Rosacea Treatment: Review and Update

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Rosacea is a chronic and inflammatory disease with a series of facial skin manifestations, including flushing, nontransient erythema, papules/pustules, telangiectasia, and phymatous changes [1‐4]. Secondary manifestations, such as itching, burning, or stinging, are often observed in patients with rosacea [5]. The pathogenesis and pathophysiology of rosacea are not fully understood [6‐8], but immune dysfunction, Demodex infection, and exposure to ultraviolet radiation are considered to be contributing factors [2]. In 2002, rosacea was classified into the following four subtypes: erythematotelangiectatic, papulopustular, phymatous, and ocular [9]. In 2017, a phenotype-based approach for diagnosis and classification was recommended [2, 10‐12]. Fixed centrofacial erythema and phymatous changes are independently considered as diagnostic criteria for rosacea [10]. In recent years, a variety of treatment options have been provided in rosacea treatment guidelines and expert consensuses [13‐16], including topical therapies, oral therapies, light devices, skin care, and lifestyle management [13]. High-quality clinical trials have been conducted in recent years on rosacea treatment [17, 18]. A systematic review, including GRADE assessments on interventions for rosacea, has been especially helpful for clinical decision-making [19, 20]. However, treatment options for rosacea should also be expanded because managing rosacea remains a challenge [21]. The focus of this review is the expansion of treatment options rather than the level of evidence and the degree of recommendations, with the aim to summarize and update treatment options for rosacea and to supplement recent guidelines and expert consensuses.

This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.

Patients with rosacea are encouraged to practise gentle skin care, with a focus on moderation in cleansing and moisturizing and the use of sun screens, due to the impairment of the epidermal barrier function as well as the sensitive and easily irritated nature of their facial skin [13, 22‐24]. A recent study of 999 rosacea cases and 1010 controls revealed that a high frequency of cleansing and expansive use of cleansers were positively correlated with rosacea occurrence [22]. Rosacea occurs on the face, and it has a waxing and waning course, and negative impacts on emotional and overall well-being [5]. Dermatologists should educate patients with rosacea on the characteristics of the disease, the need to avoid triggers, and the importance of skin care and lifestyle management [5].

In 2018, the Society for Dermopharmacy published a guideline on dermocosmetics for use in rosacea [25]. The efficacy of and tolerance to these cosmetics should be demonstrated. The product documentation should be available to dermatologists and pharmacists. Guertler and colleagues evaluated the efficacy and safety of micellar water, cream, and serum in 50 Caucasian patients with rosacea and observed a significant reduction of facial erythema and rosacea-associated symptoms [26]. Baldwin and colleagues assessed the efficacy and tolerability of a tinted daily SPF‐30 facial moisturizer on rosacea‐prone skin in 33 females with mild to moderate rosacea and nontransient erythema in terms of coverage of skin redness and feelings of skin dryness and tightness/tension, reporting that the moisturizer did improve the skin appearance of rosacea‐prone patients [27]. A study including 42 subjects demonstrated that a regimen consisting of a wash foam, daily sunscreen cream, and night cream improved skin hydration and skin barrier function [28], with > 90% of the subjects reporting that the regimen was pleasant and effective and that they would continue to use this regimen and buy the products.

In a recent systematic review on rosacea interventions based on a phenotype approach, topical brimonidine (high-certainty evidence) and topical oxymetazoline (moderate-certainty evidence) were recommended for temporarily persistent erythema [19]. Topical azelaic acid (high-certainty evidence), topical ivermectin (high-certainty evidence), topical metronidazole (moderate-certainty evidence), and topical minocycline (moderate-certainty evidence) were recommended for the treatment of papules/pustules [19]. In a systematic review and meta-analysis, topical ivermectin was demonstrated to be the most effective topical treatment for papulopustular rosacea and to provide the greatest psychological benefit to these patients [29]. Topical ivermectin can be applied not only to skin almost clear of papulopustular rosacea or with mild rosacea, but also to skin with moderate to severe rosacea [4].

