Rosacea Update

Judy Seraphine, Medical Editor, Maui Derm News

In this presentation, Dr Webster provides an update for the management of patients with rosacea.

There have been a number of theories about rosacea. In the past, clinicians believed that it had to do with blushing but that was never clear. Since then, newer observations have been made trying to explain the cause of rosacea.

Helicobacter pylori and Rosacea

Dermatologists should recognize that rosacea can improve during H. pylori therapy as H. pylori drugs may be active in rosacea independent of effects on the GI tract. It is important to understand that H. pylori is as common in rosacea as it is in normal controls and a blinded study showed no greater effect on the controls for H. pylori therapy. What was found that the therapy used to treat the GI effects of H. pylori, namely doxycycline, also tended to treat the rosacea.

Demodex in Rosacea

It is difficult to say what the role of Demodex is in rosacea. Demodex is present on both normal and rosacea skin, yet elevated demodex counts are seen in rosacea; however, demodex quantification is flawed, prone to error and difficult to do. Demodex is most increased in inflammatory rosacea. Follicles with demodex in normal skin tend to be inflamed. Dr Webster feels that an important study with regards to Demodex is that of it killing Lindane. The results were is ineffective.

B. oleronius in Rosacea

More recently, Dr Frank Powell and his colleagues discovered a Demodex-related bacteria that is more active in rosacea patients. They cultured mites and one mite grew a bacterium that was different from other skin flora, Bacillus oleronius. They found that ruptured activate mononuclear cells [16/23 (73%) rosacea patients versus 5/17 (29%) controls]. Rosacea patients seem to recognize a few antigens in western blots.

Dr Li and colleagues found an even greater reaction between B. oleronius and ocular rosacea. There are problems however, as in the first study only one mite out of 40 contained the bug. In addition to that and more importantly, PCR of many new Demodexs did not reveal the bug.. The cross-reactivity of the bug antigens with other more common bugs hasn’t been investigated. Many patients did not react and some normal patients did.  As of now, this information is on hold.

Etiology of Rosacea

What do we know about the etiology of rosacea? We know that there is excessive vascular reactivity and those who have rosacea tend to be “blushers and flushers.”  We know that the papules and postules, when cultured, are sterile and in some small genetic analyses, the skin does not show bacteria so we know that it is not some sort of infection. Rosacea does respond to anti-inflammatory drugs.  It is becoming clearer and clearer that the nerves are involved in skin “things” that we don’t quite understand, for example the sebaceous gland.  It is also pretty clear that there is a defect in control of the innate immune system. The inflammatory subunits are present in rosacea skin and if you purify them and inject them into mice, you can make rosacea-like inflammation in the back of the mouse.

Neuro-vascular Factors in Rosacea

The blush reflex to thermal stimuli is more easily triggered in rosacea patients than in normal patients. Also, plasma leakage from the blood vessels may incite inflammation. There are multiple flush/blush mechanisms, these include thermal, hormonal, nicotinamide, and autonomic and they are different among each patient.

Clinical Issues with Rosacea

The tried and true topical agents for the treatment of rosacea include:

  • Metronidazole (FDA approved)
    • 0.75 and 1%
  • Tacrolimus/pimecrolimus
    • “overlap” rosacea (e.g. eczema and rosacea)
  • BP/clindamycin
    • acne/rosacea
  • Azeleic acid (FDA approved)
  • Sodium sulfacetamide/sulfur
  • Tretinoin
    • Sun damage or rosacea? (data unclear)
Oral Flush Blockers

The flushing and the redness is the most difficult to treat.

