Rosacea

Richard Gallo, MD, PhD

In this presentation at MauiDerm 2014, Dr Richard Gallo, an expert in the field, provides us with an update on the management of rosacea…

Remember that rosacea almost exclusively affects the face, making it both a cosmetic and medical issue for those it affects. For the clinician, rosacea is a prevalent, serious, recurring and progressive dermatological condition that requires chronic therapy to prevent long-term sequelae.  Rosacea affects approximately 14 million Americans and possibly more. Unfortunately, the condition is often times not recognized; however, we have found that early recognition and treatment are important in order to prevent progression and disfigurement.  Therapeutic regimens must be tailored to the individual patients and need to address acute symptoms, help patients remain asymptomatic, and minimize the recurrence of symptoms.

Rosacea can be categorized into four sub-types: subtype 1-erythematotelangiectatic; subtype 2-papulopustular; subtype 3-phymatous; and subtype 4-ocular. (Wilkin J, et al. J Am Acad Derm 2002;46:584-587; Wilkin J, et al. J Am Acad Derm. 2004;50:907-912.) There are also many different variants of this disorder that do not always clearly fit into the above-mentioned subtypes such as vascular, sebaceous hyperplasia/rhinophyma and inflammatory causes.

The diagnosis of rosacea is based upon consensus opinions. We don’t have a clinical test or laboratory value, i.e., some sort of objective measurement that can determine rosacea.

Primary Diagnostic Features of Rosacea

  • Central facial erythema (fixed)
  • Flushing
  • Telangiectasias
  • +/- inflammatory lesions

Secondary Diagnostic Features

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

(Del Rosso, J.Q., Thiboutot, D., Gallo, R.L. et al. Consensus Recommendations from the American Acne & Rosacea Society on the Management of Rosacea, Part 1. Cutis 2013; 234-240;

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.)

Unfortunately, rosacea is often misdiagnosed. Rosacea is variable in that there are various combinations of cutaneous signs, such as flushing, erythema, telangiectasia, edema, papules, pustules, ocular lesions and rhinophyma. Diagnostic confusion can occur because most patients only have some, rather than all, of these signs and symptoms. Other dermatological disorders and co-morbid conditions affecting the face can also cause confusion. Rosacea is often confused with acne and it may coincide with actinic keratosis, acne, seborrheic dermatitis, and contact dermatitis.

Inflammation is a major culprit! Inflammation in rosacea may result in capillary cell wall weakening secondary to dermal-matrix deterioration. It may also result in lymphatic failure secondary to elastin degradation and/or the production of vascular mediators. Inflammation precipitates episodic signs and symptoms of rosacea.

In order to really understand this disease, we need to understand the origin of inflammation. To come up with a way to effectively treat our patients we need to understand what causes this disease.

There are several environmental exposures that can trigger rosacea:

(Patient reported survey in rank order)

  •             Sun exposure
  •             Emotional stress
  •             Hot weather
  •             Wind
  •             Heavy exercise
  •             Alcohol consumption
  •             Hot baths
  •             Cold weather
  •             Spicy foods
  •             Humidity
  •             Indoor heat
  •             Certain skin-care products
  •             Heated beverages
  •             Certain cosmetics
  •             Medications
  •             Medical conditions
  •             Certain fruits
  •             Marinated meats
  •             Certain vegetables
  •             Dairy products

Can all of the subtypes and all of the different triggers really be the same disease?

Normal facial skin uses pattern recognition molecules to detect danger. Toll-like receptors are just one of many types of molecules that exist on the surface of keratinocytes and every cell type of the skin. Their goal is to detect patterns of the environment around them. Multiple microbes, dry skin and UV are all triggers of the pattern recognition system. Researchers began looking at biopsies of rosacea patients on non-inflamed skin. One particular concept was that rosacea patients have too much PRR (pattern recognition receptor) activity as seen by TLR2 protein staining.  This is an important issue to understand as it explains the essential role of general skin care as the skin has an excess of the molecular sensors of damage. UV injury as well as excessive dryness and even excessive oilyness triggers PRRs. This idea helps to put other theories into context.