Minocycline foam is a novel drug that was first used to treat moderate to severe acne vulgaris [30]. The efficacy and safety of minocycline foam for the treatment of moderate to severe papulopustular rosacea were evaluated and confirmed in two phase 3, randomized clinical trials (751 and 771 participants, respectively) [18]. A prospective, 12-week, double-blinded study including 270 patients showed that 3% topical minocycline gel benefitted patients with papulopustular rosacea, significantly decreasing inflammatory lesions compared to vehicle [31]. A higher proportion of patients using minocycline gel achieved success according to an Investigator's Global Assessment.

A significant association exists between Demodex infestation and rosacea [32, 33]. High mean Demodex densities are observed in rosacea with papulopustules [34]. The impact of topical benzyl benzoate (+ crotamiton) treatment on Demodex densities and clinical symptoms of rosacea and demodicosis was assessed in a retrospective study with 394 patients (117 with rosacea and 277 with demodicosis) [35], with similar results observed in both patient cohorts. The treatment was effective in 46% of the patients and curative in 20% of the patients, and higher dose regimens were more effective than lower dose regimens. In an additional study including 344 patients, Demodex densities normalized with topical benzyl benzoate (+ crotamiton) treatment, with the symptoms clearing up in > 80% of patients with good compliance; however, the treatment was less effective and slower in poorly compliant patients [34]. The higher dose was associated with better compliance and faster results, suggesting that the higher dose of topical benzyl benzoate (+ crotamiton) might be useful for patients with rosacea and demodicosis.

Topical or systemic tranexamic acid is a conventional treatment for melasma [36, 37]. Recent research has expanded the use of tranexamic acid in rosacea treatment. Tranexamic acid may improve the symptoms of patients with rosacea by regulating the immune response and angiogenesis [38]. In 2013, Kim and colleagues treated six Korean women diagnosed with papulopustular rosacea or rosacea with irritant contact dermatitis using tranexamic acid solution soaking [39]. Marked decreases in the quartile scores for erythema were observed in all cases. In addition, there were notable decreases in the visual analog scale scores for itching, flushing, and burning, and no significant adverse events were observed [39]. Topical tranexamic acid was also used to treat erythematotelangiectatic rosacea in two other studies (with 20 patients and 1 patient, respectively), with the results of both studies implying promising therapeutic effects with a good safety profile [40, 41].

A systemic treatment or combination therapy should be considered for managing moderate to severe papulopustular rosacea [15]. The US Food and Drug Administration has approved modified-release oral doxycycline capsules for the treatment of inflammatory papules/pustules of rosacea [13]. Doxycycline 40 mg modified release (moderate-to-high-certainty evidence), isotretinoin (moderate-to-high-certainty evidence), and minocycline (moderate-certainty evidence) have been recommended as treatment for reducing papules/pustules in the updated systematic review on interventions for rosacea [19].

Oral β-blockers might be useful to treat persistent erythema and flushing because they antagonize the effects of sympathetic nerve stimulation and circulating catecholamines at β-adrenoceptors [42‐44]. In a systematic review including nine studies, Logger and colleagues concluded that oral nonselective β-blockers, especially carvedilol and propranolol, may be an effective treatment option for rosacea-associated facial flushing and erythema [43]. In a monocentric retrospective study, five Caucasian rosacea patients received carvedilol treatment titrated up to 12.5 mg twice daily for at least 6 months [45]. All patients had a remarkable decrease in the self-assessment and clinician’s erythema assessment grades, and they reported a major improvement of satisfaction. Large, prospective, clinical trials are needed to confirm the effect of β-blockers in rosacea treatment. The optimal dosage and long-term effects also need to be determined.

Hydroxychloroquine, which is used in patients with systemic autoimmune diseases, is a new treatment option for rosacea patients [46, 47]. In a rosacea-like mouse model, hydroxychloroquine was shown to ameliorate rosacea-like dermatitis, possibly by regulating the immune response of mast cells [46]. A randomized, double-blind, double-dummy study of 66 patients showed that the difference in changes in total rosacea-specific quality of life scores in the hydroxychloroquine group was noninferior to that in the doxycycline group. However, no noninferior results were observed in the clinician’s erythema assessment success rate, the investigator’s global assessment success of “clear” or “almost clear” rate, and excellent improvement rate [47]. Dry skin (14.3%), dry eye (7.1%), and dizziness (7.1%) were the most common adverse events in the hydroxychloroquine group. Hydroxychloroquine has the advantage of being a generally safe medication during pregnancy; however, more studies with larger sample size are warranted to demonstrate the effectiveness and safety of hydroxychloroquine.