  • Clonidine
    • Blocks carcinoid and menopause flush
    • No effect in chocolate, red wine, thermal flushing
  • Nadolol
    • No effect in rosacea thermal blush
  • Aspirin
    • Blocks Nicotinic acid flush

(Arch Derm 119:211, 1983; 118:109, 1983; Clin Pharm Ther 31:478, 1982; JAAD 20:202, 1989)

Topical Treatment of Erythema

Metronidazole and azelaic acid may diminish peri-lesional erythema. Oxymetazolone has also been shown to reduce erythema. A phase II study with topical brimonidine, which is an Alpha-2 inhibitor, has shown a clear benefit when reducing erythema.  Its effect has been very dramatic and produces 4-8 hours of reduced erythema.

One of the questions when using vasoconstrictors is “Do you get a rebound?”  In Dr Webster’s experience, he has only seen one rebound that lasted about one day.

Rosacea in Darker Skin

It is important to remember that rosacea is not a disease just of the fair skinned. Symptoms of rosacea in darker skinned patients include irritable skin, stinging, facial warmth, and a history of ocular rosacea. Darker skinned patients can be treated using the standard approaches.

Steroid Rosacea

When patients are applying steroids to their face, it becomes very irritable, There are lots of “homeopathic” products that have vasoconstrictor activity.  Rosacea under the nares is a tip-off.  Dermatologists should be aware that a “gentle withdrawal” does not work to treat this condition. TIMs and minocycline/doxycycline is the standard treatment.

Atopic/Seb Derm-Rosacea Overlap

Overlap is common among these patients and can also be very resistant to traditional rosacea treatment. It is important as dermatologists to remember to avoid irritants when managing these patients. Topical treatment includes tacrolimus/pimecrolimus and ciclopirox. Oral therapy includes the tetracyclines and cyclosporine followed by a topical treatment.

Defective Barrier in Rosacea

The fact that rosacea patients sting and burn is not just because they are blushy, but also because of the microscopic ruptures in their skin barrier, i.e., their stratum corneum is not in tact. There are areas that are extremely “leaky”. Sun damage can also affect the barrier. We also know that irritants can provoke rosacea by provoking inflammation and proteases. Moisturizing improves rosacea TEWL and the associated symptoms.

The graph below demonstrates barrier improvement as rosacea gets better with Metronidazole, which is designed to take the inflammation away.


What do we know about the pathogenesis and treatment of rosacea? We know that it is very complex. Improving the barrier,  can improve rosacea and it is important to remember that rosacea skin is extremely sensitive, such as that of atopic skin.


Diet and Acne & Rosacea

Diet and Acne & Rosacea
Alan Shalita, MD

In this presentation, Dr Shalita discusses the role of one’s diet and its relationship to acne and rosacea. Unfortunately, there is not a lot of information about diet and acne; however, there is a tremendous amount of interest in this subject. Dr Whitney Bowe conducted various aspects of this review, during the time she spent at SUNY Downstate with Dr Shalita.

With regards to rosacea, recent research by Dr. Richard Gallo and co-workers suggests an important role for innate immunity. Patients should avoid foods that cause vasodilatation, e.g. spicy, hot, etc. This has not been demonstrated in clinical trials; however, Dr Shalita feels it is something that should be studied.

Acne and Diet
Historically, any food that teenagers enjoyed were said to provoke or aggravate acne, e.g. chocolate, sodas, french fries, other candy. We know that the common denominator was that all of these foods were rich in sugars. In the 1970’s, Fulton et al conducted a study looking at chocolate bars versus control bars (carob), and they found no difference, i.e., both had same sugar and fatty acid content. The glycemic index between both bars was about the same. The researchers concluded that chocolate does not cause acne.

Dr Anderson studied 27 students assigned to consume chocolate, peanuts, milk or coca cola for one week. He, too, found no relationship to acne; however, the study was too short, underpowered, there were no lesion counts and no statistics.

In 1931, published in the British Journal of Dermatology, Dr Campbell showed that there was impaired glucose tolerance in patients with acne. In 1951, Dr Belisario, who published research in the Australian Journal of Dermatology, found that acne patients should avoid excessive carbohydrates and food that was high in sugar. Unfortunately, these reports were largely ignored. More recently, the relationship between diet and acne has been called back into question. It appears that carbohydrates and dairy products are considered by some to be the “real offenders.”
Researchers are examining the glycemic index and the glycemic load of various foods.

