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CME

New Insights Into the Science of Treating Rosacea

  • Authors: Richard L. Gallo, MD, PhD
  • CME Released: 9/24/2012
  • THIS ACTIVITY HAS EXPIRED
  • Valid for credit through: 9/24/2013
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Target Audience and Goal Statement

This activity is intended for dermatologists, primary care physicians, ophthalmologists, and other clinicians who treat patients with rosacea.

The goal of this activity is to review current research into the pathophysiology of rosacea and describe how this research informs current and future treatments

Upon completion of this activity, participants will be able to:

  1. Review new research into the pathophysiology of rosacea
  2. Relate this research to the mode of action of current and future treatments for rosacea


Disclosures

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Medscape, LLC, encourages Authors to identify investigational products or off-label uses of products regulated by the US Food and Drug Administration, at first mention and where appropriate in the content.


Author(s)

  • Richard L. Gallo, MD, PhD

    Professor and Chief of Dermatology, University of California, San Diego, La Jolla, California

    Disclosures

    Disclosure: Richard L. Gallo, MD, PhD, has disclosed the following relevant financial relationships:
    Served as an advisor or consultant for: Galderma Laboratories, L.P.; Bayer HealthCare Pharmaceuticals; Allergan, Inc.
    Received grants for clinical research from: Galderma Laboratories, L.P.; Bayer HealthCare Pharmaceuticals; Allergan, Inc.; National Institutes of Health; National Rosacea Society

    Dr Gallo does not intend to discuss off-label uses of drugs, mechanical devices, biologics, or diagnostics approved by the FDA for use in the United States.

    Dr Gallo does not intend to discuss investigational drugs, mechanical devices, biologics, or diagnostics not approved by the FDA for use in the United States.

Editor(s)

  • Lisa Tushla, PhD, H(ASCP)

    Scientific Director, Medscape, LLC

    Disclosures

    Disclosure: Lisa Tushla, PhD, H(ASCP), has disclosed no relevant financial relationships.

  • Kristin M. Richardson

    Group Scientific Director, Medscape, LLC

    Disclosures

    Disclosure: Kristin M. Richardson has disclosed no relevant financial relationships.

  • Devon Schuyler

    Clinical Editor, Medscape, LLC

    Disclosures

    Disclosure: Devon Schuyler has disclosed no relevant financial relationships.

CME Reviewer(s)

  • Nafeez Zawahir, MD

    CME Clinical Director, Medscape, LLC

    Disclosures

    Disclosure: Nafeez Zawahir, MD, has disclosed no relevant financial relationships.

Peer Reviewer

This activity has been peer reviewed and the reviewer has disclosed no relevant financial relationships.


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CME

New Insights Into the Science of Treating Rosacea

Authors: Richard L. Gallo, MD, PhDFaculty and Disclosures
THIS ACTIVITY HAS EXPIRED

CME Released: 9/24/2012

Valid for credit through: 9/24/2013

processing....

  • Hello, I am Dr Richard Gallo, professor and chief, Division of Dermatology, University of California, San Diego. I would like to welcome you to this Medscape video lecture titled "New Insights into the Science of Treating Rosacea."

  • Slide 1.

    Slide 1.

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  • Our primary approach to the therapy of rosacea is based on the belief that in order to provide effective treatment we need to better understand the pathophysiology of the disease. So let me begin by going over some general concepts about the disease rosacea.

    We all know rosacea as a chronic skin disorder of the central face that is characterized by flushing, erythema, telangiectasias, edema, papules, pustules, and, occasionally, ocular lesions and rhinophyma. Typically, the onset of this disease is in adulthood, after the age of 30 years, with a preponderance in women (the female to male ratio is 3 to 1). The prevalence has been reported to be up to 10% of the general population. In the United States, we believe that more than 15 million individuals have some form of rosacea. It is clearly an ancient disease and has been with us for as long as we have recorded skin conditions.

  • Slide 2.

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  • The clues to the pathophysiology of rosacea come from some of its primary signs. For example, we know that rosacea includes flushing, persistent redness, bumps and pimples, and visible blood vessels.

  • Slide 3.

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  • This translates into 4 general clinical subtypes: subtype 1, erythematotelangiectatic rosacea; subtype 2, papulopustular rosacea; subtype 3, phymatous rosacea, which occurs less frequently than the other subtypes; and subtype 4, ocular rosacea. In my presentation, I will focus primarily on subtype 2, the papulopustular form of rosacea. However, I will also touch on subtype 1 and some of the changes that lead to phymatous rosacea.