Theories About Triggers

O’Reilly and colleagues published a paper demonstrating the positive correlation between serum immunoreactivity to Demodex-associated Bacillus proteins and erythematotelaniectatic rosacea. Eighty percent (21/26) of patients with erythematotelangiectatic rosacea showed serum reactivity to B. oleronius, compared with forty percent (9/2) of controls. (O’Reilly N, et al. Br J Dermatol. 2012) However, there are problems with this hypothesis. First of all this is fairly rare, one mite out of forty contained the bug and cross-reactivity of the bug antigens with other more common bugs has not yet been investigated. Many normal patients have this bug and did not react to it. Lastly, trying to kill Demodex is not usually effective for patients with rosacea. The take home message for current trigger data is that we, as clinicians, need to care for the barrier and remember that there is probably no single trigger for everyone. This makes patient history, clinical exam and your relationship with patients incredibly important.

What do the triggers do?

LL-37 expression is increased in rosacea. LL-37 is a very important molecule in a number of skin diseases in that it kills microbes as well as increases vasculature and inflammation upon its release. The other part of the equation that is important is the molecule KLK5, which is an enzyme that activates LL-37. So when we think about rosacea, remember that there are various signals that are activated by the environmental triggers.  This is variable based on genetic makeup and the ecological organisms on the skin. A normal innate immune system reacts to infection and true danger, there is no inflammation in a resting state. Rosacea patients; however, have a molecular sensitive skin because of too much PRR. Once that is triggered, the trigger system makes too much KLK5 that can activate LL-37 and initiate certain aspects of this disease.

It is important to understand the role of KLK and LL37 in rosacea because they explain the benefits of current therapies. They may also serve as a potential objective biomarker as well as aiding in future new drug development. Dr Gallo and many others have worked in larger studies to validate and confirm these observations.  A blinded study conducted by Coda and colleagues looked at the KLK enzyme on the skin and found that rosacea patients have elevated enzyme activity but divide into two populations that weren’t necessarily distinguishable on clinical presentation. This may be important because protease level can predict topical azeleic acid response. Patients with high enzyme activity who were treated with azeleic acid showed a significant drop in activity over sixteen weeks, whereas patients who started off with low protease activity showed no response. (Coda, et al. JAAD. 2013)

Other therapies that we currently have may also be working because of a similar process. The tetracycline class drugs have shown to inhibit this enzyme. When we look back at old literature, we see that some of the biochemists found that one of the things that tetracycline seemed to do was inhibit enzyme activity completely independent of any action on a bacteria.

Testing the Hypothesis: Does targeted inhibition of KLK5 activity improve rosacea?

Dr Gallo and colleagues conducted a pilot clinical trial using an FDA-approved serine protease inhibitor that was formulated into a topical cream. It was a 12-week, double-blind, placebo controlled BID application to measure both protease and clinical response. The only patients who improved in this trial were those who applied the protease inhibitor. (Two, A.M. et al. J Invest Dermatol. 2013) This is not necessarily proof of a new therapy, but it is intriguing data that may prove the theory relevant.

In summary, rosacea patients have high KLK5 and LL37. KLK5 activates cathelicidin and more LL-37 and KLK5 is associated with disease severity. Successful therapies are associated with decreased KLK5 activity or cathelicidin.

Neuromediators Are Important!

Neuromediators increase vasodilatation, nerve endings, neuropeptides and they stimulate mast cells. What can we do about this? We have alternative neuromediators that fight these vasodilitation effects. The alpha-adrenoceptor agonists are the stimuli are the alpha1 and alpha2 receptors. They have the ability to initiate smooth muscle contraction in a dilated vessel. When topically applied, both brimonidine (a2 agonist) and oxymetazoline (a1 agonist and a2 agonist) have shown to be successful therapies for the erythematous stage of rosacea. (Fowler J et al. J Drugs Dermatol. 2013; Shanler and Ondo Arch Derm 2007)  These are alternative mechanisms thinking about the pathology of the disease. The drivers of the disease are the molecules that initiate inflammation and vascular growth. We now have strategies for inhibiting or reducing LL-37 and limiting vasoactive response.