Laser and intense pulsed light (IPL) therapy (low-to-moderate-certainty evidence) are recommended for the treatment of erythema and mainly telangiectasia in the updated systematic review on interventions for rosacea [19]. No significant difference in either the melanin or erythema index was observed between short-pulsed ILP therapy and pulsed dye laser therapy for rosacea treatment when used at the same energies and pulse [48]. In a retrospective study of 807 patients with different subtypes of rosacea, including erythema/telangiectasia, papules/pustules, and rhinophyma, Zhang and colleagues also noted that the multiple, sequential light/laser devices may be used to treat nasal rosacea [49]. In a study including 40 patients, treatment with a 577-nm pro-yellow laser was also demonstrated to be an effective and safe treatment for erythematotelangiectatic rosacea, facial erythema, and facial telangiectasia [50].

In a previous case report, a patient with recalcitrant granulomatous rosacea was treated with δ-aminolaevulinic acid-photodynamic therapy (ALA-PDT) [15, 51], but six sessions were required. Two studies have also shown that ALA-PDT is an effective and safe treatment for erythematotelangiectatic or papulopustular rosacea [52, 53]; however, the sample size in these studies was small, with only 17 and 20 patients enrolled, respectively. Of note, the selection of proper parameters is required in studies involving laser- and light-based therapies because flares of rosacea may be triggered at high levels of photodynamic therapy [53].

The combination of laser- and light-based therapies and other therapies has also been investigated in recent studies. The findings of a phase 4, multicenter, interventional, open‐label study with 46 patients suggest the benefit of oxymetazoline as adjunctive therapy with energy‐based therapy for the treatment of moderate to severe persistent facial erythema associated with rosacea [54]. A retrospective study including 31 subjects revealed that the combination of pulsed dye laser and 1.0% oxymetazoline cream reduced erythema and telangiectasias both safely and effectively [55]. An open-label study including 21 subjects assessed the efficacy and tolerability of topical skin care and sun protection combined with IPL therapy [56]. After using a topical skin care regimen (TSCR) monotherapy for 12 weeks, subjects received a single IPL light therapy, following which they continued the TSCR monotherapy for another 6 weeks. When used as a monotherapy, TSCR decreased investigator‐rated erythema, but the improvement did not achieve significance. All subjects agreed that TSCR improved their skin redness, and 80% of the subjects felt satisfied or very satisfied with the TSCR at week 18.

To date, two injection therapies have been demonstrated to be useful in rosacea treatment, namely, botulinum toxin and interleukin (IL)-17 inhibitors. In a double-blinded, placebo-controlled, split-face study, 24 participants were randomized to the intervention and placebo groups and given intradermal injections of botulinum toxin and normal saline in both cheeks, respectively [57]. A significant decrease in the erythema index and improved skin elasticity were observed in the group receiving the botulinum toxin injection. A case report also showed that intradermal injections of botulinum toxin significantly reduced erythema, edema, telangiectasias, and flushing [58]. In another study, 20 rosacea patients received the combination therapy of pulsed dye laser and intradermal botulinum toxin [59]. A synergistic effect was observed in this combination therapy, which showed high efficacy, received a high satisfaction rating by patients, and had a low side-effect profile. However, the cost and the need for repeated injections must also be taken into consideration.

Another injection therapy recently used in rosacea treatment are IL-17 inhibitors. Ali and colleagues reviewed the role of IL-17 in papulopustular rosacea [60] and found that IL-17 links Demodex folliculorum to angiogenesis, telangiectasias, inflammation, and pustules. Although treatment with IL-17 inhibitors are costly, these agents might be used to treat severe and treatment-resistant papulopustular rosacea. The authors of an exploratory, open-label, investigator-initiated study of 20 patients receiving secukinumab (300 mg weekly for 5 weeks and then monthly for 2 months) reported a significant reduction in papules and global severity score [61]. However, 39% of the patients in this study receiving at least one dose experienced at least one infection. Larger, randomized controlled studies that included comparison groups are necessary to evaluate the efficacy and safety of IL-17 inhibitors.

Rosacea has been associated with a series of cardiovascular diseases, gastrointestinal disorders, neurologic disorders, and psychiatric disorders [12, 76, 77]. Wollina noted that rosacea was associated with metabolic, psychiatric, and neurologic disorders and specific types of cancer, and Wollina suggested that rosacea should be considered a systemic disease [78].