Examples of Low and High Glycemic Foods

In more recent studies, Dr Cordain et al, in 2002, examined 1300 subjects in Kitavan Islanders of Papua New Guinea or Ache hunter-gatherers of Paraguay. The researchers found no acne among the subjects. The reason, they feel, is due to diets low in carbohydrates and low glycemic loads. There are ways to criticize this study, in that, there were no controls and perhaps this group is not genetically predisposed to acne. Nonetheless, their conclusions led them to believe that the western diet may lead to hyperinsulinemia resulting in hormonal effects on acne.

A studied conducted in Australia by Dr Smith among students with acne found a positive correlation between glycemic index and acne; yet, a study by Dr Kaymak et al, in Turkey found no relationship in acne patients with a high carbohydrate load versus those on a low carbohydrate diet.

Dr Brian Berman, at the University of Miami, conducted a preliminary study looking at the South Beach Diet. In a survey, individuals who were on the South Beach Diet claimed to have had less acne.

It is important for Dermatologists to remember that a true low-carbohydrate diet can be very difficult to follow and requires very careful monitoring. Patients may benefit from food diaries and reminders. Dr Shalita mentions that he has seen a failure in compliance among the Caribbean population at Downstate because they do not want to give up certain foods.

Many believe in the effect of dairy on acne because of the hormones; however, it may very well be due to the sugar in the diary products. In 2005, a paper published in JAAD, showed the correlation between dairy products and acne. Dr Shalita believes that it may be due to the sugar content but this has not been confirmed.

There are other dietary factors that have been studied such as zinc. Dr Shalita conducted a study many years ago looking at whether or not zinc could be beneficial in acne. The study looked at students in a reform school in Hartford, CT. It was a placebo washout study and demonstrated that after one month of placebo there was a 50% improvement, so the question is could they have gotten better if they had taken zinc? They did not.

Vitamin A, when taken in high doses, can have the same effect as isotretinoin. No one has established whether or not fish oil and antioxidants have an effect on acne.

In conclusion, there may very well be a role for diet and acne, but at this point we do not know what it is. Dr Shalita suspects that it is related to the glycemic index of foods, but further studies are needed.

Acne: Pathogenesis Revisited

Panelists: James Del Rosso, MD, Alan Shalita, MD, Guy Webster, MD, PhD

For decades the pathogenesis of acne has centered on the formation of the microcomedones as the initiating event followed by an inflammatory cascade. This dogma is now being questioned in a “chicken vs. egg” scenario as being raised as to whether the microcomedone came first or was it precipitated by inflammation that came first.  Data coming out of the lab of Sewon Kang has taken a close look at the issue of what initiates the acne process.  In their work using immunohistochemical and histologic methods, they looked at patients with active acne lesions, normal skin in acne patients and compared them to a control group of people without acne. It was found that in acne patients there appeared a population of inflammatory cells with an absence of neutrophils in the majority of the locations that were evaluated.  This inflammation appeared before the development of hyperkeratinization and microcomedone formation indicating that the microcomedone might not be the initiating lesion. Dr. Kang’s group tracked the development of acne lesions and they found that about three out of ten of the lesions developed into an inflammatory lesion without a visible comedonal lesion.

The take home point is that when looking at an acne patient even normal appearing skin may be harboring inflammation in the follicle that can lead to follicular hyperkeratosis and microcomedone formation so it is important to treat the entire acne prone area proactively and possibly more aggressively.

Case Study

A 33 year-old Asian female presents with a several year history of late onset facial acne and had “clear skin as a teen”.  Her acne has been poorly responsive to treatment with over-the-counter medications as well as topical BPO gel and 0.025% tretinoin cream (“irritates my sensitive skin”) and only modestly response to a 3-month course of oral doxycycline.  She notes some flaring around menses. Her frustration led her to stop all meds and she is not on oral contraception and has two children.