Topical Rosacea Therapy

The goal of topical therapy is barrier repair, decrease triggers, decrease LL-37 and vasoconstriction. Don’t forget to always include appropriate barrier care such as sunscreen, gentle cleansers and moisturizers.

  • Azeleic acid
  • Sodium sulfacetamide/sulfur
  • Brimonidine
  • Metronidazole
  • Tretinoin
  • Tacrolimus/pimecrolimus
  • BP/Clinda
  • Ivermectin

Oral Rosacea Therapy

Oral therapy targets triggers and drivers.

  • Tetra/doxy/mino
  • Cipro
  • Bactrim
  • Isotretinoin

Clinical Pearls

Early Rosacea

  1. Trying to minimize triggers
  2. Rosacea drivers not major yet
  3. Complaint is erythema

What should we do?

  1. Trigger avoidance
  2. Barrier care
  3. Topical agent
  4. Adrenergic agonist

Moderate/severe Papulopustular

  1. Still need to minimize triggers
  2. Rosacea drivers active
  3. Complaint is red papules

What should we do?

  1. Oral agent (TCN)
  2. Barrier care ±sunscreen
  3. Topical agent
  4. Adrenergic agonist
  5. Second line Isotretinoin

Perioral Rosacea

  1. Spared vermillion
  2. Microbial influence?
  3. Ask about steroid

What should we do?

  1. Oral agent (TCN)
  2. Barrier care
  3. Possible TIM

In conclusion, we are finally getting a mechanistic understanding of rosacea. There is a need for an individual approach and both rosacea triggers and drivers need to be identified and targeted. We have good and complementary options for medical therapy. Do not forget the importance of barrier care!!

 

MauiDerm News Editor-Judy Seraphine

Systemic Medications: Top Ten Take Home Points

Matthew J. Zirwas, MD 

  1. Prednisone is drug of choice for expected short term therapy – weeks.
  2. Cyclosporine is drug of choice for expected “medium term therapy” – months.
  3. Methotrexate is drug of choice for chronic therapy in patients without liver, kidney, or hematologic co-morbidities.
  4. Mycophenolate is drug of choice for chronic therapy in patients with liver, kidney, or hematologic co-morbidities.
  5. Cyclosporine has many drug interactions – must use a computerized drug interaction checker.
  6. Methotrexate has a few drug interactions but they are extremely serious and can be fatal.
  7. Mycophenolate has few drug interactions.
  8. Patients on methotrexate should take folic acid on days they do not take the methotrexate.
  9. Older patients on mycophenolate, in particular, are at high risk of zoster.
  10.  If patients on cyclosporine have elevations in creatinine, they need to stop the medication.

Pigmented Lesions: Clinical Pearls

Ashfaq Marghoob, MD

Dr Marghoob provides us with his clinical pearls on pigmented lesions….

  1. The larger the congenital nevus the greater is the risk for developing melanoma.
  2. The risk of a melanoma developing in a small congenital nevi is small enough that prophylactic excision is not required.
  3. Presence of many nevi and dysplastic nevi are strong risk factors for melanoma.
  4. Analytical, Differential and comparative recognition are all helpful in differentiating nevi from melanoma.
  5. Total body photography assists clinicians in finding concerning lesions.
  6. Dermoscopy assists clinicians in deciding which lesions require a biopsy.
  7. Unna’s theory of nevogenesis is not supported by recent cross sectional and longitudinal studies.
  8. Nevi with a peripheral globular pattern or a starburst pattern are growing nevi (not yet in senescence).
  9. Most halo nevi have a globular pattern.
  10. Patient driven healthcare with the use of Apps is likely to help in finding early melanomas.

Immunology 101: The Basics

Andrew Blauvelt, MD

Dr Blauvelt provides us with the 10 most important take-home messages from his immunology presentation at MauiDerm NP+PA Summer 2014….