Chronic inflammation in rosacea patients may be systemic, and inflammation may link rosacea and cardiometabolic disease [79]. Skin microbiota may also act as a link between rosacea and its comorbidities [80]. Recognizing and screening systemic disorders in rosacea patients may be beneficial in the early diagnosis and treatment of these diseases [79, 81]. To date, however, no direct treatment options have focused on the comorbidities of rosacea. In 2018, Kallis and colleagues reviewed a biologically based approach to treat acne and rosacea [82]. Complementary and alternative medicine therapies have been used to treat acne and rosacea due to the chronicity of these dermatologic conditions. These publicly approved holistic approaches suggest that rosacea is a systemic disease [82]. Studies on comorbidities that contribute to or arise from rosacea are needed in further research [11].

Combination therapy to target specific features is necessary to achieve effective treatment, especially in patients with severe rosacea or multiple rosacea features [13, 14]. Oral therapy combined with topical therapy [83], laser-/light-based therapy combined with topical therapy [54], and a combination of topical therapies [84] have all been documented in recent publications. Fractional microneedling radiofrequency, a new device in dermatology, has also been used to treat recalcitrant papulopustular rosacea combined with pulsed dye laser and oral isotretinoin [85]. This novel combination regimen showed satisfactory efficacy and acceptable safety profiles in the 25 patients enrolled in the study.

In a large cohort analysis of 72,173 patients diagnosed with rosacea, Lev-Tov and colleagues found that more than 20% of rosacea patients treated with topical agents (n = 62,074) received combination topical therapy [86]. However, the combined medications have similar working mechanisms and have not been studied together. Thus, the remaining question is whether to combine or not to combine the medications. More studies, especially cost-effectiveness studies, are needed to identify efficient and cost-efficient treatments for rosacea patients [86].

Rosacea treatment remains challenging for dermatologists, especially in refractory or recalcitrant cases. The pathogenesis of rosacea is not well understood. Immune dysfunction [87], Demodex [88], ultraviolet radiation exposure [89], and vascular hyperreactivity [90] may all play a role in the pathogenesis of rosacea. The pathogenesis and related mechanisms need further exploration to develop more etiological treatment modalities. The waxing and waning course of rosacea may disturb patients to a large extent, and rosacea is also related to many psychiatric disorders, such as anxiety and depression [91]. Dermatologists should focus on patient experience and patient education, and they should schedule regular follow-ups if necessary.

The evolvement of rosacea classification from subtyping to phenotyping may make the selection of treatment more rational by emphasizing the specific presentation and concerns of the individual patient [2]. This evolvement is also in accordance with the “patient-centric approach” [92‐94]. Individualized treatment should be applied to rosacea patients [95]. In the era of the phenotype approach, van Zuuren and colleagues systematically reviewed interventions for rosacea based on the new approach, using the GRADE guidelines to assess certainty of evidence [19]. Based on the systematic review published in 2019, we completed the descriptive review on treatment modalities in rosacea presented here, with special focus on the newly emerged modalities, with more emphasis on the expansion of treatment options and less emphasis on GRADE assessments. The treatment modalities that have newly emerged in the last 2 years might not be that helpful to clinical decision-making compared to those modalities recommended in that systematic review of 20,944 participants [19]. However, these emerged modalities may be applied to and be potentially useful in the treatment of refractory or recalcitrant cases. These modalities should be emphasized, and they may attract the attention of investigators who need a broader perspective and comprehensive understanding of rosacea treatment. Researchers should expand and verify rosacea treatment options, with a major focus on large-scale clinical research based on the phenotype approach.

In this review we summarize recent advances in rosacea treatment, including skin care and cosmetic treatments, topical therapies, oral therapies, laser-/light-based therapies, injection therapies, treatments for specific types of rosacea and treatments for systemic comorbidities, and combination therapies, in the era of phenotype-based diagnosis and classification for rosacea. There is still much to accomplish for precise treatment modalities for rosacea patients, and additional modalities also need to be developed and validated. This review may act as a supplement of recent rosacea treatment guidelines and expert consensuses. Large-scale clinical research based on the phenotype approach is highly warranted in the future.