  • Slide 4.

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  • Patient surveys have played an important role in our understanding of this disease, and the consensus is that environmental exposures trigger rosacea. A few years ago, the National Rosacea Society conducted a large patient survey and reported the most important triggers for rosacea, in rank order, as sun exposure, emotional stress, hot weather, wind, heavy exercise, alcohol consumption, hot baths, cold weather, spicy foods, and so on, as listed on the slide. We believe that in order to find the root cause of this disorder, we need to look at how rosacea patients react to the environment. This is a critical point in thinking about the pathophysiology of the disorder.

  • Slide 5.

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  • A key breakthrough in understanding the importance of the environment and the sensing of that environment in rosacea is a branch of science known as innate immunity. Innate immunity essentially explains how organisms are genetically encoded to sense the environment and react to it, and then overcome environmental challenges. In this slide you see an hourglass that shows, at the broadest upper point, the number of environmental events, because clearly our environment has many diverse triggers that can cause problems. So the environment is diverse but then the detection system becomes less diverse yet can be promiscuous. We know that several genes can detect several different types of environmental exposures. From that point we get a narrower, genetically programmed early response, which is typically simple and focused. Downstream of these responses, we get more and more complex reactions that depend on the genetic makeup of the individual. Those individual responses eventually lead to outcomes that, for clinical medicine, describe multiple phenotypes for different individuals exposed to the same type of challenge.

  • Slide 6.

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  • We believe that rosacea closely reflects the behavior of innate immunity. There are clearly genetic influences involved with rosacea, and there are broad but very predictable triggers that set off rosacea, as I've mentioned earlier. There is a fast initial response, such as the blushing response, but then slowly over time we see an onset of broad clinical phenotypes.

  • Slide 7.

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  • The first step in understanding rosacea from an innate immunity perspective is to apply molecular diagnostics to determine if the innate environmental detection system is, in fact, abnormal in rosacea.

    One of our early research efforts involved examining those genetically encoded molecular detection systems that sense our environment. A key component of that system is a group of genes known as the Toll-like receptors (TLRs). In a recent study published in the Journal of Investigative Dermatology, we have shown that patients with rosacea have much more abundant Toll-like receptor 2 (TLR2) expression in their skin than normal patients do. Therefore, patients with rosacea have that receptor for the environment that may make them more sensitive to environmental triggers. In other words, it gives a molecular explanation for increased skin sensitivity. This finding gains further relevance when one considers what TLR2 does.

    In a companion study, we showed that TLR2 senses many types of organisms that live on the skin, in particular the organism Propionibacterium acnes, which is very good at triggering TLR2 in human skin cells.

    In addition to TLR2, other TLRs and other molecular detection systems may play a role in rosacea. Future research will bear that out, but it is noteworthy that Toll-like receptor 4 (TLR4) can detect chemical or physical injury to the skin, and Toll-like receptor 3 (TLR3) has recently been reported as a very sensitive mechanism for detecting injury from ultraviolet (UV) light. All of these are environmental triggers for the disease rosacea.

  • Slide 8.

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  • So how does this make sense therapeutically? Of course, the first line of therapy should be to identify and eliminate triggers of the disease. We know from our clinical experience that common triggers stimulate TLRs, so we should eliminate the TLR triggers when possible.

    The second step, now that we understand some of the genetic basis of increased sensitivity to the environment, is to understand the molecular mechanisms of the response once these triggers have occurred. We know from clinical observation that erythema and flushing are related to neuromediators that act transiently on vessels. We also know that inflammation and new blood vessel growth are related to the immune system. So next I would like to focus on the response molecules that relate to inflammation and new blood vessel growth.

  • Slide 9.

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  • Another breakthrough that has become important to rosacea is the recognition that a molecule known as LL-37 (also known as a cathelicidin), which is expressed in the skin and triggered by activation of receptors such as TLR2, induces blood vessel growth. In the slide shown here, we see how LL-37, when added to an aortic ring in a dish, can cause blood vessel growth to the same extent that a classic angiogenic factor like basic fibroblast growth factor (bFGF) does, whereas scrambled versions of the peptide used as control or a buffer alone are inactive. This research tied 2 things together that made this particular molecule very interesting in rosacea. Here is an innate immune gene that is evolutionarily ancient that can do 2 things in human skin: induce vessel reactivity and also induce inflammation, as I will show you in a minute.

