A Systemic Approach to the Treatment of Rosacea

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Learning Objectives:

-    Assess the role of inflammation in rosacea
-    Identify the role of systemic agents in the treatment of rosacea
-    Distinguish between the different systemic therapies currently used for the treatment of rosacea
-    Recognize the need for systemic therapies that target inflammation, without antibacterial activity

An overview of rosacea

Rosacea is a chronic inflammatory skin condition affecting over two million Canadians.1,2,3 As a result of the social and psychological impacts it can have on a person’s well-being, accurate diagnosis and treatment of this chronic condition are critical.3 Rosacea typically develops in the third and fourth decades of life and occurs more often in women than men.4,5 The clinical presentation of rosacea primarily involves the central face and is characterized by periods of exacerbation and remission.6,7 Most commonly, patients present with facial redness and flushing in erythematotelangiectatic rosacea (ETR), and papules and pustules in papulopustular rosacea (PPR; Figure 1). Additional subtypes include phymatous and ocular rosacea (Table 1).8,9 Although the disease is commonly classified using these four subtypes, recent publications have stressed the importance of focusing on manifestations in the individual patient at the time of presentation, to allow for more directed therapy.4,6,10

While the etiology of rosacea is unknown, recent reports suggest that it is a complex skin disease thought to involve dysregulation of immune and neurovascular systems.2,6,11 The heightened inflammatory response observed in rosacea is not thought to be caused by a bacterium or microbial source.11 Instead, patients with rosacea-prone skin have an abnormal immune detection and response system.11,12 Triggers that have been reported to incite an exaggerated immune response and induce rosacea include ultraviolet light, increased ambient heat, spicy foods and alcohol.4,12 As a result of our increased understanding of rosacea, it is now recognized that treatment should involve minimizing factors that precipitate the disease and the use of therapies which are anti-inflammatory in nature.13


Systemic therapies for the treatment of rosacea

Current treatments for rosacea can be divided into two groups, topical and systemic (oral) therapies.14 The focus of this article is on systemic therapies, which are extensively used for moderate-to-severe cases of PPR.14 There is limited data on systemic therapies in the treatment of other rosacea subtypes, including ETR, phymatous and ocular rosacea.11 Tetracycline antibiotics have been the major class of systemic agents used in the treatment of PPR.4,9 Researchers were attracted to the use of tetracycline agents because, in addition to their antibiotic properties, they also exhibit multiple anti-inflammatory mechanisms.11 In addition, second-generation agents, such as doxycycline and minocycline, have improved the bioavailability of tetracycline agents.9 Alternatives to oral tetracycline therapies include oral metronidazole and the macrolide azithromycin, although they are less widely used due to concerns with adverse events and variable treatment response.11 For severe refractory cases of PPR, oral isotretinoin may be an option in carefully selected cases.15
Although all of the therapies mentioned above have been used in rosacea for several decades, clinical trials are limited and none have been approved by Health Canada for the treatment of rosacea.4,11,16 In addition, treatment with standard-dose antibiotics can lead to the development of antibiotic-resistant bacterial strains, which has become a growing public health concern worldwide.9 The Government of Canada has recognized the inappropriate use of antimicrobials as a key driver in the spread of antibiotic resistance and has developed a federal framework for action on antimicrobial resistance and use in Canada.17 One action outlined in this federal framework is to strengthen the promotion of the appropriate use of antimicrobials in medicine.17 Since there has been no bacterial component identified in the pathophysiology of rosacea, therapies that target the inflammatory process, but avoid antibiotic exposure, are recommended for its treatment.11,14 Currently, there is only one therapy that provides anti-inflammatory effects with subantimicrobial dosing: anti-inflammatory-dose doxycycline.11