  1. Key features of the innate immune system include: rapid response, non-specificity, phagocytosis, no memory.
  2. Key features of the  acquired immune system include: slow response, very specific, lymphocyte-mediated, memory.
  3. Keratinocytes are active participants in generating immune responses by secreting numerous cytokines upon activation.
  4. 4.Toll-like receptors are pattern recognition receptors on keratinocytes that recognize foreign antigenic material.
  5. Antimicrobial peptides are natural antibiotic molecules found in skin that are abundant in psoriasis skin and sparse in atopic dermatitis skin.
  6. 6.Epidermal Langerhans cells are antigen presenting cells that recognize/process skin antigens and migrate to lymph nodes, where they present antigen to T cells.
  7. 7.T cells require 3 signals to become fully activated: 1) recognition of antigen by the T cell receptor via MHC on the surface of antigen presenting cells; 2) binding of co-stimulatory molecules on T cells and antigen presenting cells to one another; and 3) secretion of soluble cytokines by the T cells.
  8. CD4+ T cells are T helper cells that recognize antigen via MHC class II and secrete cytokines to enhance CD8+ T cell and B cell immune responses, whereas CD8+ T cells are cytotoxic T cells that recognize antigen via MHC class I and kill cells upon contact.
  9. B cells secrete antibodies that specifically bind to antigen.
  10. Primary immune responses are slow, occur after first exposure to antigen, and involve creation of memory cells, whereas secondary immune responsesare fast, occur after subsequent exposures to antigens, and involve reactivation of memory cells.

 

 

Dermatitis Overview: 2014

Matthew J. Zirwas, MD

Are you treating dermatitis? Dr Zirwas provides us with ten clinical pearls…

  1. The main goal in dermatitis patients is figuring out WHY they have dermatitis.
  2. Acute allergic contact dermatitis starts 1-3 days after exposure to the allergen and takes 1-3 weeks to go away.
  3. Chronic allergic contact dermatitis takes 3-6 months to go away.
  4. Hypoallergenic rubber gloves are not hypoallergenic.  Hypoallergenic gloves include: vinyl gloves, Microtouch Nitra-Free, Dermaprene Ultra.
  5. Shampoo and conditioner are the main causes of eyelid dermatitis, both irritant and allergic.
  6. Atopic dermatitis is the combination of inadequate skin barrier and an immune system that was genetically primed to go in an allergic direction.
  7. Food avoidance and chelation do not work in adults.
  8. There are probiotics that work, but it is very specific – patients can’t just take any old probiotic.
  9. Seborrheic dermatitis is an inflammatory reaction to Malassezia yeast on the skin – treat by reducing amount of yeast and targeting the inflammation.
  10. Xerosis is too little water in the skin.  Need to add water and prevent it from just evaporating away.

 

Dermoscopy: Clinical Pearls

Ashfaq Marghoob, MD

Are you performing dermsocopy in your clinical practice? Dr Marghoob provides us with his clinical pearls…

  1. Dermoscopy helps in differentiating benign lesions from skin cancer.
  2. The presence of network (reticular network, negative network, polygonal lines), streaks (radial streaming, pseudopods), aggregated globules/peripheral globules, homogeneous blue pigmentation is most often seen in melanocytic lesions.
  3. Melanocytic lesions that deviate from the 10 benign patterns and has at least one of the 10 melanoma-specific structures needs to be biopsied to rule out melanoma.
  4. The presence of spoke wheel structures and/or leaf like areas is 100% specific for BCC.
  5. Comedo like openings and milia cyst are often seen in SK but can also be seen in other lesions including melanoma.
  6. Polarized light makes blood vessels and crystalline structures more conspicious, and makes milia cyst less conspicuous.
  7.  A polymorphous vascular pattern in an amelanotic lesion should raise concern for melanoma.
  8. Dermoscopy improves the clinician’s diagnostic accuracy.
  9. All structureless or featureless or not-otherwise-diagnosable lesions should be viewed with suspicion.
  10. Raised lesions should never be monitored for change.

Cutaneous Oncology: Talking Points

Marc Brown, MD

Here are some of the key points from Dr Brown’s presentation at MauiDerm NP+PA Summer 2014….

  1. High risk parameters for BCC include location on the central face, larger size, recurrence, prior radiation and aggressive histology.

 

  1.  High risk histology for BCC includes the following:  infiltrating, morpheaform, micronodular, basosquamous, sclerosing, desmoplastic, and perineural invasion.