  • Slide 10.

    Slide 10.

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  • With the observation that LL-37, or cathelicidin, could do these things, we have gone back and looked at many patients with rosacea to determine if they have an abnormal response to this particular response molecule. In fact, it is clearly seen that patients with rosacea have much higher cathelicidin levels than patients without the disease and have abnormal processing of this peptide by enzymes in their skin, leading to forms of the peptide that are more likely to be inflammatory and cause blood vessel growth. Importantly, as I will show when we discuss therapy for this disease, the levels of enzymes that contribute to inflammation are also too high in rosacea patients. Shown on this slide is the enzyme kallikrein 5 (KLK5), staining in red. Kallikrein 5 is in great abundance in rosacea patients, much more so than in normal patients, and it is expressed in the same place as cathelicidins. Kallikrein 5 and cathelicidin work together.

  • Slide 11.

    Slide 11.

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  • What is the consequence? Well, you can test this in animal models. If you inject the type of rosacea peptides that we found to be abundant in all patients with rosacea, they induce inflammation and a vascular response, which, in mouse skin, mimics in many ways the type of disease we see in our patients. In fact, the concentration of these peptides necessary to cause this disease is the same as the concentration measured in patients with rosacea.

    Putting this together with the TLR2 response, we also have observed that factors that trigger TLR2 not only make more cathelicidin but also increase the enzyme KLK5, which is critical to the pathophysiology of the disease. To sum up, we have environmental triggers and a molecular detection system. That detection system is triggering response molecules, including a protease that is cleaving a peptide that induces inflammation and vascular responses.

  • Slide 12.

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  • At this point I would like to summarize the steps that we believe are important in increasing rosacea and exacerbating this disease. We have multiple environmental triggers -- factors such as UV light, certain microbes, chemicals, and many other environmental exacerbating agents. In patients with rosacea, we have a hypersensitive innate immune response, clearly too much TLR2, and likely, based on the diversity of types of responses, other sensing molecules in the skin that are functioning abnormally and causing response genes to trigger before they would in a normal person.

  • Slide 13.

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  • Then we have a group of response genes. I talked about the proteases KLK5, cathelicidin, and LL-37, but other response genes are also involved in this disease, such as nitric oxide, inflammatory cytokines such as tumor necrosis factor, and neuromediators that are involved in the burning sensation as well as vasodilatation.

  • Slide 14.

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  • Once these response genes are activated in the abnormally sensitive patient with rosacea, we go downhill to a very poor outcome. We have vessels responding, leukocytes recruited, and eventually, with chronic exposure, weakened capillary walls. These changes tie in with an aging population with skin weakened by chronic UV exposure and altered elastin and collagen. With increasing triggers, we then get accumulation of extravascular fluid and perhaps start going from patients with ETR, which is the immediate reaction to the triggers, to the papulopustular type, in which individuals accumulate more white blood cells in the skin. In some situations in which everything is lined up in a certain way, the result is overwhelmed lymphatic vessels and a chronic disease that can lead to the phymatous type of rosacea.

  • Slide 15.

    Slide 15.

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  • Now let's apply this knowledge to the treatment of rosacea. Step 1 is to identify exacerbating factors and eliminate the clinical mimics. Remember that sun exposure, emotional stress, hot weather, wind, alcohol consumption, and other triggers may be involved. It is useful to take a specific, targeted history to try to identify the environmental stimuli that trigger disease in a particular individual and perhaps counsel the patient on avoidance strategies.

    It is important to have a correct diagnosis. Remember that there are several clinical mimics of rosacea, and in some cases, such as seborrheic dermatitis, these mimics can occur at the same time. Think about other photosensitive disorders. Think about acne; acne is a disease that is distinct from rosacea. Other conditions can cause the face to become red and inflamed, such as allergic dermatitis. Be sure you have eliminated those clinical mimics before considering the molecular basis of the treatment for rosacea.

  • Slide 16.

    Slide 16.

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  • Once you have established a diagnosis, think about the diagnostic subtype. Is it subtype 1, erythematotelangiectatic rosacea (ETR)? Is it subtype 2, papulopustular rosacea? Subtype 3, phymatous rosacea? Subtype 4, ocular rosacea?