It was noted by the panel that this age group of women have a high level of frustration regarding their acne and several management issues need to be considered including pregnancy.  These “issues” include resistance to the idea of taking oral antibiotics, oral contraceptives and potentially oral medications like spironolactone. Skin sensitivity is also clearly an issue patients such as this one.

Topical Formulations for this Patient Subset

Data for tretinoin 0.05% aqueous gel show that the percent of patients reporting adverse reactions over the 12-week treatment period experienced significantly less incidence of skin related adverse events than with tretinoin microsphere gel 0.1%.

Other topical retinoids available for use with lower potential for cutaneous irritation include Tretinoin Microsphere Gel 0.04%, Adapalene Lotion 0.1%, and Adapalene Gel 0.3%.

Data looking at Clindamycin/Tretinoin 0.025% Gel over one year show that the researchers did see patient improvement increased over time. The percentage of patients with “clear” or “almost clear” skin increased with longer use of CLIN/RA Gel. 57% of patients had “clear” or “almost clear” skin at 12 months. The majority of the patients (78%) were being treated with CLIN/RA Gel as monotherapy; 22% were receiving one or more products (oral antibiotics [12%]; topical therapy [9%]; and isotretinoin [<1%]).

One important consideration is that of P. acnes and antibiotic resistance. Results from a 16-week single-center, double-blind, randomized, parallel-group study of 79 patients with acne who used either a 1% clindamycin/5% BPO gel or clindamycin 1% gel alone show that the combination gel reduced total mean baseline P. acnes count by 99% at week 4, and this was maintained throughout the study. In the clindamycin monotherapy group, the total mean bacterial count was reduced by 87.9% at week 16. Clindamycin-resistant P. acnes counts remained at or below baseline values with the combination gel throughout the treatment while they increased to >1600% of baseline by week 16 with clindamycin monotherapy (P=0.018 vs. combination gel). In addition, drug-resistant, coagulase-negative staphylococci were increased to > 3500% of baseline by week 16. (P<0.001)

A pooled data analysis from pivotal studies stratified by gender looked at male and female patients aged 12 and older with facial acne vulgaris who were randomized to receive either topical dapsone gel (n = 1453; 48% male/52% female) or vehicle gel (n = 1445; 47% male/53% female). The results show that females tended to have better results than males, in both treatment arms. The researchers have not broken the study down by age at this point, nor can they confirm that the results were related to better adherence/compliance.

Hormonal Therapy for Post-teen Acne

Spironolactone is highly effective in post-teenage acne in females. The majority of patients will do well at or below 100mg/day. It is important that clinicians realize that this therapy is highly individualized based upon what dose works best for each patient. Spironolactone can also be used in combination with other topical treatments and oral antibiotics. Safety considerations for oral spironolactone include pregnancy plans and any underlying disorders such as PCOS or endocrinopathies, a risk for hyperkalemia (e.g., use of ACE inhibitors, cardiac disease, diabetes), high intake of K+ containing sports drinks and any significant or potential drug interactions.  There is a question as whether or not clinicians should monitor serum K+ levels. Generally it is not needed, provided there are no risk factors; however, that is the decision of the individual clinician. The general consensus regarding breast cancer history and oral spironolactone is that there does not appear to be a risk; yet, there is no definitive answer about that at this point.


Update on Topical Therapies:

The panel discussed vehicle selection, active ingredients, combination regimens, regimens for application/sequencing, and long term data. The major players in the topical therapy playing field today are benzoyl peroxide (BP), retinoids, and clindaymycin (1%). Combination therapy provides incremental improvement and tolerability is based upon selecting products with favorable vehicles.

Can Benzoyl Peroxide reduce comedonal acne lesions?