 

  1. Risk factors for the development of SCC include:  UV light exposure, X ray exposure, HVP infection, immunosuppression, chronic non-healing or inflammatory wounds, an rare genetic syndromes.

 

  1. High risk locations for SCC are ear, lip, genitalia and scalp.

 

  1. Other risk factors for aggressive SCC include:  poorly differentiated histology, depth of invasion, perineural invasion, size (greater than 2 cm.).

 

Emerging Therapies in Psoriasis: Clinical Pearls

Bruce Strober, MD, PhD

What’s new in the field of psoriasis? Dr Strober provides us with some clinical pearls…

  1. TNF-inhibitors cause weight gain.
  2. Ustekinumab does not cause weight gain.
  3. IL-23 inhibitors block p19 and are more specific than IL-12/23 inhibitors, which block p40.
  4. Apremilast achieves PASI75 in approximately 30% of patients after 16 weeks.
  5. IL-17 pathway inhibitors achieve PASI75 in approximately 80% of patients after 12-16 weeks.
  6. IL-17 pathway inhibitors may slightly increase the risk of mucocutaneous candidiasis.
  7. JAK kinase inhibitors will require monitoring for liver function, renal function, lipids and creatinine phosphokinase.
  8. JAK kinase inhibitors might increase the risk of varicella zoster infection.
  9. Apremilast treats psoriatic arthritis.
  10. Apremilast does not need laboratory monitoring.

 

 

 

 

Pediatric Dermatology: Clinical Pearls

James Treat, MD

1.  Coxackie Virus can superinfect atopic dermatitis and look similar to eczema herpeticum

2.  Kwashiorkor can mimic severe atopic dermatitis in patients with severe nutritional restrictions

3.  Scabies almost never affects the face in children over two years of age

4. Mycoplasma can cause mucosal predominant stevens johnson with little to no skin lesions

5. Drug reaction with associated fevers are much more concerning and should be evaluated promptly

10 Pearls from Dermatopathology – The Biopsy, Analysis & Report

Whitney J. High, MD, JD, MEng

  • Dermatopathology is one of  two ABMS-recognized subspecialties in dermatology, and one may become fellowship trained after first being a board-certified dermatogist or general pathologist.
  • Biopsy use is increasing.  In nine geographic areas of the USA, over the time period 1986-2001, the biopsy rate among those >65 years of age rose 2.5-fold, and the melanoma rate rose 2.4-fold.
  • There are multiple steps involved in taking a specimen from a piece of “wet” tissue, in formalin, to an interpretable slide and to a typewritten report.  These steps include:

Screen Shot 2014-06-25 at 9.14.06 AM

  • The dermatopathologist is examining but a small portion of your original sampling, and    this must always be considered when one assesses the “representative nature” of the results.
  • There is an old mantra in pathology in general: crap in = crap out.  No dermatopathologist, regardless of skill or expertise, can weave a poor sampling into an outstanding result.
  • It is the clinician responsibility to secure a “representative biopsy”, and if this is not done, eventually, this inadequacy  will be discovered.  Over the period of 1998-2005 the number of shaves increased but the volume of shaves decreased.
  • The technique employed (shave, punch, excision) must be adapted to the clinical situation – there are no fixed rules that may be applied to every situation.  This is why the clinician is being paid an “evaluation/management” code; namely, to select a biopsy that is appropriate for the circumstances.
  • A recent study of pigmented lesions showed the odds of misdiagnosis (overall and associated with an adverse outcome) were much higher with a punch biopsy than with an excisional biopsy, whereas a shave biopsy was only weakly associated with misdiagnosis. (Ng et al. 2010)
  • Situations where the biopsy technique should be carefully considered include suspected:

Screen Shot 2014-06-25 at 9.16.42 AM

  • The pathology report itself should be carefully read and scrutinized to understand precisely what the dermatopathologist is trying to convey. Demographic data should be confirmed. The technique and specimen size should be verified. Data used by the dermatopathologist to formulate the diagnosis should be noted  (i.e., step levels, immunostains, special stains, etc.). If questions still exist, a phone call should be placed to the dermatopathologist for expanded dialog.