  • Slide 17.

    Slide 17.

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  • How do we approach the management of subtype 1? Unfortunately, in my experience, ETR is the most common subtype of rosacea but also the most difficult to treat. It requires a combined approach. Limit the exacerbating stimuli. Think about topical agents. Vasoconstrictive approaches are on the horizon for our patients, which should be extremely beneficial. In patients who have controlled disease, vascular lasers clearly have a role in minimizing the cosmetic manifestations.

  • Slide 18.

    Slide 18.

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  • Next, let's talk about the therapy for rosacea subtype 2, the papulopustular form. In my experience, these patients have the best chance for dramatic clinical improvement. Again, we need to take a combined approach: identify the exacerbating stimuli and consider either topical or combined topical and systemic therapy.

  • Slide 19.

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  • The understanding of the pathophysiology of rosacea has given us exciting new information that explains why certain currently used rosacea therapies are effective. Many of you think about oral therapy with tetracyclines for the treatment of rosacea, and clearly there is a large subset of patients that has dramatic improvement in the papulopustular form once started on antibiotics of the tetracycline class.

    The question for us was why should an antibiotic, even some antibiotics used at doses below concentrations that kill bacteria, have such a dramatic effect on this disease? We observed that when patients are started on minocycline, their enzyme activity, which I told you earlier is too high and leads to the development of the forms of peptides that induce redness, is actually inhibited. If you remove oral minocycline, the enzyme activity increases again and will decrease again when administration of the antibiotic is resumed.

    Therefore we performed a series of experiments to try to explain why antibiotics of the tetracycline class should have this effect. We observed that many types of tetracyclines, including doxycycline, directly inhibit the ability to activate the KLK5 enzyme. Therefore, one possible explanation for why tetracyclines are effective is that they inhibit enzyme activity. The clinical response of these patients helps support the hypothesis that these enzymes are critical to disease.

    Another commonly used therapeutic approach in rosacea is topical creams such as azelaic acid. In an ongoing study, it has been clearly seen that patients treated with azelaic acid who show a clinical response are those patients whose surface enzyme activity and cathelicidin levels decrease. So we see a consistent correlation between the ability of existing medications to improve rosacea and perhaps potential biomarkers for predicting disease activity in these patients.

  • Slide 20.

    Slide 20.

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  • In conclusion, we should consider how to use currently available therapies based on our increased understanding of the pathophysiology of the disease in order to improve outcomes for our patients. In the immediate future, I believe we can better exploit this information for more effective therapeutic approaches. For example, we have the tetracycline antibiotics, which inhibit enzymes, but clearly there is an opportunity for more targeted enzyme inhibitors. We have topical drugs such as azelaic acid that affect enzyme activity and may also influence TLR2 activity. Here is another opportunity, not only through eliminating the environmental triggers of the TLRs but perhaps by blocking their ability to trigger downstream responses. Further along the pathophysiologic pathway, we have molecules such as LL-37 and the cathelicidins that induce inflammation and vascular responses. Here is a prime therapeutic target. If we can interfere with their biological activity, we can potentially cut short the exacerbations in patients with rosacea.

  • Slide 21.

    Slide 21.

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  • I would like to close by putting it all together. We think about the pathophysiologic process of rosacea: environmental triggers, hypersensitive innate immune responses, the response genes, and the downstream effects. First and foremost, we need to identify environmental triggers for individuals and counsel avoidance. In most patients, sun exposure is clearly a trigger, so think about sunscreens. Sunscreen use is important not only to protect against the trigger of sun exposure but also probably to prevent the worsening of some of the contributing factors that lead to the chronic manifestations of the disease.

    We have various topical agents. Metronidazole and azelaic acid both have the potential to act on important areas of the pathophysiology of this disorder. When you are trying these drugs in your patients, think about the pathophysiologic pathway on which these drugs may be having their maximum effect. Also think about the tetracyclines acting as direct protease inhibitors. Finally, when you have achieved good control of all of these steps, think about other modalities to help improve the damage that has been done -- surgery or laser, when appropriate.

    I would like to thank you for participating in this activity. You may now take the posttest by clicking on the "Earn CME Credit" link. Please also take a moment to complete the program evaluation that follows.

  • Slide 22.

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This transcript has been edited for style and clarity.

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