Yes, and sometimes, markedly.  Sometimes, using BP can give patients a “jump-start” to getting a quicker effect against comedonal lesions.

Is Benzoyl Peroxide 2.5 Enough?

Yes, but it depends largely on the formulation’s ability to deliver the BPO. Combining multiple therapies can provide patients with a faster and greater response. Several studies have demonstrated this benefit.

Studies have shown that Clindamycin has a therapeutic benefit. A thorough literature reviewof five recent studies (N>2000)2 have shown a relative benefit in combination with other agents and it adds to efficacy of benzoyl peroxide/retinoid.

Optimal Oral Antibiotic Use for Acne

Dermatologists prescribe less than 1% of all oral antibiotics, but dermatologists do prescribe 20% of the oral tetracyclines for treating acne and rosacea. Doxycycline and minocycline are the two most commonly prescribed.  Oral antibiotics are used to augment the therapeutic benefit and to speed up the response for moderate -to-severe acne vulgaris, especially for inflammatory lesions. Reduction of P. acnes correlates with therapeutic benefit.

It is important to remember that doxycycline has reported adverse events of serious ulcerations and esophagitis, so it is extremely important to remind your patients to take this medication with large glasses of water and not before reclining. Patient education is key to the therapeutic success of this drug. Minocycline does have a higher risk of drug-induced hypersensitivity however a few cases that have also been reported with doxycycline. Both doxycycline and minocycline have a “grandfathered” approval for acne by the FDA.








Update in the Management of Rosacea

Panelists: James DelRosso, MD; Alan Shalita, MD; Guy Webster, MD, PhD

The diagnosis of rosacea is based upon clinical findings; there are no specific diagnostic tests. The National Rosacea Society Expert Committee on the classification and staging of rosacea has developed provisional diagnostic guidelines for rosacea.1

The guidelines recommend the presence of one or more of the following primary features:

  • Flushing (transient erythema)
  • Non-transient erythema
  • Papules and pustules
  • Telangiectasia

In addition, one or more of the following secondary features often appear with the primary features listed above, although can occur independently in some patients:

  • Burning or stinging
  • Plaque
  • Dry appearance and scale
  • Edema
  • Ocular manifestations
  • Peripheral location
  • Phymatous changes






Case 1

The panel was presented with the case of a 41 year old white female with a 6-7 year history of waxing/waning facial redness that waxes and wanes and is associated with red bumps and pustules on the nose, cheeks and forehead.  She has “sensitive skin” which is often dry and flaky. Her skin improved on an oral antibiotic for a respiratory infection. She is seeing you to “get rid of the condition”.

It is important to identify the subtype of the disease as that will help dictate the response to treatment. Clinicians should recognize that these patients have increased transepidermal water loss (TEWL) from the central face. Dermatologists need to understand the importance of appropriate skin care in order to address the symptoms and, ultimately reduce the baseline symptoms. Studies have demonstrated that the skin characteristics of patients with rosacea show that about half of the patients scale and become itchy, about one third of the patients experience stinging and burning and these patients do not always have seborrheic dermatitis.

Etiology of Rosacea

The etiology of rosacea is unknown, although research suggests that symptoms are exacerbated by factors that trigger innate immune responses, such as the release of cathelicidin antimicrobial peptides. Studies have shown that patients with rosacea express abnormally high levels of cathelicidin in their facial skin and the proteolytically processed forms of cathelicidin peptides found in rosacea are different from those present in normal individuals. These cathelicidin peptides are a result of a post-translational processing abnormality associated with an increase in stratum corneum tryptic enzyme in the epidermis.2

Therapeutic Options: Topical Agents for the Treatment of Rosacea

 Metronidazole works through the inhibition of ROS generation from neutrophils. Azelaic Acid also works through the inhibition of ROS generation from neutrophils. Azelaic Acid also has decreased KLK-5 activity (serine protease activity); therefore,  decreasing the cathelicidin. It also downregulates the Toll-like receptor 2 (TLR2), similar to topical retinoids.