Anti-inflammatory-dose doxycycline

Anti-inflammatory-dose doxycycline was approved by Health Canada in 2011 for the treatment of inflammatory lesions (papules and pustules) of rosacea in adult patients.18 It contains 40 mg of doxycycline in a modified-release capsule for once-daily dosing. This formulation allows for the immediate release of 30 mg and the delayed release of 10 mg of doxycycline, producing a pharmacokinetic profile shown to be devoid of antibiotic selection pressure.11,18 Evidence supporting the unique pharmacokinetic profile of anti-inflammatory-dose doxycycline was obtained by comparing the steady state plasma concentration of anti-inflammatory-dose ­doxycycline with standard-dose doxycycline 50 mg after 7 days of treatment. It was found that the mean plasma concentration of doxycycline 50 mg was more than twice that of anti-inflammatory-dose doxycycline, with only anti-inflammatory-dose doxycycline achieving plasma levels below the antimicrobial threshold.19 In addition, as with other tetracycline antibiotics, anti-inflammatory-dose doxycycline has several non-antibiotic properties that are thought to contribute to its efficacy, including inhibition of neutrophil activity and the downregulation of pro-inflammatory cytokines.18,20
The efficacy and safety of anti-inflammatory-dose doxycycline has been evaluated in multiple trials. In two randomized double-blind trials in patients with moderate-to-severe PPR, anti-inflammatory-dose doxycycline demonstrated a significantly greater decrease from baseline in the total number of inflammatory lesions compared to placebo at Week 16. It was also found to be safe and well tolerated in these trials, with no reports of vaginal candidiasis or photosensitivity.21 When compared to doxycycline 100 mg in a randomized double-blind trial, anti-inflammatory-dose doxycycline was found to be as effective at reducing inflammatory lesions, with less adverse events (Figure 2). Most notably, patients on anti-inflammatory-dose doxycycline experienced five times less gastrointestinal adverse events compared to those on doxycycline 100 mg.22 To determine whether there may be additional benefits to combining anti-inflammatory-dose doxycycline to a topical therapy, a randomized double-blind trial was conducted comparing anti-inflammatory-dose doxycycline plus metronidazole gel 1% to metronidazole gel 1% alone. A reduction in inflammatory lesions was significantly greater in patients on combination therapy, with comparable safety and tolerability to metronidazole gel 1% alone.23 Taken together, these results suggest that anti-inflammatory-dose doxycycline is an effective and safe treatment option capable of achieving the desired anti-inflammatory effect, without antimicrobial activity.

 

Recommendations for rosacea treatment

As the Canadian guidelines for rosacea are currently under development, clinicians can refer to the American Acne and Rosacea Society consensus recommendations as a guide to assist them in the management of patients with rosacea. In these guidelines, they recommend systemic therapies that are anti-inflammatory and not antibiotic in nature, to avoid the production of bacterial strains that are less sensitive to antibiotics. Oral antibiotics, on the other hand, are recommended only in cases where the patient responds poorly to a reasonable trial of topical therapy and/or anti-inflammatory-dose doxycycline, keeping in mind that access to therapeutic options may also influence how therapies are selected.15 The combination of systemic and topical agents is recommended and should be considered in patients with mild, moderate and severe cases of rosacea.1,15 The combination of anti-inflammatory-dose doxycycline with a topical therapy may be the optimal approach in patients with PPR.1,15 Potential topical therapeutic options include topical metronidazole 1% gel or topical ivermectin 1% cream, both of which can be prescribed once-daily.24,25 

Concluding remarks

Rosacea is a chronic inflammatory skin condition, which can have a significant impact on a patient’s quality of life.1,2,3 Once the diagnosis is made, it is important to counsel patients on the avoidance of known triggers and to focus on the manifestations in the individual patient at the time of presentation, to allow for more directed therapy.4,6,10,13 Sytemic treatments are extensively used for moderate-to-severe PPR and are often added to topical therapies to improve treatment outcomes.14,15  While tetracycline derivatives have traditionally been used for the systemic treatment of PPR, growing concerns regarding antibiotic resistance have prompted interest in the use of anti-inflammatory-dose doxycycline as a safer means of treating the inflammation central to rosacea’s pathophysiology.4,26

Development of this article was sponsored through an educational grant from Galderma Canada. The authors had complete editorial independence in the development of this article and are responsible for its accuracy. The sponsor exerted no influence in the selection of the content or material published. 
References:
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