.92–1.81, I2 = 46%	Moderate	Draelos et al., 2013²⁷ Draelos et al., 2015²⁸
Topical azelaic acid is superior to topical metronidazole	15% gel azelaic acid, 0.5% gel metronidazole	Mean nominal lesion count reduction –12.9 vs. –10.7, P = 0.003	Moderate; non-reproducible by other RCTs	N/A	Moderate	Elewski et al., 2003²⁹
Antiparasitics
Topical ivermectin	1% cream	Compared to vehicle/placebo; RR 1.84, 95% CI 1.62–2.09, P < 0.001, I2 = 0%; NNTB 3, 95% CI 3–4	High	Equal to vehicle/placebo; RR 0.83, 95% CI 0.54–1.28, I2 = 26%	Moderate	Stein et al., 2014³²
Topical ivermectin is superior to topical metronidazole	1% cream ivermectin, 0.75% cream metronidazole	Topical ivermectin compared to topical metronidazole; RR 1.14, 95% CI 1.07–1.22, P <0.001; NNTB 10, 95% CI 7–17	Moderate	N/A	N/A	Taieb et al., 2015³³
Retinoids
Oral isotretinoin	0.25 mg/kg, 0.30 mg/kg	Compared to vehicle/placebo; RR 5.51, 95% CI 2.37–12.83, P < 0.001; NNTB 2, 95% CI 2–3	High	Higher than vehicle/placebo; RR 1.59, 95% CI 1.12–2.24, P = 0.009, NNTH 4, 95% CI 2–11	Moderate	Sbidian et al., 2016³⁴
Antibiotics
Topical metronidazole	1% cream	Compared to vehicle/placebo; RR 1.98, 95% CI 1.29–3.02, P = 0.002	Moderate	Equal to vehicle/placebo; RR 1.19, 95% CI 0.94–1.51, I2 = 0%	Moderate	Bjerke et al., 1989³⁶ Breneman et al., 1998³⁷ Nielsen, 1983³⁸
Topical minocycline	1.5% or 3% foam	Compared to vehicle/placebo; MD – 13.30, 95% CI -15.82 to -10.78, P < 0.001	Moderate	Higher than vehicle/placebo; RR 1.47, 95% CI 1.05–2.04, P = 0.02; NNTH 5, 95% CI 3–32	Moderate	Mrowietz et al., 2018³⁹
Oral doxycycline	40 mg MR	Compared to vehicle/placebo; RR 1.69, 95% CI 1.26–2.28, P < 0.001, I2 = 0; NNTB 9, 95% CI 6–20	Moderate	Equal to vehicle/placebo; RR 1.27, 95% CI 1.08–1.49	Moderate	Di Nardo et al., 2016⁴⁰
Oral tetracycline	250 mg	N/A	Low	N/A	Moderate	Marks, 1971⁴¹ Sneddon, 1966⁴²
Oral doxycycline is just as effective as oral minocycline	40 mg doxycycline, 100 mg minocycline	Oral doxycycline compared to oral minocycline; RR 1.10, 95% CI 0.72–1.67	Moderate	Equal to minocycline; RR 1.17, 95% CI 0.83–1.65	Low	van der Linden et al., 2017⁴⁴
Oral doxycycline is similar to oral azithromycin	100 mg doxycycline, 500 mg three times a week then tapered azithromycin	Mean nominal lesion count reduction N/A, 95% CI –30.1 to –32.4, P = 0.771	Very low	N/A	N/A	Akhyani et al., 2008⁴⁵
Oral doxycycline (low dose) is similar to oral doxycycline (high dose)	40 mg, 100 mg doxycycline	N/A	Low	N/A	N/A	Del Rosso et al., 2008⁴⁶
Telangiectasias
PDL, Nd:YAG, IPL	N/A	N/A	Low-to-moderate	N/A	N/A	van Zuuren et al., 2019²¹
Clinically non-inflamed phyma
Ablative laser surgery, Er:YAG modalities, electrosurgery, cryosurgery	N/A	N/A	No RCTs but recommended by experts	N/A	N/A	Ogé et al., 2015¹⁹
Clinically inflamed phyma
Oral doxycycline	N/A	N/A	No RCTs but recommended by experts	N/A	N/A	Ogé et al., 2015¹⁹
Oral isotretinoin	N/A	N/A	No RCTs but recommended by experts	N/A	N/A	Ogé et al., 2015¹⁹
Ocular rosacea
Omega-3 fatty acids	180 mg eicosapentaenoic acid and 120 mg docosahexaenoic acid	N/A	Moderate	N/A	N/A	Bhargava et al., 2016⁴⁷
Cyclosporine ophthalmic emulsion is superior to artificial tears	0.05% cyclosporine ophthalmic emulsion	N/A	Low	Similar to artificial tears; N/A	Low	Schechter et al., 2009⁴⁸
Cyclosporine ophthalmic emulsion is superior to artificial tears	0.05% cyclosporine ophthalmic emulsion	N/A	Low	Similar to artificial tears; N/A	Low	Schechter et al., 2009⁴⁸
Cyclosporine ophthalmic emulsion is superior to oral doxycycline	0.05% cyclosporine ophthalmic emulsion, 100 mg doxycycline	N/A	Low	N/A	N/A	Arman et al., 2015⁴⁹
Combination therapies
Topical brimonidine with topical ivermectin	0.33% gel brimonidine, 1% topical ivermectin	RR 1.84, 95% CI 1.38–2.46, P < 0.001; NNTB 3, 95% CI 2–5	N/A	N/A	N/A	Gold et al., 2017⁵⁰
Topical metronidazole with oral doxycycline is superior to topical metronidazole alone	1% gel metronidazole, 40 mg MR doxycycline	N/A	N/A	N/A	N/A	Fowler, 2007⁵¹
Oral minocycline with topical azelaic acid is just as effective as oral minocycline without azelaic acid	45 mg minocycline, 15% gel azelaic acid	N/A	Moderate	N/A	N/A	Jackson et al., 2013⁵²
Topical clindamycin phosphate with tretinoin	1.2% clindamycin phosphate, 0.025% gel tretinoin	N/A	Moderate	Higher than vehicle/placebo; N/A	Moderate	Chang et al., 2012⁵³
Maintenance therapies
Topical metronidazole 0.75% gel for papules and pustules	0.75% gel	N/A	N/A	N/A	N/A	Stein Gold et al., 2014⁵⁴
Topical ivermectin for papules and pustules	1% cream	N/A	N/A	N/A	N/A	Stein Gold et al., 2014⁵⁴
Topical azelaic acid for papules and pustules	15% gel	N/A	N/A	N/A	N/A	Stein Gold et al., 2014⁵⁴

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 riskInformation from van Zuuren et al., 2019.²¹