Retinoids also have a variety of ways in which they can modulate the disease, for instance they work through the inhibition of ROS generation from neutrophils and also have the downregulation of TLR2 and modulation of MMP activities, i.e., repair of dermal matrix degradation.

The tetracycline derivatives have a variety of down-regulating properties that appear to help with rosacea. They reduce inflammatory cytokines: IL-1b, IL-6, and TNF-1-a. They inhibit the serine protease activation of catheclicidin. They inhibit MMPs collagenase-8, -13, gelatinase -2, -9, elastase -12 and pro MMP activation and protect TIMP. Tetracyclines also inhibit nitric oxide activity and the arachidonic acid pathway.

Data on minocycline show the suppression of serene protease activity. Specifically, when patients were on minocylcine, the serene protease activity decreased, when they stopped it increased, and when they went back on the minocycline, it again decreased. (Yamasaki et al. Nature Medicine (2007) Aug 13 (8) 975-80)

As far as oral therapies for the treatment of rosacea, the tetracyclines are used; however, they are not FDA approved and there is reason to believe that dermatologists only need to use the subantimicrobial doses in order to garner the anti-inflammatory effect. These doses have widespread use and years of clinical experience. There are multiple pharmacokinetic and microbiologic studies. They are FDA-approved with large pivotal trials. Data exists with regards to the combination with topical therapy. Their efficacy is comparable to doxycycline 100 mg daily and there are potential safety advantages.

With the use of doxycycline (40mg Extended Release, QD) once can see demonstrated efficacy in papulopustular rosacea, there is a lack of antibiotic effect, efficacy is the same as that of doxycycline 100mg/QD, and there is a favorable safety profile. One 12-week study looking at doxycycline 40mg demonstrated that by week 4, close to half of the patients achieved clear or near-clear skin and by week 12, about 75% of the patients achieved clear or near-clear skin. The data were similar to that of patients utilizing add-on therapy in addition to doxycycline.

In conclusion, healthcare providers should be aware that there are a lot of data that show the efficacy of these agents for the management of papulopustular rosacea.

When comparing doxycycline 100mg to doxycycline 40mg, the effects were essentially the same based on one trial. Patients do not need to be exposed to changing their bacterial flora unnecessarily by starting with this treatment first, and; therefore, patients are not exposed at an antibiotic effect.

Case 2

The second case presented to the panel was a 42 year-old White female presents with a 7 year history of central facial (nose/malar eminences/chin) redness which waxed and waned in intensity over the years but is now persistently red There is central facial predominance.  She does not relate ever having any “red bumps” or “pus bumps” developing on her face, including during flares.  She has “sensitive skin”. She occasionally complains of itching and burning. She is interested in the correct diagnosis and treatment. Her health history is unremarkable otherwise.

Medical Treatments for the Redness of Rosacea

Erthematotalngiectatic rosacea (ETR) is more common than papulopustular rosacea. Available therapies include topical agents, such as metronidazole, azelaic acid, and oral agents such as the tetracyclines all of which improve primarily perilesional erythema. These products can occasionally help patients with their rosacea, but the background redness type does not always respond very well.  The critical issue is the presence of persistent telangiectatic mats in the affected areas.  The telangiectasias can be reduced when treated with laser/light devices.  Topical vasoconstrictors that can be used to reduce erythema (Oxymetazoline and Brimonidine) are in clinical trials and have shown excellent clincial responses during these clinical trials.



1. Wilkin, J, Dahl, M, Detmar, M, et al. Standard classification of rosacea: Report of the National Rosacea Society Expert Committee on the Classification and Staging of Rosacea. J Am Acad Dermatol 2002; 46:584.

2. Yamasaki K, et al. Increased serine protease activity and cathelicidin promotes skin inflammation in rosacea. 2007. Nat Med;13(8)975-980.